UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

The effects of antihypertensive drugs in different clinical settings : lessons learned from two systematic… Perez Garcia, Marco Antonio I. 2010

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata

Download

Media
24-ubc_2010_fall_perez_marco.pdf [ 1.66MB ]
Metadata
JSON: 24-1.0069978.json
JSON-LD: 24-1.0069978-ld.json
RDF/XML (Pretty): 24-1.0069978-rdf.xml
RDF/JSON: 24-1.0069978-rdf.json
Turtle: 24-1.0069978-turtle.txt
N-Triples: 24-1.0069978-rdf-ntriples.txt
Original Record: 24-1.0069978-source.json
Full Text
24-1.0069978-fulltext.txt
Citation
24-1.0069978.ris

Full Text

 THE EFFECTS OF ANTI-HYPERTENSIVE DRUGS IN DIFFERENT CLINICAL SETTINGS; LESSONS LEARNED FROM TWO SYSTEMATIC REVIEWS AND A CLINICAL TRIAL   by  MARCO ANTONIO I. PEREZ GARCIA  M.D. University of Guadalajara Mexico, 1991      A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  DOCTOR OF PHILOSOPHY   in   THE FACULTY OF GRADUATE STUDIES  (Pharmacology and Therapeutics)     THE UNIVERSITY OF BRITISH COLUMBIA  (Vancouver)     May 2010   © Marco Antonio I. Perez Garcia, 2010   ii  ABSTRACT Context: The ultimate goal when using anti-hypertensive drugs is to reduce adverse health outcomes. In acute clinical settings, total all-cause mortality is the best measure of net health effect (benefit minus harm). Objectives: a) To determine the effects of anti-hypertensive drugs on all-cause mortality compared to a control in hypertensive emergencies and acute cardiovascular events b) To learn randomized controlled trial (RCT) methodology. Methods: Two systematic reviews were conducted of published RCTs evaluating blood pressure (BP) lowering drugs.  The first review was limited to patients with a hypertensive emergency. The second was limited to patients treated within 24 hours of an acute cardiovascular event. A parallel RCT was conducted in hypertensive outpatients comparing the blood pressure lowering effect of hydrochlorothiazide with two psychological interventions. Results: In hypertensive emergency patients, 15 RCTs (N=869) studying nitrates, ACE inhibitors, calcium channel blockers (CCBs), alpha-1 adrenergic antagonists, diuretics, and direct vasodilators were analyzed. There was no evidence for an effect on mortality with any of these drug classes. In the acute cardiovascular event review, sixty-five RCTs (N=166,206) were analyzed, involving four classes of anti-hypertensive drugs. Acute stroke was studied in 6 RCTs and acute myocardial infarction (AMI) in 59 RCTs. Immediate treatment with nitrates in patients with AMI significantly reduced all-cause mortality at 2 days (RR 0.81, 95%CI [0.74, 0.89], p<0.0001, ARR 0.4 %). Immediate treatment with ACE-inhibitors significantly reduced mortality only when continued for  iii 10 days (RR 0.93, 95%CI [0.87, 0.98] p=0.01, ARR 0.4%). The other classes did not reduce all-cause mortality. Conducting the RCT assisted with and improved the critical appraisal of RCTs analyzed in the systematic reviews and prepared me to design and conduct a large high-quality RCT. Conclusion: In patients with suspected or definite acute myocardial infarction nitrates administered immediately and continued for 2 days reduce all-cause mortality at 2 days. In the same clinical setting ACE inhibitors started within 24 hours and continued for 10 days reduce mortality at 10 days. There is no RCT evidence that anti-hypertensive drugs reduce mortality in hypertensive emergencies.   iv TABLE OF CONTENTS ABSTRACT....................................................................................................................................................ii TABLE OF CONTENTS.............................................................................................................................. iv LIST OF TABLES ......................................................................................................................................viii LIST OF FIGURES ......................................................................................................................................ix GLOSSARY....................................................................................................................................................x ACKNOWLEDGEMENTS........................................................................................................................xiv DEDICATION.............................................................................................................................................xvi CO-AUTHORSHIP STATEMENT .........................................................................................................xvii 1 INTRODUCTION ................................................................................................................................1 1.1 CONCEPTION OF THE RESEARCH QUESTION ...................................................................................1 1.1.1 Hypertension in acute cardiovascular emergencies: pathological or physiological response2 1.1.2 Other drugs in the acute phase of cardiovascular events ........................................................2 1.2 RESEARCH OUTLINE.......................................................................................................................3 1.3 WHAT IS A SYSTEMATIC REVIEW? .................................................................................................5 1.4 WHAT IS THE COCHRANE COLLABORATION?.................................................................................6 1.5 WHAT IS THE OVERALL OBJECTIVE OF THIS THESIS?......................................................................6 1.6 ADDITIONAL TOOLS USED FOR PERFORMING COCHRANE SYSTEMATIC REVIEWS ..........................7 1.7 CLINICAL BACKGROUND: ACUTE CARDIOVASCULAR EVENTS........................................................7 1.7.1 Acute myocardial infarction.....................................................................................................7 1.7.2 Unstable angina .....................................................................................................................11 1.7.3 Stroke .....................................................................................................................................13 1.7.4 Cardiogenic pulmonary edema ..............................................................................................15 1.7.5 Acute aortic dissection ...........................................................................................................17 1.8 PHARMACOLOGICAL BACKGROUND: ANTI-HYPERTENSIVE DRUGS ..............................................19 1.8.1 Angiotensin converting enzyme inhibitors (ACE-I) ...............................................................20 1.8.2 Angiotensin II receptor blockers (ARBs) ...............................................................................22 1.8.3 Beta-adrenergic receptor blockers (BB)................................................................................23 1.8.4 Calcium channel blockers (CCB) ..........................................................................................25 1.8.5 Diuretics.................................................................................................................................27 1.8.6 Nitrates (including nitroprusside)..........................................................................................28 1.8.7 Direct vasodilators (hydralazine, diazoxide) .........................................................................30 1.9 SUMMARY....................................................................................................................................31 1.10 REFERENCES................................................................................................................................32 2 PHARMACOLOGICAL INTERVENTIONS FOR HYPERTENSIVE EMERGENCIES........37 2.1 BACKGROUND .............................................................................................................................37 2.2 OBJECTIVES .................................................................................................................................38 2.2.1 General...................................................................................................................................38 2.2.2 Specific ...................................................................................................................................39 2.3 METHODS ....................................................................................................................................39 2.3.1 Criteria for considering studies for this review .....................................................................39 2.3.1.1 Types of studies ........................................................................................................................... 39 2.3.1.2 Types of participants ................................................................................................................... 39 2.3.1.3 Types of interventions ................................................................................................................. 41 2.3.1.4 Types of outcome measures ........................................................................................................ 41 2.4 SEARCH METHODS FOR IDENTIFICATION OF STUDIES ...................................................................41 2.5 DATA COLLECTION AND ANALYSIS..............................................................................................42  v 2.5.1 Data abstraction ....................................................................................................................42 2.5.2 Analyses .................................................................................................................................43 2.6 RESULTS ......................................................................................................................................44 2.6.1 Description of studies.............................................................................................................44 2.6.2 Risk of bias in included studies ..............................................................................................49 2.6.3 Effects of interventions: comparisons according to outcomes...............................................49 2.6.3.1 Total serious adverse events ........................................................................................................ 49 2.6.3.2 All-cause mortality ...................................................................................................................... 49 2.6.3.3 Non-fatal cardiovascular events .................................................................................................. 50 2.6.3.3.1 Composite .............................................................................................................................. 50 2.6.3.3.2 Myocardial infarction............................................................................................................. 50 2.6.3.3.3 Pulmonary edema requiring mechanical ventilation.............................................................. 50 2.6.3.4 Withdrawal due to adverse events ............................................................................................... 51 2.6.3.5 Weighted mean change in blood pressure and heart rate during treatment................................. 51 2.6.3.5.1 Drug versus placebo or no treatment...................................................................................... 51 2.6.3.5.2 Nitrates versus diuretics ......................................................................................................... 52 2.6.3.5.3 Nitrates versus alpha-1 antagonist.......................................................................................... 52 2.6.3.5.4 Nitrates versus dopamine agonist........................................................................................... 52 2.6.3.5.5 Nitrates versus ACE-inhibitors .............................................................................................. 53 2.6.3.5.6 Nitrates versus calcium channel blockers .............................................................................. 53 2.6.3.5.7 Nitrates versus direct vasodilator ........................................................................................... 53 2.6.3.5.8 ACE inhibitors versus calcium channel blockers................................................................... 53 2.6.3.5.9 ACE inhibitors versus alpha-1 adrenergic antagonist ............................................................ 54 2.6.3.5.10 Diazoxide versus hydralazine................................................................................................. 54 2.7 DISCUSSION .................................................................................................................................55 2.8 AUTHORS’ CONCLUSIONS............................................................................................................59 2.8.1 Implications for practice ........................................................................................................59 2.8.2 Implications for research .......................................................................................................60 2.9 REFERENCES................................................................................................................................61 3 EFFECT OF EARLY TREATMENT WITH ANTI-HYPERTENSIVE DRUGS ON SHORT AND LONG-TERM MORTALITY IN PATIENTS WITH AN ACUTE CARDIOVASCULAR EVENT..........................................................................................................................................................67 3.1 BACKGROUND .............................................................................................................................67 3.2 DESCRIPTION OF THE INTERVENTION...........................................................................................69 3.2.1 How do the interventions might work? ..................................................................................70 3.2.1.1 Angiotensin converting enzyme inhibitors (ACE-I) ................................................................... 70 3.2.1.2 Angiotensin II receptor blockers (ARBs).................................................................................... 71 3.2.1.3 Beta- adrenergic receptor blockers (BB) ..................................................................................... 71 3.2.1.4 Calcium channel blockers (CCB) ................................................................................................ 71 3.2.1.5 Diuretics....................................................................................................................................... 72 3.2.1.6 Nitrates (including nitroprusside)................................................................................................ 72 3.3 WHY IS IT IMPORTANT TO DO THIS REVIEW?................................................................................73 3.4 OBJECTIVES .................................................................................................................................76 3.4.1 Primary ..................................................................................................................................76 3.4.2 Secondary...............................................................................................................................76 3.5 METHODS ....................................................................................................................................77 3.5.1 Criteria for considering studies for this review .....................................................................77 3.5.1.1 Types of studies ........................................................................................................................... 77 3.5.1.2 Types of participants ................................................................................................................... 77 3.5.1.3 Types of interventions ................................................................................................................. 77 3.5.1.4 Types of outcome measures ........................................................................................................ 78 3.5.2 Search methods for identification of studies ..........................................................................79 3.5.2.1 Search strategy............................................................................................................................. 79 3.5.2.2 Medline search............................................................................................................................. 79 3.5.2.3 EMBASE search.......................................................................................................................... 79 3.5.2.4 CENTRAL search........................................................................................................................ 79 3.5.3 Data collection and analysis..................................................................................................80 3.5.3.1 Data extraction............................................................................................................................. 80  vi 3.5.3.2 Analysis ....................................................................................................................................... 80 3.6 RESULTS ......................................................................................................................................82 3.6.1 Description of studies.............................................................................................................82 3.6.1.1 Results of the search .................................................................................................................... 82 3.6.1.2 Excluded studies .......................................................................................................................... 84 3.6.1.3 Included studies ........................................................................................................................... 89 3.6.2 Risk of bias in included studies ..............................................................................................95 3.6.3 Effects of interventions according to outcomes .....................................................................97 3.6.3.1 Primary outcome: all-cause mortality.......................................................................................... 97 3.6.3.1.1 Nitrates ................................................................................................................................... 98 3.6.3.1.2 Angiotensin converting enzyme (ACE) inhibitors............................................................... 100 3.6.3.1.3 Beta-adrenergic antagonist or beta-blockers (BB) ............................................................... 102 3.6.3.1.4 Calcium channel blockers (CCB)......................................................................................... 106 3.6.3.2 Secondary outcome: total non-fatal serious adverse events ...................................................... 107 3.6.3.3 Secondary outcome: weighted mean change in blood pressure and heart rate during the first 24 hours of treatment ........................................................................................................................................... 107 3.6.3.3.1 Nitrates ................................................................................................................................. 108 3.6.3.3.2 Angiotensin converting enzyme inhibitors (ACEi).............................................................. 108 3.6.3.3.3 Beta- adrenergic antagonist or beta-blockers (BB) .............................................................. 109 3.6.3.3.4 Calcium channel blocker (CCB) .......................................................................................... 110 3.7 DISCUSSION ...............................................................................................................................111 3.7.1 Summary of main results......................................................................................................111 3.7.2 Summary of findings tables ..................................................................................................122 3.7.3 Overall completeness and applicability of evidence............................................................126 3.7.4 Quality of the evidence.........................................................................................................128 3.7.5 Potential biases in the review process .................................................................................129 3.7.6 Agreements and disagreements with other studies or reviews ............................................130 3.7.6.1 Nitrates....................................................................................................................................... 130 3.7.6.2 Angiotensin converting enzyme inhibitors (ACEi) ................................................................... 133 3.7.6.3 Beta-adrenergic antagonists or beta-blockers (BB)................................................................... 134 3.7.6.4 Calcium channel blockers (CCB) .............................................................................................. 135 3.8 AUTHORS’ CONCLUSIONS ..........................................................................................................137 3.8.1 Implications for practice ......................................................................................................137 3.8.1.1 Acute myocardial infarction. ..................................................................................................... 137 3.8.1.2 Other acute cardiovascular conditions....................................................................................... 138 3.8.2 Implications for research .....................................................................................................138 3.8.2.1 In patients with acute myocardial infarction ............................................................................. 138 3.8.2.2 In patients with acute stroke, unstable angina, acute pulmonary edema, cerebral hemorrhage or acute aortic dissection:.................................................................................................................................... 139 3.9 ACKNOWLEDGEMENTS ..............................................................................................................139 3.10 REFERENCES..............................................................................................................................141 4 FAILURE OF PSYCHOLOGICAL INTERVENTIONS TO LOWER BLOOD PRESSURE: RANDOMIZED CONTROLLED TRIAL ..............................................................................................158 4.1 INTRODUCTION ..........................................................................................................................158 4.2 METHODS ..................................................................................................................................159 4.2.1 Design ..................................................................................................................................159 4.2.2 Setting and participants .......................................................................................................159 4.2.3 Protocol................................................................................................................................160 4.2.4 Recruitment, clinical evaluation and follow-up ...................................................................161 4.2.5 Outcome measures ...............................................................................................................162 4.2.6 Statistical analysis................................................................................................................162 4.3 RESULTS ....................................................................................................................................163 4.3.1 Study population ..................................................................................................................163 4.3.2 Primary outcome: change in ambulatory blood pressure (24-h monitoring)......................166 4.3.3 Secondary outcome: change in resting clinic blood pressure .............................................166 4.3.4 Adverse events......................................................................................................................167 4.4 DISCUSSION ...............................................................................................................................168  vii 4.5 FUNDING SOURCE ......................................................................................................................172 4.6 TRIAL REGISTRATION.................................................................................................................172 4.7 ADDITIONAL INFORMATION: DETAILS OF PSYCHOLOGICAL INTERVENTIONS. ...........................172 4.7.1 Individualized behavioural therapy .....................................................................................172 4.7.2 Self-help therapy ..................................................................................................................173 4.7.3 Assessment tools for all treatment arms: .............................................................................174 4.8 REFERENCES..............................................................................................................................175 5 CONCLUDING CHAPTER............................................................................................................178 5.1 CLINICAL AND RESEARCH FOCUS...............................................................................................178 5.1.1 Acute-phase therapy.............................................................................................................178 5.1.1.1 Findings for the immediate intervention (start < 24 h, maximum therapy 48 hours) ............... 180 5.1.1.2 Findings for short-term intervention (start < 24 h, maximum therapy 10 days) ....................... 182 5.1.2 Discussion on timing and duration of therapy.....................................................................185 5.1.3 Post-acute phase therapy .....................................................................................................187 5.2 THE FOCUS ON ALL-CAUSE MORTALITY.....................................................................................187 5.3 HYPERTENSIVE THRESHOLDS AND ANTI-HYPERTENSIVE THERAPY............................................189 5.4 DO THE FINDINGS OF THESE SYSTEMATIC REVIEWS SUPPORT THE CURRENTLY APPROVED INDICATIONS FOR ANTIHYPERTENSIVE DRUGS IN THESE ACUTE SETTINGS? .............................................190 5.4.1 Nitrates (including nitroprusside)........................................................................................190 5.4.2 Angiotensin converting enzyme inhibitors (ACE-I) .............................................................192 5.4.3 Angiotensin II receptor blockers (ARBs) .............................................................................193 5.4.4 Beta-adrenergic receptor blockers (BBs) ............................................................................193 5.4.5 Calcium channel blockers (CCBs) .......................................................................................194 5.4.6 Diuretics...............................................................................................................................195 5.5 STUDY BIAS AND LIMITATIONS OF SYSTEMATIC REVIEWS .........................................................195 5.5.1 Recruitment bias ..................................................................................................................195 5.5.2 Randomization, concealment of allocation and blinding.....................................................196 5.5.3 Performance bias .................................................................................................................197 5.5.4 Funding bias ........................................................................................................................197 5.6 CONDUCTING AN RCT AS AN ADDITIONAL TOOL FOR COMPLETING SYSTEMATIC REVIEWS ......199 5.7 WHAT ARE OVERALL CONCLUSIONS OF THIS THESIS?................................................................202 5.7.1 Clinical implications ............................................................................................................202 5.7.2 Research implications ..........................................................................................................203 5.7.3 Findings of the randomized controlled trial comparing HCTZ to two psychological interventions: ......................................................................................................................................203 5.7.4 Clinical implications of the randomized controlled trial: ...................................................204 5.8 REFERENCES..............................................................................................................................205 APPENDIX I: UBC RESEARCH ETHICS BOARD CERTIFICATE OF APPROVAL ..................208 APPENDIX II: SEARCH STRATEGY, CHAPTER 2 ..........................................................................209 APPENDIX III: CHARACTERISTICS OF INCLUDED STUDIES, CHAPTER 2...........................211 APPENDIX IV: MEDLINE AND EMBASE SEARCHES, CHAPTER 3 ...........................................239 APPENDIX V: CHARACTERISTICS OF INCLUDED STUDIES, CHAPTER 3 ............................242  viii  LIST OF TABLES TABLE 1-1. PHARMACOKINETICS OF ACE-INHIBITORS...................................................................................21 TABLE 1-2. PHARMACOKINETICS OF ARBS ....................................................................................................22 TABLE 1-3. PHARMACOKINETICS OF BETA-ADRENERGIC BLOCKERS (BB) .....................................................24 TABLE 1-4. PHARMACOKINETICS OF CALCIUM CHANNEL BLOCKERS (CCBS) ...............................................26 TABLE 1-5. PHARMACOKINETICS OF DIURETICS.............................................................................................27 TABLE 1-6. PHARMACOKINETICS OF NITRATES (INCLUDING NITROPRUSSIDE) ...............................................29 TABLE 2-1. SUMMARY OF INCLUDED STUDIES. ...............................................................................................46 TABLE 3-1 REASONS FOR EXCLUSION OF STUDIES ..........................................................................................86 TABLE 3-2 OVERVIEW OF INCLUDED STUDIES ACCORDING TO GROUP............................................................91 TABLE 3-3 ACUTE EVENT AND TIMING OF INCLUSION IN INCLUDED STUDIES .................................................93 TABLE 3-4 SUMMARY OF FINDINGS TABLE FOR NITRATES ............................................................................122 TABLE 3-5 SUMMARY OF FINDINGS TABLE FOR ACE-INHIBITORS ................................................................123 TABLE 3-6 . SUMMARY OF FINDINGS TABLE FOR BETA-BLOCKERS. ..............................................................124 TABLE 3-7. SUMMARY OF FINDINGS TABLE FOR CALCIUM CHANNEL BLOCKERS ..........................................125 TABLE 4-1 PATIENTS CHARACTERISTICS AT BASELINE ................................................................................165 TABLE 4-2 TWENTY-FOUR-HOUR AMBULATORY BLOOD PRESSURE MEASUREMENTS AT BASELINE AND CHANGE FROM BASELINE AT WEEK 12.................................................................................................166 TABLE 4-3 RESTING CLINIC BLOOD PRESSURE MEASUREMENTS AT BASELINE AND CHANGE FROM BASELINE OVER 12 WEEKS...................................................................................................................................167 TABLE 5-1 EFFECT OF IMMEDIATE DRUG THERAPIES* ON MORTALITY AT DIFFERENT TIMES AFTER ACUTE MYOCARDIAL INFARCTION ..................................................................................................................181 TABLE 5-2. EFFECT OF SHORT-TERM DRUG THERAPIES* ON MORTALITY IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION, AT DIFFERENT TIMES..............................................................................185   ix LIST OF FIGURES  FIGURE 2-1 QUORUM FLOWCHART OF STUDIES ..............................................................................................45 FIGURE 3-1 QUORUM FLOWCHART OR CITATIONS (RCTS) ............................................................................83 FIGURE 3-2 RISK OF BIAS IN INCLUDED TRIALS...............................................................................................97 FIGURE 3-3 META-ANALYSIS OF THE EFFECT OF NITRATES IN ALL-CAUSE MORTALITY AT TWO DAYS ...........98 FIGURE 3-4 META-ANALYSIS OF THE EFFECT OF ACE-INHIBITORS IN ALL-CAUSE MORTALITY AT TWO DAYS. ............................................................................................................................................................101 FIGURE 3-5 META-ANALYSIS OF THE EFFECT OF IMMEDIATE AND SHORT-TERM TREATMENT WITH ACE- INHIBITORS IN ALL-CAUSE MORTALITY AT 10 DAYS...........................................................................102 FIGURE 3-6 META-ANALYSIS OF THE EFFECT OF IMMEDIATE TREATMENT WITH BETA-BLOCKERS ON MORTALITY AT TWO DAYS.................................................................................................................104 FIGURE 3-7 META-ANALYSIS OF THE EFFECT OF IMMEDIATE TREATMENT AND SHORT-TERM TREATMENT WITH BETA-BLOCKERS ON MORTALITY AT 10 DAYS ..........................................................................105 FIGURE 3-8 SENSITIVITY ANALYSIS: EFFECTS OF CONTINUATION OF NITRATES ON ALL-CAUSE AT DIFFERENT TIMES ..................................................................................................................................................116 FIGURE 3-9 SENSITIVITY ANALYSIS: EFFECT OF ACE-I CONTINUATION ON ALL-CAUSE MORTALITY AT DIFFERENT TIMES. ...............................................................................................................................120 FIGURE 4-1 FLOW DIAGRAM FOR PATIENTS IN THE STUDY. .........................................................................164 FIGURE 5-1. EFFECTS OF CONTINUATION OF NITRATES ON MORTALITY AT DIFFERENT TIMES. ..................183 FIGURE 5-2. FUNNEL PLOT OF ALL-CAUSE MORTALITY AT 10 DAYS FOR THE COMPARISON NITRATES VS. CONTROL .............................................................................................................................................198   x GLOSSARY ACC: American College of Cardiology ACE-i (ACEi): Angiotensin converting enzyme inhibitors ACUTE MYOCARDIAL INFARCTION (ICD-9 410): Commonly called a “heart attack”, an acute myocardial infarction is a manifestation of ischemic heart disease, describing a severe sudden onset of myocardial necrosis due to the formation of a thrombus in the coronary arterial system obstructing arterial blood flow to that section of cardiac muscle. AHA: American Heart Association AMI: Acute myocardial infarction ARBs (ARB’s): Angiotensin II receptor blockers ARR: Absolute risk reduction ASA: American Stroke Association AT1: Angiotensin II type 1 receptor BB: Beta-adrenergic receptor blockers BHS: British Hypertension Society BP: Blood pressure BPM: Beats per minute CARDIOVASCULAR DISEASES (ICD-9 390-459): All diseases of the circulatory system, including acute myocardial infarction, ischemic heart disease, valvular heart disease, peripheral vascular disease, arrhythmias, high blood pressure and stroke.  xi CCB: Calcium channel blockers CVD: Cerebrovascular disease (ICD-9 430-438): Disease of one or more blood vessels of the brain. CHF: Congestive heart failure CK: Creatine kinase CPK: Phosphocreatine kinase CVE: Cardiovascular event DBP: Diastolic blood pressure EOF: End of follow-up ESC: European Society of Cardiology ESH: European Society of Hypertension FDA: Federal Drug Administration HR: Heart rate ICD: International Classification of Diseases is a disease classification system created by the World Health Organization (WHO). Version 9 of the ICD is currently used in Canada; this was revised in 1977. There is also a "Clinical Modification" version (ICD9-CM) being used in Canada, which has extended coding for more precise disease classification. Version 10 of the ICD has been released and will be introduced in Canada in the next few years. ICH: International Conference of Harmonization IHD: Ischemic Heart Disease (ICD-9 410-414): Any condition in which heart muscle is damaged or works inefficiently because of an absence or relative deficiency of its blood supply; most often causes by atherosclerosis, it includes angina pectoris, acute myocardial infarction, chronic ischemic heart disease and sudden death. It is also called coronary heart disease (CHD).  xii ISH: International Society of Hypertension IU: International units IV: Intravenous JNC: Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure LVFP: Left ventricular filling pressure MAP: Mean arterial pressure MESH: Medical subject headings Mo: Month N/A: Not applicable NA: Not available NNH: Number needed to harm NNT: Number needed to treat NO: Nitric oxide NR: Not reported NS: Not significant NSTEMI: Non-ST elevation myocardial infarction NTG: Nitroglycerin RAAS: Renin angiotensin aldosterone system  xiii RCT: Randomized controlled trial RR: Relative risk RRR: Relative risk reduction SAE: Serious adverse events SBP: Systolic blood pressure SD: Standard deviation SE: Standard error SNP: Sodium nitroprusside STROKE: A condition which results in a reduction of blood flow to a region of the brain resulting in the "death" of brain tissue; specifically, infarction from hemorrhage (ICD-9 430- 432), thrombolitic/embolitic stroke (ICD-9 433-434) or rupturing aneurysm. Thrombolytic strokes are due to cerebral thrombosis and are often superimposed on a plaque of atherosclerosis; symptom onset ranges from minutes to days. Embolic strokes are due to cerebral embolism; they usually have a sudden onset of symptoms reflecting abrupt loss of blood flow to the brain region of the occluded artery. THROMBUS (THROMBOSIS): An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causes vascular obstruction at the point of its formation. UA: Unstable angina WHO: World Health Organization  xiv ACKNOWLEDGEMENTS There are not enough words to express my immense debt of gratitude towards my supervisor, Professor Dr, James Wright. His sound advice and careful guidance were invaluable and enabled me to write these lines. He shared his vast knowledge and skills when I was writing reports for publication, grant proposals and scholarship applications. This thesis would not have been possible, nor would it have been useful, if it were not for Professor Wright’s wise and punctual input.  I would like to thank the other members of my supervisory committee -Dr. Ken Basset, Dr. Casey van Breemen and Dr. Thomas Perry- for their insightful suggestions and constructive critiques. I am particularly grateful to Dr. Vijaya Musini, who, through expert tutelage, taught me the necessary skills to critically appraise clinical trials.  For his enthusiasm and assistance, a special note of thanks goes out to Stephen Adams. His help in retrieving articles was incalculable. In addition, I want to thank my co- workers and colleagues –especially Balraj Heran (Benji), Ciprian Jauca, Christopher Adlparvar, Michelle Wong, Jenny Chen and Gavin Wong- for their great collaboration and endless support.  Apart from my colleagues, I would like to thank my wonderful and loving parents: they never lost faith in my ability to achieve this long-term commitment. They deserve special recognition for not hesitating to give “life” (in its most extensive meaning), as they gave  xv me mine, even though they had raised 10 children before me. They sacrificed their entire lives in order to give each of us a superior education.   xvi DEDICATION    To my wonderful wife and kids, Elizabeth, you are the most precious gift that God has given to me. It is a great honor to be your spouse. You are incredibly amazing and charming. I love you in a way that I could never have imagined. With your unconditional giving and your unlimited power of love, you have given me my beautiful and intelligent daughter, Liz, and my handsome and charming son, Paco. Thanks to you and to my kids, I am the most fortunate man in the world. This work is dedicated to all of you, With all of my Love and Soul,  Marco A.   xvii CO-AUTHORSHIP STATEMENT  Chapter 2: Pharmacological Interventions for Hypertensive Emergencies Marco Perez and James Wright formulated the idea for the review and developed the basis for the protocol. Marco Perez took the lead roles in searching for, identifying and assessing studies, in data extraction methodology, analysis and in writing up the review. Vijaya Musini independently checked the trials for inclusion and exclusion and independently checked the data extraction as well as helped with the methodology of the review. James Wright assisted with the methodology of the review and with the interpretation and writing of the review. Chapter 3: Effects of Early Treatment with Anti-hypertensive Drugs on Short and Long-term Mortality in Patients with an Acute Cardiovascular Event  Marco Perez formulated the idea for the review and developed the basis for the protocol. Marco Perez took the lead roles in searching for, identifying and assessing studies and in data extraction, methodology, analysis, interpretation and in writing up the review. Vijaya Musini independently checked the trials for inclusion and exclusion and independently checked the data extraction.  James Wright helped with the methodology of the review, interpretation and writing of the review. Chapter 4: Failure of Psychological Interventions to Lower Blood Pressure: a Randomized Controlled Trial Marco Perez participated in the design of the trial, did the majority of the recruiting, clinical assessments, clinic blood pressure measurements, analysis, interpretation, and writing of the manuscript.  Wolfgang Linden, Lorri Puil and James  xviii Wright participated in the conception of the study as well as the design, conduct and revisions of the manuscript. Lorri Puil, Thomas Perry, Jr., and James Wright assisted in the conduct of the trial.  .  1 1 INTRODUCTION 1.1 Conception of the research question My interest in this research project began in the intensive care unit of a teaching hospital in Mexico in the year 2000 when I questioned whether or not to use blood pressure lowering medications in my acutely ill cardiovascular patients. At the time, I knew almost nothing about evidence-based medicine, nor had I had any experience in conducting or evaluating clinical research.  For the most part, I uncritically accepted the opinions of local experts and rigorously followed clinical practice guidelines; both recommended prescribing blood pressure-lowering drugs to these patients. I questioned this approach recognizing that blood pressure changes in acute cardiovascular injuries could be appropriate physiological adjustments to injury and perhaps necessary to achieve homeostasis. Lowering blood pressure, in these instances, could increase rather than decrease harm.  However, while I could raise these questions, I recognized that I had no capacity to answer them. I gradually realized that no one in my institution or country (that I could find) had the capacity to answer these questions either. I tried to build my research skills by becoming a co-investigator in a local clinical trial. Unfortunately, although the trial was conducted in a leading university teaching hospital, the methodological standards were too low to achieve scientifically valid results.  I also tried and failed to get scientific justification from local experts as to why they recommended blood pressure lowering therapy. This led me to go elsewhere both to learn high quality clinical trial methodology and to  2 attempt to establish the scientific basis of blood pressure treatment during acute cardiovascular events. From the beginning my thesis committee strongly supported my interest in both learning clinical trial and systematic review methodology, recognizing the obvious synergy between these two dimensions of clinical research. 1.1.1 Hypertension in acute cardiovascular emergencies: pathological or physiological response The acute phase of cardiovascular event is the period when organs are most vulnerable to local and systemic changes. This high vulnerability is substantiated by the high mortality rate during this critical period, e.g., during acute myocardial infarction the highest mortality rates occur within the first 24 hours1. Finding interventions to halt this increased mortality has been the goal of many investigations. An acute cardiovascular event is a sudden manifestation of a cardiovascular disease (e.g., myocardial infarction or stroke). Cardiovascular diseases are the leading cause of death in the world2 and the leading cause of hospitalization in Canada3 The hypothesis behind this research work is that the timing for initiation of blood pressure lowering drugs determines their effects (benefit or harm). The primary objective of this thesis is to study the effects of these drugs in the acute phase (<24 hr after the event) of different cardiovascular clinical settings. 1.1.2 Other drugs in the acute phase of cardiovascular events The most successful drugs at reducing mortality during the acute phase of a cardiovascular event have been anti-platelets and thrombolytics for patients with acute  3 myocardial infarction or stroke. These drugs have been shown to be most effective when administered as early as possible after the event and within the first 24 hours. For example, in a meta-analysis of randomized controlled trials, published in 1994, for thrombolytics in acute myocardial infarction it was demonstrated that there were 30 lives saved per 1000 treated within 6 hours of the onset, 20 lives saved per 1000 treated between 7-12 hours, and uncertain benefit for those treated between 13-18 hours4. This meta-analysis was conducted based on pathophysiological mechanisms thought to be the cause of acute myocardial infarction (thrombotic occlusion at the site of atherosclerotic plaques). These results established that the timing of initiation of this type of pharmacological intervention was critical in obtaining the benefits in clinical outcomes. In other words, in the initial hours and days after the insult has occurred there is a dynamic and changing sequence of events and effective treatments in the initial hours after the event may not be effective when started 2 days after the event and vice versa. 1.2 Research outline I began by researching the most accepted acute clinical setting where blood pressure- lowering drugs could logically be used: “Hypertensive Emergencies”. This clinical entity is defined, by The JNC 7- as “marked blood pressure elevation associated with acute end organ damage” 5. Examples of acute end organ damage include acute cardiovascular events (myocardial infarction, unstable angina, acute cardiogenic pulmonary edema, acute aortic dissection, hypertensive encephalopathy and stroke). This interest led me to embark on my first systematic review (Chapter 2 of this thesis). The hypertensive emergencies project was limited to patients with a marked elevation in BP and as such restricted the number of RCTs that would fit the inclusion criteria. It thus,  4 did not allow a study of the benefits and harms of antihypertensive therapy in a broader spectrum of patients. Therefore, I developed a second research project, which includes the same acute cardiovascular events mentioned in the hypertensive emergency definition but without being limited by any specific BP criterion. This second, broader research project represents chapter 3 of this thesis. Since patients with these acute clinical settings could have “normal” blood pressure they are simply referred as “acute cardiovascular events”. However, in this second research project RCTs were only included if the treatment was initiated within the first 24 hours of the onset in order to measure the effect of the drugs during this early vulnerable period of the clinical setting. The importance of this second research project is exemplified by the fact that blood pressure lowering drugs are recommended during this time-frame independent of the BP by most current clinical guidelines6-8, despite the fact that elevated blood pressure is not present in most cases in these clinical settings. At the present time there has not been a systematic review study to assess whether blood pressure-lowering drugs administrated to patients in an acute clinical setting provide mortality and morbidity benefits. Others have attempted to study this, but with the wrong approach or with different objectives. In each of my two systematic reviews, I discuss in detail the weakness of these other systematic reviews. Basically, all of the reviews accept patients in these “acute” clinical settings but also accept patients who are identified and treated more than 24 hours after the onset of the condition. For example, these systematic reviews include trials where the treatment started days after the onset of the acute cardiovascular event9-13, when the patients are not in the high-risk most vulnerable phase. Another difference and disadvantage of those reviews is that they are out of date. By  5 conducting Cochrane collaboration systematic reviews I am committing to update these two reviews every two years so that they continue to represent current information. 1.3 What is a systematic review? Systematic review is a scientific technique that summarizes and appraises large quantities of information from randomized controlled trials in order to clarify controversial research findings and to inform therapeutic recommendations that can improve population health. In this modern time, publications about health care interventions have increased so much that researchers, health care providers and policy makers can no longer keep up with the large and often contradictory literature. A systematic review answers a specific research question following a standard methodology. First, a pre-specified plan or protocol (outlining the objectives, search strategy, criteria for inclusion and exclusion of trials, risk of bias check points, etc.) is developed; then the critical appraisal is performed (identification of the strengths and weaknesses of the primary trials as well as contacting the authors for missing information). Next comes the phase of summarizing the overall benefits and harms of the intervention in question. However, since all of these steps are documented, the chances for introducing bias in the results are minimized. Furthermore the rigorous transparent methods allow replication and validation of the work. A systematic review can be qualitative or quantitative (if it has a meta-analysis component). A meta-analysis involves combining the quantitative data from individual studies, thereby increasing the statistical power and precision of the estimate of the effect size. A systematic review is subject to difficulties and limitations. It is a retrospective study and therefore is subject to bias. Possible sources of bias are those inherent in the primary literature, such as publication bias (which describes the tendency of positive-result  6 studies to be more likely to be published, sometimes multiple times, than negative-result studies). In a quantitative systematic review with meta-analysis this can lead to an overestimate of the true treatment effect. Fortunately, there are some statistical methods to correct for this type of bias. Another source of bias is selection and observer bias: these can be minimized by having at least two independent reviewers selecting studies and extracting the relevant data. Despite these potential limitations, systematic reviews have become the gold standard of evidence-based medicine. 1.4 What is the Cochrane collaboration? The Cochrane Collaboration is a national and international, not-for-profit, independent organization dedicated to improve healthcare decision-making by promoting, preparing, maintaining and disseminating up-to-date systematic reviews of randomized controlled trial (RCT) evidence. The major product of this organization is the Cochrane Database of Systematic Reviews, an electronic publication that is updated quarterly. Cochrane systematic reviews are prepared and published using special software, Review Manager, which facilitates the update of reviews by easily incorporating missed or newly published trials. This user-friendly format continues to be developed through an ongoing process of consultation with its users. A study that compared Cochrane reviews with articles published in paper-based journals concluded that Cochrane reviews were conducted with greater methodological rigor and were more likely to be updated14 1.5 What is the overall objective of this thesis? To find and quantify, using Cochrane systematic review methodology, the randomized controlled trial evidence for the use of anti-hypertensive drugs in acute clinical settings, specifically acute cardiovascular events.  7 1.6 Additional tools used for performing Cochrane systematic reviews In addition to completing two Cochrane systematic reviews, requiring meticulous analysis, and critical appraisal of randomized controlled trials (RCTs), I decided that I needed to also participate in an RCT. This was decided with two main purposes: to gain a deeper appreciation of the difficulties, strengths and potential biases, which occur while conducting an RCT (something I was analyzing and criticizing on the regular basis while performing my systematic reviews); and to become proficient in the steps involve in conducting a clinical trial in order to get the necessary skills and experience so that after I graduate, I would be in a position to design, get funding for and run a high quality randomized controlled trial. The trial I was fortunate to be able to participate in represents Chapter 4 of this thesis. This RCT involved patients with hypertension and included an antihypertensive drug as one of the arms of the trial. 1.7 Clinical background: acute cardiovascular events Although different acute cardiovascular events could be considered different clinical entities, they have two things in common: they are life threatening and have a high rate of initial mortality; and, therefore, they require prompt management with the goal of reducing that mortality. The following is a description of the incidence, prevalence, pathophysiology, diagnosis and current recommended management of various acute cardiovascular events. 1.7.1 Acute myocardial infarction Incidence and prevalence: According to the 2008 update of Heart Disease and Stroke Statistics, acute myocardial infarction is highly prevalent. It comprises half (~ 8 million) of all coronary heart disease in the United States15. The estimated annual incidence of  8 acute myocardial infarction is 600,000 new attacks and 320,000 recurrent attacks. The average age at first myocardial infarction (MI) is 64.5 years for men and 70.4 years for women.  In Canada, unfortunately, the existing surveillance system relies on administrative physician billing and hospitalization rates. Thus, the incidence of the disease has not been routinely determined3. However, the annual hospitalization rates for acute myocardial infarction have increased steadily since 1980 and are projected to increase further, especially for men, beginning at age 40 and for women at age 503. In 2000/01 the MI hospitalization rates for men and women, age 40-79, were reported as 1/35 and 1/80, respectively3. Diagnosis: The following three components are used: clinical, electrocardiogram and serum cardiac biomarkers. The first two are sufficient to initiate a therapeutic intervention and the third one is usually used to confirm the diagnosis and also for prognosis purposes. The clinical component consists of signs and symptoms (typical chest discomfort, diaphoresis, pale complexion, fatigue, lightheadedness, syncope, paraesthesias, nausea, vomiting, etc.). The electrocardiogram: a more accurate diagnosis of the acute myocardial infarction has evolved thanks to the better understanding of the correlation between the findings in the electrocardiogram and the pathology, therapeutic interventions and prognosis. In fact, acute myocardial infarction now is referred conventionally as ST-segment elevation myocardial infarction (STEMI)6 to distinguish it from non-STEMI myocardial infarction (see below). Although, there are still some diagnostic controversial issues, such as whether 0.2 mV ST elevation in leads V1 through V4 is a preferable threshold for diagnosis of STEMI rather than 0.1 mV elevation, a 12- lead electrocardiogram (ECG) remains the most important diagnostic tool for therapeutic  9 decisions6. The diagnosis of MI by detecting proteins (biomarkers) released into the circulation due to damage of myocytes has also changed over the years. In the past (60- 70’s), non-specific biomarkers such as glutamic-oxaloacetic transaminase (SGOT), lactate dehydrogenase (LDH) and total creatine kinase (CK) were used. Now, highly specific cardiac biomarkers (MB fraction of creatine kinase [CK-MB], cardiac troponin I [cTnI], cardiac troponin T [cTnT]) are used to confirm the diagnosis6. The latter biomarkers have higher sensitivity to detect very small infarcts that would not have been considered MI in an earlier era. Thus, by accepting that any amount of myocardial necrosis caused by ischemia is evidence of infarct, individuals who formerly would not have been diagnosed as having an MI are diagnosed today as having an MI. The American College of Cardiology and the European Society of Cardiology declared cardiac troponins the preferred biomarker for diagnosis of MI6. An abnormal value that exceeds that of 99% of a reference control detected at least once within 24 hours of the clinical event is diagnostic. Pathophysiology: Acute myocardial infarction occurs due to an inadequate supply of oxygen caused by an occlusion of one or more coronary arteries. This occlusion is usually caused by rupture of an atherosclerotic coronary artery plaque with subsequent acute thrombosis. The pathophysiological processes that occur following acute myocardial infarction are very complex. They are influenced by many factors, particularly the site and magnitude of the infarction. However, in general, as soon as the coronary blood flow is decreased the myocardial mechanics are altered (even before the actual myocardial cell death) due the acute oxygen deprivation, resulting in systolic and diastolic dysfunction. This activates a cascade of events with an increase of left-  10 ventricular filling pressure and decrease of cardiac output, decrease of blood pressure and activation of the sympathetic system. The sympathetic release of catecholamines increases the heart rate and vascular tone resulting in an increase of oxygen consumption and workload of the heart potentially worsening the ischemia and leading to a vicious circle with further dysfunction. There are, however, many clinical presentations specific for different pathophysiological processes16. Management: Restoration of blood flow to the myocardium is the cornerstone and ultimate goal of the treatment. Pharmacological treatments have been used to attempt to accomplish this blood flow restoration with some success. For example, randomized controlled trial (RCT) evidence has demonstrated a reduction in mortality with the use of thrombolytic drugs4;17 and anti-platelet drugs18. Although, both of these pharmacological interventions by themselves have been able to reduce mortality, the effect of their interaction seems to be additive. In the ISIS-2 trial19, treatment with aspirin caused an absolute risk reduction (ARR) in mortality of 2.4% at 35 days. When both treatments (aspirin and streptokinase) were given concomitantly the ARR was 5.2% at 35 days. The use of a non-pharmacological intervention, PCI (angioplasty with or without stent), has also been proven to reduce mortality and has been compared with the effectiveness of thrombolysis. There is still some controversy whether these non-pharmacological interventions are superior to the pharmacological ones for all types of AMI. However, these controversies have not been entirely resolved by meta-analysis mainly because of the use of different sub-modalities of these interventions in different randomized controlled trials (RCT) or because these interventions have been combined with other  11 pharmacological interventions across RCTs making it difficult to pool them all. Indications for blood pressure lowering drugs for this setting and the other acute cardiovascular settings are discussed under the individual blood pressure lowering classes below. 1.7.2 Unstable angina Incidence and prevalence: The recent prevalence and incidence of unstable angina (UA) is difficult to estimate accurately as this entity has been included within a broader term the “acute coronary syndrome”, which comprises three main sub-settings: unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI). Few epidemiological studies have reported unstable angina separately. A national U.S report of first-listed inpatient hospital discharges from hospitals in 2005 estimated that unstable angina was the diagnosis at discharge in 89,000 (11.5 %) out of 772,000 patients with acute coronary syndrome. But, when including secondary discharge diagnoses 558,000 (39%) were reported with unstable angina out of 1,430,000 patients with ACS15. Diagnosis and Pathophysiology: Unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI) are two acute settings that form a similar clinical syndrome7. The most common cause of this syndrome is a reduction in myocardial perfusion that results from coronary artery narrowing caused by thrombus that developed on a disrupted atherosclerotic plaque that is usually non-occlusive7. It has been defined as having typical signs and symptoms (chest pain-usually for more than 20 minutes- or anginal equivalent, shortness of breath, diaphoresis, dyspnea, fatigue) as well as changes in the electrocardiogram such as ST-segment depression or prominent T-wave inversion  12 and/or absence of ST-segment elevation 7. The main distinction between these two entities is whether or not the ischemia was severe enough to cause sufficient myocardial damage to release detectable quantities of markers of myocardial injury (troponin or CK- MB). Since the detection of these biomarkers can be delayed for some hours after the onset, patients with either of these two are indistinguishable clinically at the time of presentation. However, as these biomarkers become available they allow the differentiation between UA (i.e., no release of biomarkers) and NSTEMI (i.e., elevated biomarkers) 7. There are 3 principal presentations of UA: 1) rest angina, 2) new onset and, 3) increasing angina (increasing in intensity, duration and/or frequency) 7. Management: The management generally consists of two different approaches: an invasive or conservative approach. In the former, in addition to pharmacological treatment, coronary angiography and revascularization is usually performed within the first 4-24 hours after admission. In the conservative approach, the pharmacological treatments (nitrates, beta-blockers, calcium channel blockers, ACE-inhibitors, anti- platelets and anti-coagulants) are administered during the first 24-72 hours and depending on the clinical course an invasive procedure is performed later. Thus, the main difference between the two approaches is the treatment received during the first 24 hours. This emphasizes the importance that clinicians give to the acute or immediate period following the onset of this event.  There is still controversy as to which of these two approaches is superior. Some not so contemporary RCTs had shown no differences in hard outcomes20-22. A more recent meta-analysis reported an 18% relative reduction in death or MI in favor of the invasive intervention approach23. However, a recent large trial compared invasive versus  13 conservative approach in patients receiving currently recommended concomitant pharmacological therapies in both groups and found no difference in mortality or in the primary composite outcome24. 1.7.3 Stroke Incidence and prevalence: According a nation-wide U.S survey it is reported that 2.7% of men and 2.5% of women 18 years or older have a history of stroke25. Thus, in 2005 the estimated number of U.S residents with a history of stroke was 5,839,00025. Also in the U.S. the estimated annual incidence of acute stroke has been reported as 600,000 new attacks and 180,000 recurrent attacks15; and this incidence was greater for men than women except for those aged ≥ 85 where the incidence for women was reported to be higher than that for men15.  In Canada, the annual hospitalization rates for acute stroke for men and women, age 40-79, were reported as 1/67 and 1/95, respectively, whereas, those rates for those aged 90+ were 1/45 and 1/53, respectively3. Diagnosis: Stroke is caused by a reduction in cerebral blood flow to a region of the brain. It has been broadly classified as ischemic (most cases) or hemorrhagic. The former could ensue after a large vessel occlusion (usually the middle cerebral artery) or after small vessel occlusions. Hemorrhagic strokes have been described as those occurring in the parenchyma; intraventricular, subarachnoid and subdural. Chronic hypertension is the main risk factor. The diagnosis of the stroke is usually made using two components: clinical and brain imaging (CT scan or MRI). There are some validated clinical tools currently used26;27. The World Health Organization had defined stroke as “ a clinical syndrome consisting of rapidly developing clinical signs of focal (or global in case of coma) disturbance of  14 cerebral function lasting more than 24 hours or leading to death with no apparent cause other than a vascular origin”. A transient ischemic attack (TIA) is defined as stroke symptoms and signs that resolve within 24 hours.  Pathophysiology: The pathophysiological processes that occur following a stroke are very complex and vary depending on type, localization and size of the stroke. For example, a hemorrhage of 60 ml in the basal ganglia is usually fatal within hours, whereas the same size bleed in the frontal or occipital lobe could have a good long-term outcome. Under normal circumstances the cerebral blood flow (CBF) is maintained constantly at 50 ml/ 100 g brain tissue per minute. CBF is a function of cerebral perfusion pressure (CPP), and cerebrovascular resistance (CVR), where CBF= CPP/ CVR; while CPP is equal to mean arterial pressure (MAP) minus intracranial pressure (ICP). In a normal individual ICP is negligible, therefore CPP is determined almost entirely by MAP; thus, CBF is held constant by adjusting CVR (autoregulation). In an acute stroke, the ability to adjust CVR is decreased and the autoregulation within and around the stroke area is impaired (global impairment may also be present). Furthermore, the ICP might be increased due to cerebral edema. As a result, small changes in MAP may cause dramatic changes in CBF, putting the brain at higher risk of further damage (further ischemia if MAP falls or hemorrhage if MAP increases). Management: There is randomized controlled trial (RCT) evidence that early use of thrombolysis (especially within six hours) of an ischemic stroke significantly reduced the proportion of patients who were dead or dependent at three to six months28. The initial  15 management for hemorrhagic stroke is to decrease the intracranial pressure in order to reduce the risk of further bleeding and neuronal deficit. Neurosurgery is sometimes required to evacuate a hematoma, though, the benefits of this are still in doubt. In a recent large multicenter randomized controlled trial involving 1,033 patients, the evacuation of the hematoma failed to show a benefit on survival or neurologic functioning at 6 months29. On the other hand, no mortality or dependency benefit has been documented for any pharmacological agents to reduce intracranial pressure such as mannitol or barbiturate-inducing coma. 1.7.4 Cardiogenic pulmonary edema Incidence and prevalence: There are two classes of pulmonary edema: cardiogenic and non-cardiogenic. The latter is referred to that resulting from an alteration in the permeability of the pulmonary capillary membrane such as in acute respiratory distress syndrome (ARDS). Non-cardiogenic pulmonary edema is not considered an acute cardiovascular event and is not within the scope of this thesis. Cardiogenic pulmonary edema arises when there is a sufficient increase in left ventricular end-diastolic pressure to provoke backward elevation in pulmonary capillary hydrostatic pressure resulting in leakage of fluid from capillaries and venules into the alveolar space30. Acute cardiogenic pulmonary edema most commonly occurs as a consequence of an anterior myocardial infarction, left-sided valvular disorders, acute dysrhythmias, myocardiopathies, drug-induced, and acute exacerbation of chronic left ventricular failure (most commonly due to a sudden increase in plasma volume)30. The exact incidence and prevalence of this clinical setting is not known. In a recent epidemiological study of 1,477 patients admitted to a tertiary hospital with diagnosis of  16 heart failure, 176 (12%) had acute pulmonary edema at admission in the emergency department. Of those, 106 (60%) patients suffered from an acute coronary event. The other 70 (40%) patients suffered from a non-ischemic event31. Diagnosis: Clinically patients with acute pulmonary edema are characterized by severe dyspnea, orthopnea, tachypnea, rales and “pink” sputum. They may also present with a gallop rhythm, third heart sound or murmurs (suggesting valvular dysfunction). Other tests that can help to make the diagnosis are the chest X-ray (to confirm pulmonary congestion), electrocardiogram (ischemia, dysrhythmia) and echocardiography (size of chambers, valvular structure and function, dyskinesis etc.). As it was pointed out above, the development of pulmonary edema secondary to an acute myocardial infarction is quite common. In fact, there is a clinical classification of severity of heart failure in the context of an AMI, the Killip classification, which is described in four stages: I – No heart failure; II – Heart failure with S3 gallop, wet rales in the lower half of lung fields; III- frank pulmonary edema with rales throughout the lung fields; IV- cardiogenic shock (SBP <90 mm Hg), oliguria, cyanosis, sweating. Pathophysiology: Whatever the initial insult causing the left ventricular dysfunction and increase of left ventricular end-diastolic pressure, it eventually turns on a cascade of events leading to death if no intervention is given.  When the pulmonary capillary hydrostatic pressure exceeds pulmonary interstitial pressure, the fluids start to build up in the pulmonary interstitium and alveolar space resulting in impaired gas exchange and hypoxia. This leads to increased catecholamine production and activation of the renin - angiotensin - aldosterone system (RAAS), which in turn increases the systemic vascular resistance (afterload), causing greater myocardial wall tension and oxygen demand,  17 resulting in myocardial ischemia (if not already present), and more systolic and/or diastolic dysfunction. Ultimately, cardiac output decreases, which compromises kidney perfusion and activates the sympathetic system and RAAS. The kidney tries to compensate by increasing the reabsorption of salt and water to increase intravascular volume32. Management: The specific management depends on the underlying cause. However, some general measures include oxygen and the use of pharmacological interventions (such as morphine) to reduce preload or afterload of the heart; and non-pharmacological interventions (such as ventilatory support) to improve the alveolar patency. 1.7.5 Acute aortic dissection Incidence and prevalence: The incidence has been estimated in some epidemiological studies. In the 1950’s and 1960’s, Sorenson et al., reported an incidence of 5 to 10 cases per 100,000 per year33. In a more recent study published in 2004, Clouse et al., reported an incidence of 3.5 per 100,000 per year between 1980 and 199434.  Diagnosis: Most patients with acute aortic dissection present with sudden, severe, chest pain. They usually described it as “ripping” or “tearing” chest pain. Back pain could be present with distal or descending dissection. The chest pain must be differentiated from that of an acute coronary syndrome. The latter has been more often described as a “crescendo” form. In contrast, in aortic dissection the pain has an abrupt onset. Patients may also present with a neurologic complication such as acute stroke, ischemic peripheral neuropathy (where the limb ischemia would be evident) or paraplegia due to occlusion of an artery to the spinal cord. The diagnosis is made with the use of ECG (to  18 rule out acute coronary syndrome), chest X-ray, transesophageal echocardiogram, helical CT scan and MRI. Pathophysiology: Acute aortic dissection is a tear in the aortic intima through which blood flows into the aortic media, separating the intima from the adventitia. Generally the tear and disruption of these layers is caused by degeneration or chronic insult. Chronic hypertension, congenital bicuspid aortic valve and connective tissue disease (eg., Marfan syndrome) are among the list of associations with this condition. The two main serious consequences are: propagation of the dissection with occlusion of branching arteries or aortic wall rupture. The speed with which the maximal systolic pressure is attained (referred as dP/dTmax) in the aorta has been shown to be one of the most important factors in the propagation of dissection. When this occurs it could cause occlusion of aortic branch arteries, or prolapse of aortic valve cusps, resulting in aortic insufficiency. If the aortic wall is ruptured it can cause cardiac tamponade or hemorrhage into the pleural space. Rupture of the aorta is the most common cause of death 35. Management: In addition to control of pain, reduction of systolic blood pressure and pulse wave (dP/dT) is important. Anti-hypertensive drugs have been used include: Labetalol (alpha and beta1 and 2 adrenergic blocker) - decreases peripheral resistance, heart rate and myocardial contractility (dP/dTmax); esmolol decreases heart rate and myocardial contractility (dP/dTmax); sodium nitroprusside decreases peripheral resistance and preload; Trimethaphan camsylate –autonomic ganglion blocker- decrease peripheral resistance. The latter two are usually used in combination with beta-blocker. Definitive management usually involves surgical repair, especially in dissections involving the ascending aorta. Those patients in whom only the descending aorta is  19 involved are initially managed medically unless there is a definite indication for surgery. Overall, untreated aortic dissection has been reported to have a mortality rate of 21% within the first 24 hours and 60% within 2 weeks36. Dissection of the ascending aorta has been reported to have a mortality rate of 60% within 24 hours and 80% within two weeks37. In a recent epidemiological study of 547 patients with dissection of the ascending aorta the in-hospital mortality rate was 26.6% for those treated with surgery and 55.9% for those treated medically38. Although there have been improvements in technologies and surgical techniques, recent epidemiological studies have not shown improvement in mortality in this setting over the last 2 decades39;40. 1.8 Pharmacological background: anti-hypertensive drugs Blood-pressure lowering drugs or anti-hypertensives are defined here as those pharmacological agents indicated and used to treat elevated blood pressure or hypertension. According to the World Health Organization / International Society of Hypertension41 and other international committees (such as JNC-7)5 these include the following classes of drugs: angiotensin converting enzyme inhibitors (ACE-I), angiotensin II receptor blockers (ARBs), beta-adrenergic receptor blockers (BB), calcium channel blockers (CCB), diuretics, nitrates (including nitroprusside), alpha-adrenergic antagonists, direct vasodilators (diazoxide, hydralazine) and others (such as reserpine). However, it is important to emphasize that many anti-hypertensive drugs have pharmacological actions other than lowering BP (for example, reducing heart rate), which which makes them usable for indications other than the management of hypertension. In contrast, there are drugs that have the potential to reduce blood pressure (for example:  20 morphine in certain doses and setting) but are not classified as anti-hypertensive drugs. The latter classes of drugs are not covered in this thesis. In the next section a description of the mechanism of action, pharmacokinetics, indications and dosage of the major anti-hypertensive drug classes is covered. Indication and dosing information is limited to those drugs with an indication listed in the Compendium of Pharmaceutical and Specialties (CPS) of Canada42 or approved by the U.S. Food & Drug Administration (FDA) for the treatment of any acute cardiovascular event. 1.8.1 Angiotensin converting enzyme inhibitors (ACE-I) Mechanism of action: ACE-I competitively block the conversion of angiotensin I, a relatively inactive peptide, to angiotensin II, a potent vasoconstrictor and stimulator of the release of aldosterone, from the adrenal cortex. ACE-I probably lower blood pressure by reducing the blood pressure increasing effects of Angiotensin II. There are numerous drugs under this class such as captopril, enalapril (a complete list can be found in the following 2 chapters), but all of these drugs are thought to act in a similar manner.  Pharmacokinetics: Except for enalaprilat, ACE inhibitors are administered orally. Most ACE inhibitors are pro-drug esters that must be converted in the liver and/or GI mucosa to active metabolites. The pharmacokinetic properties vary depending on the specific drug. (See Table 1-1)  21 Table 1-1. Pharmacokinetics of ACE-inhibitors Elimination (%) Parent Drug Active Metabolite Bioavailability (%) Protein Bound (%) tmax (h) t1/2 (h) Hepatic Renal Benazepril  37 97 0.5-1 10-11 12 88 Captopril  65 30 1-1.5 4 60 40^ Enalapril Enalaprilat 40-60 <50 3-4 1.3 11  94 Lisinopril  25  7 12 <1 98^ Perindopril 30-35 10-20 0.5-1 1.2 >90 4-12^ Quinapril 60 97 1 2 40 60 Ramipril 28-44 73 1 2-4 40 60 Trandolapril  4-14 94 1-6      >90 <0.5^ ^ Eliminated (%) unchanged - tmax = time to maximum plasma concentration - t½ = half-life  Other pharmacokinetic properties may differentiate ACE inhibitors including lipophilicity, tissue binding, peak-trough ratio, etc. However, it is not known whether these differences have any clinical significance.  Indications and dosing for acute cardiovascular events: Captopril: Post MI: initial dose 6.25 or 12.5 mg 3 times a day.  Dose can be gradually increased up to 450 mg per day. Lisinopril Post MI: 5 mg within 24 hours of acute myocardial infarction follow by 5 mg after 24 hours and 10 mg per day after 48 hours and thereafter.  22 1.8.2 Angiotensin II receptor blockers (ARBs) Mechanism of action: ARBs inhibit the binding and action of Angiotensin II at the angiotensin II type 1 (AT1) receptor, which is the site of action to cause vasoconstriction and release of aldosterone. They, thus, similar to ACE-I probably reduce BP by blocking the BP increasing effects of Angiotensin II. The drugs under this category or class are candesartan, irbesartan, losartan, telmisartan, valsartan.  Pharmacokinetics: There are differences in pharmacokinetic properties of drugs within the class that result in differences in the magnitude and duration of their blood pressure lowering effect (Table 1-2).  Table 1-2. Pharmacokinetics of ARBs Elimination (%) Drug  Bioavailability (%) Protein Bound (%) tmax (h) t1/2 (h) Hepatic Renal unchanged Candesartan  15 99.5 2-5 6-13 67 33 Eprosartan  13 98.0 1-3 5-9 90 10 Irbesartan  60-80 90.0 1.3-3 11-18 80 20 Losartan  29-43 98.7 1-1.5 1-3 65 35 Telmisartan  30-60 99.5 0.5-1 21-38 98 2 Valsartan 10-35 95.0 2-4 6-10 80 20  - tmax = time to maximum plasma concentration - t½ = half-life   23 Indications and dosing for acute cardiovascular events: Valsartan Post MI: start as early as 12 hours after myocardial infarction in clinically stable patients at 20 mg two times a day. Increase at 7 days to 40 mg twice daily, and then progressively, over weeks, up to 160 mg twice daily. 1.8.3 Beta-adrenergic receptor blockers (BB) Mechanism of action: In general, beta-adrenergic receptor blocking drugs, or beta-blockers (BB), are drugs that competitively inhibit the effect of the catecholamines, noradrenaline and adrenaline, on beta-adrenergic receptors. There are subtypes of beta-blockers depending on their relative affinity for B1 and B2 receptors, partial agonist activity, and ability to also block alpha- adrenergic receptors. Catecholamines have a positive chronotropic and inotropic actions on the heart, can cause vasoconstriction or vasodilatation of blood vessels and stimulate renin release from the kidney. Thus, BB drugs could lower BP by a number of these differing effects. The exact mechanism by which beta-blockers lower BP in humans is not known. Pharmacokinetics: The pharmacokinetics of beta-adrenergic blocking agents differs widely. This is mainly due to the variation in the aromatic ring structure. Pharmacokinetically, these drugs can be sub-divided into two general categories: those that are lipid soluble and primarily metabolized by the liver, and those that are water soluble and predominantly excreted unchanged by the kidney. See Table 1-3 for more details.   24 Table 1-3. Pharmacokinetics of Beta-adrenergic blockers (BB) Elimination (%) Drug  Bioavailability (%) Protein Bound (%) tmax (h) t1/2 (h) Hepatic Renal unchanged Acebutolol  40 25 2.5 3-4 60 12-29 Atenolol  5.0 <5 2-4 5-8  40 Carvedilol  30 98 1 6-10 98 <1 Esmolol  NA 55  9 min Ery <2 Labetalol  20 50 1-2 4-6 95 5 Metoprolol 40 12  3-4 95 5  Nadolol 30 20  10-20  25  Propranolol 25 93 1-4 3-6 99 <1  Timolol 50 60  4-5 80 20  - tmax = time to maximum plasma concentration - t½ = half-life Ery = mainly erythrocytes elimination  Indications and dosing for acute cardiovascular events: Labetalol Hypertensive emergencies: start with 20 mg IV, max: 300 mg IV bolus; or IV infusion 2 mg/min. convert to PO 200-400 mg q6-12 hours. Metoprolol Acute myocardial infarction: start with 5 mg IV, every 2 min (3 times); after 15 min, give 50 mg PO q6h x 48 h. Then gradually increase over the weeks to a maximum dose of 400 mg/day. Post myocardial infarction: start as soon as possible with 50 mg PO bid. Then, gradually increase over the weeks to a maximum dose of 400 mg/day.  25 1.8.4 Calcium channel blockers (CCB) Mechanism of action: Calcium channel blockers reduce the cytosolic free-calcium concentrations by blocking transmembrane calcium influx through L-type calcium channels. Dihydropyridines (such as nifedipine), benzothiazepines (diltiazem) and phenylalkylamines (verapamil) bind to the pore-containing the α1-subunit of the L-type calcium channel. In general, calcium channel blockers relax arteriolar smooth muscle, resulting in vasodilatation and decreased peripheral resistance. The decreased systemic resistance is thought to cause the blood pressure reduction. Agents that slow the rate of recovery of L-type calcium channels (verapamil, diltiazem) have negative chronotropic and dromotropic (AV node conduction) effects on the heart's conducting system. The CCBs also have a natriuretic effect on the kidney that may contribute to their ability to lower blood pressure Pharmacokinetics: In general CCBs drugs are well absorbed from the gastrointestinal tract but undergo first- pass hepatic metabolism resulting in low bioavailability. Early calcium antagonists were short acting, with time to maximum concentration occurring within about 2 hours.  The rapid decreases in blood pressure gave rise to many side effects, especially tachycardia from reflex sympathetic nervous system activation, flushing, headache and dizziness. Newer CCBs such as amlodipine and slow-release formulations of older CCBs were developed to produce a more gradual decrease in blood pressure with a longer duration of BP control and less side effects.  26 The metabolism of CCBs occurs via oxidative enzymes in the liver, primarily the 3A4 isoenzyme of the cytochrome P450 family.  See Table 1-4 for more details Table 1-4. Pharmacokinetics of Calcium Channel Blockers (CCBs) Elimination (%) Drug  Bioavailability (%) Protein Bound (%) tmax (h) t1/2 (h) Hepatic metabolism Renal unchanged Dihydropyridines Amlodipine  63 97.5 6-12 35-50 60 10 Felodipine  15 99 2.5-5 11-16 70 <0.5 Isradipine  15-24 95 2-4 8 65 <1 Nicardipine  10-17 98 0.5-1 2 60 <1 Nifedipine 45-75 95 0.5-2 2-5 75 0.1  Nimodipine 13 99 1.5 1 e 8-9 t 95 1  Non-dihydropyridines  Diltiazem  40-67 70-80 2-4 3-6  2-4 Verapamil 10-20 >90 1-2 3-7 86 3  - tmax = time to maximum plasma concentration - t½ = half-life  Indications and dosing for acute cardiovascular events: Nimodipine: Post-subarachnoid hemorrhage (SAH): Therapy should commence as soon as possible or within 4 days of the diagnosis. The recommended dosage is 60-90 mg every 4 hours for 21 consecutive days.     27 1.8.5 Diuretics Mechanism of action: Thiazide diuretics inhibit the Na+Cl- co-transporter in the proximal part of the distal convoluted tubule of the kidney. This decreases tubular reabsorption of sodium and chloride, and increases urinary excretion of sodium and water Furosemide and other loop diuretics inhibit sodium reabsorption in the ascending limb of loop of Henle as well as in both proximal and distal tubules. The mechanism by which diuretics lower blood pressure has not been established The drugs under this category are the thiazide and thiazide-like diuretics (hydrochlorothiazide, chlorthalidone, indapamide) and loop diuretics (furosemide, ethacrynic acid). Pharmacokinetics: The pharmacokinetic parameters are shown in Table 1-5 Table 1-5. Pharmacokinetics of Diuretics Elimination (%) Drug  Bioavailability (%) Protein Bound (%) tmax (h) t1/2 (h) Hepatic  Renal Thiazide diuretics Chlorthalidone  60-70 75 2-6 44 0 30-65 HCTZ  65-75 58 4-6 3-15 0 95 Indapamide  93 76 2 4-22 90 7 unchanged Loop-diuretics Furosemide  60 98 2 4-6 10-15 60 Ethacrynic acid   2 6-8 - tmax = time to maximum plasma concentration - t½ = half-life -HCTZ = hydrochlorothiazide   28 Indications and dosing for acute cardiovascular events: Furosemide and ethacrynic acid are indicated for acute pulmonary edema. Furosemide: 40 -80 mg IV as single dose or it can be repeated every 4-8 hours Ethacrynic acid: oral 50 mg or IV 0.5 to 1 mg /kg one or two doses. Maximum dose is 100 mg. 1.8.6 Nitrates (including nitroprusside) Mechanism of action:  Organic nitrates and sodium nitroprusside (SNP) are nitric oxide (NO) donors. Organic nitrates, such as glyceryl trinitrate (nitroglycerin) require enzymatic metabolism to generate NO. In contrast, SNP spontaneously generates NO. There are a number of theories about how nitrates cause vasodilatation: 1) acting on specific nitrate receptor (containing a sulfhydryl group-SH), 2) NO exerts a potassium channel activation (hyperpolarizing the cell membrane) and 3) NO activates the enzyme guanylate cyclase increasing cGMP levels, which in turn inhibits Ca+ entry into smooth muscle cells and increases Ca+ uptake by the smooth endoplasmic reticulum resulting in vascular smooth muscle relaxation. Included in this category of drugs are organic nitrates (including isosorbide dinitrate, isosorbide mononitrate, and nitroglycerin) and nitroprusside. Pharmacokinetics: The organic nitrates are well absorbed from the gastrointestinal track and nitroglycerin is also absorbed through intact skin.  They undergo first pass denitration in the liver yielding active metabolites.  Isosorbide dinitrate is metabolized to isosorbide 2 and 5- mononitrate, the latter being available commercially as isosorbide mononitrate (as  29 sustained –release tablets). The onset and duration of action varies depending on the formulation and route of administration (See Table 1-6).  Table 1-6. Pharmacokinetics of Nitrates (including nitroprusside) Elimination (%) Drug  Bioavailability (%) Protein Bound (%) Onset (min) Duration (min) Hepatic metabolism Renal unchanged Nitrates Nitroglycerin (sub-lingual) 90 -- 1-3 10-30 99 <1 Nitroglycerin (intravenous)   1-2 3-5 99 <1 Isosorbide mono-nitrate (oral IR)  99 5 2-5 120-240 99 2 Isosorbide dinitrate (sub-lingual)  90  2-5 60-180 99 <1  Nitroprusside (intravenous)   -- 0.5 2-3 Wall Ery Hepatic -- - min = minutes - wall = vascular wall - Ery = erythrocytes - IR = immediate release   Indications and dosing for acute cardiovascular events: Nitroglycerine: Hypertension in acute coronary syndrome: Intravenous (IV) nitroglycerin can be used as an initial dosage of 5 µg/min with increments every 3-5 min until blood pressure is controlled or increments of 10 to 20 µg/min (but the interval of the increments should be lengthened) up to a maximum of 100 µg per minute.  30 Nitroprusside: Hypertensive emergency: The usual dose regimen is 0.25 to 10 µg / kg/ min as an IV infusion 1.8.7 Direct vasodilators (hydralazine, diazoxide) Hydralazine Mechanism of action: Hydralazine has a direct vasodilatory effect that leads to a reduction in peripheral vascular resistance. The exact mechanism of this vasodilatory effect has not been established. Pharmacokinetics: Hydralazine is rapidly absorbed. The peak plasma concentration could be achieved at 2 hours. There are large inter-individual differences in plasma concentration after oral administration. Acetylator phenotype is an important determinant of these differences42. The half-life is about 2 to 4 hours but may range up to 8 hours. It is metabolized in the gastrointestinal mucosa and in the liver. Indications and dosing for acute cardiovascular events: Hypertensive emergencies: initial bolus of 5 to 10 mg IV, followed by 5 to 10 mg IV every 20 to 30 minutes as necessary. Or it may be infused at a rate of 0.5 to 10 mg per hour. Diazoxide: Although an oral formulation is still on the market as a glucose-control agent in patients with hyperinsulinism, IV diazoxide has been discontinued from the market as an anti- hypertensive drug. It was formerly used as a potent intravenous antihypertensive. Its  31 mechanism of action is related to ATP-sensitive K channel activation, causing arteriolar relaxation. Indications and dosing for acute cardiovascular events: Hypertensive emergencies: 50 to 150 mg IV bolus or 15 to 30 mg /min in IV infusion.  1.9 Summary This thesis consists of four chapters in addition to this introductory chapter.  Chapter 2 is the published Cochrane systematic review, documenting all of the available RCT evidence supporting the use of blood pressure-lowering drugs in hypertensive emergencies.  Chapter 3 is the published Cochrane systematic review assessing the effect of the early use of blood pressure-lowering drugs in acute cardiovascular events. Chapter 4 is the published randomized controlled trial, comparing the blood pressure-lowering effects of the antihypertensive drug hydrochlorothiazide with two psychological interventions. Chapter 5 interprets and discusses the relationships and conclusions coming from chapters 1 to 4.  32  1.10 References    (1)  Fulton M, Julian DG, Oliver MF. Sudden death and myocardial infarction. Circulation 1969; 49:I82-89.  (2)  WHO. Gloabal burden disease. http://www who int/healthinfo/global_burden_disease/GBD_report_2004update_full pdf 2004.  (3)  Health Canada. The Growing Burden of Heart Disease and Stroke. http://www cvdinfobase ca/cvdbook/CVD_En03 pdf 2003.  (4)  FTT. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Lancet 1994; 343(8893):311-322.  (5)  JNC-7, Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289(19):2560-2572.  (6)  ACCAHA, Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction--executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). Circulation 2004; 110(5):588-636.  (7)  ACCAHA, Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 2007; 116(7):e148-e304.  33  (8)  AHA-ASA, Adams RJ, Albers G, Alberts MJ, Benavente O, Furie K et al. Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke 2005; 39(5):1647-1652.  (9)  AMICG. Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. ACE Inhibitor Myocardial Infarction Collaborative Group.[see comment]. Circulation 1998; 97(22):2202-2212.  (10)  Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta Blockade after myocardial infarction: systematic review and meta regression analysis.[see comment]. BMJ 1999; 318(7200):1730-1737.  (11)  Held PH, Yusuf S, Furberg CD. Calcium channel blockers in acute myocardial infarction and unstable angina: an overview.[see comment]. BMJ 1989; 299(6709):1187-1192.  (12)  Rodrigues EJ, Eisenberg MJ, Pilote L. Effects of early and late administration of angiotensin-converting enzyme inhibitors on mortality after myocardial infarction.[see comment]. American Journal of Medicine 2003; 115(6):473-479.  (13)  Yusuf S, Peto R. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985; XXVII(5):335-371.  (14)  Jadad AR, Cook DJ, Jones A, Klassen TP, Tugwell P, Moher M et al. Methodology and reports of systematic reviews and meta-analyses: a comparison of Cochrane reviews with articles published in paper-based journals. JAMA 1998; 280(3):278-280.  (15)  Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N et al. Heart disease and stroke statistics--2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2008; 117(4):e25-146.  (16)  Wong SC, Sanborn T, Sleeper LA, Webb JG, Pilchik R, Hart D et al. Angiographic findings and clinical correlates in patients with cardiogenic shock complicating acute myocardial infarction: a report from the SHOCK Trial Registry. SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK? J Am Coll Cardiol 2000; 36(3 Suppl A):1077-1083.  (17)  Boersma E, Maas AC, Deckers JW, Simoons ML. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour (Structured abstract). Lancet 1996; 348:771-775.  (18)  ATC, Antiplatelet Therapy Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death , myocardial infarction, and stroke in high risk patients. Br Med J 2002; 324:71-86.  34  (19)  ISIS-2. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.[see comment]. Lancet 1988; 2(8607):349-360.  (20)  Anonymous. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction. Results of the TIMI IIIB Trial. Thrombolysis in Myocardial Ischemia. Circulation 1994; 89(4):1545-1556.  (21)  Boden WE, O'Rourke RA, Crawford MH, Blaustein AS, Deedwania PC, Zoble RG et al. Outcomes in patients with acute non-Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy. Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital (VANQWISH) Trial Investigators. N Engl J Med 1998; 338(25):1785-1792.  (22)  McCullough PA, O'Neill WW, Graham M, Stomel RJ, Rogers F, David S et al. A prospective randomized trial of triage angiography in acute coronary syndromes ineligible for thrombolytic therapy. Results of the medicine versus angiography in thrombolytic exclusion (MATE) trial. J Am Coll Cardiol 1998; 32(3):596-605.  (23)  Mehta SR, Cannon CP, Fox KA, Wallentin L, Boden WE, Spacek R et al. Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials. JAMA 2005; 293(23):2908- 2917.  (24)  de Winter RJW. Early invasive versus selectively invasive management for acute coronary syndromes. N Engl J Med 2005; 353(11):1095-1104.  (25)  Centers for Disease Control and Prevention (CDC). Prevalence of stroke--United States, 2005. MMWR Morb Mortal Wkly Rep 2007; 56(19):469-474.  (26)  Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non-neurologists in the context of a clinical trial. Stroke 1997; 28(2):307-310.  (27)  Nor AM, Davis J, Sen B, Shipsey D, Louw SJ, Dyker AG et al. The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. Lancet neurol 2005; 4(11):727-734.  (28)  Wardlaw JM, Zoppo Gd, Yamaguchi T, Berge E. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2003; CD000213:DOI.  (29)  Mendelow AD, Gregson BA, Fernandes HM, Murray GD, Teasdale GM, Terence HD et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): A randomised trial. Lancet 2005; 365(9457):387-397.  35  (30)  Mattu A, Martinez JP, Kelly BS. Modern management of cardiogenic pulmonary edema. Emergency Medicine Clinics of North America 2005; 23(4):1105-1125.  (31)  Shamagian LG, Roman AV, Ramos PM, Acuna JMG, Veloso PR, Gonzalez- Juanatey JR. Acute pulmonary edema in patients with decompensated heart failure. Role of underlying cardiopathy on the prognosis. Int J Cardiol 2007; 121(3):302-305.  (32)  Cohen-Solal A, McMurray JJV, Ponikowski P, Poole-Wilson PA, Stromberg A, van Veldhuisen DJ et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008. The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur J Heart Fail 2008; 10(10):933-989.  (33)  Sorenson HR. Ruptured and Dissecting aneurysms of the aorta: incidence and prospects of surgery. Acta Chir Scand 1964;128, 644.  (34)  Clouse WD, Hallett JW, Jr., Schaff HV, Spittell PC, Rowland CM, Ilstrup DM et al. Acute aortic dissection: population-based incidence compared with degenerative aortic aneurysm rupture. Mayo Clinic Proceedings 2004; 79(2):176- 180.  (35)  DeSanctis RW, Doroghazi RM, Austen WG, Buckley MJ. Aortic dissection. [Review] [83 refs]. N Engl J Med 1987; 317(17):1060-1067.  (36)  Hirst AE., John VJ, Kime SW. Dissectinganeurysm of the aorta: A review of 505 cases. Medicine 1958; 37(217): 279..  (37)  Cohn LH. Aortic dissection: new aspects of diagnosis and treatment. Hosp Pract (Off Ed) 1994; 29(3):47-56.  (38)  Mehta RHS. Predicting death in patients with acute type a aortic dissection. Circulation 2002; 105(2):200-206.  (39)  Estrera AL, Huynh TTT, Porat EE, Miller III CC, Smith JJ, Safi HJ. Is acute type A aortic dissection a true surgical emergency? Seminars in Vascular Surgery 2002; 15(2):75-82.  (40)  Narayan P, Rogers CA, Davies I, Angelini GD, Bryan AJ. Type A aortic dissection: has surgical outcome improved with time? Journal of Thoracic & Cardiovascular Surgery 2008; 136(5):1172-1177.  (41)  WHO-ISH. 2003 World Health Organization (WHO)/ International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003; 21:1983-1992.  36  (42)  CPS. Monographs.Compendium of Pharmaceuticals and Specialties 2008.                37  2 PHARMACOLOGICAL INTERVENTIONS FOR HYPERTENSIVE EMERGENCIES1 2.1 Background A hypertensive emergency is the clinical setting in which a marked elevation of blood pressure is associated with acute end organ damage; for example, hypertensive encephalopathy or aortic dissection. As such, a hypertensive emergency is a life- threatening condition. The goal of treatment is to reverse the end organ damage, prevent adverse outcomes and prolong life. This review focuses on the blood pressure-lowering drugs that are used in this emergency setting. The management of hypertension in these emergency situations represents a significant therapeutic challenge. Many antihypertensive drug classes have been used with the objective of rapidly reducing blood pressure, and the expectation of reducing adverse clinical outcomes. This approach was first recommended by Gifford in 19591 based on a series of 8 cases with hypertensive encephalopathy that were treated with sodium nitroprusside. Based on this case series evidence this approach has become and remained the standard of care and is currently recommended by most, if not all, guideline committees (such as JNC-7 2). At issue in this review is whether RCT evidence supports this approach and which drug classes are the most effective.  1 A version of this chapter has been published. Perez MI, Musini VM, Wright JM. Pharmacological interventions for hypertensive emergencies. Cochrane Database of Systematic Reviews 2008, Issue 1 Art No. CD003653. DOI:10.1002/14651858.pub3. A version of this chapter has been co-published in the Journal of human hypertension 2008;22[9]:596-607  38 Two published systematic reviews attempted to address these issues. However, they have different methodology and some deficiencies. For example, Cherney et al 20023 accepted data from patients who were not part of a randomized controlled trial. In addition, they incorrectly placed some “urgency” trials in the “emergency” category of trials, even though the authors correctly defined and studied emergencies and urgencies as two separate settings. Hypertensive urgencies are defined as marked elevated blood pressure in an otherwise stable patient (i.e., without acute end organ damage). Hypertensive emergency patients are at higher risk of death than hypertensive urgency patients due to the presence of significantly more life-threatening circumstances in the former category 4. Because of these differences in risk the urgency and emergency settings need to be reviewed separately. The second systematic review, a Cochrane review of interventions that alter blood pressure after acute stroke, is not limited to RCTs studying drugs to reduce blood pressure and includes RCTs involving interventions or approaches with the aim of increasing blood pressure5. Therefore, it also does not answer the question raised here. 2.2 Objectives 2.2.1 General To find and quantify the randomized controlled trial (RCT) evidence for antihypertensive drug treatment of patients with a hypertensive emergency, defined as marked hypertension associated with acute end organ damage.  39 2.2.2 Specific To answer the following two questions: does anti-hypertensive drug therapy, as compared to placebo or no treatment, affect mortality and morbidity in patients with a hypertensive emergency; and does one first-line antihypertensive drug class offer a therapeutic advantage, in terms of mortality and morbidity, over another in patients with a hypertensive emergency? 2.3 Methods 2.3.1 Criteria for considering studies for this review 2.3.1.1 Types of studies All unconfounded, truly randomized control trials* that compare a first-line antihypertensive drug class versus placebo, no treatment or another first-line antihypertensive drug class. Crossover trials are excluded. There is no language restriction. * Trials where it is explicitly stated that randomization took place; quasi-randomization or pseudo-randomization methodology is not accepted for inclusion. 2.3.1.2 Types of participants Participants must meet the following hypertensive emergency definition: any clinical setting where patients present with marked elevation of blood pressure in the presence of acute end organ damage. Examples of acute end organ damage are the following: myocardial infarction, unstable angina, acute left ventricular failure with pulmonary edema, acute aortic dissection, encephalopathy, stroke, and life-threatening bleeding (intracerebral hemorrhage, subarachnoid hemorrhage).  40 Thus, patients with marked elevation of blood pressure but without acute end organ damage (defined as urgencies) are not included. There is no evidence as to what constitutes "marked blood pressure elevation". Therefore, we have chosen blood pressure level(s) commonly used in clinical practice to mandate the use of antihypertensive drugs (along with other acute therapy such as pain management) in relevant clinical settings. For example, for patients with acute myocardial infarction a SBP greater or equal to 180 and or DBP ≥ 110 mm Hg is the threshold above which thrombolysis is contraindicated [ACC/AHA-2004 6].For patients with acute aortic dissection or with left ventricular failure and pulmonary edema a SBP greater or equal to 120 mm Hg and or DBP ≥ 70 mm Hg is the threshold for therapy 7;8. For patients with intracranial hemorrhage or subarachnoid hemorrhage a SBP ≥ 160 mm Hg is the threshold because of a higher incidence of re-bleeding above this level 9. For patients with any other acute end organ damage setting a SBP ≥ 180 and or DBP ≥ 110 mm Hg is the defined threshold. We included all RCTs that included patients with these minimum or higher thresholds. In the case that a RCT does not define blood pressure inclusion criteria but had included only one category of patients (patients with pulmonary edema, for example), then the mean base-line blood pressure had to be equal to or greater than these defined thresholds. In the event that an RCT had included patients with different end organ damage clinical settings, a mean base-line blood pressure of SBP ≥180 and or DBP ≥ 110 mm Hg is acceptable for inclusion. Note: Pregnancy-related hypertensive emergencies are excluded from this review.  41 2.3.1.3 Types of interventions Intervention: A first-line anti-hypertensive drug class. (First-line anti-hypertensive drug classes included: nitrates, beta-blockers, ACE-inhibitors, diuretics, calcium channel blockers, dopamine agonists, alpha-adrenergic antagonists and direct vasodilators (diazoxide, hydralazine). Control: placebo, no treatment or a different first-line anti-hypertensive drug class. 2.3.1.4 Types of outcome measures Primary • Total serious adverse events^ • All cause mortality • Composite of non-fatal cardiovascular events including: myocardial infarction, unstable angina, dissection of aortic aneurysm, acute renal failure, stroke, and respiratory failure (necessitating mechanical ventilation). ^ Serious adverse events are defined as any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of hospitalization, or results in persistent or significant disability10 Secondary • Weighted mean change in systolic blood pressure (SBP), diastolic blood pressure (DBP) and in heart rate (HR), during the treatment period. • Withdrawal due to adverse events 2.4 Search methods for identification of studies We searched randomized controlled trials of all antihypertensive drugs used for hypertensive emergencies through the following databases of articles published from  42 1966 to August 2007: MEDLINE, EMBASE, COCHRANE clinical trial register. A comprehensive search strategy was used to identify all relevant articles. Review articles and trials reference lists were also checked. Key words: controlled clinical trial, randomized controlled trials, meta-analysis, severe/ accelerated/ crisis (es), hypertension, antihypertensive, emergencies: hypertensive encephalopathy, myocardial infarction, unstable angina, acute left ventricular failure, pulmonary (o) edema, stroke, subarachnoid / intracranial h (a) emorrhage, aortic dissection. For a complete search strategy see Appendix II: Search Strategy Chapter 2. 2.5 Data collection and analysis 2.5.1 Data abstraction Two reviewers (M.I.P. & V.M.) independently decided whether or not a trial was included. They also independently extracted and entered the data from the included studies. Discrepancies were resolved by discussion. Absence of consensus was resolved by a third reviewer (J.M.W.). A modified Cochrane quality scoring system was used for concealment of allocation and blinding: A (adequate & double-blind), B (unclear & single-blind or open label), C (clearly inadequate & open-label). The two reviewers (M.I.P. & V.M.) also independently assessed the quality of studies. Authors were contacted in case of missing information.  43 2.5.2 Analyses For the synthesis and analysis of the data, Cochrane Review Manager 4.2.9 was used. Relative and absolute risk differences (with 95% confidence interval) were calculated for dichotomous outcomes for each trial on an intention to treat basis. Heterogeneity between trials results was tested using chi-squared test, where p less than 0.05 was taken to indicate significant heterogeneity. The fixed effect model was used when there was homogeneity and the random effect model was used to test for statistical significance where there was heterogeneity. Trials were not sub-classified according to dose or dosing regimen. Data for blood pressure was combined using a weighted mean difference method, whereby the trials are weighted according to the number of subjects in the trial and the within-study variance. Some of the trials did not report a within-study variance for blood pressure reduction. In these studies standard deviation (SD) was imputed using the following hierarchy: 1. Pooled standard deviation calculated either from the t-statistic corresponding to an exact p-value reported or from the 95% confidence interval of the mean difference between treatment group and comparative group. 2. Standard deviation of blood pressure/heart rate at the end of treatment 3. Standard Deviation of blood pressure/heart rate at baseline (except if this measure is used for entry criteria). 4. Weighted mean standard deviation of change in blood pressure/heart rate calculated from at least 3 other trials using the same drug and dose regimen. 5. Weighted mean standard deviation of change in blood pressure/heart rate calculated from other trials using the same drug.  44 6. Weighted mean standard deviation of change in blood pressure/heart rate calculated from all other trials (any drug and dose). Several sensitivity analyses were pre-planned to test robustness including the use of both fixed and random effects models, 95 and 99% confidence intervals, and quality of trials. Also sensitivity analyses were pre-planned according to the clinical setting and to the class of drug. 2.6 Results 2.6.1 Description of studies Our search strategy yielded 86% of citations showing no relation to this work in the first screening stage by reading titles and abstracts (see Figure 2-1).  Fifteen randomized controlled trials (869 patients) were found that satisfied the inclusion criteria11-25 (see Summary of Included Studies, Table 2-1). Two trials were placebo-controlled14;20. Only one trial14 was confirmed to be double-blind, while the rest were open-label. No trial was designed for or had the power to detect differences in clinical outcomes. The largest trial consisted of 133 patients 22. The longest trial 13 lasted 10 days. Most of the trials reported data for only two to six hours. (Please see appendix III: for full details of the characteristics of Included Studies). Seven drug classes were evaluated: nitrates (nine trials), ACE-inhibitors (seven), calcium channel blockers (six), peripheral alpha-1 blockers (four), diuretics (three), direct vasodilators (two) and dopamine agonists (one).      45 Figure 2-1 Quorum flowchart of studies   All included trials had patients with elevated blood pressure in the presence of acute end organ damage. Blood pressure entry criteria differed among trials. Four trials were included on the basis of their mean blood pressure values at baseline 12;14;19;20 . Seven trials included exclusively patients with acute pulmonary edema12;14;16;19;22;23;25. One trial included exclusively patients with hypertensive encephalopathy18. There was no trial that Citations excluded by reading title and abstract. (clearly no relation to our work)  n=4,660   Citations retrieved for more detailed evaluation: n=753 Excluded:  n= 711 Reasons :  Non-randomized: 354  Non-acute end organ damage (AEOD) setting: n= 270  AEOD setting but BP below our pre-established thresholds defining a hypertensive emergency: n= 87  Potentially appropriate randomized controlled trials: n= 42 Citations identified in literature search: N= 5,413  Included: n= 15 Excluded: n= 27 Reasons: (see text for details)  46 included exclusively patients with acute aortic dissection or acute myocardial infarction. Thus, the rest of seven trials included a diverse population with different acute end organ damage. Only two trials 11;17 reported the standard deviation of the change of blood pressure. In the rest of the trials this measure of variability was imputed from the standard deviation at endpoint. Additional information was required and requested from all included trials. One trialist11 provided missing information in the original publication. The rest of the trialists did not reply to our request. Table 2-1. Summary of included studies.  Author   Comparators and dose   n  Blood pressure (mm Hg) Inclusion Criteria  Mean SBP/DB P (mmHg) at base- line  Clinical inclusion criteria   Mean SBP/DBP (mmHg) at end-point  D E A T H S  Angeli 199111  Nifedipine 10 mg sublingual (sl)  Captopril 25mg sl 10   10  DBP > 140 247/ 158   245/145  Acute end organ damage† 204/115   190/116 0   0 Beltrame 199812  Nitroglycerine 2.5-10 mcg IV infusion  Furosemide 40mg IV boluses 37   32  Not defined* 161/ NR   164/ NR  Acute pulmonary edema 133/ NR   139/NR    3 Elliot 199013  Nitroprusside 0.5-mcg/kg/min IV infusion  Fenoldopan 0.1 mcg/kg/min IV infusion 15   13   DBP> 120 222/137   214/136  Acute end organ damage† 174/105   180/106  N R Halminton 199614  Placebo  Captopril 25 mg sl 25   23  Not defined* 160/100   172/112  Acute pulmonary edema NR   NR  N R Hirschl 199715  Nitroprusside 0.5-3 mcg/k/min IV infusion  Urapidil 12.5 mg IV boluses 35   46  SBP>200 and/or DBP> 110  211/109   215/107  Acute end organ damage† 151/74   162/88  N R Hirschl Nitroglycerin 23  206/116  136/71  47  Author   Comparators and dose   n  Blood pressure (mm Hg) Inclusion Criteria  Mean SBP/DB P (mmHg) at base- line  Clinical inclusion criteria   Mean SBP/DBP (mmHg) at end-point  D E A T H S  199916  0.8 mg sl  Enalaprill 2.5 mg IV boluses   23 SBP>200 or DBP> 100     211/115 Acute pulmonary edema   139/70  0 Marigliano 198817 Nifedipine 10 mg sl  Captoprill 25 mg sl 22   22   SBP>210  208/139   230/120  Acute end organ damage† 154/70   163/90  N R Mcnair 198618  Diazoxide 75-150 mg IV boluses  Dihydralazine 6.25-12.5 mg I. M. boluses 28   24  DBP> 135   228/118   218/142  Hypertensive encephalopathy 179/110   169/101   2 Nelson 198319 Isosorbide 50-200 mcg/kg/h IV infusion  Furosemide 1 mg/kg IV boluses 14   14  Not defined* 130/75   119/72  Acute left ventricular failure 118/70   116/70 0   0 Pastorelli 199120   Placebo  Nifedipine 10 mg sl Captopril 50 mg sl & oral  Ketanserine 40mg S.L. 20  16  41   15  Not defined* 188/111  195/114  196/114   185/117   Acute end organ damage† 179/101  162/92  168/97   165/100  N R Rubio 199921  Isosorbide aerosol 1.25 mg oral  Nifedipine 10mg sl 30   30  MAP >130  187/121   190/115  Acute end organ damage† 153/92   153/86  N R Schreiber 199822  Nitroglycerine 0.8 mg sl  Urapidiil 12.5 mg IV boluses 73   60  SBP >200 DBP > 100  216/116   218/118  Acute pulmonary edema 134/72   134/70 0    0 Verma 198723  Furosemide 1 mg/kg iv bolus  Isosorbide 50-200 mcg IV 12   12   SBP >100  117/73   131/75   Acute left ventricular failure 112/70   118/70  0   0   48  Author   Comparators and dose   n  Blood pressure (mm Hg) Inclusion Criteria  Mean SBP/DB P (mmHg) at base- line  Clinical inclusion criteria   Mean SBP/DBP (mmHg) at end-point  D E A T H S  infusion  Hydralazine 0.15 mg/ kg IV bolus    12  134/77  128/71  1 Wu 199324  Nifedipine 10 mg sl  Captopril 25 mg sl  Prazosin 10 mg sl 30   35   27  SBP >190 and / or DBP > 120  198/124   198/122   198/128  Cerebral signs or symptoms 140/78   134/78   160/90  N R Yang 200425  Nitroprusside 1 mcg/ kg/min  IV infusion  Nicardipine 3 mcg /kg/min IV infusion 20   20  SBP >160 and/or DBP> 100  195/115   196/114  Acute pulmonary edema 144/85   135/79  N R † As stated in the article reflecting the inclusion of patients with different acute end organ damage settings *This RCT was included on the basis of the mean blood pressure values at baseline according to our pre- defined thresholds for this category of patients  We excluded 27 clinical trials for several reasons: • Several trials mixed patients with and without acute end organ damage in the same RCT  [12 trials 26-37] • Other trials included patients without explicitly stating whether patients had acute end organ damage or not [7 trials 38-44] • Some trials included non-randomized participants in the trial's results [1 trial-45] • One trial did not report any of the outcomes of interest [1 trial 46] • Two trials did not fulfilling blood pressure threshold criteria 47;48. • One was a cross-over trial 49.  49 • Two trials had wrong comparators (one compared different doses of the same combination therapy 50; another compared two drugs of the same class51. • RCT only included responders to a previously given antihypertensive therapy 52. Two out of 27 excluded trials involved a beta-blocker arm and 18 / 27 excluded trials involved a calcium channel blocker arm. One excluded trial studied exclusively patients with acute aortic dissection51. 2.6.2 Risk of bias in included studies All studies, except one14, were open-label trials. The method of randomization was not reported in eight trials. The method to achieve concealment of allocation was reported in only two trials14;18. 2.6.3 Effects of interventions: comparisons according to outcomes 2.6.3.1 Total serious adverse events No trial reported the total number of patients with at least one serious adverse event. 2.6.3.2 All-cause mortality Mortality was reported in 7 trials 11;12;16;18;19;22;23 and totaled 6 deaths in 3 RCTs. The group to which the dead patients were originally allocated was not reported for 5 of the deaths. In one RCT, a patient treated with hydralazine died of a rupture of the inter- ventricular septum23. In four trials mortality was reported as nil. In eight trials there was no mention of mortality. It is possible that there were no deaths during the short range of follow-up (6-24 hours), but it is impossible to be certain.  50 2.6.3.3 Non-fatal cardiovascular events 2.6.3.3.1 Composite Cardiovascular events were reported in five trials12;14;16;18;22. No trial reported cardiovascular events as a composite. It was not possible to extract events from the original trials and analyze them as a composite due to a risk of double-counting the events. 2.6.3.3.2 Myocardial infarction One placebo-controlled trial14 reported this outcome. There was no statistically significant difference between ACE inhibitors and placebo (RR 0.72, 95%CI 0.31 -1.72). Three head-to-head trials reported this outcome12;18;22: there was no statistical difference in myocardial infarction between nitrates (2.7%) and alpha-adrenergic antagonist ( 5%) (RR 0.55, 95%CI 0.09-3.17); nitrates (16%) versus diuretics (12.5%) (RR 1.30,95%CI 0.40-4.19);  or diazoxide (3.5%)  versus dihydralazine (4%), (RR 0.86, 95%CI 0.06- 12.98). 2.6.3.3.3 Pulmonary edema requiring mechanical ventilation Three trials reported this outcome14;16;22. There was no meta-analysis performed as there was only one trial for each comparison. There was no statistically significant difference between captopril and placebo (RR 0.40, 95%CI 0.09 -1.86), nitrates and alpha- adrenergic antagonist (RR 4.12, 95%CI 0.20-84.24) or between nitrates and ACE- Inhibitor (RR 0.33, 95%CI 0.01-7.78). Other than the above, the trials did not report any of our list of CV events (unstable angina, dissection of aortic aneurysm, acute renal failure, or stroke). An additional  51 cardiovascular event was reported that was not on our list: asystole, which happened in one patient randomized to an ACE inhibitor16. 2.6.3.4 Withdrawal due to adverse events Only one trial comparing an alpha-blocker with nitroglycerine reported withdrawal due to adverse events 22.  There were no significant differences between these two drugs classes (5% vs 2.7%) (RR 3.38, 95%,CI 0.17-68.84). 2.6.3.5 Weighted mean change in blood pressure and heart rate during treatment For this secondary outcome all trials provided some data and we were able to pool these data. 2.6.3.5.1 Drug versus placebo or no treatment Although we included two placebo-controlled trials, only one provided systolic or diastolic blood pressure (BP) data20 and this was limited to one hour of follow-up. In this trial, 3 classes of antihypertensives were included: calcium channel blocker, angiotensin converting enzyme inhibitors, and alpha-1 adrenergic antagonists. The pooled effect showed a statistically significant greater reduction in both systolic (WMD -13.14, 95%CI, -19.48,-6.80) and diastolic (WMD -8.03, 95%CI, -12.61,-3.45) blood pressure with antihypertensive therapy. There was no data on heart rate It was not possible to extract BP data from the other placebo-controlled trial14. In addition to not reporting any measurement of variability, this trial reported BP data as change in mean arterial pressure (MAP).    52 2.6.3.5.2 Nitrates versus diuretics Three trials compared nitrates to diuretics12;19;23. Furosemide was the common diuretic used in all of them with two nitrates, nitroglycerine and isosorbide as comparators. Neither systolic nor diastolic blood pressure lowering effect was statistically different between the two classes of drugs. However, in Beltrame 1998, the systolic blood pressure lowering effect of both  drugs was greater (-21 mm Hg for furosemide; -23.75 mm Hg for nitroglycerin) than that reported in the other two trials (+1.0, +1.6 mm Hg for furosemide groups; and -6,-8 mm Hg for isosorbide groups, respectively). The reasons for that difference across trials are not clear. Despite these differences, heterogeneity was not present when pooling all these three trials. Heart rate change was also not significantly different for both classes of drugs. 2.6.3.5.3 Nitrates versus alpha-1 antagonist Two trials compared the alpha-1 adrenergic antagonist (A1A), urapidil, with nitrates15;22. The first trial used nitroprusside and the second used nitroglycerine as comparator. The systolic blood pressure lowering effect of the two nitrates was similar (-58.4 mmHg for nitroprusside and -59.5 mmHg for nitroglycerine). However, the effect of urapidil (administrated at the same dose in both trials) was very different (-37.6 mmHg and -73.5 mmHg). A similar discrepancy was seen for diastolic blood pressure. This heterogeneity precluded the pooling of these trials in a meta-analysis for these outcomes. 2.6.3.5.4 Nitrates versus dopamine agonist For this comparison one trial was included13. During 4 hours of treatment, nitrates were associated with a statistically significant greater reduction in systolic blood pressure as  53 compared with a dopamine agonist (WMD -14.00, 95% CI [-27.72, -0.28]). There were no differences between these classes in diastolic blood pressure or heart rate. 2.6.3.5.5 Nitrates versus ACE-inhibitors One trial compared a nitrate with an ACE inhibitor16. No statistically significant difference was found between the two groups in systolic or diastolic blood pressure or heart rate. 2.6.3.5.6 Nitrates versus calcium channel blockers By pooling two trials21;25 calcium channel blockers were not associated with statistically significant differences in systolic or  diastolic blood pressure as compared to nitrates. Using the fixed effect model, CCBs were associated with statistically significant increase in heart rate as compared to the nitrates (WMD 11.76 95% CI [4.45, 19.07]). However there was significant heterogeneity across trials and this increase was no longer statistically significant when a random effect model was used. 2.6.3.5.7 Nitrates versus direct vasodilator For this comparison one trial was included 23. There was no statistical difference in systolic or diastolic blood pressure reduction between the two drugs. There was also no significant difference between these classes in heart rate change. 2.6.3.5.8 ACE inhibitors versus calcium channel blockers Four trials11;17;20;24 compared an ACE-Inhibitor with a CCB. The pooled data shows that CCBs were associated with a significantly greater reduction in diastolic blood pressure as compared with ACE-I (WMD 7.86, 95% CI [4.92, 10.81]). No statistically significant  54 difference was found between the two groups in the reduction of systolic blood pressure. In three trials that reported heart rate changes11;17;24, CCBs were associated with a significant increase in heart rate as compared with ACE-Inhibitors (WMD 22.91, 95% CI [19.8, 26.01]). However, there was significant heterogeneity across trials and this increase was no longer significant when a random effect model was used. 2.6.3.5.9 ACE inhibitors versus alpha-1 adrenergic antagonist Two trials20;24 compared an ACE-inhibitor with an alpha-1 adrenergic antagonist (A1A). Both trials used captopril as comparator but one trial used prazosin and the other used ketanserin. The pooled data shows that ACE-inhibitors were associated with a significantly greater reduction in both systolic and diastolic blood pressure as compared with A1A (SBP WMD -20, 95% CI [-22.85,-17.39]; DBP WMD -3.70, 95% CI [-7.08,- 0.31]). For SBP outcome there was statistically significant heterogeneity across trials. However the difference was still significant when the random effects model was used. No statistically significant difference was found between the two groups in the heart rate change in the only trial reporting that outcome 24. 2.6.3.5.10 Diazoxide versus hydralazine For this comparison, one trial18, which dealt with exclusively hypertensive encephalopathy patients, was included. During four hours of treatment, hydralazine was associated with a statistically significant greater reduction in both systolic (WMD 13.56, 95% CI [3.06, 24.06]) and diastolic (WMD 14.67, 95% CI [8.01, 21.33]) blood pressure as compared with diazoxide (WMD -14.00, 95% CI [-27.72, -0.28]). It is important to mention, though, that there was no measure of variability reported in this trial. Therefore,  55 we imputed the standard deviation of the change according to our hierarchy from other trials (last option: weighted mean standard deviation of change from all trials; any drug any dose).  There was no heart rate data reported. 2.7 Discussion This is the first systematic review investigating mortality and morbidity outcomes for all RCTs of drug treatment for hypertensive emergencies. A systematic review that combined hypertensive emergencies and urgencies3 did not include 11 trials included in our systematic review. Furthermore, Cherney's review mixed randomized with non- randomized trials. The only other relevant systematic review in relation to hypertensive emergencies is that conducted for acute stroke by BASC 20015.  We excluded one trial48 [n =16 patients] that the BASC 2001systematic review had included. The reason for excluding it was because the blood pressure criteria in this trial (>170/95 mmHg) did not meet our blood pressure threshold criteria (SBP≥ 180 and or DBP ≥ 110 mm Hg). This exclusion does not affect our conclusion for clinical outcomes as this trial did not report clinical outcomes. The other BASC 2001 trials were not included because blood pressure at baseline was not elevated. Thus, these clinical trials did not include hypertensive emergency patients as we have defined them. One of the limitations in our review is that most of the included trials were small (average 58 patients per trial).  Furthermore, with the exception of Hamilton (1996)14 all trials were of poor quality. Three included trials deserve further discussion. Hamilton 199614, the only double-blind trial, includes patients with acute pulmonary edema and high blood pressure, and it  56 compared captopril versus placebo. It demonstrates that this high quality and double- blind trial was ethical and feasible. The DANISH II 198618 trial was the only trial that included patients exclusively with hypertensive encephalopathy. This was a well- organized multicentre trial, conducted in Denmark, comparing diazoxide to dihydralazine. Due to its study design, the ethical committee accepted that the informed consent could not be obtained from patients as all of them had symptoms of hypertensive encephalopathy. A downside of this study is the fact that the trialists reported their results in duplicate publications that did not cite the other publications (the original publication, Krogsgaard 198353, is not cited in the other duplicate publications,18;54;55). In addition, blood pressure values were not the same in the different publications, and none of the publications reported measures of systolic or diastolic blood pressure variability. The largest trial, Schreiber 199822, included 133 patients with acute pulmonary edema plus high blood pressure, in an out-of- hospital setting, who were randomized to receive either nitroglycerin or urapidil. The ethical committee (Vienna, Austria) agreed that no informed consent had to be obtained at the time of inclusion for randomization. However, the pitfall of this trial is that 16% of all randomized patients were excluded from the analyses, which potentially biased the results. Consistent with this, there was significant heterogeneity when this trial was combined with another trial studying the same comparison groups. In 19 of the excluded trials26-44 it was not possible to determine how many patients had acute end organ damage or merely had elevation of blood pressure. We believe that it would be misleading to include these trials in this review as the impact of  57 antihypertensive drugs is potentially different. If individual patient data could be obtained, the patients with acute end organ damage could be added to our review. It was perhaps surprising and definitely disappointing that we could find no randomized controlled trial evidence to answer the first question we have posed: Does antihypertensive therapy as compared to placebo or no treatment change mortality and morbidity in patients with hypertensive emergencies? The one available placebo- controlled trial demonstrated that blood pressure was reduced with drugs as compared to the control treatment, however, it was too small and of too short duration to assess morbidity and mortality. We feel it is important for physicians to know that this is one of the clinical settings where treatment is not supported by RCT evidence. Despite the lack of evidence it is not hard to accept the necessity of lowering blood pressure in those clinical settings where the excessive increases in blood pressure are the cause of the end organ damage. However, this is not necessarily the best approach in settings where the excessive elevations of blood pressure are probably caused by end organ damage such as high BP in the presence of a cerebrovascular accident. The presently accepted approach for the immediate treatment of hypertensive emergencies in clinical practice is primarily based on a series of cases published in 1959 (Gifford 19591). In this study, carried out over a period of 18 months, the author demonstrated the ability to reduce blood pressure with nitroprusside, within minutes, in eight patients with hypertensive emergencies (mostly patients with hypertensive encephalopathy), whose blood pressures had remained elevated after treatment with reserpine or hydralazine. However, he did not report clinical outcomes so we do not know whether these patients did better as a result of the blood pressure lowering. Gifford recommended prompt blood  58 pressure reduction in clinical settings other than hypertensive encephalopathy such as intracerebral or subarachnoid hemorrhage or acute left ventricular failure.  The lack of RCT evidence leaves the distinct possibility that in some clinical settings defined as hypertensive emergencies immediate antihypertensive therapy could be doing more harm than good. These is a hypertensive emergency not included in the present systematic review, eclampsia. Due to its pathophysiology and the involvement of the infant as well as the mother, we felt this clinical entity must be studied separately from other hypertensive emergencies and include outcomes in the infant as well as the mother. There is a Cochrane systematic review [Duley 200656] that has studied the drugs for treatment of very high blood pressure during pregnancy. However, Duley's systematic review was not limited to patients with eclampsia and did not separately report outcomes in the eclampsia patients. To the best of our knowledge, there is no systematic review dealing exclusively with eclampsia and anti-hypertensive treatment. Thus, a systematic review in this specific area is currently needed. The present review also does not provide any mortality and morbidity evidence from RCTs to inform clinicians as to which first-line antihypertensive drug class provides more benefit than harm in hypertensive emergencies. This lack of evidence was due to the fact that the trials were too small, did not follow the patients for a long enough period of time and frequently failed to report all important outcomes. In addition all the RCTs except one were open-label trials and therefore concealment of allocation was not possible in most cases. Although, these shortcomings of the trials would not likely affect mortality and morbidity outcomes, they could bias blood pressure and heart rate data.  59 Neither did we find RCTs that compared different strategies to reduce blood pressure. Thus, how fast or how much blood pressure should be lowered in hypertensive emergencies remains unknown. Although it is unproven, it is highly likely that antihypertensive therapy is an overall benefit in a hypertensive emergency and therefore a placebo controlled trial to prove this would be unethical. What is clear is that this is a clinical area where properly conducted randomized trials are badly needed. At the present time RCTs could be conducted to compare different drug classes and treatment strategies; for example, aggressive rapid lowering of blood pressure to a target versus lowering the blood pressure slowly at a defined rate such as 5-10 % every 2 hours. What is also clear from this review is that any trial must follow patients in the long term and document mortality and morbidity. One of the best examples of an adequate RCT in an emergency setting is the CRASH trial57 where 10,000 patients with acute head injury were randomized to intravenous steroids or placebo. Its approach to handle ethical issues could serve as a model when conducting a trial with hypertensive emergency patients. 2.8 Authors’ Conclusions 2.8.1 Implications for practice There is no evidence from RCTs that anti-hypertensive drugs reduce mortality or morbidity in patients with hypertensive emergencies, defined as marked hypertension associated with acute end organ damage. Furthermore, there is insufficient RCT evidence to determine which drug or drug class is most effective in reducing mortality and morbidity. There were some minor differences in degree of blood pressure lowering between drug classes; however, the clinical significance of this is unknown.  60 This review demonstrates blood pressure-lowering efficacy for nitrates, ACE inhibitors, diuretics, alpha-adrenergic antagonist, calcium channel blockers and dopamine agonists. Nitrates (including nitroprusside) have been the most studied. Therefore, if a hypertensive emergency patient cannot be treated as part of an RCT and a nitrate is available, it is a reasonable choice of therapy. 2.8.2 Implications for research Randomized controlled trials are needed to assess different blood pressure lowering strategies and different first-line drug classes in patients with hypertensive emergencies. Outcomes in such trials must be mortality and total serious adverse events at different times of follow-up such as seven days, one month and including at least six months of follow-up of all patients.  61  2.9 References     (1)  Gifford RW. Treatment of Hypertensive Emergencies, including use of Sodium Nitroprusside. Mayo Clin Proc 1959; 34 (16):387-394.  (2)  Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jr. et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289(19):2560-2572.  (3)  Cherney D, Straus S. Management of patients with hypertensive urgencies and emergencies: A systematic review of the literature. J Gen Intern Med 2002; 17(12):937-945.  (4)  Zampaglione B, Pascale C, Marchisio M, Cavallo-Perin P. Hypertensive urgencies and emergencies. Prevalence and clinical presentation. Hypertension 1996; 27(1):144-147.  (5)  BASC. Interventions for deliberately altering blood pressure in acute stroke. Blood pressure in Acute Stroke Collaboration (BASC).[Cochrane Review]. Cochrane Library 2001;  Issue 3. CD000039.  (6)  Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M et al. ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction—Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). Circulation 2004; 110:588-636.  (7)  Dalen JE, Howe JP, III. Dissection of the aorta. Current diagnostic and therapeutic approaches. JAMA 1979; 242(14):1530-1532.  (8)  Mattu A, Martinez JP, Kelly BS. Modern management of cardiogenic pulmonary edema. Emergency Medicine Clinics of North America 2005; 23(4):1105-1125.  (9)  Wilson SR, Hirsch NP, Appleby I. Management of subarachnoid haemorrhage in a non-neurosurgical centre. Anaesthesia 2005; 60(5):470-485.  (10)  ICH-FDA. International conference on harmonization of technical requirements for registration of pharmaceuticals for human use. Clinical safety data  62 management; definitions and standards for expedited reporting document E2A. FDA-Federal Register 1995; 60:11284-11287.  (11)  Angeli P, Chiesa M, Caregaro L, Merkel C, Sacerdoti D, Rondana M et al. Comparison of sublingual captopril and nifedipine in immediate treatment of hypertensive emergencies. A randomized, single-blind clinical trial. Arch Intern Med 1991; 151(4):678-682.  (12)  Beltrame JF, Zeitz CJ, Unger SA, Brennan RJ, Hunt A, Moran JL et al. Nitrate therapy is an alternative to furosemide/morphine therapy in the management of acute cardiogenic pulmonary edema. Journal of Cardiac Failure 1998; 4(4):271- 279.  (13)  Elliott WJ, Weber RR, Nelson KS, Oliner CM, Fumo MT, Gretler DD et al. Renal and hemodynamic effects of intravenous fenoldopam versus nitroprusside in severe hypertension. Circulation 1990; 81(3):970-977.  (14)  Hamilton RJ, Carter WA, Gallagher EJ. Rapid improvement of acute pulmonary edema with sublingual captopril. Acad Emerg Med 1996; 3(3):205-212.  (15)  Hirschl MM, Binder M, Bur A, Herkner H, Mullner M, Woisetschlager C et al. Safety and efficacy of urapidil and sodium nitroprusside in the treatment of hypertensive emergencies. Intensive Care Med 1997; 23(8):885-888.  (16)  Hirschl MM, Schreiber W, Woisetschlager C, Kaff A, Raab H. [Sublingual nitroglycerin or intravenous enalaprilat in preclinical treatment of hypertensive patients with pulmonary edema]. [German]. Z Kardiol 1999; 88(3):208-214.  (17)  Marigliano V, Santilli D, Fiorani M, Ariani A, Cacciafesta M, Ferri C et al. Hypertensive emergencies in old age: effects of angiotensin converting enzyme inhibition. J Hypertens Suppl 1988; 6(1):S91-S93.  (18)  McNair A, Krogsgaard AR, Hilden T, Nielsen PE. Severe hypertension with cerebral symptoms treated with furosemide, fractionated diazoxide or dihydralazine. Danish Multicenter Study. Acta Med Scand 1986; 220(1):15-23.  (19)  Nelson GI, Silke B, Ahuja RC, Hussain M, Taylor SH. Haemodynamic advantages of isosorbide dinitrate over frusemide in acute heart-failure following myocardial infarction. Lancet 1983; 1(8327):730-733.  (20)  Pastorelli R, Ferri C, Santucci A, Balsano F. New therapeutic possibilities in hypertensive emergencies. Current Therapeutic Research, Clinical & Experimental 1991; 50(6):857-868.  (21)  Rubio-Guerra AF, Vargas-Ayala G, Lozano-Nuevo JJ, Narvaez-Rivera JL, Rodriguez-Lopez L. Comparison between isosorbide dinitrate aerosol and nifedipine in the treatment of hypertensive emergencies. J Hum Hypertens 1999; 13(7):473-476.  63  (22)  Schreiber W, Woisetschlager C, Binder M, Kaff A, Raab H, Hirschl MM. The nitura study - Effect of nitroglycerin or urapidil on hemodynamic, metabolic and respiratory parameters in hypertensive patients with pulmonary edema. Intensive Care Med 1998; 24(6):557-563.  (23)  Verma SP, Silke B, Hussain M. First-line treatment of left ventricular failure complicating acute myocardial infarction: A randomised evaluation of immediate effects of diuretic, venodilator, arteriodilator, and positive inotropic drugs on left ventricular function. J Cardiovasc Pharmacol 1987; 10(1):38-46.  (24)  Wu SG, Lin SL, Shiao WY, Huang -WH, Lin CF, Yang YH. Comparison of sublingual captopril, nifedipine and prazosin in hypertensive emergencies during hemodialysis. Nephron 1993; 65(2):284-287.  (25)  Yang HJ, Kim JG, Lim YS, Ryoo E, Hyun SY, Lee G. Nicardipine versus nitroprusside infusion as antihypertensive therapy in hypertensive emergencies. The Journal of international medical research 2004; 32(2):118-123.  (26)  Bussmann WD, Kenedi P, von Mengden HJ, Nast HP, Rachor N. Comparison of nitroglycerin with nifedipine in patients with hypertensive crisis or severe hypertension. Clin Investig 1992; 70(12):1085-1088.  (27)  Conen D, Ruttimann S, Noll G, Schneider K, Muller J. Short- and long-term cerebrovascular effects of nitrendipine in hypertensive patients. J Cardiovasc Pharmacol 1988; 12(Suppl 4):S64-S68.  (28)  Dadkar VN, Karnik ND, Izar M, Sharma SR, Gandhi YP, Narawane NM et al. Sublingual nifedipine and captopril in hypertensive urgencies and emergencies. Indian Heart J 1993; 45(3):185-187.  (29)  Marghli S, Bouida W, Elatrous S, Boujdaria R, Nouira S, Abroug F. A prospective, randomized and controlled study of three intravenous antihypertensive drugs in severe hypertension. Reanimation Urgences 1997; 6(3):289-296.  (30)  Moritz RD, de Queiroz LP, Pereira MR, Scotinni MA. [Comparative study of the use of nifedipine and captopril in hypertensive emergencies]. [Portuguese]. Arq Bras Cardiol 1989; 52(6):323-326.  (31)  Neutel JM, Smith DH, Wallin D, Cook E, Ram CV, Fletcher E et al. A comparison of intravenous nicardipine and sodium nitroprusside in the immediate treatment of severe hypertension. Am J Hypertens 1994; 7(7 Pt 1):623-628.  (32)  Nielsen PE, Krogsgaard A, McNair A, Hilden T. Emergency Treatment of Severe Hypertension Evaluated in a Randomized Study. Acta Med Scand 1980; 208:473-480.  64  (33)  Panacek EA, Bednarczyk EM, Dunbar LM, Foulke GE, Holcslaw TL. Randomized, prospective trial of fenoldopam vs sodium nitroprusside in the treatment of acute severe hypertension. Fenoldopam Study Group. Acad Emerg Med 1995; 2(11):959-965.  (34)  Perez C, Dougnac A, Alvarez M, Andresen M, Diaz O, Geni R et al. [Sublingual captopril versus nifedipine in the treatment of hypertensive crisis]. [Spanish]. Rev Med Chil 1991; 119(4):402-405.  (35)  Risler T, Bohm R, Wetzchewald D, Nast HP, Koch HH, Stein G et al. A comparison of the antihypertensive efficacy and safety of felodipine IV and nifedipine IV in patients with hypertensive crisis or emergency not responding to oral nifedipine. Eur J Clin Pharmacol 1998; 54(4):295-298.  (36)  Rohr G, Reimnitz P, Blanke P. Treatment of hypertensive emergency. Comparison of a new dosage form of the calcium antagonist nitrendipine with nifedipine capsules. Intensive Care Med 1994; 20(4):268-271.  (37)  Spah F, Grosser KD. Treatment of hypertensive urgencies and emergencies with nitrendipine, nifedipine, and clonidine: effect on blood pressure and heart rate. J Cardiovasc Pharmacol 1988; 12(Suppl 4):S154-S156.  (38)  Ceyhan B, Karaaslan Y, Caymaz O, Oto A, Oram E, Oram A et al. Comparison of sublingual captopril and sublingual nifedipine in hypertensive emergencies. Jpn J Pharmacol 1990; 52(2):189-193.  (39)  Guerrera G, Melina D, Capaldi L, Mauro R, Colivicchi F, Cardillo C et al. [Sublingually administered captopril versus nifedipine in hypertension emergencies]. [Italian]. Minerva Cardioangiol 1990; 38(1-2):37-44.  (40)  Pascale C, Zampaglione B, Marchisio M. Management of hypertensive crisis: Nifedipine in comparison with captopril, clonidine and furosemide. Current Therapeutic Research, Clinical & Experimental 1992; 51(1):9-18.  (41)  Pilmer BL, Green JA, Panacek EA, Elliot WJ, Murphy MB, Rutherford W et al. Fenoldopam mesylate versus sodium nitroprusside in the acute management of severe systemic hypertension. J Clin Pharmacol 1993; 33(6):549-553.  (42)  Pujadas R, Jane J, Fornos C, Gago MJ, de la CN. Comparison of sublingual captopril and nifedipine in hypertensive crises. Arch Intern Med 1987; 147(1):175-176.  (43)  Reisin E, Huth MM, Nguyen BP, Weed SG, Gonzalez FM. Intravenous fenoldopam versus sodium nitroprusside in patients with severe hypertension. Hypertension 1990; 15(2 Suppl):I59-I62.  65  (44)  Zampaglione B, Pascale C, Marchisio M, Santoro A. The use of lacidipine in the management of hypertensive crises: a comparative study with nifedipine. J Cardiovasc Pharmacol 1994; 23(Suppl 5):S116-S118.  (45)  Franklin C, Nightingale S, Mamdani B. A randomized comparison of nifedipine and sodium nitroprusside in severe hypertension. Chest 1986; 90(4):500-503.  (46)  Bertel O, Conen D, Radu EW, Muller J, Lang C, Dubach UC. Nifedipine in hypertensive emergencies. Br Med J (Clin Res Ed) 1983; . 286(6358):19-21.  (47)  Borghi C, Bacchelli S, Esposti DD, Bignamini A, Magnani B, Ambrosioni E. Effects of the administration of an angiotensin-converting enzyme inhibitor during the acute phase of myocardial infarction in patients with arterial hypertension. SMILE Study Investigators. Survival of Myocardial Infarction Long-term Evaluation. American journal of hypertension : journal of the American Society of Hypertension 1999; 12(7):665-672.  (48)  Lisk DR, Grotta JC, Lamki LM, Tran HD, Taylor JW, Molony DA et al. Should hypertension be treated after acute stroke? A randomized controlled trial using single photon emission computed tomography. Archives of Neurology 1993; 50(8):855-862.  (49)  Nelson GI, Verma SP, Silke B, Abdulali S, Taylor SH. Management of hypertension complicating acute myocardial infarction ( MI): comparison of sympathetic (labetalol) and calcium channel ( nifedipine) blockade. [abstract]. Aust NZ J Med Suppl 1984; 14(4):577.  (50)  Cotter G, Metzkor E, Kaluski E, Faigenberg Z, Miller R, Simovitz A et al. Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Lancet 1998; 351(9100):389-393.  (51)  Yoshida N. Antihypertensive Effect of the Long-Acting Ca Antagonist Amlodipine vs. Sustained-Release Nifedipine in Patients with Acute Aortic Dissection. Rinsho to Kenkyu (The Japanese Journal of Clinical and Experimental Medicine) 1998; 75(6):1419-1422.  (52)  Annane D, Bellissant E, Pussard E, Asmar R, Lacombe F, Lanata E et al. Placebo-controlled, randomized, double-blind study of intravenous enalaprilat efficacy and safety in acute cardiogenic pulmonary edema. Circulation 1996; 94(6):1316-1324.  (53)  Krogsgaard AR, Hilden T, McNair A, Nielsen PE. Cerebral symptoms and blood pressure during parenteral administration of chlorpromazine, dihydralazine and diazoxide. Danish multicentre study on acute severe hypertension. Acta Med Scand 1983; Suppl 678:51-60.  66  (54)  Krogsgaard AR, McNair A, Hilden T, Nielsen PE. Reversibility of cerebral symptoms in severe hypertension in relation to acute antihypertensive therapy. Danish Multicenter Study. Acta Med Scand 1986; 220(1):25-31.  (55)  McNair A, Krogsgaard AR, Hilden T, Nielsen PE. Reversibility of cerebral symptoms in severe hypertension in relation to acute antihypertensive therapy. Danish Multicenter study. Acta medica Scandinavica Supplementum 1985; 693:107-110.  (56)  Duley L, Henderson-Smart DJ, Meher S. Drugs for treatment of very high blood pressure during pregnancy.[Cochrane Review]. Cochrane Library 2006;  Issue 3. CD001449.  (57)  Roberts I, Yates D, Sandercock P, Farrell B, Wasserberg J, Lomas G et al. Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial. Lancet 2004; 364(9442):1321-1328.      67 3 EFFECT OF EARLY TREATMENT WITH ANTI- HYPERTENSIVE DRUGS ON SHORT AND LONG- TERM MORTALITY IN PATIENTS WITH AN ACUTE CARDIOVASCULAR EVENT2  3.1 Background Acute cardiovascular events represent a significant therapeutic challenge as they are the number one cause of hospitalizations in many countries, including Canada1. A wide range of pharmacological interventions administrated for these conditions have been studied in great detail, worldwide. However, some questions remain unanswered. For instance, it is not known whether blood pressure-lowering drugs given in the early phase of these events is beneficial or harmful. The best time of initiation of treatment with these drugs is also not known, although most clinical guidelines recommend starting treatment within 24 hour of the onset. For example, it is recommended that ACE inhibitors be started within the first 24 hours of an acute myocardial infarction2. In the setting of an acute cardiovascular event, blood pressure is often not elevated and sometimes it is low. Thus, the rationale for the early administration of a blood pressure-lowering drug is not completely clear. The objective of this review is to find randomized controlled trial (RCT) evidence for the use of blood pressure-lowering drugs in this early phase of an acute CVE.  2 A version of this chapter has been published. Perez MI, Musini VM, Wright JM. Cochrane Database of Systematic Reviews 2009, Issue 4 Art No. CD006743. DOI:10.1002/14651858.pub2. Effect of early treatment with anti-hypertensive drugs on short and long-term mortality in patients with an acute cardiovascular event.  68 An acute cardiovascular event is a sudden manifestation of a cardiovascular disease (e.g., myocardial infarction or stroke). According to the World Health Organization, cardiovascular diseases are the leading cause of death in the world3. Acute cardiovascular events include acute myocardial infarction (AMI), unstable angina (UA), acute stroke, acute aortic dissection, and left-ventricular failure with acute pulmonary edema. Although these could be considered different clinical entities they share one thing in common; they are life-threatening and have a high rate of initial mortality if left untreated. For example, epidemiological studies from the 1960's showed that 75% of patients died within 24 hours of the onset of acute myocardial infarction4. The best way to understand the rationale for this review is to consider another well- studied intervention, fibrinolysis, which is administered in the early phase of an acute myocardial infarction or stroke. Consider the example of a large RCT [ISIS-2 1988]5 where 17,187 patients within 24 hours of the onset of a suspected acute myocardial infarction were randomized to receive one-hour streptokinase IV infusion or placebo. The patients were followed for 35 days and relative mortality between the two groups was measured over time. By inspecting the survival curves it was possible to determine that 75% of the deaths in the placebo group occurred during the first 10 days. Streptokinase had no effect on mortality at 48 hours (RR=1.04, 95%CI [0.89,1.21]), but reduced mortality at 10 days (RR= 0.82, 95%CI[0.74,0.91]) and at 35 days (RR=0.77, 95%CI [0.70,0.84]). From this it can be deduced that this immediate and short treatment had a beneficial effect, but this was only manifest when measured at 10 days and 35 days. This trial, therefore, represents the ideal design we are looking for in this review where an early (within 24 hours) antihypertensive intervention is given for a short time (up to 48  69 hours) to patients with an acute cardiovascular event, and the key outcomes are reported at 48 hours, 10 days and ≥30 days. We have chosen these times as it has been emphasized that when the severity of a disease changes quickly over time, the follow-up periods need to be subdivided into an early period, an intermediate period and a late period6. In addition to this ideal trial design, we have also studied and analyzed trials in which the intervention was started within 24 hours and continued for up to 10 days. We refer to the 1 - 48 hour intervention as "immediate" and the intervention started within 24 hours and continued up to 10 days as “short-term”. For trials where the experimental treatment and control was continued for more than 10 days we limited our analysis to the 2 day and 10 day mortality. Most patients are stable after 10 days and drug effects occurring after the acute period are not within the purview of this review. 3.2 Description of the intervention Anti-hypertensive or blood pressure-lowering drugs are defined as those pharmacological agents indicated and used to treat elevated blood pressure or hypertension. According to the World Health Organization (WHO) / International Society of Hypertension (ISH)7, and other international guideline committees (such as ESH-ESC 20078, BHS-IV 20049, JNC-7, 200310) these include angiotensin converting enzyme inhibitors (ACE-I), angiotensin II receptor blockers (ARBs), beta-adrenergic receptor blockers (BB), calcium channel blockers (CCB), diuretics, nitrates (including nitroprusside). It is important to emphasize that anti-hypertensive drugs have the potential to cause pharmacological actions other than lowering BP (for example, reducing heart rate) when administrated to humans, which makes them usable for indications other than treating  70 hypertension. In contrast, there are drugs that have the potential to reduce blood pressure (for example: morphine in certain doses and settings) but are not classified as anti- hypertensive drugs. The latter types of drugs are not considered in this review.  Anti-hypertensive drugs are commonly used11 and recommended in the early phase of an acute cardiovascular event. The most common anti-hypertensive drugs that are recommended are ACEI [for acute myocardial infarction2;12; and for unstable angina or non-ST elevation myocardial infarction (UA/NSTEMI)13, BB [for AMI2;12; for UA/NSTEMI13, and for Stroke (hypertensive)14, CCB [for AMI2, and for Stroke (hypertensive)14], diuretics [for AMI with acute pulmonary edema2,  and nitrates [ for AMI 2;8, for UA/NSTEMI13, and for Stroke (hypertensive)14. 3.2.1 How do the interventions might work? The exact mechanism of action of blood pressure-lowering drugs, antihypertensives, is often not known with certainty, but each of the different classes of drugs acts at different sites and by different mechanisms. 3.2.1.1 Angiotensin converting enzyme inhibitors (ACE-I) ACE-I inhibit the conversion of angiotensin I, a relatively inactive peptide, to angiotensin II, which is a potent vasoconstrictor and causes release of aldosterone from the adrenal cortex. The ACE-I probably lower blood pressure by reducing the blood pressure- increasing effects of Angiotensin II.  71 3.2.1.2 Angiotensin II receptor blockers (ARBs) ARBs inhibit the binding and action of Angiotensin II at the angiotensin II type 1 (AT1) receptor, which is the site of action to cause vasoconstriction and release of aldosterone. They, thus, also probably reduce blood pressure by blocking the blood pressure- increasing effects of Angiotensin II. 3.2.1.3 Beta- adrenergic receptor blockers (BB) In general, beta-adrenergic receptor-blocking drugs or beta-blockers (BB) are drugs that competitively inhibit the effect of the catecholamines, noradrenaline and adrenaline, on beta-adrenergic receptors. There are subtypes of beta-blockers depending on their relative affinity for B1 and B2 receptors, partial agonist activity, and ability to also block alpha- adrenergic receptors. Catecholamines have a positive chronotropic and inotropic actions on the heart, can cause vasoconstriction or vasodilatation of blood vessels and stimulate renin release from the kidney. Thus, BB drugs could lower blood pressure by a number of these differing effects. The exact mechanism by which beta-blockers lower blood pressure in humans is not known. 3.2.1.4 Calcium channel blockers (CCB) Calcium channel blockers reduce the cytosolic free-calcium concentrations by blocking transmembrane calcium influx through L-type calcium channels. Dihydropyridines (such as nifedipine), benzothiazepines (diltiazem) and phenylalkylamines (verapamil) bind to the pore-containing the α1 subunit of the L-type calcium channel. In general, calcium channel blockers relax arteriolar smooth muscle, resulting in vasodilatation and decreased peripheral resistance.  The decreased systemic resistance is thought to cause the blood pressure reduction. Agents that slow the rate of recovery of L-type calcium channels  72 (verapamil, diltiazem) have negative chronotropic and dromotropic effects on the heart's conducting system. The CCBs also have a natriuretic effect on the kidney that may contribute to their ability to lower blood pressure. 3.2.1.5 Diuretics Thiazide diuretics inhibit the Na+Cl- co-transporter in the proximal part of the distal convoluted tubule of the kidney. This decreases tubular reabsorption of sodium and chloride, and increases urinary excretion of sodium and water. Furosemide and other loop diuretics inhibit sodium reabsorption in the ascending limb of the loop of Henle as well as in both proximal and distal tubules. The mechanism by which diuretics lower blood pressure has not been established. 3.2.1.6 Nitrates (including nitroprusside) Organic nitrates and sodium nitroprusside (SNP) are nitric oxide (NO) donors. Organic nitrates, such as glyceryl trinitrate (nitroglycerine) require enzymatic metabolism to generate NO. In contrast SNP spontaneously generates this NO. There are a number of theories about how nitrates cause vasodilatation: Nitrates act on specific nitrate receptor (containing a sulfhydryl group-SH, NO exerts a potassium channel activation (hyperpolarizing the cell membrane); and NO activates the enzyme guanylate cyclase increasing cGMP levels, which in turn inhibits Ca+ entry into smooth muscle cells and increases Ca+ uptake by the smooth endoplasmic reticulum resulting in vascular smooth muscle relaxation.  73 3.3 Why is it important to do this review? The main goal is to answer the question, “does blood pressure-lowering by all classes of blood pressure-lowering drugs during the early phase of an acute cardiovascular event affect mortality and morbidity?” It is important to appreciate that during the first hours after an acute cardiovascular event, complex hemodynamic changes are occurring, making the organs involved especially vulnerable to local and systemic changes. Blood pressure reduction during this time could be beneficial, but it is equally likely that it is detrimental. Recently, thanks to the advances in the understanding of the underlying pathophysiological mechanisms involved in some acute cardiovascular events (such as the thrombotic occlusion at the site of atherosclerotic plaques in AMI) different pharmacological interventions have been implemented and proven beneficial. For example, randomized controlled trial (RCT) evidence has demonstrated a reduction in mortality with the use of thrombolytic drugs15;16 and anti-platelet drugs17 in acute AMI. There is also RCT evidence for benefit with the use of anti-platelet drugs17 in the acute treatment of stroke. The benefits of these pharmacological therapies have been claimed to be greater when they are administrated in the early phase (for example: thrombolysis within 6 hours) of the onset of the acute cardiovascular event. Thus, the time of the administration can be an important determinant as to whether an intervention is beneficial or harmful to patients with an acute cardiovascular event. The rationale for administering blood pressure lowering drugs in the early phase of an acute cardiovascular event is less well understood. In acute cardiovascular events associated with marked elevation of blood pressure (defined as hypertensive emergencies  74 by JNC-7, 200310) blood pressure lowering makes some pathophysiological sense as if the elevated blood pressure is causing organ damage, reducing blood pressure is likely to be beneficial. However, there is no RCT evidence to demonstrate mortality and morbidity benefits of the use of blood pressure lowering drugs in hypertensive emergencies18. This lack of evidence for situations where blood pressure is elevated emphasizes the importance of attempting to assess the benefits and harms in acute cardiovascular events in general. In the setting of acute cardiovascular event in general most of the time blood pressure is not elevated and sometimes it is low. We have deliberately chosen outcomes in this review that are a measure of both benefit and harm in order to avoid selective reporting bias. Due to the standardized definition of serious adverse events, SAEs, (any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of hospitalization, or results in persistent or significant disability19), measuring total number of people with at least one serious adverse event would provide a pretty close estimate of the net health effect (benefit minus harm) of an intervention20. However, in acute, critically-ill hospitalized patient settings, measuring SAE could be problematic and/or impractical. The main reason for this is because physician must make a judgment as to whether an event led to prolongation of hospitalization. Therefore, in these acute clinical settings total all-cause mortality, a subgroup of total SAEs, is the best measure of net health effect21. All cause mortality is an outcome measure that is not subject to physician judgment and which is usually reported in trials. It is easy to appreciate that an intervention that decreases mortality as compared to placebo is beneficial, while an intervention that increases mortality compared to placebo is harmful. Thus, we have chosen all-cause mortality as  75 our primary outcome and total non-fatal serious adverse event as one of our secondary outcomes anticipating that trials might not consistently report this outcome. Secondly to answer, whether blood pressure lowering by the different subclasses of blood pressure-lowering drugs during the early phase of an acute cardiovascular event affects mortality and morbidity? This question can be answered by performing a subgroup analysis where the effect of the drugs in the different classes of blood pressure lowering drugs are analyzed separately and compared with each other. There are other published systematic reviews of randomized controlled trials dealing with antihypertensive drugs for acute cardiovascular events (specifically for acute myocardial infarction or stroke). For acute myocardial infarction, reviews have been published for each different class of anti-hypertensive drug: for CCB22 ; for BB23-25; for nitrates26, and ACE inhibitors27;28. In addition, there are three published systematic reviews dealing with acute stroke: Horn et al 200029 for CCB, Bath et al 2002 for nitrates30, and Geeganage et al 200831 for diverse interventions These systematic reviews all have significant drawbacks and none were designed to assess the specific objective of this review. Some were not limited to immediate treatment (Rodrigues 200328; AMICG 199827; Held 198922; Yusuf 198526; Al-Reesi 200825; Bath 200230; Freemantle 199924) and included trials where the treatment started days after the onset of the acute cardiovascular event. One review mixed trials with control group (no treatment or placebo) with trials that have an active comparator as control, Yusuf 198826. Except for Geeganage 200831, all these reviews are limited by not being up-to-date.  76 This is the first systematic review with the objective to assess the effects of all blood pressure lowering drugs administrated as immediate treatment (starting within 24 hours) in patients with an acute cardiovascular event, on mortality, morbidity and blood pressure outcomes. 3.4 Objectives 3.4.1 Primary To determine the effect of immediate^ and short-term^^ treatment with antihypertensive drugs on mortality at 2 days, 10 days and ≥ 30 days in patients with an acute cardiovascular event. ^ Immediate treatment is defined as treatment started within 24 hours of the onset of an acute cardiovascular event and lasting for a maximum of 2 days. ^^Short-term treatment is defined as treatment started within 24 hours of the onset of an acute cardiovascular event and lasting for a maximum of 10 days. 3.4.2 Secondary To determine the effect of anti-hypertensive drugs on blood pressure and heart rate during the first 24 hours of treatment in patients with an acute cardiovascular event.  77 3.5 Methods 3.5.1 Criteria for considering studies for this review 3.5.1.1 Types of studies Randomized controlled trials (RCTs) with parallel design, comparing an anti- hypertensive drug with placebo, or no treatment, in patients with an acute cardiovascular event. The intervention (anti-hypertensive treatment) must be started within 24 hours of the onset of the acute cardiovascular event. Patient must be followed for at least 24 hours and mortality or SAE data must be provided at least one of the specified time periods, 2 days, 10 days or ≥ 30 days. 3.5.1.2 Types of participants Participants with any of the following acute cardiovascular events: myocardial infarction, unstable angina, acute left-ventricular failure with pulmonary edema, acute aortic dissection, stroke, intracranial hemorrhage, sub-arachnoid hemorrhage 3.5.1.3 Types of interventions Intervention: any anti-hypertensive drug Anti-hypertensive drug belonging to any of the following classes of drugs: Nitrates (including nitroprusside), beta adrenergic antagonists (BB), angiotensin converting enzyme inhibitors (ACE-I), calcium channel blockers (CCB), dopamine agonists, alpha- adrenergic antagonists, diuretics [furosemide and thiazides], direct vasodilators (diazoxide, hydralazine) and others (reserpine, clonidine, alpha-methyldopa, trimethaphan)  78 Control: Placebo or no early antihypertensive treatment Placebo is defined as inert substance designed to resemble the drug being tested but which has no active ingredient and has no treatment effect. In trials, where a placebo is used as a comparator, all patients in the placebo group usually receive the same medical treatment, except for the drug being tested, as the experimental group. This is achieved by the utilization of a double-blind study design in these trials. In trials where no treatment is used as a comparator it is assumed that all medical treatments other than antihypertensive treatment intervention being studied are the same in both groups. In these trials the design is open-label and not blinded. 3.5.1.4 Types of outcome measures Primary outcome All-cause mortality at 2 days, 10 days and ≥ 30 days. Operational definitions: • At 2 days also accepts cumulative mortality at times less than 48 hours if that is the only data available. • At 10 days also accepts cumulative mortality reported after 2 days and at times less than 10 days if that is the only data available. • At ≥ 30 days also accepts cumulative mortality reported as 1-month or 4-week mortality and for any duration of follow up longer than 30 days. Secondary outcome Total number of patients with at least one non-fatal Serious Adverse Event (SAE) at the same time periods for all cause mortality.  79 Weighted mean change in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR), during the first 24 hours of treatment. 3.5.2 Search methods for identification of studies 3.5.2.1 Search strategy We used wild symbols and letters for this extensive search. MEDLINE, EMBASE, and Cochrane clinical trial register from Jan 1966 to February 2009 was searched for randomized controlled trials. We also browsed the reference lists in review articles and trials for any studies that may have not been identified by the search strategy. In case of missing information in the retrieved articles, authors were contacted. The search strategy applied to identify all antihypertensive drugs and trials using a comprehensive search strategy and key words: controlled clinical trial, randomized controlled trials and other terms listed in the search strategies. 3.5.2.2 Medline search Please see appendix IV: MEDLINE and EMBASE Searches for a detailed list of search criteria. 3.5.2.3 EMBASE search Please see appendix IV: MEDLINE and EMBASE Searches for a detailed list of search criteria. 3.5.2.4 CENTRAL search This search was identical to EMBASE and MEDLINE searches but without the "trials" component as CENTRAL only deals with randomized-related studies.  80 3.5.3 Data collection and analysis 3.5.3.1 Data extraction Two reviewers (MIP & VM) independently decided whether a trial was included. They also extracted and verified data entry from included studies. Discrepancies were resolved by discussion. Absence of consensus was resolved by a third reviewer (JMW). 3.5.3.2 Analysis For the analysis of the data, Cochrane review manager software, RevMan 5 was used. Quantitative analyses of outcomes were based on intention- to-treat principles as much as possible. We used weighted mean difference to combine continuous variables and expressed relative and absolute risk difference (with 95% confidence interval) for dichotomous outcomes to accept significant differences. Pooled risk differences obtained from Mantel-Haenszel fixed effect model were converted to numbers needed to treat (NNTs) where appropriate. Heterogeneity between trial results was tested using the I2 statistic where percentages greater than 50% were taken to indicate significant heterogeneity. The effects of immediate treatment with antihypertensive drugs on 2 day, 10 day and ≥30 day mortality in patients with an acute cardiovascular event were explored. The effects of short-term treatment with antihypertensive treatment were explored at 10 days and ≥30 days. In trials where the study treatment was continued longer than day 10, data was not included for the ≥30 day time period. To quantify the occurrences of deaths the cumulative incidence reported in each trial (based on full Intention to Treat principles) was used. For example, for our day-10 mortality measure we included the cumulative incidence from time of randomization to day-10 inclusive (or at discharge from hospital  81 when trial did not report the time - the assumption here is that the average hospitalization is about 7-10 days). A sensitivity analysis was performed to test the impact of the design of the trial, double- blind vs. open label trials. Sensitivity analysis was also performed according to the class of drug, clinical condition, dose regimen, duration of treatment and concomitant pharmacological interventions. Non-fatal serious adverse events (NF-SAEs) were included only if they were reported as total, not as individual non-fatal SAE. The reason for doing this was to avoid double counting individual NF-SAE (as one patient may suffer from one or more NF-SAE and could be included more than once in the original report) and to prevent selection reporting bias (as many trials could omit certain NF-SAEs). Data for blood pressure and heart rate were combined using a weighted mean difference method, whereby the trials are weighted according to the number of subjects in the trial and the within-study variance. Some of the trials did not report a within-study variance for blood pressure change; in these studies standard deviation (SD) of change was imputed using the following hierarchy. 1. Pooled standard deviation calculated either from the t-statistic corresponding to an exact p-value reported or from the 95% confidence interval of the mean difference between treatment group and comparative group. 2. Standard deviation of blood pressure/heart rate at the end of treatment. 3. Standard deviation of blood pressure/heart rate at baseline (except if this measure is used for entry criteria).  82 4. Weighted mean standard deviation of change in blood pressure/heart rate calculated from at least 3 other trials using the same drug and dose regimen. 5. Weighted mean standard deviation of change in blood pressure/heart rate calculated from other trials using the same drug. 6. Weighted mean standard deviation of change in blood pressure/heart rate calculated from all other trials (any drug and dose). 7. Weighted mean standard deviation in blood pressure/heart rate at end of treatment calculated from at least 3 other trials using the same drug and dose regimen. 8. Weighted mean standard deviation in blood pressure/heart rate at end of treatment calculated from all other trials (any drug and dose). 3.6 Results 3.6.1 Description of studies 3.6.1.1 Results of the search The search strategy yielded 3412 citations and 82% of these were excluded after reading titles and abstracts. The remaining 623 citations were retrieved for detailed evaluation and 410 were excluded for the reasons shown in (see Figure 3-1). Of the 213 citations of randomized controlled trials we identified, 102 (65 trials) were included in this review. The specific reasons for exclusion of the other 111 (70 trials) are explained in Table 3-1. Most of these trials had to be excluded because they did not report mortality data.  83  Figure 3-1 Quorum Flowchart or Citations (RCTs)    Citations excluded by reading title and abstract [clearly no relation to our work]:  n=2,791   Citations retrieved for more detailed evaluation: n=621 Excluded:  n= 410 (103) Reasons:  Reviews/ sec. analysis: n=125  Active comparator: n=18 (17)  Included patients after 24 hours of symptom onset: n=210 (86)  Other (non-randomized, non-acute setting, etc): n=57       Citations of potentially appropriate randomized controlled trials: n= 211 Citations identified in literature search*: N= 3,412 Included: n= 100 (65) Excluded: n= 111 (70) Reasons:  Follow-up < 24 h: n=8 (5)  Uncertain time of patient’s inclusion:  n=26 (18)  Primary outcome not reported: n=77 (47)     84 3.6.1.2 Excluded studies There were 70 excluded trials. Although these trials could have been excluded for several reasons, the following are the primary reasons:  Mortality not reported or not reported in a form or time period that we could use: 47 trials.  Uncertain time of patient inclusion following the acute event: 18 trials.  Follow-up of less than 24 hours: 5 trials. Forty-seven trials were excluded due to lack of mortality data or mortality data that were not reported in a form or time period that we could use. There were three sub-types: A) Not reporting mortality at all, in either original, additional publications or after being requested to provide such data [18 trials]. B) Reporting mortality but not according to our pre-specified time-frame [22 trials]; or reporting it in an abstract but not confirmed by additional publications or after being requested it [2 trials]; and C) Reporting mortality but not based on intention to treat (ITT) principles [7 trials]. An example of the latter sub- category is a multicenter double-blind trial conducted by Walker 198832 et al. Mortality rate was reported as 7/106 in the nifedipine group and 7/120 in the placebo group. After detailed reading of Walker's original and additional publications, it was found that the actual number of randomized patients was 217 in each group. Thus, the investigators failed to report mortality in approximately 50% of the randomized patients. As this population represents a selected sub group of patients, if the information in this trial had been included in our review, it would have been misleading. Other trials that fell into this category were Eveson 200733, Szczechowski 199434, DAVIT I 198435, HINT 198636 , Barber 197637 and Balcon 196638 et al.  85 Our justification for excluding those trials, which had an uncertain time of patient inclusion following the acute event, was to avoid having a heterogeneous population that could lead to erroneous conclusions. The uncertain time inclusion applies to those trials that failed to explicitly state a specific time for inclusion, or trials that included their patients "on admission" or "immediately after admission". We believe that this is too imprecise to determine the exact time that had elapsed from symptom onset to the inclusion of the patient and therefore to the initiation of therapy. It is possible that some patients could have had a delayed admission (symptoms began > 24 hours). This also would likely bias for survivors. In addition, having a delayed admission was more common in trials conducted before 1980-90, when infrastructure for emergency response to assist patients with acute cardiovascular event was not as uniformly developed as it is today. An illustrative example of this category of excluded trials is that of a double-blind trial where patients were to be included "immediately after admission" in 16 Danish centres (DAVIT I 198435). It was determined that the treatment was started after 24 hours in >15% of patients with AMI; mortality data were not reported separately for these patients. Therefore, data from 65 trials (those excluded due to uncertain timing and those due to improper or non-extractable mortality data) out of 70 excluded trials could potentially be added to our review. Of these 65 excluded trials, 14 involved an ACE inhibitor (N=4,407); 21 trials involved a B-adrenergic Blocker (N=2,524); 8 trials involved a nitrate (N=1,475) and 20 trials involved a CCB (N=10,958). If these excluded patients were added to the included patients it would have only a small impact on the ACE inhibitor data (increase by 5.2%), BB data (increase by 3.5%), and nitrate data (increase  86 by 1.7%). However, it could have a large impact on the calcium channel blocker data (increase by ~600%, from 2,141 to 13,099). There were 3/65 studies (N=126) that involved other classes of blood pressure lowering drugs (2 trials for the alpha-1 adrenergic antagonist, prazosin39;40; and 1 trial for alpha-2 centrally acting agonist, clonidine41) Of 70 excluded studies, 52 trials involved patients with AMI, 9 trials included patients with acute stroke, 6 trials- unstable angina, 3 trials- acute pulmonary edema, and 1 trial - subarachnoid hemorrhage patients (See Table 3-1). There was no trial identified that included patients with acute aortic dissection and compared an active drug vs. placebo or no treatment within 24 hours of the onset. To the best of our knowledge there is only one randomized controlled trial that has included exclusively patients with acute aortic dissection and randomized their patients within 24 hour of the onset, Yoshida 199842. However, this trial compared two active treatments. Table 3-1 Reasons for exclusion of studies  Trial  Reason for exclusion Annane 199643 Follow-up less than 24 hours. A secondary reason for exclusion was that this trial only included responders to another anti-hypertensive before entering to the trial Setting: Acute cardiogenic pulmonary edema Ardissino 199744 Uncertain time of inclusion of patients Setting: unstable angina Azancot 198245 Mortality not reported Setting: AMI Azcona 199046 Mortality not reported. No publication was found for the results of the trial. Setting: acute stroke Balcon 196638 Mortality not reported according to our time-frame. A secondary reason for exclusion was that results are not given on an intention to treat basis. Setting: AMI Basu 199747 Mortality not reported according to our time-frame. Setting: AMI Blanc 198948 Mortality not reported. Setting: AMI  87 Trial  Reason for exclusion Briant 197049 Uncertain time of inclusion of patients Setting: AMI Bussmann 198450 Mortality not reported. Setting: AMI CATS 199451 Mortality not reported according to our time-frame. Letter sent to trialists on July 19, 2008, trying to obtain data. We have not got a response yet CHHIPS 200552 Mortality not reported. Publication of the trial results were never found published Davalos 199253 Mortality not reported according to our time-frame DAVIT I 198435 Uncertain time of inclusion of patients. For example, It is stated that patients were to be included "on admission", but treatment started after 24 hours in >15% of patients with AMI and mortality data was not reported separately for those starting earlier or later than the 24 hours. An additional problem was that these AMI patients were part of a subset of the entire randomized patients (AMI-41% + suspected AMI-59%) based on intention to treat analysis. Therefore, it should not be dismissed the possibility of the inclusion of additional patients being admitted later than 24 hours if all randomized patients were considered Emanuelsson 198454 Mortality was not reported EMIP 199455 Mortality not reported according to our time-frame. Evemy 197856 Uncertain time of inclusion of patients Eveson 200733 Mortality results are not given on an intention to treat basis. Letter sent to trialists on March 4, 2008, trying to obtain data. We have not got a response yet FAMIS 199857 Mortality not reported according to our time-frame. Sent letter to trialists on June 20,2008, trying to obtain data. We've got no response yet Franke 199658 Mortality not reported according to our time-frame. Sent letter to trialists on August 12,2008, trying to obtain data. We have not got a response yet. French 199959 Mortality not reported according to our time-frame. Sent letter to trialists on July 1, 2008, trying to obtain data. We have not got a response yet. Gardtman 199960 Uncertain time of inclusion of patients Gebalska 200061 Mortality not reported Gelmers 198462 Uncertain time of inclusion of patients Gerstenblith 198263 Uncertain time of inclusion of patients. Chronic Unstable angina GISSI-3p 199464 Mortality not reported according to our time-frame. Pilot trial for AMI Gonzalez- Fernandez 199365 Uncertain time of inclusion of patients Gordon 198466 Mortality not reported Gottlieb 198667 Mortality not reported according to our time-frame. Gottlieb 198868 Mortality not reported according to our time-frame. Letter sent to trialists on August 13, 2008, trying to obtain data. We have not got a response yet Gupta 198469 Incomplete reporting- only abstract Gupta 198570 Mortality not reported according to our time-frame. Hamilton 199671 Follow-up less than 24 hours. Haude 199172 Follow-up less than 24 hours.  88 Trial  Reason for exclusion HEART 199773 Mortality not reported. Letter sent to trialists on August 4, 2008, trying to obtain data. We have not got a response yet HINT 198636 Uncertain time of inclusion of patients, A secondary reason for exclusion was that results are not given on an intention to treat basis Jaffe 198774 Mortality not reported Just 198675 Mortality not reported Kahler 199576 Mortality not reported according to our time-frame. Karlberg 199877 Mortality not reported according to our time-frame. Kolettis 198339 Mortality not reported according to our time-frame. Kumada 199578 Uncertain time of inclusion of patients Lejemtel 199379 Mortality not reported. Letter sent to trialists on July 20,2008, trying to obtain data. We have not got a response yet. Publication of the trial results were never published Lloyd 198880 Mortality not reported Loogna 198581 Mortality not reported Macleod 198082 Mortality not reported. There was only an abstract reported Manolis 199941 Uncertain time of inclusion of patients. It could be argued that it was within 24 hours since study treatment was given right after thrombolysis, but we could not confirm this Matias-Gutierrez 199283 Mortality not reported according to our time-frame. McGrath 198684 Mortality not reported. Morris 199585 Mortality not reported according to our time-frame. Letter sent to trialists on August 13,2008, trying to obtain data. We have not got a response yet Mueller 198086 Uncertain time of inclusion of patients Murdock 199040 Uncertain time of inclusion of patients Oldroyd 199187 Mortality not reported according to our time-frame. Letter sent to trialists on July 24, 2008, trying to obtain data. We have not got a response yet. Oshima 199788 Mortality not reported according to our time-frame. Osuna 198589 Uncertain time of inclusion of patients Ramsdale 198890 Mortality not reported Reinert 200491 Uncertain time of inclusion of patients Renard 198792 Follow-up less than 24 hours Reynolds 197293 Uncertain time of inclusion of patients. A secondary reason for exclusion was that results were not given on intention to treat basis. Schrader 200394 Mortality not reported according to our time-frame. This trial included patients within 24h and within 36 h, but results are not reported separately for those two categories. Letter sent to trialists on May 1,2008, trying to obtain data. We have not got a response yet Sloman 196795 Uncertain time of inclusion of patients SMILE 199596 Mortality not reported according to our time-frame. Letter sent to trialists on June 20,2008, trying to obtain data. We have not got a response yet. Szczechowski 199434 Mortality results are not given on an intention to treat basis Waagstein 197697 Follow-up less than 24 hours  89 Trial  Reason for exclusion Walker 198832 Mortality results are not given on an intention to treat basis. Letter sent to trialists on August 13, 2008, trying to obtain data. We have not got a response yet Wilcox 1980a98 Mortality not reported according to our time-frame. Wilcox 1980b99 Mortality not reported according to our time-frame Wilcox 1986100 Mortality not reported according to our time-frame. Last letter sent to trialists on August 13, 2008, trying to obtain data. We have not got a response yet Wimalaratna 1994101 Mortality not reported. Letter sent to trialists on August 13, 2008, trying to obtain data. We have not got a response yet Zochowski 1986102 Uncertain time of inclusion of patients  3.6.1.3 Included studies Sixty-five randomized controlled trials (N=166,206) were found that satisfied the inclusion criteria. Of those, 40 (60%) were double-blind placebo-controlled trials, involving 75% (N=125,487) of the entire studied population (Table 3-2). All included trials reported mortality for at least one of the time points of interest (please see appendix V for details of all included studies); none of the trials reported the total number of non- fatal serious adverse events. The largest trial included 58,050 patients103. Twenty-one trials studied immediate treatment and 44 trials studied short-term treatment. The duration of treatment was for more than 10 days in 27/65 trials. We were able to extract short-term mortality (at day 10) in 62 trials. Four classes of blood pressure lowering drugs were evaluated: ACE inhibitors (12 trials), B-blockers (20 trials), Calcium channel blockers (18 trials) and nitrates, including nitroprusside (18 trials). The included trials studied patients with only 2 types of cardiovascular events: acute myocardial infarction (59 trials) and stroke (6 trials) (Table 3-3). All included trials enrolled their patients within 24 hours of the onset of an acute cardiovascular event. In this review, we have assumed that enrollment, randomization and administration of the study drug occurred simultaneously. The details of the process  90 involved were not described in any of the trial reports. The objective for accepting these types of trials was to evaluate the effects of early anti-hypertensive treatment in an acute setting. In the acute myocardial infarction (AMI) trials the average time of initiation of the study drug was 6.35 ± 4.74 hours after the onset. No stroke trial reported the time that treatment started. However, the included AMI studies scheduled their randomization 5 hours earlier than the stroke studies (12.6 ± 7.8 and 17 ± 8, respectively). We did find trials dealing with acute pulmonary edema and acute aortic dissection where patients were randomized within 24 hours. However, these trials had to be excluded for different reasons (see above, Excluded Studies).  91  Table 3-2 Overview of included studies according to group  Active drug Placebo or No treatment Participants in trials* involving (No.of trials): ACE inhibitors(12) 42,260 42,196 B-blockers(20) 36,338 36,262 CCB(18) 1,111 1,030 Nitrates(18) 42,206 42,207 All trials (65)^ 83,234^ 82,972^  Participants in trial design (No. of trials):  Double-blind (40) 62,849(76%) 62,638(75%) Not double-blind (25) 20,385 (24%) 20,334 (25 %)  Weighted mean age (years) [trials / participants with data] 60.91 [49 / 43,243] 60.85 [49/ 43,000]  Weighted mean blood pressure (mm Hg) @ baseline [trials / participants with data]  Systolic 133.7 [34 / 41,862] 133.7 [34 / 41,669] Diastolic 82.2 [25 / 7,125] 82.7 [25 / 7,043] Female patients (%) [Based on trials reporting gender] 26% [47 / 82,342] 25% [47 / 82,036]   ^ This total is less than the sum of all four categories as 2 trials (GSSI-3, ISIS-4) used 2x2 factorial design and one trial (Hargreaves 1992) compare drugs from two different categories of anti-hypertensive with the same placebo or control  group.   92 High blood pressure at baseline was not part of the inclusion criteria in any of the 65 included trials. However, most of the trials explicitly stated that patients had to be free from shock or had a minimum BP (in general, SBP of 90-110 mmHg and/or DBP of 50- 60 mm Hg) to enter the trial. For the included trials the overall weighted mean blood pressure at baseline was 133/82.2 mm Hg for those randomized to an active drug and 133/ 82.7 mm Hg for those randomized to the placebo or no treatment group. One quarter of patients was female and the overall weighted mean age was 60.85 years. (See Table 3-2 for generalities; See Appendix V for full details of the characteristics of included studies)  93 Table 3-3 Acute event and timing of inclusion in included studies Included Trial Cardiovascular event  Patients included within hours of onset Beaufils 1988104  Acute myocardial infarction 6 Branagan 1986105 Acute myocardial infarction 6 Bussmann 1981106  Acute myocardial infarction 24 Bussman 1992107 Acute myocardial infarction 18 Charvat 1990108 Acute myocardial infarction 6 Chiche 1979109  Acute myocardial infarction 12 Clausen 1966110 Acute myocardial infarction 24 Cohn 1982111 Acute myocardial infarction 24 COMMIT 2005112 Acute myocardial infarction 24 CONSENSUS-II 1992113 Acute myocardial infarction 24 Crea 1985114 Acute myocardial infarction 12 Di Pasquale 1994115  Acute myocardial infarction 4 Di Pasquale 1997116  Acute myocardial infarction 4 Durrer 1982117  Acute myocardial infarction 12 Eichler 1985118 Acute myocardial infarction 12 Erbel 1988119 Acute myocardial infarction 6 ESPRIM 1994120  Acute myocardial infarction 24 Fitzgerald 1990121  Acute myocardial infarction 8 Flaherty 1983122 Acute myocardial infarction 12 Galcera 1993123 Acute myocardial infarction 24 Gelmers 1988124 Acute Stroke 24 GISSI-3 1994125 Acute myocardial infarction 24 Hargreaves 1992126 Acute myocardial infarction 24 Heber 1987127 Acute myocardial infarction 6 Hildebrandt 1992128 Acute myocardial infarction 8 ICSG 1984129 Acute myocardial infarction 4 Infeld 1999130 Acute stroke 12  94 Included Trial Cardiovascular event  Patients included within hours of onset INWEST 1994131  Acute myocardial infarction6 24 ISIS-1 1986132  Acute myocardial infarction 12 ISIS-4 1995103 Acute myocardial infarction 24 Jaffe 1983133 Acute myocardial infarction 12 Johannessen 1987134 Acute myocardial infarction 6 Jugdutt 1983135 Acute myocardial infarction 6 Jugdutt 1988136 Acute myocardial infarction 12 Limburg 1990137  Acute stroke 24 Lis 1984138  Acute myocardial infarction 24 Marangelli 2000139 Acute myocardial infarction 4 MIAMI 1985140  Acute myocardial infarction 24 MILIS 1984141  Acute myocardial infarction 18 Mitchell 2002142  Acute myocardial infarction 12 Muller 1984143  Acute myocardial infarction 6 Nabel 1991144 Acute myocardial infarction 6 Natale 1999145 Acute myocardial infarction 12 Norris 1978146 Acute myocardial infarction 4 Norris 1980147 Acute myocardial infarction 4 Norris 1984148 Acute myocardial infarction 4 Owensby 1985149 Acute myocardial infarction 12 Paci 1989150 Acute stroke 12 Peter 1978151  Acute myocardial infarction 12 Pimenta 1985152  Acute myocardial infarction 6 Pizzetti 2001153  Acute myocardial infarction 3 PRACTICAL 1994154 Acute myocardial infarction 24 Salathia 1985155 Acute myocardial infarction 6 Schulman 1995156 Acute myocardial infarction 24 Sirnes 1984157 Acute myocardial infarction 12  95 Included Trial Cardiovascular event  Patients included within hours of onset Theroux 1998158 Acute myocardial infarction 6 TIMI-IIB 1991159 Acute myocardial infarction 4 Tonkin 1981160 Acute myocardial infarction 24 Van-de 1993161  Acute myocardial infarction 5 VENUS 2001162  Acute Stroke 6 von Essen 1982163  Acute myocardial infarction 24 Wagner 2002164 Acute myocardial infarction 6 Yusuf 1983165 Acute myocardial infarction 12 Zannad 1988166  Acute myocardial infarction 6 Zharov 1991167 Acute myocardial infarction 12  Of the 22 trials for which we requested additional information, only 4 trialists responded to our request and provided additional information. Blood pressure changes during the first 24 hours of treatment were reported in 19 trials (N=3,261). However, none of the trials reported on standard deviation of the change. Thus, this measure of variability was imputed from: the end point standard deviation (second-choice in our pre-specified hierarchy) in 14 trials; from the baseline value (third- choice) in 1 trial; and from the weighted mean standard deviation at end point (last- choice) in 4 trials. 3.6.2 Risk of bias in included studies Forty trials (60%) of the 65 included studies were double-blind, involving 75% (N=125,487) of the entire studied population. Less than 50% of the included trials reported adequate sequence generation, and only 23 trials (35%) reported concealment of  96 allocation (see Figure 3-2) .Although the number of trials reporting adequate concealment of allocation was relatively small [13/40(32%) for double-blind and 10/25(40%) for open-label design trials], the number of patients randomized with adequate concealment of allocation was very high (121,618 patients out of the total 125,487 in double-blind trials and 37,055 out of the total 40,719 in open-label trials ); in other words the trials that did not report concealment of allocation were small in sample size. Thus, this type of risk of bias is considered to be low in this review. Similarly, although more than 75% of trials had an incomplete reporting or did not report on immediate all-cause mortality (Figure 3-2), the studies that reported it were large enough (N=131,603) to keep this risk of incomplete outcome bias to a minimum. That was not the case for the ≥ 30 day mortality in which less than 25 % reported mortality at times equal or greater than day 30 and the trials that reported it were small, therefore there is a significant risk of bias for mortality data at this time. Selective outcome reporting bias was not an issue in this review by limiting to include trials where our primary outcome, mortality, was reported in the RCTs.  97  Figure 3-2 Risk of bias in included trials  3.6.3 Effects of interventions according to outcomes 3.6.3.1 Primary outcome: all-cause mortality Foundation: Twelve trials (N=152,029) were designed for or had the power to detect differences in mortality (CONSENSUS-II 1992113; GISSI-3 1994125; ISIS-4 1995103, COMMIT 2005112; ISIS-1 1986132; MIAMI 1985140; Norris 1984148; Salathia 1985155; VENUS 2001162; Cohn 1982111; Durrer 1982117; ESPRIM 1994120) but any trial reporting mortality, regardless of its design and size, was included in our meta-analysis. We were able to assess the effects of immediate or short-term treatment with 4 antihypertensive classes of drugs: ACE inhibitors, B-blockers, calcium channel blockers and nitrates, on all-cause mortality data at 2, 10 or ≥ 30 days; in patients presenting with acute myocardial infarction or stroke.   98 3.6.3.1.1 Nitrates Immediate treatment (started within 24 hours of the onset and lasting for maximum 2 days)  All- cause mortality at 2 days (18 eligible trials, N=84,413): Six trials (N=82,624) reported mortality at day 2. Nitrates were associated with a statistically significant reduction in all-cause mortality (RR 0.81, 95%CI [0.74, 0.89], p<0.0001; I2 = 0%) ( Figure 3-3). Figure 3-3 Meta-analysis of the effect of nitrates in all-cause mortality at two days       99  All- cause mortality at 10 days (10 eligible trials, N=6,007): All 10 trials (N=6,007) reported mortality at day 10. Nitrates were not associated with a statistically significant delayed reduction in all-cause mortality (RR 0.84, 95%CI [0.69, 1.01], p=0.07, I2 = 63%).  All-cause mortality at ≥ 30 days (10 eligible trials, N=6,007): Seven trials (N=5,771) reported mortality at ≥30 days. Nitrates were not associated with a statistically significant delayed reduction in all-cause mortality (RR 0.92, 95%CI [0.82, 1.04], p=0.20, I2 = 42%) during a weighted average of 12 months of follow-up. Short-term treatment (started within 24 hours of the onset and lasting for a maximum of 10 days)  All- cause mortality at 10 days: (8 eligible trials, N=78,406): Six trials (N=78,178) reported mortality at 10 days. Nitrates were associated with a statistically significant reduction in all-cause mortality (RR 0.91, 95%CI [0.86, 0.97], p=0.003; I2=0%)  All-cause mortality at ≥ 30 days (5 eligible trials, N=969): Three trials (N=570) reported mortality at ≥30 days. Nitrates were not associated with a statistically significant delayed reduction in all-cause mortality (RR 0.72, 95%CI [0.48, 1.10], p=0.13, I2=81%) during a weighted average of 4 months of follow-up.       100 3.6.3.1.2 Angiotensin converting enzyme (ACE) inhibitors Immediate treatment (started within 24 hours of the onset and lasting for maximum 2 days)  All-cause mortality at 2 days: (12 eligible trials, N=84,456): Three trials (N=77,414) reported mortality at 2 days. ACE inhibitors were not associated with statistically significant reduction in all-cause mortality (RR 0.91, 95%CI [0.82, 1.00]), p=0.05, I2=0%] (Figure 3-4)  All-cause mortality at 10 days (2 eligible trials107,164, N=145) : Both trials (N=145) reported mortality at 10 days. ACE inhibitors were not associated with a statistically significant delayed reduction in mortality at 10 days (RR 0.68, 95%CI [0.12, 3.98], p=0.67). (Figure 3-5)  All- cause mortality at ≥ 30 days (2 eligible trials, N=145): No trial reported mortality at this time. Short-term treatment (started within 24 hours of the onset and lasting for a maximum of 10 days)  All-cause mortality at 10 days (10 eligible trials, N=84,311): All 10 trials (N=84,311) reported mortality at 10 days. ACE inhibitors were associated with a statistically significant reduction in all cause mortality as compared to placebo (RR 0.93, 95%CI [0.87, 0.98] p=0.01). (Figure 3-5)  All- cause mortality at ≥ 30 days (2 eligible trials115,116, N=432): No trial reported mortality at ≥ 30 days    101 Figure 3-4 Meta-analysis of the Effect of ACE-inhibitors in All-cause Mortality at two days.                102 Figure 3-5 Meta-analysis of the Effect of Immediate and Short-term Treatment with ACE-inhibitors in All-cause Mortality at 10 days  3.6.3.1.3 Beta-adrenergic antagonist or beta-blockers (BB) Immediate treatment (started within 24 hours of the onset and lasting for maximum 2 days)  All- cause mortality at 2 days (20 eligible trials, N=72,600):  103 Six trials (N=68,007) reported mortality at 2 days. BB drugs were not associated with a statistically significant reduction in all-cause mortality (RR 0.95, 95%CI [0.85, 1.07],p=0.39, I2=67% ). (Figure 3-6)  All-cause mortality at 10 days (6 eligible trials, N=1,143): All 6 trials (N=1,143) reported mortality at 10 days. BB drugs were not associated with a statistically significant delayed reduction in all-cause mortality (RR 1.12, 95%CI [0.60, 2.07], p=0.73, I2=0%). (  Figure 3-7)  All-cause mortality at ≥ 30 days (6 eligible trials, N=1,143): Only one trial (N=108) reported mortality at ≥30 days. There were no deaths in either group. Short-term treatment (started within 24 hours of the onset and lasting for a maximum of 10 days)  All-cause mortality at 10 days (14 eligible trials, N=71,457): All 14 trials (N=71,457) reported mortality at 10 days. BB drugs were not associated with a statistically significant reduction in all-cause mortality (RR 0.96, 95%CI [0.91, 1.02], p=0.21, I2=0%). (See  Figure 3-7)  All-cause mortality at ≥ 30 days (8 eligible trials, N=18,645): Five trials (N=18,373) reported mortality at ≥ 30 days. BB drugs were associated with a statistically significant reduction in all-cause mortality (RR 0.91, 95%CI [0.84, 0.99], p=0.03, I2=0%) during a weighted average of 12 months of follow-up.   104  Figure 3-6 Meta-analysis of the Effect of Immediate Treatment with Beta- blockers on Mortality at Two Days              105   Figure 3-7 Meta-analysis of the Effect of Immediate Treatment and Short- Term Treatment with Beta-blockers on Mortality at 10 Days   106 3.6.3.1.4 Calcium channel blockers (CCB) Immediate treatment (started within 24 hours of the onset and lasting for maximum 2 days)  All- cause mortality at 2 days (18 eligible trials, N=2,141): Only 3 trials (N=242, Erbel 1988119; Theorox 1998158; Zannad 1988166) reported mortality at 2 days. CCB were not associated with a statistically significant reduction in all-cause mortality (RR 2.33, 95%CI [0.62, 8.78], p=0.21, I2=2%).  All cause mortality at 10 days (3 eligible trials105, 118,139, N=241): Only one trial Marangelli 2000139 (N=88) reported mortality at 10 days. There was one death in the CCB group and none in the control group.  All cause mortality at ≥ 30 days (3 eligible trials, N=241): Only one trial Branagan 1986105 (N=108) reported mortality at ≥ 30 days. There were 7/54 deaths in the CCB group and 5/54 in the control group. The relative risk for this trial was 1.40, 95%CI [0.47,4.14]. Short-term treatment (started within 24 hours of the onset and lasting for a maximum of 10 days)  All- cause mortality at 10 days (15 eligible trials, N=1,900): All 15 trials (N=1,900) reported mortality at 10 days. CCB were not associated with a statistically significant effect on all-cause mortality (RR 1.01, 95%CI [0.73, 1.38], I2=0%)  All- cause mortality at ≥ 30 days (5 eligible trials, N=730): One trial (N=90), Pizzetti 2001 reported mortality at ≥ 30 days. There were three deaths in the CCB group and two in the placebo group.  107 3.6.3.2 Secondary outcome: total non-fatal serious adverse events No trial reported total non-fatal serious adverse events (SAE). It was not possible to extract individual non-fatal SAE from the original trials and analyze them as a composite due to a risk of double-counting the events and due to the risk of missing particular non- fatal SAEs that were not reported. 3.6.3.3 Secondary outcome: weighted mean change in blood pressure and heart rate during the first 24 hours of treatment Many trials did not report these secondary outcomes. In general, trials that reported blood pressure data and also mortality data were small trials (average 170 patients). We carefully looked at all trials to see if they have blood pressure data for the entire population or for a subset of the entire study. Cohn 1982111 was the only trial designed to detect mortality differences and that reported blood pressure data. The MIAMI 1985140 trial had a subset study with blood pressure data and was included in our meta-analysis. It was not possible to do a secondary analysis (meta-regression or correlation) comparing the effects of blood pressure lowering during the first 24 hours and health outcomes. No trial reported the standard deviation of the change for blood pressure or heart rate. Thus, this measure of variability was imputed from: the end point (second-top choice in our pre-specified hierarchy) in 14 trials; from the baseline value (third choice) in 1 trial; and from the weighted mean standard deviation at end point (last choice) in 4 trials.      108 3.6.3.3.1 Nitrates Systolic blood pressure change There were 7 trials (N=1,958) included in the systolic meta-analysis. The pooled effect showed a statistically significant greater reduction in SBP with nitrates drugs compared to placebo or no treatment during the first 24 hours of an acute myocardial infarction (WMD -12.67, 95%CI [-14.51, -10.83], p<0.00001; I2=81%). The statistical significance remained when random effects model was applied. Diastolic blood pressure change: There were 6 trials (N=1146) included in the diastolic meta-analysis. The pooled effect showed a statistically significant greater reduction in DBP with nitrates drugs as compared to placebo or no treatment during the first 24 hours of an acute myocardial infarction (WMD -7.50, 95%CI [-9.07,-5.93], p<0.0001; I2=75%). The statistical significant effect remained when a random effect model was applied. Heart rate change: There were 6 trials (N=810) included in the heart rate change meta-analysis. There was no significant difference in heart rate change between nitrates and placebo or no treatment during the first 24 hours of a cardiovascular event (WMD -0.83, 95%CI [- 2.83,1.17], p=0.42; I2=57%). 3.6.3.3.2 Angiotensin converting enzyme inhibitors (ACEi) Systolic blood pressure change: There were no included trials providing SBP data for ACEi. Diastolic blood pressure change: There were no included trials providing DBP data for ACEi  109 Heart rate change: There were no included trials providing HR data for ACEi. 3.6.3.3.3 Beta- adrenergic antagonist or beta-blockers (BB) Systolic blood pressure change: There were 6 trials (N=738) included in the systolic meta-analysis. The pooled effect showed a statistically significant greater reduction in SBP with beta-blockers drugs compared to placebo or no treatment during the first 24 hours of a cardiovascular event (WMD -12.54, 95%CI [-15.63,-9.45], p<0.00001; I2=0%). Diastolic blood pressure change: There were 6 trials (N=738) included in the diastolic meta-analysis. The pooled effect showed a statistically significant greater reduction in DBP with beta-blockers drugs as compared to placebo or no treatment during the first 24 hours of a cardiovascular event (WMD -3.35, 95%CI [-5.43,-1.28], p=0.002; I2=60%). The statistically significant difference persisted when a random effects model was applied. Heart rate change: There were 5 trials (N=594) included in the heart rate change meta-analysis. The pooled effect showed a statistically significant greater reduction in HR with beta-blockers drugs as compared to placebo or no treatment during the first 24 hours of a cardiovascular event (WMD -9.68, 95%CI [-11.99,-7.37], p<0.00001; I2=4%).      110 3.6.3.3.4 Calcium channel blocker (CCB) Systolic blood pressure change: There were 7 trials (N=755) included in the systolic meta-analysis. The pooled effect showed statistically significant difference in SBP between calcium channel blocker drugs and placebo or no treatment during the first 24 hours of a cardiovascular event (WMD - 5.49, 95%CI [-8.42,-2.56];p=0.0002; I2=80%). The effect was no longer statistically significant when a random effects model was applied. Diastolic blood pressure change: There were 6 trials (N=565) included in the diastolic meta-analysis. The pooled effect showed a statistically significant greater reduction in DBP with calcium channel blocker drugs as compared to placebo or no treatment during the first 24 hours of a cardiovascular event (WMD -5.08, 95%CI [-7.00,-3.15], p<0.0001; I2=64%). The statistical significant difference between groups remained when a random effects model was applied. Heart rate change: There were 5 trials (N=410) included in the heart rate change meta-analysis. There was no significant difference in heart rate change between calcium channel blocker drugs and placebo or no treatment during the first 24 hours of a cardiovascular event (WMD -1.10, 95%CI [-4.60,2.40];p=0.54; I2=54%).   111 3.7 Discussion 3.7.1 Summary of main results Randomized controlled trials (RCT) comparing an intervention with no treatment or placebo is the method of choice for determining efficacy and effectiveness. The optimal measure of net health effectiveness is the total number of patients with at least one serious adverse event (SAE) 20. However, in acute life-threatening cardiovascular events (CVEs) where the patient is hospitalized, total SAEs are particularly difficult to be documented and thus rarely measure it. In this review this was proven to be true as no trial reported this outcome. One possible reason is the subjectivity when physician must make a judgment as to whether a particular event led to prolongation of hospitalization as compared to the underlying life-threatening disease. Therefore, in acute clinical settings total all-cause mortality has been considered the best measure of net health effect21. All- cause mortality is an outcome measure that is not subject to physician judgment and which is usually reported in trials. This is the reason why we have focused primarily on total all-cause mortality in this systematic review. The primary objective of this review was whether 24 to 48 hour (immediate) administration of blood pressure lowering drugs used within the first 24 hours of an acute cardiovascular event reduced mortality at three different time periods, 2 days, 10 days and ≥30 days. Our initial plan to pool the effects of all blood pressure lowering drugs proved to be inappropriate as the effects of the different classes of drugs was clearly heterogeneous. We have therefore presented the outcome data separately for each of the drug classes.  112 In studying the immediate intervention, the 2-day mortality provides a measure of the immediate benefits or harms and the 10 day and ≥30 day time periods provides a measure of delayed beneficial or harmful effects that only become manifest later. The principle here has been amply demonstrated by the fibrinolysis trials where early treatment leading to preservation of myocardium leads to reductions in mortality that are not manifest at 2 days, but which increase over time. For example, in the ISIS-2 19885 where 17,187 patients within 24 hours of the onset of a suspected acute myocardial infarction were randomized to receive immediate treatment with a thrombolytic drug or placebo resulted in having no effect on mortality at 48 hours (RR=1.04, 95%CI[0.89,1.21]), but reduced mortality at 10 days (RR= 0.82, 95%CI[0.74,0.91]) and at 35 days (RR=0.77, 95%CI[0.70,0.84]). Unfortunately, in this blood pressure-lowering systematic review the number of trials that reported mortality at 10 days and ≥30 days after immediate treatment was insufficient to ascertain whether there were delayed benefits or harms. The data that are available suggest that the benefits at 10 days and ≥30 days are less than at 2 days, if anything. The most important conclusion of this review comes from the mortality data at two days after immediate blood pressure lowering. At 2 days there was a highly significant reduction in mortality for nitrates (RR 0.81, 95%CI [0.74, 0.89], p<0.0001) and no significant reduction in mortality for the other classes of drugs. Since the data is incomplete, we cannot be very confident whether the hemodynamic effect among the different drug classes during the first 24 hours contributed to mortality differences. However, by indirectly comparing the two classes of drugs where statistically significant effects were seen (compared to placebo or no treatment) in these early hemodynamic  113 changes, this review showed that the weighted mean systolic blood pressure lowering effect for beta-blockers (-12.54 mm Hg) and for nitrates (-12.67 mm Hg) was very similar, whereas the heart rate change was significantly different between the two classes (-9.68 vs. -0.83 bpm, respectively). Despite these similarities and differences in these hemodynamic changes, the day-2 mortality effect was favorable for nitrates (RR 0.81, 95%CI [0.74, 0.89]) but not for beta-blockers (RR 0.95, 95%CI [0.85, 1.07]). Unfortunately, we do not have hemodynamic data for ACE-inhibitors; and the data for CCB was too heterogeneous to yield statistical significance versus control.  This significant mortality benefit at 2 days for nitrates is based predominantly on the two largest trials (ISIS-4103, GISSI-3125), but the authors of those trials have dismissed the finding, as the effect was no longer significant at 35 days. It is thus worth examining these two trials in more detail. The ISIS-4 1995103 trial (N=58,050) was a factorial-design trial with three independent interventions: isosorbide mononitrate vs. placebo; captopril versus placebo and magnesium versus open control. The nitrate used was control-released isosorbide starting with 30 mg every 12 hours for the first day and followed by a maintenance dose of 60 mg daily for 28 days. However, during the first few days, all patients were allowed to receive non-study intravenous (IV) nitrates (approximately 47 % of patients in each group ultimately received these). The other large study (N=19,394) was an open-label, factorial design trial, GISSI-3 1994125, with two independent comparisons: lisinopril versus control; and glyceryl trinitrate versus control. In the nitrate group patients were initiated with IV infusion of nitroglycerin at 5 - 20 µg/min (to achieve at least 10% of SBP reduction) during the first 24 hours. After that, the IV  114 infusion was replaced by a transdermal patch providing 10 mg of nitrate per day for 6 weeks. Also in this trial patients were allowed to receive non-study nitrates. The percentage of patients who received these in the control group was 57.1%, but the corresponding percentage for those allocated to the nitrate group was not reported. In general, these two trials (ISIS-4 1995103 and GISSI-3 1994125) were similar in terms of population studied but dissimilar in design and drugs used. Despite the differences, the benefit for the nitrates at 2 days, was the same for both trials (RR 0.82, 95%CI [0.73, 0.92]) and (RR 0.82, 95%CI [0.68, 0.99]), respectively. Furthermore, the fact that the control group also received non-study nitrates makes it likely that this significant mortality benefit is underestimated. Based on this RCT evidence it is concluded that nitrates should be used routinely within 24 hours of the onset of an acute myocardial infarction as per baseline characteristics outlined in the RCTs. Unfortunately, since treatment in these trials continued for more than 2 days, these two trials cannot be used to measure the delayed effect of the immediate use of nitrates on mortality at 10 days and ≥ 30 days. In the available trials the immediate use of nitrates had no significant delayed mortality reduction at 10 days, (RR 0.84, 95%CI [0.69, 1.01],p=0.07) or ≥30 days(RR 0.92, 95%CI[0.82,1.04],p=0.20) . The lack of a statistically significant effect is partly due to less data, but also due to the fact that the effect estimate appears to be diminishing over time. This opposes the effect seen with fibrinolytic agents and it some evidence against a delayed benefit of immediate nitrate administration. On the other hand these large trials, because they continued nitrates for 35 days, can be used to assess the mortality benefit of nitrates given from 3 to 10 days and from 11 to ≥30  115 days. The effect of nitrates administered from 3 to 10 days is shown in the sensitivity analysis (Figure 3-8) RR 0.98 [0.91 to 1.06]. This provides evidence for no benefit or harm, when nitrates are administered during this time period after an acute myocardial infarction. Furthermore, when the effect of nitrates on mortality was assessed for the period from 11 to ≥30 days it is clear that nitrates are not beneficial (RR 1.10, 95%CI [1.00 to 1.22]). This provides relatively robust evidence for the lack of benefit from nitrates administered beyond day 2 after an acute myocardial infarction. This does not preclude the use of nitrates if other appropriate indications exist, such as angina post- infarction.   116 Figure 3-8 Sensitivity Analysis: Effects of Continuation of Nitrates on All- cause at Different Times    The present systematic review did not find statistical evidence that immediate treatment with ACE inhibitors reduces mortality at 2 days after a myocardial infarction. Although most of the evidence comes from the same two large trials where the nitrates were studied, the evidence is of borderline significance (RR 0.91, 95%CI [0.82, 1.00], p=0.05), so it remains possible that a real benefit has been missed. Other possible explanation is that ACE inhibitors could increase other serious adverse events in this early period. Evidence in favor of this possibility in ISIS-4 1995103 is that cardiogenic shock or  117 profound hypotension requiring termination of study treatment was significantly higher in the ACE-inhibitor group as compared to placebo (p<0.01 and p<0.001, respectively) during the first 24-48 hours. It is also possible that the beneficial effect from ACE- inhibitors is specific to a certain sub-group(s) of patients (such as those patients with anterior infarction 103. If that was the case the significant beneficial effect would be diluted in the overall effect. The best way to resolve this uncertainty is to do an individual patient meta-analysis of the available trials to try to identify subgroups of patients who benefit from routine use of ACE-inhibitors in this early phase of an MI. Unfortunately, there were only two small trials in which a delayed effect of the immediate treatment with ACE-inhibitors could be assessed. Therefore, there was insufficient RCT evidence to ascertain the delayed effects of these drugs when given as immediate treatment (within 24 hours and lasting for up to 48 hours) following an acute myocardial infarction. The present systematic review demonstrated that the immediate treatment with beta- blockers was not associated with significant mortality benefit at 2 days (RR 0.95, 95%CI [0.85, 1.07], p=0.39), 10 days (RR 1.12, 95%CI [0.60, 2.07], p=0.73) or ≥30 days. However, there was very little data to assess the delayed effect of immediate treatment with beta-blockers. In addition, there was significant heterogeneity for the day-2 mortality outcome (I2=67%): the heterogeneity was not explained by the type of beta- blocker. However, when a pre-planned sensitivity analysis was performed according to trial design (double-blind; open-label), beta-blockers were not associated with a significant reduction in mortality as compared with placebo or no treatment among 51,814 patients in double-blind trials (RR 1.04, 95%CI [0.91,1.19]; I2=30%); but were  118 associated with a significant reduction in mortality among 16,193 patients in open-label trials (RR 0.73, 99%CI [0.58,0.91]; p=0.006; I2=69%). Given the clear lack of benefit in the double-blind trials, the most likely explanation for the benefit of beta blockers in the open label trials is that the two groups had other treatment differences than the planned intervention (performance bias). In keeping with that possibility, significantly more patients in the control group as compared to the beta-blocker group received calcium channel blockers drugs (RR 1.89 [1.74,2.06]; p<0.00001) in the largest trial of this meta- analysis, the ISIS-1 trial132  . If calcium channel blockers increase mortality this would lead to false evidence of a mortality benefit for beta-blockers. The evidence of a clear lack of mortality benefit in the more robust double-blind trials makes us confident that routine use of beta-blockers early after an MI is not useful. The present systematic review also showed that immediate treatment with CCB was not associated with a statistically significant reduction in all-cause mortality at 2 days, 10 or ≥30 days. This conclusion is weak due to the fact that the included trials do not report mortality at all of these times and because there were many CCB trials excluded from this meta-analysis, due to lack of reporting or improperly reported mortality data. The reason for this lack or improper reporting of mortality is not known; however, we feel that it is unlikely that trials demonstrating a mortality benefit would not have reported their results in full. We suspect that publication bias exists as we excluded 84% of the calcium channel blocker trials due to a lack of or insufficiency mortality reporting. Therefore, if anything, we think that the data showing no benefit or harm from CCB’s in this review is likely biased and that the full mortality data would show a statistically significant harm from CCBs.  119 The effects of short-term treatment provide additional information to what we have learned from the immediate treatment. Nitrates were again associated with a significant reduction in mortality at 10 days; however, as discussed above, this reduction was entirely accounted for by the immediate treatment reduction in mortality at 2 days. In contrast, ACE inhibitors after short-term treatment now show significant effect at 10 days (RR 0.93, 95%CI [0.87, 0.98]). The reason for the significant mortality benefit at 10 days is that, in contrast to the nitrates, in the two large trials (GISSI-3125, ISIS-4 1995103), the effect of the continued administration of ACE inhibitors was similar from 0 to 2 days (RR 0.91 ), from 3 to 10 days (RR 0.93, 95%CI [0.86 to 1.01]); and from day 11 to day 35 or 42 (RR 0.93, 95%CI [0.85 to 1.03]) (See Figure 3-9). This resulted in a significant mortality benefit for ACE inhibitors continued for 35-42 days (RR 0.93, 95%CI [0.88 to 0.97]) as compared to a non-significant mortality effect of nitrates continued for 35-42 days (RR 0.97, 95%CI [0.92 to 1.02]). However, it is emphasized that in a trial where it was possible to compare nitrates vs. ACE inhibitors in a head to head comparisons, GISSI-3125, there was no differences in mortality at 42 days (7% vs. 6.6%). This led us to conclude that the routine use of ACE inhibitors post MI reduces mortality to a modest degree. However, it remains uncertain as to the optimal time of starting these drugs, and whether ACE inhibitors should be targeted at a subgroup of patients where the mortality benefit is larger. The data to assess the effects of short-term treatment (start within 24 hour of the onset and lasting maximum 10 days) on mortality at ≥ 30 days was sparse for nitrates (7 trials) and nil for the ACE-inhibitors.   120 Figure 3-9 Sensitivity analysis: effect of ACE-I continuation on all-cause mortality at different times.  In the present systematic review, short-term treatment with beta-blockers showed no statistically significant effect on mortality at 10 days (RR 0.96, 95%CI [0.91, 1.02]; 14 trials, N=71,457), but a statistically significant effect at ≥ 30 days (RR 0.91, 95%CI [0.84, 0.99], p=0.03; 5 trials, N=18,373). Although the effect at ≥ 30 days is statistically significant, suggesting a delayed benefit with beta-blockers, we believe this is a chance effect and probably not real.  When mortality was analyzed separately for the periods 0- 10 days and 11 to ≥ 30 for these 5 trials, a significant benefit is seen only during the first 10 days, contradicting the "suggested delayed benefit" shown above. Furthermore, these results contradict the lack of significant mortality effect, during the first 10 days, when all  121 14 trials with available data are considered. A potential explanation of these contradictions is publication bias from the 5 trials that reported data at ≥ 30 days. In addition, the apparent exaggerated benefit in two trials (ISIS-1 1986132 and Yusuf 1983165) is possible due to performance bias as in both trials significantly more patients received calcium channel blockers (CCBs) in the control group. This could potentially increase mortality in the control group and exaggerate the benefit from the beta-blocker. The adverse effect of CCBs is in accordance with the findings of this review (see below).  Our systematic review showed that short-term treatment with CCB was not associated with a statistically significant reduction in all-cause mortality at 10 or ≥30 days. Similar to the effect of the immediate treatment, this conclusion is not robust because only a small percentage of CCB trials could be included in this review. In our sensitivity analysis, there was a trend towards a greater mortality among MI patients treated short- term with calcium channel blockers as compared to placebo (RR 1.60 95%CI [0.90, 2.86]); particularly in those receiving dihydropyridine CCBs (RR 1.91, 95%CI [0.98, 3.72]). Only 5 acute stroke RCT’s were included in the present systematic review and all of these studied calcium channel blocker (CCB) drugs. CCBs were not associated with significant effect on mortality at 10 days (RR 0.81, 95%CI [0.54, 1.21]) in this setting. This evidence is clearly insufficient to show whether CCBs are beneficial or harmful in acute stroke patients.  122 3.7.2 Summary of findings tables The following tables represent key findings for the immediate and short-term treatment of the four classes of blood pressure-lowering drugs. Table 3-4 Summary of findings table for nitrates Immediate and short term administration of nitrates in patients with acute cardiovascular events Patient or population: patients with acute myocardial infarction1 Settings: hospitalized within 24 hours of the symptom onset Intervention: Nitrates Comparison: Placebo or no treatment Illustrative comparative risks* (95% CI) Assumed risk Corresponding risk Outcomes Placebo or no treatment Nitrates Relative effect (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Low risk population2 20 per 1000 16 per 1000 (15 to 18) High risk population2 All-cause mortality at 2 days - immediate treatment Follow-up: 0- 48 hours 40 per 1000 32 per 1000 (30 to 36) RR 0.81 (0.74 to 0.89) 82624 (6 studies)  high Highly significant benefit was achieved. 125 or 250 patients, with high or low risk, need to be treated to prevent 1 death Low risk population2 50 per 1000 46 per 1000 (43 to 49) High risk population2 All-cause mortality at 10 days- short-term treatment Follow-up: 0- 10 days 80 per 1000 73 per 1000 (69 to 78) RR 0.91 (0.86 to 0.97) 78178 (6 studies)  high Significant benefit is demonstrated, but this is the same absolute magnitude as day 2. Thus, likely reflects the mortality benefit at day 2. *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Mortality results for this clinical condition, at the different times, and according to the different modalities of treatment (immediate and short term) displayed here, are considered the key points for this summary of findings table .The other results can be found in text. 2 These low and high risk values were chosen based on the second lowest, and second highest risks in the control group of the included studies  123   Table 3-5 Summary of findings table for ACE-inhibitors Immediate and short term administration of ACE inhibitors in patients with acute cardiovascular events Patient or population: acute myocardial infarction1 Settings: hospitalized within 24 hours of the symptom onset Intervention: ACE-inhibitors Comparison: Placebo or no treatment Illustrative comparative risks* (95% CI) Assumed risk Corresponding risk Outcomes Placebo or no treatment ACE-inhibitors Relative effect (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Low risk population2 20 per 1000 18 per 1000 (16 to 20) High risk population2 All-cause mortality at 2 days - immediate treatment Follow-up: 0- 48 hours 40 per 1000 36 per 1000 (33 to 40) RR 0.91 (0.82 to 1) 77414 (3 studies)  high No statistically significant effect, but possible benefit. Low risk population3 40 per 1000 37 per 1000 (35 to 39) High risk population3 All-cause mortality at 10 days - short-term treatment Follow-up: 0- 10 days 70 per 1000 65 per 1000 (61 to 69) RR 0.93 (0.87 to 0.98) 84311 (10 studies)  high Significant benefit was achieved. 200 or 333 patients, with high or low risk, need to be treated for 10 days to prevent 1 death *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Mortality results for this clinical condition, at the different times, and according to the different modalities of treatment (immediate and short term) displayed here, are considered the key points for this summary of findings table . The other results can be found in text. 2 These low and high risk values were chosen based on the lowest and highest risks in the control group of these 3 included studies 3 These low and high risk values were chosen based on the second lowest, and second highest risks in the control group of the included studies  124  Table 3-6 . Summary of findings table for beta-blockers. Immediate and short term administration of Beta-blockers in patients with acute cardiovascular events Patient or population: patients with acute myocardial infarction1 Settings: hospitalized within 24 hours of symptom onset Intervention: Beta-blockers Comparison: Placebo or no treatment Illustrative comparative risks* (95% CI) Assumed risk Corresponding risk Outcomes Placebo or no treatment Beta-blockers Relative effect (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Medium risk population2 All-cause mortality at 2 days - immediate treatment Follow-up: 0-48 hours 15 per 1000 14 per 1000 (13 to 16) RR 0.95 (0.85 to 1.07) 68007 (6 studies) ⊝⊝ low3,4 No statistically significant effect. Medium risk population5 All-cause mortality at 10 days - short- term treatment Follow-up: 0-10 days 42 per 1000 40 per 1000 (38 to 43) RR 0.96 (0.91 to 1.02) 71457 (14 studies)  high No statistically significant effect. *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Mortality results for this clinical condition, at the different times, and according to the different modalities of treatment (immediate and short term) displayed here, are considered the key points for this summary of findings table . The other results can be found in text 2 Medium risk was chosen as there was little variation in the control group risk across included trials 3 Performance bias was highly suspected in a large open label-trial 4 There was significant variability in the effect estimate 5 This is the medium control group risk from the included studies  125  Table 3-7. Summary of findings table for calcium channel blockers Immediate and short term administration of calcium channel blockers (CCB) in patients with acute cardiovascular events Patient or population: patients with acute myocardial infarction or stroke1 Settings: hospitalized within 24 hours of the onset Intervention: CCB Comparison: Placebo or no treatment Illustrative comparative risks* (95% CI) Assumed risk Corresponding risk Outcomes Placebo or no treatment CCB Relative effect (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Medium risk population2 All-cause mortality at 2 days - immediate treatment Follow-up: 0- 48 hours 13 per 1000 30 per 1000 (8 to 114) RR 2.33 (0.62 to 8.78) 242 (3 studies) ⊝⊝⊝ very low3,4,5 No statistically significant effect. Not enough trials/patients or events. Medium risk population6 All-cause mortality at 10 days - short- term treatment Follow-up: 0- 10 days 70 per 1000 71 per 1000 (51 to 97) RR 1.01 (0.73 to 1.38) 1900 (15 studies) ⊝⊝⊝ very low3,4,5 No statistically significant effect. Not enough trials/patients or events. *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Mortality results for these clinical conditions, at the different times, and according to the different modalities of treatment (immediate and short term) displayed here, are considered the key points for this summary of findings table .The other results can be found in text 2 Only the medium risk was chosen as there was little variation in the control group risk across included trials 3 These were very small open-label trials 4 The 95 % confidence intervals of the effect estimate goes in opposite direction across trials reaching the threshold for clear benefit (RR=0.75) and clear harm (RR=1.25) 5 Probably there are many missing reports 6 This is the median control group risk from the included studies  126  3.7.3 Overall completeness and applicability of evidence Out of 135 potentially appropriate randomized controlled trials we excluded 65 studies in which mortality data was non-extractable or non-usable for our review. Thus this data, if made available by the authors, it could be added to our review. Of these 65 excluded trials, 14 involved an ACE inhibitor (N=4,407); 21 trials involved a B-adrenergic Blocker (N=2,524); 8 trials involved a nitrate (N=1,475) and 20 trials involved a CCB (N=10,958). These excluded patients make up a small proportion of the available included patients: for the ACE inhibitors, 5.0%; beta-blockers 3.4%; and nitrates 1.7%; but a large proportion to the calcium channel blocker population, 84%. Due to the relatively small number of excluded patients and trials for the ACE inhibitor, beta- blocker and nitrate groups, we are pretty confident that the effect sizes calculated in these meta-analyses are a good estimate of the true effect. However, that is not the case for the calcium channel blockers, where it is more likely that the non-significant increase in short-term mortality among those patients with acute myocardial infarction found in this review (RR 1.60 95%CI[0.90, 2.86]) would become statistically significant. We have no information about the effects on mortality of other blood pressure lowering drugs (such as clonidine, prazosin and hydralazine, etc) used within 24 hours of the onset of an acute myocardial infarction or stroke. Likewise, we have no information regarding the effects on mortality produced by drugs embraced in this review started within 24 hours of the onset of other cardiovascular events such as acute aortic dissection, acute pulmonary edema, sub-arachnoid hemorrhage or unstable angina because mortality data was not assessed or reported in these conditions. To the best of our knowledge, only the randomized controlled trial by Yoshida (1998)42 included only patients with acute aortic  127 dissection and randomizing the patients within 24 hour of the onset. This trial compared two active treatments. Thus, this systematic review evidence is primarily applicable to patients with acute myocardial infarction receiving blood pressure lowering treatment within 24 hours of the onset of the event and having a level of risk similar to those participants from the randomized trials included in this review. Since the evidence for effectiveness of nitrates and ACE-inhibitors mostly comes from two large trials [ISIS-4 1995103; GISSI-3 1994125], the practical recommendations primarily apply to patients having the following characteristics: ISIS-4 1995103: Patients with suggestive of suspected or definite acute MI (with or without electrocardiographic changes) within 24 hours of symptom onset and with no clear indications for, or clear contraindications to any of the trial treatments. In this trial the contraindications were not set by the protocol, but by the responsible physician and might include: negligibly low risk of MI death (e.g. normal electrocardiogram), major life-threatening disease other than acute MI, or a high risk of adverse effects of trial treatment such as: decreased blood pressure-cardiogenic shock or severe hypotension (eg., SBP persistently <90-100 mm Hg, especially with right ventricular infarction or poor peripheral perfusion); severely decreased plasma volume- clinical evidence of severe fluid depletion, perhaps due to chronic diuretic use. Overall, 74% were male; 28% were 70 years of age or older; 92% were ultimately confirmed to have an AMI; 86% had Killip class I (no signs or symptoms of heart failure) and 17% had previous MI.  128 The co-interventions given in the overall trial were: non-study intravenous nitrates (~47%); anti-platelets (~93%); fibrinolytic agents (~68%) and intravenous beta-blockers (~9%) GISSI-3 trial125. Inclusion criteria: patients with chest pain accompanied by ST elevation or depression of at least 1 mm in one or more peripheral leads of the electrocardiogram (ECG), or at least 2 mm in one or more precordial leads; within 24 hours of symptoms onset; and having no contraindications to the study treatments. Exclusion criteria: severe heart failure requiring any of the study treatments; Killip class 4; high risk of further serious hemodynamic deterioration after treatment with vasodilators (SBP ≤ 100 mm Hg), contraindications to study drugs -namely a history of clinically relevant renal failure (serum creatinine ≥ 177 mol/L, proteinuria > 500 mg per 24 hours or both), history of bilateral stenosis of the renal arteries, allergies to one of the study drugs, other life threatening disorders (eg., tumors or serious respiratory diseases). Overall, 78% were male; 27% were 70 years of age or older; 93% were ultimately confirmed to have an AMI; 83% had Killip class I and 14% had previous MI. The co-interventions given in the overall trial were: non-study intravenous nitrates (~57%- only reported for the control group); aspirin (~84%); fibrinolytic agents (~72%) and intravenous beta-blockers (~30%). 3.7.4 Quality of the evidence Forty trials (60%) out of 65 included studies were double-blind, involving 75% (N=125,487) of the entire studied population. Although the number of trials reporting adequate concealment of allocation was relatively small [13/40 (32%) in double-blind  129 and 10/25 (40%) in open-label design trials], the number of patients randomized with concealment of allocation was very high (121,618 in double-blind trials out of a total 125,487 and 37,055 in open-label trials out of a total 40,719 ). Similarly, although more than 75% of trials had an incomplete or not reported all-cause mortality at 2 days, the studies that indeed reported it were large enough (N=131,603) to decrease this risk of incomplete outcome to a minimum. That was not the case for ≥30 day mortality, which was reported by less than 25 % of trials, and the trials were not large enough (24,918) to dismiss the possibility of bias for this outcome. 3.7.5 Potential biases in the review process One limitation of the present review is that we did not consider many trials that claimed enrolling their patient in the early period of an acute cardiovascular event, (i.e., within 48 to 72 hours). Evidently, in these types of studies it is anticipated that some patients could be enrolled and have started their study treatment within 24 hours; therefore, data from these patients are missing from our review.  Including such patients would require obtaining individual patient data from these studies, which was not possible. We have tried to get information from some recent trials of this type (for example from the ACCESS 2003 trial94), with no success. Even though we accept this as a limitation, we feel that adding these trials would create a more unacceptable limitation as we are interested in determining the specific effects of early treatment and we do not want to contaminate that with patients enrolled after the early or acute vulnerable period. Another limitation of this review is that we assessed blood pressure and heart rate changes for only the first 24 hours of the initiation of treatment. The objective was to assess whether these early changes can be related to mortality at 2, 10 or ≥30 days.  130 Expanding the time window for these measures would likely have made more data available; however, we believe that the effects during the first 24 hours are the most important. An additional problem encountered in acute life-threatening settings is the significant number of patients censored in terms of blood pressure and heart rate data due to death, withdrawal or losses to follow-up. It is difficult, therefore, to have BP data in the same population that is contributing to the mortality data. We are aware that due to the fact that BP and heart rate data were only available from a small number of trials that we do not have a high degree of confidence in the magnitude of these measures. 3.7.6 Agreements and disagreements with other studies or reviews 3.7.6.1 Nitrates There is a previous overview and meta-analysis that assessed the effects of nitrates in patients with acute myocardial infarction, Yusuf 198826 et al. With only 2,000 patients they found a significant effect (OR 0.55, 95%CI [0.39, 0.76]) on early (first week or in hospital) mortality. These authors did not distinguish between immediate treatment or short-term treatment. Our overall results at 10 days (or in hospital) including both immediate and short-term treatment are not in accordance with their effect estimate: OR 0.90, 95%CI [0.85, 0.96] p=0.0008. Our result with the inclusion of more recent larger trials in 84,185 patients is clearly a better estimate of the true treatment effect.  Our results are also in disagreement with the guidelines from the American College of Cardiology and the American Heart Association ACC/AHA, 20042. In chapter VI regarding the initial management of MI in the emergency department these guidelines  131 have relegated the use of nitrates (nitroglycerin exclusively) to patients with ongoing ischemic discomfort or control of hypertension or management of pulmonary congestion. The present systematic review demonstrates that the use of nitrates within 24 hours significantly reduces all-cause mortality (RR 0.81, 95%CI [0.74, 0.89], p<0.0001) at 2 days. This is consistent with 4 or 8 deaths prevented for 1000 low or high risk patients treated, respectively (See summary of findings Table 3-4). Therefore, routine nitrates should be administered to all patients with suspected acute myocardial infarction, who do not have the specific contraindications outlined above. Due to its proven effectiveness in the ISIS-4 trial103  and ease of administration, controlled-release oral isosorbide-5- mononitrate 30 mg twice a day the first day and 60 mg the second day is the best choice. However, the use of routine nitrates should be restricted to the first 48 hours as there was no further reduction in mortality associated with their use beyond day 2. The mechanism whereby nitrates reduce mortality in the immediate period after an acute MI and not after that is not known. Since it appears from this review that blood pressure reduction is not the explanation, there must be another mechanism. Nitrates have been used for more than a century to relieve myocardial ischemia and chest pain. This has been thought to be due to their vasodilatory effects: venous, arterial and coronary vessels and on the redistribution of blood flow towards the ischemic sub-endocardium. These mechanisms may explain the early mortality benefit. A second possible mechanism is that nitric oxide donors such as nitrates and nitroprusside inhibit platelet adhesion and aggregation. In the late 1980's in vivo animal experiments demonstrated that an infusion of nitroglycerin reduced platelet deposition on damaged arteries168. These findings were confirmed in the early 1990's in vivo by De  132 Caterina 1990169 et al, showing that isosorbide mono-nitrates produced, a dose- dependent, inhibition of platelet aggregation and thromboxane production induced by adenosine diphosphate and adrenaline in patients with objectively proven coronary artery disease. A controlled study by Butterworth 1998170 et al, demonstrated that nitroprusside given at dose which reduced MAP by 10 mm Hg, significantly inhibited platelet aggregation and improved regional cerebral blood flow. Furthermore, the results from ISIS-4 1995103 and ESPRIM 1994120 trials support this theory, as they showed a greater mortality benefit with nitrates in patients who never received anti-platelets drugs. For example, in the former trial, the difference in mortality between the nitrate group and placebo group in patients who never received anti-platelets was 15.7% versus 17.7%, respectively (RR 0.89). In contrast, this difference was negligible in patients who did receive anti-platelet drugs, 6.9% versus 7.0%, respectively (RR 0.99). An explanation for the early and not late nitrate benefit is that the activation of the sympathetic nervous system (outflow of catecholamines: epinephrine and norepinephrine) is increased in the immediate period of myocardial infarction171. At this early time catecholamines would be the most prominent inductive mechanism for platelet aggregation. It has been shown that nitric oxide donors such as nitrates exert a platelet aggregation inhibitory response only induced by ADP and catecholamines169. That is, nitrates do not interfere with the ongoing thrombotic stimulus induced by thrombin, collagen or other stronger inducers of thromboxane generation and platelet aggregation. A third potential explanation for the early mortality benefit conferred by nitrates is that in addition to their hemodynamic and cardiac work-load benefits, they might interfere with the heart excitability and/or conduction system in the early hours following the  133 myocardial infarction. Before the identification of the endothelium-derived relaxing factor as nitric oxide in the late 80's there were some reports showing that nitrates have anti-arrhythmic effects in acute myocardial ischemia animal models172;173. At that time the theory that nitrates work through the release of nitric oxide (NO), increasing guanosine 3':5'- cyclic monophosphate (cGMP), was presented174;175. More recently, others have reported the effects of nitric oxide on the excitability of the autonomic cells (sinoatrial node or atrioventricular node176-178 or directly on myocytes179. The fact that neural nitric oxide synthase (nNOS) has now been identified in the nerve fibers of the heart180;181, suggest a broader role of NO in the heart's electrophysiology . An augmented expression on nNOS during acute myocardial infarction in animal models has been demonstrated182. Thus, an anti-arrhythmic effect from nitrates/nitric oxide remains a possibility183-186. 3.7.6.2 Angiotensin converting enzyme inhibitors (ACEi) The effects of ACE inhibitors on AMI patients have been reported in two systematic reviews (AMICG 199827 and Rodrigues 200328 et al). In the former, 98,496 patients were included from trials comparing ACE inhibitors to placebo or no treatment. The authors demonstrated a mortality reduction with ACEi obtained at 7 days and 30 days (RR 0.92, 95%CI [0.86, 0.97]; and RR 0.93, 95%CI [0.89, 0.98], respectively. Thus, these 7-day findings are very similar to our 10-day results. The other ACEi systematic review (Rodrigues et al 200328), had the objective to assess the effect of long-term treatments as they did not limited the length of treatment in the trials and quantified mortality at 30 days, 6 months and 1 year. Thus, the Rodrigues 200328 review cannot be compared to ours.  134 The American College of Cardiology and the American Heart Association2 have recommended that an angiotensin converting enzyme (ACE) inhibitor should be administered orally within the first 24 hours of STEMI (ST-elevation myocardial infarction) to patients with anterior infarction, pulmonary congestion or LVEF less than 0.40 in the absence of hypotension or known contraindications to that class of medications. However, in a second paragraph they further state that ACE inhibitor administered within the first 24 hours of STEMI can be useful without the above characteristics. In our ACE inhibitors analysis the effect estimates for open-label trials and double-blind trials differ, at 2 days RR 0.86, 95%CI [0.71,1.03]) and RR 0.93, 95%CI [0.83,1.04]), respectively, calling into question the borderline overall mortality benefit at 2 days (RR 0.91, 95%CI [0.82,1.00]), p=0.05. Furthermore, nitrates confer a superior relative 0.81 versus 0.91, and absolute mortality benefit 4 - 8 per 1000 versus 2 to 4 per 1000, respectively. Thus, we feel that the optimal time of administration of ACE inhibitors post-acute MI is presently unknown and that further research is required.  3.7.6.3 Beta-adrenergic antagonists or beta-blockers (BB) Other systematic reviews (SRs) have evaluated the effect of beta-blockers (BB) in AMI (Yusuf 198523 et al, Freemantle 199924 et al, and Al-Reesi 200825 et al). All of these reviews have accepted trials where treatment was started later than 24 hours after the onset of AMI. Yusuf et al (198523) concluded that reliable estimation of the effects of early beta blockade on mortality has not yet been achieved. Freemantle et al (199924) also concluded that there were no mortality benefits from BB in "short-term" trials. The most  135 recent review (Al-Reesi et al 200825) inexplicably excluded 11 trials that we included in our review. Despite that, their conclusion stating that "acute intervention with B-blockers does not result in statistical significant short-term survival benefit following AMI" is in agreement with ours. Despite these systematic reviews, the ACC/AHA 20042 recommended that oral beta- blocker therapy should be administered promptly to those suspected MI patients without a contraindication irrespective of concomitant fibrinolytic therapy or performance of primary PCI. Based on our systematic review we do not recommend routine BB for the immediate or short-term treatment of patients with suspected MI. However, it should be emphasized that these findings and recommendations are not contradictory to the long-term mortality benefits for BB post MI when these drugs are started a few days or weeks after myocardial infarction and continued for some months (Yusuf 198523 and Freemantle 199924).  3.7.6.4 Calcium channel blockers (CCB) In Acute Myocardial Infarction The one other systematic review that has assessed CCB drug in patients with acute myocardial infarction or unstable angina, Held et al (198922) also included trials in which treatment was started after 24 hours or trials where the time of entry was not specified. However, they also concluded that "CCBs do not reduce the risk of initial or recurrent infarction or death when given routinely to patients with acute myocardial infarction or unstable angina”.  136 The ACC/AHA, 20042 have restricted the use of CCB by stating that it is reasonable to give verapamil or diltiazem to patients in whom beta-blockers are ineffective or contraindicated for relief of ongoing ischemia or control of a rapid ventricular response with atrial fibrillation of flutter after STEMI in the absence of CHF, LV dysfunction or atrioventricular (AV) block. In Stroke There is one Cochrane systematic review already published that assessed CCB drugs in acute stroke (Horn et al, 200029) but with a different research question from ours. Their focus was not limited to the immediate initiation of treatment and for short term treatment. They included 28 studies. Of those, 12 trials had required their patients to start treatment within 24 hours of the onset. Of those, we have excluded one trial-because it compared IV infusion vs. oral treatment, rather than CCB vs. placebo; and 5 trials because mortality data was not reported or usable in our review. Despite the differences their conclusion "No evidence is available to justify the use of calcium antagonists in patients with acute ischemic stroke" agrees with ours. Two Cochrane systematic reviews involving patients with acute stroke and blood pressure lowering drugs have been published: Bath 2002187 et al; Geeganage 200831 et al. The former assessed nitrates for acute stroke with different methodology and objectives than ours. Studies were not limited to truly randomized trials or to the immediate initiation of treatment and for short term treatment. Since only two studies were included, the authors concluded that there was insufficient evidence to recommend the use of nitrates. We did not include those two trials because treatment started days after the onset of the stroke. The Geeganage et al (200831) review also had a different approach to ours,  137 as it was not limited to RCTs studying blood pressure reducing drugs. In addition, in this review RCTs are not limited to a certain time of starting treatment after the stroke (for example, it included trials where treatment started even 7 days after the onset).  Out of their 12 included studies, 3 trials started the treatment within 24 hours. We excluded all these 3 for the following reasons. In the INTERACT (2008188) trial, patients were not allocated to a class of drug vs. placebo or no treatment. Instead, patients were allocated to two different BP targets (140 vs. 180 mm Hg) to be achieved in 1 hour and maintained for 7 days. The ACCESS (200394) trial included patients within 24 and 36 hours but without separating their results according to these times.  And the third trial, Eveson et al (200733), results were not based on ITT principles. Patients first were randomized and then withdrawn if diagnosis was wrong. Analysis was not performed based on all randomized patients. 3.8 Authors’ conclusions 3.8.1 Implications for practice 3.8.1.1 Acute myocardial infarction. Nitrates administered within 24 hours of symptom onset significantly decrease day-2 all- cause mortality (4 to 8 deaths prevented per 1000). The evidence shows that continuation of nitrates beyond day 2 does not reduce mortality. ACE inhibitors administered within 24 hours of symptom onset have not been shown to significantly reduce mortality at 2 days. ACE inhibitors administered within 24 hours of symptom onset and continued for 10 days significantly reduce day 10 all-cause mortality (3 to 5 deaths prevented per 1000).  138 The optimal time of starting ACE inhibitor therapy post myocardial infarction is not known. Beta-blockers started within 24 hours of symptom onset do not reduce all-cause mortality at 2 days or after short-term use at 10 days. Calcium channel blockers started within 24 hours of symptom onset do not decrease mortality and a trend towards increased mortality was seen after short-term use of these drugs at 10 days (RR 1.60 95%CI [0.90, 2.86]). 3.8.1.2 Other acute cardiovascular conditions Calcium channel blockers administered after acute stroke have not been shown to affect mortality but the data is insufficient. There is no RCT information regarding the effects on mortality produced by blood pressure lowering drugs started within 24 hours of the onset of other cardiovascular events such as acute aortic dissection, acute pulmonary edema, unstable angina, intracranial or sub-arachnoid hemorrhage. 3.8.2 Implications for research 3.8.2.1 In patients with acute myocardial infarction Future RCTs of early treatment should report mortality at standard times 2 days, 10 days, 30 days and 6 months. Mortality data at the times from all RCTs should be made available. This is particularly important for the existing calcium channel blocker RCTs.  139 Future trials in this condition need to be cognizant of the possibility that treatment effects may be different during the first 2 days as compared with after 2 days as demonstrated in this review. An individual patient meta-analysis of immediate treatment ACE inhibitor trials is needed to ascertain whether there is a subgroup of immediate post MI patients with a mortality benefit. More RCTs are needed to better define the optimal time to start ACE inhibitor therapy. 3.8.2.2 In patients with acute stroke, unstable angina, acute pulmonary edema, cerebral hemorrhage or acute aortic dissection: Because blood pressure-lowering drugs are frequently used in these settings there is a need for more large RCTs assessing different aspects of these interventions: eg., different drug classes, different drugs within a class, dosing regimens, timing of onset of treatment, blood pressure threshold for treatment etc. Regardless of the design of these RCTs, such trials must report total all-cause mortality at standard different times of follow-up: 2 days, 10 days, 1 month and 6 months. An international organization should standardize and mandate the documentation and reporting of total serious adverse events in hospitalized and critically-ill patients. 3.9 Acknowledgements We have deep gratitude for the trialists who provided us with additional information from their studies; for Eugenio Santoro especially, from the GISSI-3 trial, who kindly responded to all of our requests. We acknowledge the collaboration of Cochrane hypertension review group, particularly to Stephen Adams for his unconditional help in  140 retrieving all studies. We are grateful to Dr. Ken Basset, Dr. Thomas Perry, Benji Heran, Jenny Chang and Gavin Wong for their comments on a draft.  141  3.10 References     (1)  Health Canada. The Growing Burden of Heart Disease and Stroke. http://www cvdinfobase ca/cvdbook/CVD_En03 pdf 2003.  (2)  ACCAHA, Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction--executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). Circulation 2004; 110(5):588-636.  (3)  WHO. Gloabal burden disease. http://www who int/healthinfo/global_burden_disease/GBD_report_2004update_full pdf 2004.  (4)  Fulton M, Julian DG, Oliver MF. Sudden death and myocardial infarction. Circulation 1969; 49:I82-89.  (5)  ISIS-2. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.[see comment]. Lancet 1988; 2(8607):349-360.  (6)  Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br J Cancer 1977; 35(1):1-39.  (7)  WHO-ISH. 2003 World Health Organization (WHO)/ International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003; 21:1983-1992.  (8)  ESH ESC. Guidelines for the management of arterial hypertension: The task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Blood Press 2007; 16(3):135-232.  (9)  BHS IV, Williams B, Poulter NR, Brown MJ, Davis M, McInnes GT et al. British hypertension society guidelines for hypertension management 2004 (BHS-IV): Summary. Br Med J 2004; 328(7440):634-640.  (10)  JNC-7, Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA et al. The Seventh Report of the Joint National Committee on Prevention, Detection,  142 Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289(19):2560-2572.  (11)  Jackevicius CA, Alter D, Cox J, Daly P, Goodman S, Filate W et al. Acute treatment of myocardial infarction in Canada 1999-2002. Can J Cardiol 2005; 21(2):145-152.  (12)  European S, Van de WF, Ardissino D, Betriu A, Cokkinos DV, Falk E et al. Management of acute myocardial infarction in patients presenting with ST- segment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2003; 24(1):28- 66.  (13)  ACCAHA, Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 2007; 116(7):e148-e304.  (14)  AHA-ASA, Adams RJ, Albers G, Alberts MJ, Benavente O, Furie K et al. Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke 2005; 39(5):1647- 1652.  (15)  Boersma E, Maas AC, Deckers JW, Simoons ML. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour (Structured abstract). Lancet 1996; 348:771-775.  (16)  FTT. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Lancet 1994; 343(8893):311-322.  (17)  ATC, Antiplatelet Therapy Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death , myocardial infarction, and stroke in high risk patients. Br Med J 2002; 324:71-86.  (18)  Perez MI, Musini VM, Wright JM. Pharmacological interventions for hypertensive emergencies. Cochrane Database Syst Rev 2008;(1):CD003653.  (19)  ICH-FDA. International conference on harmonization of technical requirements for registration of pharmaceuticals for human use. Clinical safety data  143 management; definitions and standards for expedited reporting document E2A. FDA-Federal Register 1995; 60:11284-11287.  (20)  Wright JM, Puil L, Bassett CL. Analysis of serious adverse events. Lipid- lowering therapy revisited. Canadian Family Physician 2002; 48:486-489.  (21)  Cook D, Lauzier F, Rocha MG, Sayles MJ, Finfer S. Serious adverse events in academic critical care research. CMAJ 2008; 178(9):1181-1184.  (22)  Held PH, Yusuf S, Furberg CD. Calcium channel blockers in acute myocardial infarction and unstable angina: an overview.[see comment]. BMJ 1989; 299(6709):1187-1192.  (23)  Yusuf S, Peto R. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985; XXVII(5):335- 371.  (24)  Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta Blockade after myocardial infarction: systematic review and meta regression analysis.[see comment]. BMJ 1999; 318(7200):1730-1737.  (25)  Al-Reesi A, Al-Zadjali N, Perry J, Fergusson D, Al-Shamsi M, Al-Thagafi M et al. Do beta-blockers reduce short-term mortality following acute myocardial infarction? A systematic review and meta-analysis. [Review] [25 refs]. CJEM Canadian Journal of Emergency Medical Care 2008; 10(3):215-223.  (26)  Yusuf S, MacMahon S, Collins R, Peto R. Effect of intravenous nitrates on mortality in acute myocardial infarction: An overview of the randomised trials. Lancet 1988; 1(8594):1088-1092.  (27)  AMICG. Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. ACE Inhibitor Myocardial Infarction Collaborative Group.[see comment]. Circulation 1998; 97(22):2202-2212.  (28)  Rodrigues EJ, Eisenberg MJ, Pilote L. Effects of early and late administration of angiotensin-converting enzyme inhibitors on mortality after myocardial infarction.[see comment]. American Journal of Medicine 2003; 115(6):473-479.  (29)  Horn J, Limburg M. Calcium antagonists for acute ischemic stroke. The Cochrane Library 2000;(2).  (30)  Bath P, Bath F, Rashid P, Weaver C. Acute ischaemic stroke. Large trial of effect of reducing blood pressure in acute stroke is being set up. BMJ 2000; 321(7256):300.  144  (31)  Geeganage C, Bath PM. Interventions for deliberately altering blood pressure in acute stroke.[update of Cochrane Database Syst Rev. 2001;(3):CD000039; PMID: 11686949]. Cochrane Database Syst Rev 2008;(4):000039.  (32)  Walker LJ, MacKenzie G, Adgey AA. Effect of nifedipine on enzymatically estimated infarct size in the early phase of acute myocardial infarction. British heart journal 1988; 59:403-410.  (33)  Eveson DJ, Robinson TG, Potter JF. Lisinopril for the treatment of hypertension within the first 24 hours of acute ischemic stroke and follow-up. American Journal of Hypertension 2007; 20(3):270-277.  (34)  Szczechowski L, Wajgt A. [Evaluation of treatment efficiency of acute hemispheric strokes using intravenous nimodipine infusions]. Neurologia i neurochirurgia polska 1994; 28:299-306.  (35)  DAVIT I. Verapamil in acute myocardial infarction. Danish Multicenter Study Group on Verapamil in Myocardial Infarction. American Journal of Cardiology 1984; 54(11):24E-28E.  (36)  HINT. Early treatment of unstable angina in the coronary care unit: a randomised, double blind, placebo controlled comparison of recurrent ischaemia in patients treated with nifedipine or metoprolol or both. Report of The Holland Interuniversity Nifedipine/Metoprolol Trial (HINT) Research Group. Br Heart J 1986; 56(5):400-413.  (37)  Barber JM, Boyle DM, Chaturvedi NC, Singh N, Walsh MJ. Practolol in acute myocardial infarction. Acta Medica Scandinavica - Supplementum 1976; 587:213-219.  (38)  Balcon R, Jewitt DE, Davies JP, Oram S. A controlled trial of propranolol in acute myocardial infarction. Lancet 1966; 2(7470):918-920.  (39)  Kolettis MT, Karlas EN, Tzannetis GC, et a. Limitation of infarct size by decrease of afterload with prazosin. ACTA CARDIOL 1983; 38:425-441.  (40)  Murdock CJ, Hickey GM, Hockings BE, Pitman GF, Taylor RR. Effect of alpha 1-adrenoceptor blockade on ventricular ectopic beats inacute myocardial infarction. International journal of cardiology 1990; 26:45-48.  (41)  Manolis AJ, Tsalopoulos E, Ramos C, Katsaros K, Dalabiras P, Hatzissavas J et al. Benefits of central sympathetic suppression with clonidine after acute myocardial infarction. Advances in Therapy 1999; 16:272-282.  (42)  Yoshida N. Antihypertensive Effect of the Long-Acting Ca Antagonist Amlodipine vs. Sustained-Release Nifedipine in Patients with Acute Aortic Dissection. Rinsho to Kenkyu (The Japanese Journal of Clinical and Experimental Medicine) 1998; 75(6):1419-1422.  145  (43)  Annane D, Bellissant E, Pussard E, Asmar R, Lacombe F, Lanata E et al. Placebo-controlled, randomized, double-blind study of intravenous enalaprilat efficacy and safety in acute cardiogenic pulmonary edema. Circulation 1996; 94(6):1316-1324.  (44)  Ardissino D, Merlini PA, Savonitto S, Demicheli G, Zanini P, Bertocchi F et al. Effect of transdermal nitroglycerin or N-acetylcysteine, or both, in the long- term treatment of unstable angina pectoris. Journal of the American College of Cardiology 1997; 29:941-947.  (45)  Azancot I. Effects of acebutolol on myocardial infarct extension: a randomized electrocardiographic, enzymatic and angiographic study. Circulation 1982; 66(5):986-994.  (46)  Azcona A. Isradipine in patients with acute ischaemic cerebral infarction. An overview of the ASCLEPIOS Programme. Drugs 1990; 40:52-57.  (47)  Basu S, Senior R, Raval U, van-der DR, Bruckner T, Lahiri A. Beneficial effects of intravenous and oral carvedilol treatment in acute myocardial infarction. A placebo-controlled, randomized trial. Circulation 1997; 96:183- 191.  (48)  Blanc JJ, Monassier JP, Brochier M. Intravenous atenolol + streptokinase versus streptokinase alone in acute myocardial infarction: a pilot randomized cooperative study (abstr). EUR HEART J 1989; 10 (suppl):117.  (49)  Briant RB, Norris RM. Alprenolol in acute myocardial infarction: Double-blind trial. N Z Med J 1970; 71(454):135-138.  (50)  Bussmann WD, Seher W. Reduction of creatine kinase and creatine kinase-MB indexes of infarct size by intravenous verapamil. American Journal of Cardiology 1984; 54(10):1224-1230.  (51)  Kingma JH, van Gilst WH, Peels CH, Dambrink JH, Verheugt FW, Wielenga RP. Acute intervention with captopril during thrombolysis in patients with first anterior myocardial infarction. Results from the Captopril and Thrombolysis Study (CATS). Eur Heart J 1994; 15(7):898-907.  (52)  Potter J, Robinson T, Ford G, James M, Jenkins D, Mistri A et al. CHHIPS (Controlling Hypertension and Hypotension Immediately Post-Stroke) Pilot Trial: rationale and design. [Review] [39 refs]. J Hypertens 2005; 23(3):649- 655.  (53)  Davalos A, De Cendra E, Genis D, Teruel J, Ruibal A, Musoles S. Double blind clinical trial of nicardipine versus placebo in the treatment of the acute phase of stroke. Neurologia 1992; 7(6):157.  146  (54)  Emanuelsson H, Herlitz J, Hjalmarson A, Holmberg S, Waagstein F, Waldenstr"m A et al. Hemodynamic and clinical findings after combined therapy with metoprolol and nifedipine in acute myocardial infarction. Clinical Cardiology 1984; 7:425-432.  (55)  EMIP BB, Leizorovicz A, Alberque. Pre-hospital treatment of patients with suspected acute myocardial infarction using a beta-blocking agent: A double- blind feasibility study;EMIP-BB Pilot Study Group. CLIN TRIALS META ANALYS 1994; 29:125-138.  (56)  Evemy KL PB. Intravenous and oral practolol in the acute stages of myocardial infarction. European Journal of Cardiology 1978; 7(5-6):391-398.  (57)  Borghi C, Marino P, Zardini P, Magnani B, Collatina S, Ambrosioni E. Short- and long-term effects of early fosinopril administration in patients with acute anterior myocardial infarction undergoing intravenous thrombolysis: results from the Fosinopril in Acute Myocardial Infarction Study. FAMIS Working Party. Am Heart J 1998; 136(2):213-225.  (58)  Franke CL, Palm R. Flunarizine in stroke treatment (FIST): a double-blind, placebo-controlled trial in Scandinavia and the Netherlands. Acta Neurol Scand 1996; 93(1):56-60.  (59)  French JK, Amos DJ, Williams BF, Cross DB, Elliott JM, Hart HH et al. Effects of early captopril administration after thrombolysis on regional wall motion in relation to infarct artery blood flow. Journal of the American College of Cardiology 1999; 33:139-145.  (60)  Gardtman M. Effect of intravenous metoprolol before hospital admission on chest pain in suspected acute myocardial infarction. Am Heart J 1999; 137(5):821-829.  (61)  Gebalska J, Wolk R, Ceremuzynski L. Isosorbide dinitrate inhibits platelet adhesion and aggregation in nonthrombolyzed patients with acute myocardial infarction. Clinical Cardiology 2000; 23:837-841.  (62)  Gelmers HJ. The effects of nimodipine on the clinical course of patients with acute ischemic stroke. Acta Neurol Scand 1984; 69(4):232-239.  (63)  Gerstenblith G, Ouyang P, Achuff SC, Bulkley BH, Becker LC, Mellits ED et al. Nifedipine in unstable angina: a double-blind, randomized trial. The New England journal of medicine 1982; 306:885-889.  (64)  Latini R, Avanzini F, De NA, Rocchetti M. Effects of lisinopril and nitroglycerin on blood pressure early after myocardial infarction: the GISSI-3 pilot study. Clinical pharmacology and therapeutics 1994; 56:680-692.  147  (65)  Gonzalez-Fernandez RA, Altieri PI, Lugo JE, Fernandez MJ. Effects of enalapril on ventricular volumes and neurohumoral status after inferior wall myocardial infarction. The American journal of the medical sciences 1993; 305:216-221.  (66)  Gordon GD, Mabin TA, Isaacs S, Lloyd EA, Eichler HG, Opie LH. Hemodynamic effects of sublingual nifedipine in acute myocardial infarction. American Journal of Cardiology 1984; 53(9):1228-1232.  (67)  Gottlieb SO, Weisfeldt ML, Ouyang P, Achuff SC, Baughman KL, Traill TA et al. Effect of the addition of propranolol to therapy with nifedipine for unstable angina pectoris: a randomized, double-blind, placebo-controlled trial. Circulation 1986; 73:331-337.  (68)  Gottlieb SO, Becker LC, Weiss JL, Shapiro EP, Chandra NC, Flaherty JT et al. Nifedipine in acute myocardial infarction: an assessment of left ventricular function, infarct size, and infarct expansion. A double blind, randomised, placebo controlled trial. British heart journal 1988; 59:411-418.  (69)   Effect of IV propranolol on the extent of myocardial ischaemic injury in patients with acute anterior myocardial infarction. 1984.  (70)  Gupta RC, Sharma SK, Arora YK, Tripathi K. Reduction of infarct size by early use of oral propranolol and verapamil in acute myocardial infarction. J Assoc Physicians India 1985; 33(9):577-580.  (71)  Hamilton RJ, Carter WA, Gallagher EJ. Rapid improvement of acute pulmonary edema with sublingual captopril.[see comment]. Acad Emerg Med 1996; 3(3):205-212.  (72)  Haude M, Erbel R, Steffen W, Tschollar W, Meyer J. Sublingual administration of captopril in patients with acute myocardial ischemia. Clinical Cardiology 1991; 14:463-468.  (73)  Vaughan DE, Rouleau JL, Ridker PM, Arnold JM, Menapace FJ, Pfeffer MA. Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. HEART Study Investigators. Circulation 1997; 96:442- 447.  (74)  Jaffe AS, Biello DR, Sobel BE, Geltman EM. Enhancement of metabolism of jeopardized myocardium by nifedipine. Int J Cardiol 1987; 15(1):77-89.  (75)  Just H, Heidelbach I, Jackle B, Wollschlager H. Nifedipine in acute myocardial infarction: Can a myocardial protective effect be demonstrated in a double blind placebo controlled study? INTENSIVMEDIZIN 1986; 23:159-164.  (76)  Kahler J, Schneider CA, Ambrosius U, Neff U, Klepzig JH, Bussmann WD. Gallopamil in acute myocardial infarction. Herz Kreislauf 1995; 27:370-374.  148  (77)  Karlberg KE, Saldeen T, Wallin R, Henriksson P, Nyquist O, Sylven C. Intravenous nitroglycerin reduces ischaemia in unstable angina pectoris: a double-blind placebo-controlled study. J Intern Med 1998; 243(1):25-31.  (78)  Kumada T, Kawai C, Sasayama S, Kinoshita M, Kawamura K, Kusukawa R et al. Clinical efficacy of nicardipine by intravenous infusion in patients with acute heart failure. A multicenter randomized double-blind placebo-controlled trial. Japanese Pharmacology and Therapeutics 1995; 23:163-186.  (79)  Lejemtel T, Hochman JS, Edelstein R. Captopril before reperfusion in acute myocardial infarction: the CAPTIN experience[abstract]. J Heart Fail 256. 1993.  (80)  Lloyd EA, Charles RG. Beta-blockade by sotalol in early myocardial infarction decreases ventricular arrhythmias without increasing left ventricular volume. South African Medical Journal 1988; 74(1):5-10.  (81)  Loogna E, Sylv nC, Groth T, Mogensen L. Complexity of enzyme release during acute myocardial infarction in a controlled study with early nifedipine treatment. European Heart Journal 1985; 6:114-119.  (82)  Macleod A, Fananapazir L, Kitchin AH. Prophylactic selective beta blockade in acute myocardial infarction. Abstracts of VIII European Congress on Cardiology, Paris, 229. 1980.  (83)  Matias-Gutierrez J, Molto JM, Galiano L, Insa R, Falip R, Martin R. Pilot double blind placebo controlled trial of nicardipine versus placebo for cognitive impairment in minor stroke patients. J Neurol 1992; 239:S39.  (84)  McGrath B, Arnolda L, Saltups A. The catecholamine response to acute myocardial infarction: effect of early administration of sotalol. Australian and New Zealand journal of medicine 1986; 16:658-664.  (85)  Morris JL, Zaman AG, Smyllie JH, Cowan JC. Nitrates in myocardial infarction: influence on infarct size, reperfusion, and ventricular remodelling. Br Heart J 1995; 73(4):310-319.  (86)  Mueller HS AS. Propranolol decreases sympathetic nervous activity reflected by plasma catecholamines during evolution of myocardial infarction in man. J Clin Invest 1980; 65(2):338-346.  (87)  Oldroyd KG, Pye MP, Ray SG, Christie J, Ford I, Cobbe SM et al. Effects of early captopril administration on infarct expansion, left ventricular remodeling and exercise capacity after acute myocardial infarction.[see comment]. American Journal of Cardiology 1991; 68(8):713-718.  (88)  Oshima S, Ogawa H, Mizuno Y, Yamashita S, Noda K, Saito T et al. The effects of the angiotensin-converting enzyme inhibitor imidapril on plasma  149 plasminogen activator inhibitor activity in patients with acute myocardial infarction. American heart journal 1997; 134:961-966.  (89)  Osuna P, Garcia-Moreno LM, Arribas JA, Sala-S nchez C, MartA-n LC, nchez S et al. Isosorbide dinitrate sublingual therapy for inferior myocardial infarction: randomized trial to assess infarct size limitation. The American journal of cardiology 1985; 55:330-334.  (90)  Ramsdale DR, Llewellyn MJ, Pidgeon J, Faragher EB, Charles RG. Effects of intravenous sotalol on the Q-T interval and incidence of ventricular arrhythmias early in acute myocardial infarction. American Journal of Noninvasive Cardiology 1988; 2(1-2):52-58.  (91)  Reinert M, Wiest R, Barth L, Andres R, Ozdoba C, Seiler R. Transdermal nitroglycerin in patients with subarachnoid hemorrhage. Neurological research 2004; 26:435-439.  (92)  Renard M, Sterling I, Van CG, Coupez R, Bernard R. [Comparison of the effects of intravenous diltiazem and a placebo on hemodynamics and blood gases in the acute phase of myocardial infarction]. Annales de cardiologie et d'ang,iologie 1987; 36:509-512.  (93)  Reynolds JL, Whitlock RM. Effects of a beta-adrenergic receptor blocker in myocardial infarction treated for one year from onset. Br Heart J 1972; 34(3):252-259.  (94)  Schrader J, Lders S, Kulschewski A, Berger J, Zidek W, Treib J et al. The ACCESS Study: Evaluation of Acute Candesartan Cilexetil Therapy in Stroke Survivors. Stroke 2003; 34:1699-1703.  (95)  Sloman G, Stannard M. Beta-adrenergic blockade and cardiac arrhythmias. Br Med J 1967; 4(578):508-512.  (96)  Ambrosioni E, Borghi C, Magnani B. The effect of the angiotensin-converting- enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. The Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Study Investigators. The New England journal of medicine 1995; 332:80-85.  (97)  Waagstein F. Double-blind study of the effect of cardioselective beta-blockade on chest pain in acute myocardial infarction. Acta Medica Scandinavica - Supplementum 1976; 587:201-208.  (98)  Wilcox RG, Rowley JM, Hampton JR, Mitchell JR, Roland JM, Banks DC. Randomised placebo-controlled trial comparing oxprenolol with disopyramide phosphate in immediate treatment of suspected myocardial infarction. Lancet 1980; 2(8198):765-769.  150  (99)  Wilcox RG, Roland JM, Banks DC, Hampton JR, Mitchell JR. Randomised trial comparing propranolol with atenolol in immediate treatment of suspected myocardial infarction. Br Med J 1980; 280(6218):885-888.  (100)  Wilcox RG, Hampton JR, Banks DC, Birkhead JS, Brooksby IA, Burns-Cox CJ et al. Trial of early nifedipine in acute myocardial infarction: the Trent study. Br Med J 1986; 293:1204-1208.  (101)  Wimalaratna HS, Capildeo R. Nimodipine in acute ischaemic cerebral hemisphere infarction. Cerebrovascular Diseases 1994; 4:179-181.  (102)  Zochowski RJ, Lada W. Intravenous clonidine treatment in acute myocardial infarction (with comparison to a nitroglycerin-treated and control group). J Cardiovasc Pharmacol 1986; 8:S41-S45.  (103)  ISIS-4. A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58050 patients with suspected acute myocardial infarction. Lancet 1995; 345(8951):669-685.  (104)  Beaufils P, Kolsky H, Haiat R, Castaigne A, Slama R. The influence of molsidomine on infarct size: an acute post-infarction pilot study with 303 patients. Cardiovasc Drugs Ther 1988; 2(1):127-132.  (105)  Branagan JP, Walsh K. Effect of early treatment with nifedipine in suspected acute myocardial infarction. Eur Heart J 1986; 7(10):859-865.  (106)  Bussmann WD, Passek D, Seidel W, Kaltenbach M. Reduction of CK and CK- MB indexes of infarct size by intravenous nitroglycerin. Circulation 1981; 63(3):615-622.  (107)  Bussmann WD, Micke G, Hildenbrand R, Klepzig H, Jr. [Captopril in acute myocardial infarct: its effect on infarct size and arrhythmias]. [German]. Dtsch Med Wochenschr 1992; 117(17):651-657.  (108)  Charvat J, Kuruvilla T, al Amad H. Beneficial effect of intravenous nitroglycerin in patients with non-Q myocardial infarction. Cardiologia 1990; 35(1):49-54.  (109)  Chiche P, Baligadoo S, Derrida JP. A randomized trial of prolonged nitroglycerin infusion in acute myocardial infarction. Circulation (Suppl II) 1979; 165 :59-60.  (110)  Clausen J, Felsby M, Jorgensen FS, Nielsen BL, Roin J, Strange B. Absence of prophylactic effect of propranolol in myocardial infarction. Lancet 1966; 2(7470):920-924.  (111)  Cohn JN, Franciosa JA, Francis GS, Archibald DG. Effect of short-term infusion of sodium nitroprusside on mortality rate in acute myocardial infarction  151 complicated by left ventricular failure: results of a Veterans Administration cooperative study. N Engl J Med 1982; 306:1129-1135.  (112)  Commit, Chen ZM, Pan HC, Chen YP, Peto R, Collins R et al. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial.[see comment]. Lancet 2005; 366(9497):1622-1632.  (113)  CONSENSUS-II, Swedberg K, Held P, Kjekshus J, Rasmussen K, Ryd NL et al. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction. Results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). The New England journal of medicine 1992; 327:678-684.  (114)  Crea F. Effects of verapamil in preventing early postinfarction angina and reinfarction. American Journal of Cardiology 1985; 55(8):900-904.  (115)  Di PP, Paterna S, Cannizzaro S, Bucca V. Does captopril treatment before thrombolysis in acute myocardial infarction attenuate reperfusion damage? Short-term and long-term effects. Int J Cardiol 1994; 43(1):43-50.  (116)  Di PP, Valdes L, Albano V, Bucca V, Scalzo S, Pieri D et al. Early captopril treatment reduces plasma endothelin concentrations in the acute and subacute phases of myocardial infarction: a pilot study. J Cardiovasc Pharmacol 1997; 29:202-208.  (117)  Durrer JD, Lie KI, Capelle FJ. Effect of sodium nitroprusside on mortality in acute myocardial infarction. N Engl J Med 1982; 306:1121-1128.  (118)  Eichler HG, Mabin TA, Commerford PJ, Lloyd EA. Tiapamil, a new calcium antagonist: hemodynamic effects in patients with acute myocardial infarction. Circulation 1985; 71(4):779-786.  (119)  Erbel R, Pop T, Meinertz T, Olshausen KV, Treese N, Henrichs KJ et al. Combination of calcium channel blocker and thrombolytic therapy in acute myocardial infarction. American heart journal 1988; 115:529-538.  (120)  ESPRIM. The ESPRIM trial: short-term treatment of acute myocardial infarction with molsidomine. European Study of Prevention of Infarct with Molsidomine (ESPRIM) Group.[see comment]. Lancet 1994; 344(8915):91-97.  (121)  Fitzgerald LJ, Bennett ED. The effects of oral isosorbide 5-mononitrate on mortality following acute myocardial infarction: a multicentre study. European Heart Journal 1990; 11:120-126.  (122)  Flaherty JT, Becker LC, Bulkley BH, Weiss JL, Gerstenblith G, Kallman CH et al. A randomized prospective trial of intravenous nitroglycerin in patients with acute myocardial infarction. Circulation 1983; 68(3):576-588.  152  (123)  Galcera TJ, de-la-Rosa JA, Torres MG, Rodriguez GP, Castillo-Soria FJ, Canton MA et al. Effects of early use of captopril on haemodynamics and short- term ventricular remodelling in acute anterior myocardial infarction. European Heart Journal 1993; 14:259-266.  (124)  Gelmers HJ, Gorter K, De Weerdt CJ, Wiezer HJ. A controlled trial of nimodipine in acute ischemic stroke. N Engl J Med 1988; 318(4):203-207.  (125)  GISSI-3. Effects of lisiriopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. The Lancet 1994; 343(8906):1115-1122.  (126)  Hargreaves AD, Kolettis T, Jacob AJ, Flint LL, Turnbull LW, Muir AL et al. Early vasodilator treatment in myocardial infarction: Appropiate for the majority or minority? BR HEART J 1992; 68:369-373.  (127)  Heber ME, Rosenthal E, Thomas N, Haskett VL, Burwood RD, Lutkin J et al. Effect of labetalol on indices of myocardial necrosis in patients with suspected acute infarction. Eur Heart J 1987; 8(1):11-18.  (128)  Hildebrandt P, Torp-Pedersen C, Joen T, Iversen E, Jensen G, Jeppesen D et al. Reduced infarct size in nonreperfused myocardial infarction by combined infusion of isosorbide dinitrate and streptokinase. Am Heart J 1992; 124(5):1139-1144.  (129)  ICSG. Reduction of infarct size with the early use of timolol in acute myocardial infarction. N Engl J Med 1984; 310(1):9-15.  (130)  Infeld B, Davis SM, Donnan GA, Yasaka M, Lichtenstein M, Mitchell PJ et al. Nimodipine and perfusion changes after stroke. Stroke 1999; 30:1417-1423.  (131)  INWEST, Wahlgren NG, Macmahon DG. Intravenous nimodipine west European stroke trial (INWEST) of nimodipine in the treatment of acute ischaemic stroke. Cerebrovascular Diseases 1994; 4:204-210.  (132)  ISIS-1. Randomised trial of intravenous atenolol among 16 027 cases of suspected acute myocardial infarction: ISIS-1. First International Study of Infarct Survival Collaborative Group. Lancet 1986; 2(8498):57-66.  (133)  Jaffe AS, Geltman EM, Tiefenbrunn AJ, Ambos HD, Strauss HD, Sobel BE et al. Reduction of infarct size in patients with inferior infarction with intravenous glyceryl trinitrate. A randomised study. Br Heart J 1983; 49(5):452-460.  (134)  Johannessen KA, Nordrehaug JE, von-der LG. Increased occurrence of left ventricular thrombi during early treatment with timolol in patients with acute myocardial infarction. Circulation 1987; 75:151-155.  153  (135)  Jugdutt BI, Sussex BA, Warnica JW, Rossall RE. Persistent reduction in left ventricular asynergy in patients with acute myocardial infarction by intravenous infusion of nitroglycerin. Circulation 1983; 68:1264-1273.  (136)  Jugdutt BI, Warnica JW. Intravenous nitroglycerin therapy to limit myocardial infarct size, expansion, and complications. Effect of timing, dosage, and infarct location.[erratum appears in Circulation 1989 May;79(5):1151]. Circulation 1988; 78(4):906-919.  (137)  Limburg M, Hijdra A. Flunarizine in acute ischemic stroke: A pilot study. Eur Neurol 1990; 30(3):121-122.  (138)  Lis Y, Bennett D, Lambert G, Robson D. A preliminary double-blind study of intravenous nitroglycerin in acute myocardial infarction. INTENSIVE-CARE- MED 1984; 10(4):179-184.  (139)  Marangelli V, Memmola C, Brigiani MS, Boni L, Biasco MG, Scrutinio D et al. Early administration of verapamil after thrombolysis in acute anterior myocardial infarction. Effect on left ventricular remodeling and clinical outcome. VAMI Study Group. Verapamil Acute Myocardial Infarction. Italian heart journal : official journal of the Italian Federation of Cardiology 2000; 1:336-343.  (140)  MIAMI. Metoprolol in acute myocardial infarction (MIAMI). A randomised placebo-controlled international trial. EUR-HEART-J 1985; 6(3):199-226.  (141)  MILIS, Roberts R, Charles C, Herman KG, Tyler DH, Allan S Jaffe et al. Effect of propranolol on myocardial-infarct size in a randomized blinded multicenter trial. N Engl J Med 1984; 311(4):218-225.  (142)  Mitchell RG, Stoddard MF, Ben YO, Aggarwal KB, Allenby KS, Trillo RA et al. Esmolol in acute ischemic syndromes. American heart journal 2002; 144(5):E9.  (143)  Muller JE, Morrison J, Stone PH, Rude RE, Rosner B, Roberts R et al. Nifedipine therapy for patients with threatened and acute myocardial infarction: a randomized, double-blind, placebo-controlled comparison. Circulation 1984; 69:740-747.  (144)  Nabel EG, Topol EJ. A randomized placebo-controlled trial of combined early intravenous captopril and recombinant tissue-type plasminogen activator therapy in acute myocardial infarction. J Am Coll Cardiol 1991; 17(2):467-473.  (145)  Natale E. The effect of verapamil on left ventricular remodelling and diastolic function after acute myocardial infarction (the Verapamil Infarction Study on Remodelling and Relaxation--VISOR). Cardiovasc Drugs Ther 1999; 13(4):315-324.  154  (146)  Norris RM, Clarke ED, Sammel NL, Smith WM. Protective effect of propranolol in threatened myocardial infarction. Lancet 1978; 2(8096):907-909.  (147)  Norris RM, Sammel NL, Clarke ED, Brandt PWT. Treatment of acute myocardial infarction with propranolol. Further studies on enzyme appearance and subsequent left ventricular function in treated and control patients with developing infarcts. BR-HEART-J 1980; 43(6):617-622.  (148)  Norris RM, Barnaby PF, Brown MA, Geary GG, Clarke ED, Logan RL et al. Prevention of ventricular fibrillation during acute myocardial infarction by intravenous propranolol. Lancet 1984; 2(8408):883-886.  (149)  Owensby DA, ORourke M. Failure of intravenous pindolol to reduce the hemodynamic determinants of myocardial oxygen demand or enzymatically determined infarct size in acute myocardial infarction. Australian & New Zealand Journal of Medicine 1985; 15(6):704-711.  (150)  Paci A, Ottaviano P, Trenta A, Iannone G, De SL, Lancia G et al. Nimodipine in acute ischemic stroke: a double-blind controlled study. Acta neurologica Scandinavica 1989; 80:282-286.  (151)  Peter T. Reduction of enzyme levels by propranolol after acute myocardial infarction. Circulation 1978; 57(6):1091-1095.  (152)  Pimenta J, Pereira CB. Nifedipine in acute myocardial infarction: effect on infarct size and clinical course. Rev M,D Iamspe 1985; 16:11-16.  (153)  Pizzetti G, Mailhac A, Li VL, Di MF, Lu C, Margonato A et al. Beneficial effects of diltiazem during myocardial reperfusion: a randomized trial in acute myocardial infarction. Italian Heart Journal 2001; 2:757-765.  (154)  PRACTICAL, Foy SG, Crozier IG, Turner JG, Richards AM, Frampton CM et al. Comparison of enalapril versus captopril on left ventricular function and survival three months after acute myocardial infarction (the "PRACTICAL" study). The American journal of cardiology 1994; 73:1180-1186.  (155)  Salathia KS, Barber JM, McIlmoyle EL, Nicholas J, Evans AE, Elwood JH et al. Very early intervention with metoprolol in suspected acute myocardial infarction. Eur Heart J 1985; 6(3):190-198.  (156)  Schulman SP, Weiss JL, Becker LC, Guerci AD, Shapiro EP, Chandra NC et al. Effect of early enalapril therapy on left ventricular function and structure in acute myocardial infarction. The American journal of cardiology 1995; 76:764- 770.  (157)  Sirnes PA, Overskeid K, Pedersen TR, Bathen J, Drivenes A, Froland GS et al. Evolution of infarct size during the early use of nifedipine in patients with acute  155 myocardial infarction: the Norwegian Nifedipine Multicenter Trial. Circulation 1984; 70:638-644.  (158)  Theroux P. Intravenous diltiazem in acute myocardial infarction. Diltiazem as adjunctive therapy to activase (DATA) trial. J Am Coll Cardiol 1998; 32(3):620-628.  (159)  TIMI II, Roberts R. Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) II-B Study.[see comment]. Circulation 1991; 83(2):422-437.  (160)  Tonkin AM, Joel SE, Reynolds JL, Aylward PE, Heddle WF, McRitchie RJ et al. beta-Blockade in acute myocardial infarction. Inability of relatively late administration to influence infarct size and arrhythmias. Med J Aust 1981; 2(3):145-146.  (161)  Van-de WF, Janssens L, Brzostek T, Mortelmans L, Wackers FJ, Willems GM et al. Short-term effects of early intravenous treatment with a beta-adrenergic blocking agent or a specific bradycardiac agent in patients with acute myocardial infarction receiving thrombolytic therapy. Journal of the American College of Cardiology 1993; 22:407-416.  (162)  VENUS, Horn J, de-Haan RJ, Vermeulen M, Limburg M. Very Early Nimodipine Use in Stroke (VENUS): a randomized, double-blind, placebo- controlled trial. Stroke 2001; 32:461-465.  (163)  von Essen R. [Effect of metoprolol on infarct size after acute myocardial infarction (a double-blind study) (author's transl)]. [German]. Dtsch Med Wochenschr 1982; 107(34):1267-1273.  (164)  Wagner A, Herkner H, Schreiber W, Bur A, Woisetschl g, Stix G et al. Ramipril prior to thrombolysis attenuates the early increase of PAI-1 in patients with acute myocardial infarction. Thrombosis and haemostasis 2002; 88:180-185.  (165)  Yusuf S, Sleight P. Reduction in infarct size, arrhythmias and chest pain by early intravenous beta blockade in suspected acute myocardial infarction. Circulation 1983; 67(6 Pt2):I32-I41.  (166)  Zannad F, Amor M, Karcher G, Maurin P, Ethevenot G, Sebag C et al. Effect of diltiazem on myocardial infarct size estimated by enzyme release, serial thallium-201 single-photon emission computed tomography and radionuclide angiography. The American journal of cardiology 1988; 61:1172-1177.  (167)  Zharov EI, Vertkin AL, Martynov AI, Salnikov SN. Comparative evaluation of intravenous isosorbide dinitrate and nitroglycerin in patients with acute myocardial infarction. Cardiology 1991; 79 Suppl 2:63-69.  156  (168)  Lam JY, Chesebro JH, Fuster V. Platelets, vasoconstriction, and nitroglycerin during arterial wall injury. A new antithrombotic role for an old drug. Circulation 1988; 78(3):712-716.  (169)  De CR, Lombardi M, Bernini W, Mazzone A, Giannessi D, Moscarelli E et al. Inhibition of platelet function during in vivo infusion of isosorbide mononitrates: relationship between plasma drug concentration and hemodynamic effects. Am Heart J 1990; 119(4):855-862.  (170)  Butterworth RJ, Cluckie A, Jackson SH, Buxton-Thomas M, Bath PM. Pathophysiological assessment of nitric oxide (given as sodium nitroprusside) in acute ischaemic stroke. Cerebrovascular Diseases 1998; 8(3):158-165.  (171)  Karlsberg RP, Cryer PE, Roberts R. Serial plasma catecholamine response early in the course of clinical acute myocardial infarction: relationship to infarct extent and mortality. Am Heart J 1981; 102(1):24-29.  (172)  Borer JS, Kent KM, Goldstein RE, Epstein SE. Nitroglycerin-induced reduction in the incidence of spontaneous ventricular fibrillation during coronary occlusion in dogs. American Journal of Cardiology 1974; 33(4):517-520.  (173)  Cano JP, Guillen JC, Jouve R, Langlet F, Puddu PE, Rolland PH et al. Molsidomine prevents post-ischaemic ventricular fibrillation in dogs. Br J Pharmacol 1986; 88(4):779-789.  (174)  Katsuki S, Arnold W, Mittal C, Murad F. Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerin and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxylamine. J Cyclic Nucleotide Res 1977; 3(1):23-35.  (175)  Kukovetz WR, Holzmann S, Wurm A, Poch G. Evidence for cyclic GMP- mediated relaxant effects of nitro-compounds in coronary smooth muscle. Naunyn Schmiedebergs Arch Pharmacol 1979; 310(2):129-138.  (176)  Exner DV, Goodhart DM, Anderson TJ, Duff HJ. Prolonged sinus node recovery time in humans after the intracoronary administration of a nitric oxide synthase inhibitor. J Cardiovasc Pharmacol 1999; 34(1):1-6.  (177)  Martynyuk AE, Kane KA, Cobbe SM, Rankin AC. Nitric oxide mediates the anti-adrenergic effect of adenosine on calcium current in isolated rabbit atrioventricular nodal cells. Pflugers Arch 1996; 431(3):452-457.  (178)  Musialek P, Lei M, Brown HF, Paterson DJ, Casadei B. Nitric oxide can increase heart rate by stimulating the hyperpolarization-activated inward current, I(f). Circ Res 1997; 81(1):60-68.  (179)  Brahmajothi MV, Campbell DL. Heterogeneous expression of NO-activated soluble guanylyl cyclase in mammalian heart: implications for NO- and redox-  157 mediated indirect versus direct regulation of cardiac ion channel function. Channels (Austin) 2007; 1(5):353-365.  (180)  Hassall CJ, Saffrey MJ, Belai A, Hoyle CH, Moules EW, Moss J et al. Nitric oxide synthase immunoreactivity and NADPH-diaphorase activity in a subpopulation of intrinsic neurones of the guinea-pig heart. Neurosci Lett 1992; 143(1-2):65-68.  (181)  Tanaka K, Chiba T. The vagal origin of preganglionic fibers containing nitric oxide synthase in the guinea-pig heart. Neurosci Lett 1998; 252(2):135-138.  (182)  Takimoto Y, Aoyama T, Tanaka K, Keyamura R, Yui Y, Sasayama S. Augmented expression of neuronal nitric oxide synthase in the atria parasympathetically decreases heart rate during acute myocardial infarction in rats. Circulation 2002; 105(4):490-496.  (183)  Brack KE, Patel VH, Coote JH, Ng GA. Nitric oxide mediates the vagal protective effect on ventricular fibrillation via effects on action potential duration restitution in the rabbit heart. J Physiol (Lond) 2007; 583(Pt 2):695- 704.  (184)  Chowdhary S, Marsh AM, Coote JH, Townend JN. Nitric oxide and cardiac muscarinic control in humans. Hypertension 2004; 43(5):1023-1028.  (185)  Fei L, Baron AD, Henry DP, Zipes DP. Intrapericardial delivery of L-arginine reduces the increased severity of ventricular arrhythmias during sympathetic stimulation in dogs with acute coronary occlusion: nitric oxide modulates sympathetic effects on ventricular electrophysiological properties. Circulation 1997; 96(11):4044-4049.  (186)  Pabla R, Curtis MJ. Endogenous protection against reperfusion-induced ventricular fibrillation: role of neuronal versus non-neuronal sources of nitric oxide and species dependence in the rat versus rabbit isolated heart. J Mol Cell Cardiol 1996; 28(10):2097-2110.  (187)  Bath FJ, Butterworth RJ, Bath PM. Nitric oxide donors (nitrates), L-arginine, or nitric oxide synthase inhibitors for acute ischaemic stroke. Cochrane Database Syst Rev 2002; CD000398(2):000398.  (188)  Anderson CS, Huang Y, Wang JG, Arima H, Neal B, Peng B et al. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet neurol 2008; 7(5):391-399.  158  4 FAILURE OF PSYCHOLOGICAL INTERVENTIONS TO LOWER BLOOD PRESSURE: RANDOMIZED CONTROLLED TRIAL3 4.1 Introduction Patients with mild primary hypertension have a number of options to help lower their blood pressure. Non-pharmacological options include the DASH (Dietary Approaches to Stop Hypertension) diet1, a low-sodium diet2, exercise3, weight loss4, and relaxation therapies5. Relaxation therapies are based on the supposition that psychological stress may contribute to the elevation of blood pressure in some patients6;7. Others have suggested possible links between stress and hypertension are elevated sympathetic tone or vagal dysregulation6;8. Several systematic reviews have evaluated the efficacy of diverse psychological and relaxation therapies in reducing blood pressure in patients with primary hypertension as compared to no therapy or sham therapy5;9-13. However, these studies have yielded conflicting results. It remains important to determine whether psychological interventions lower blood pressure and the magnitude of the effect, if any, as many patients might prefer this form of therapy over drug therapy if both were equally efficacious. We were therefore interested in evaluating the efficacy of two psychological interventions in lowering blood  3 A version of this chapter has been published. Marco I Perez, Wolfgang Linden, Thomas Perry Jr., Lorri J Puil, James M Wright. Failure of psychological interventions to lower blood pressure: a randomized controlled trial. Open Medicine 2009;3[2]:62-70.  159 pressure: an individualized program of behavioural therapy and a self-help program of psychological therapy. With the objective of rigorously assessing the effects of these two psychological interventions, we compared them with pharmacotherapy using a thiazide, a first-line drug commonly used in the treatment of mild primary hypertension. A large body of evidence from randomized controlled trials (RCTs) shows that thiazides reduce blood pressure and quantifies the magnitude of their short-term effect on systolic and diastolic blood pressure as about 9/4 mm Hg14. There is considerable value in using a drug with a known effect as a positive control for a study such as this one. As far as we know, no previous RCTs have directly compared psychological interventions with a drug therapy control. 4.2 Methods 4.2.1 Design Prospective, open-label randomized controlled trial. 4.2.2 Setting and participants Adult patients (aged 18 years or older) from the community, with mild hypertension defined as resting systolic blood pressure of 140 mm Hg or above and/or diastolic blood pressure of 90 mm Hg or above, were eligible. Patients were excluded if they had cardiovascular complications or any suspected medical condition that might lead to an unacceptable risk of complications resulting from uncontrolled hypertension during the study period. Patients whose hypertension was uncontrolled while they were taking medication (systolic blood pressure ≥ 170 mm Hg or diastolic blood pressure ≥ 100 mm Hg) or who had excessively high blood pressure while they were not taking any  160 medication (≥ 180/110 mm Hg) were also excluded. Patients with suspected secondary hypertension were excluded, as were those who were pregnant or anticipated being pregnant and those with a history of allergy to, hypersensitivity to, or intolerance of thiazides. Participants were encouraged not to adopt any other changes in lifestyle, diet or exercise during the trial. 4.2.3 Protocol Patients who were taking medication at the time of initial screening underwent a washout period of 3–5 weeks. Patients who met the inclusion criteria and whose off-treatment baseline resting systolic blood pressure in clinic was 140 mm Hg or above or whose resting diastolic blood pressure was 90 mm Hg or above were randomly assigned to receive 1 of the following interventions for 12 weeks: hydrochlorothiazide 12.5 mg/d initially and then 25 mg/d if systolic blood pressure was 140 mm Hg or above or diastolic blood pressure was 90 mm Hg or above after 4 weeks of treatment; individualized behavioural psychotherapy consisting of ten 1-hour sessions with a psychologist; self- help psychological therapy, consisting of an initial 1.5-hour meeting with a psychologist and then daily sessions that involved reading a self-help manual and listening to an audiotape. Both of the psychological treatments entailed learning relaxation, biofeedback and stress management. Details of these psychological forms of management can be seen in a section below (section 4.7). Concealment of allocation was achieved by centralized randomization conducted via telephone by the Cochrane Hypertension Review Group coordinator at the University of British Columbia. This person was blinded to patients’ identification and to characteristics other than gender and previous use of antihypertensive drugs. Information about these two characteristics was needed to allow  161 block randomization. The study protocol was reviewed and approved by the institutional ethical review board at the University of British Columbia (UBC). Written informed consent was obtained from all patients. 4.2.4 Recruitment, clinical evaluation and follow-up Participants were recruited by means of newspaper advertising and/or referral by health care practitioners or friends. This recruitment was coordinated by UBC's Behavioural Cardiology Laboratory (BCL). Patients who had not previously been receiving antihypertensive drugs but who exhibited elevated blood pressure at the BCL were sent to the hypertension medical clinic for confirmation of eligibility. Patients who were already taking antihypertensive drugs were seen at the laboratory and were then sent to the clinic, where blood pressure was measured before and after washout, with the possibility of a third post-washout check in the event of borderline blood pressure readings. All of these potential participants provided a medical history and underwent a physical examination. A specific laboratory assessment was ordered if considered necessary. After enrolment, the patients attended the clinic every four weeks. At each visit, resting blood pressure was measured. All resting blood pressure measurements were reported as the average of five readings, separated by one-minute intervals, with the first reading after five minutes of rest. The patient was in a seated position and the examiner was out of the room during the readings, which were obtained with an automatic device that concealed the measurements from the patient (oscillometric VSM-100 automated blood pressure machine-VSM MedTech Ltd., Vancouver, BC, Canada15). This rigorous methodology was intended to prevent any bias in the blood pressure measurements. True blinding of the patients and investigators was not feasible in view of the type of interventions in this study. At week  162 seven, serum levels of potassium were checked for all of the patients who had been randomly assigned to receive hydrochlorothiazide, to detect hypokalemia, if present, and to allow the prescription of a potassium-sparing diuretic if required. Patients were instructed to report to the clinic immediately if they experienced any unusual symptoms during the study. Before treatment of any kind, each patient underwent 24-hour monitoring of ambulatory blood pressure, by means of the Spacelabs Medical ambulatory blood pressure monitor (model 90207, Spacelabs Inc, Redmond, Washington, USA). For this monitoring, blood pressure was recorded at 20-minute intervals between 8:00 a.m. and 8:00 p.m. (for daytime measurements) and at 1-hour intervals between 8:00 p.m. and 8:00 a.m. (for nighttime measurements). The monitoring was repeated 12 weeks later (at the end of the study). 4.2.5 Outcome measures The primary outcome measure was the mean change in ambulatory blood pressure from baseline to week 12. The secondary outcome measure was the mean change in resting clinic blood pressure, over 12 weeks of treatment. All adverse events, regardless of their nature, were documented, reviewed and reported to the ethics committee. 4.2.6 Statistical analysis The calculation of the sample size was based on a previous study16 in which there was a 7 mm Hg (standard deviation 11 mm Hg) difference in systolic pressure between individualized behavioural psychotherapy and no treatment. We calculated that a sample size of 40 patients per treatment arm would provide 80% power at α = 0.05 level for detection of the above-mentioned difference in blood pressure. However, because of the  163 potential for dropouts, the desired sample size was increased to 50 patients per treatment arm. The efficacy end-points were analyzed according to the intention-to-treat principle. All statistical analyses were performed using the statistical package NCSS 2007 (LLC, Kaysville, Utah, USA). Paired Student’s t-test was used to compare variables with continuous data before and after treatment within each group. Treatment groups were compared by analysis of variance using the general linear model approach for repeated measurements and Tukey’s test for multiple comparisons. Using baseline values as covariates analysis of covariance (ANCOVA) was also performed. A p-value less than 0.05 was considered statistically significant. 4.3 Results 4.3.1 Study population Recruitment for this single-centre study began in March 2002 and ended in May 2006. Unfortunately, because of recruitment difficulties, the desired sample size of 50 per group was not achieved. Of the 516 patients with suspected hypertension who were screened, 337 were not eligible because they did not meet the study’s inclusion criteria at the initial screening (Figure 4-1). The reasons for not qualifying varied: past medical history, desire to choose a particular treatment, required commitment of time too great, inability to come to our centre (e.g., living far away), lack of interest in stress management or in the drug. The remaining 179 patients were sent to the medical hypertension clinic for evaluation. Of these, 13 patients decided not to participate after undergoing the evaluation. An additional 101 patients were ineligible for the following reasons: 65 patients did not meet the minimum blood pressure inclusion criteria after the washout process, 8 patients had  164 excessively high blood pressure (≥180/110 mm Hg), and 28 had a medical history (such as coronary artery disease) that precluded their participation. Figure 4-1 Flow Diagram for Patients in the Study.  A total of 65 patients (with baseline characteristics as listed in Table 4-1) were randomly assigned to 1 of the 3 groups: 21 to receive hydrochlorothiazide, 23 to undergo individualized behavioural psychotherapy, and 21 to perform self-help psychotherapy. Two patients in each group acknowledged that they had sought psychological or psychiatric help in the past. One of these patients (assigned to the hydrochlorothiazide Screened: n = 516 Randomized: n=65 Ineligible by screening: n =337 Refused to participate: n = 13 Ineligible by investigator: n = 101   Minimum BP not met: n = 65   Very high BP: n=8   Medical Hx: n=28  HCTZ: n = 21  IBT: n = 23 SHT: n = 21 Unavailable for primary outcome analysis: Withdrew due to adverse event: n = 2 Withdrew for personal reasons: n = 3 missing BP data: n = 1 Unavailable for primary outcome analysis: Withdrew due to adverse event: n = 0 Withdrew for personal reasons: n = 6 Unavailable for primary outcome analysis: Withdrew due to adverse event:  n = 3 Withdrew for personal reasons:  n = 5 Protocol violation: n = 1 Available for primary outcome analysis: n = 15  Available for primary outcome analysis: n = 17  Available for primary outcome analysis: n = 12   165 group) had received self-help psychological therapy (in the form of a booklet). There was no statistically significant difference in the number of patients who had previously received hydrochlorothiazide or any other antihypertensive drug. Except for systolic blood pressure as recorded during 24-hour ambulatory monitoring, which was higher for those in the self-help psychotherapy group, the groups were similar with respect to all variables. Six patients in the hydrochlorothiazide group, 6 in the individualized behavioural psychotherapy group, and 9 in the self-help psychotherapy group withdrew from the study or did not undergo the second 24-hour monitoring of ambulatory blood pressure (at 12 weeks). Table 4-1 Patients Characteristics at Baseline Characteristics HCTZ  n = 21 IBP n = 23 SHT n = 21 Age, yr, mean (SE) 58 (1.8) 54 (1.9) 60 (1.9) Female, n (%) 11 (52) 12 (52) 11 (52) Taking antihypertensives at screening^, n (%) 15 (71) 12 (52)  13 (62) CCB 4 1 3 BB 1 2 0 ACE-I 7 5 7 ARBs 0 4 1 Thiazides 11 7 9 Duration of hypertension, yr (SE) 7.6 (1.3) 5.5 (0.8)  8.2 (1.9) Resting baseline BP, mm Hg, mean (SE) Systolic  154 (2.4) 147 (2.2) 154 (2.9) Diastolic  89 (1.6) 89 (2.0) 89 (2.1) 24-h ABPM, mm Hg, mean (SE) Systolic  146 (2.8) 143 (2.3) 153* (2.1) Diastolic 88 (2.0) 89 (2.0) 92 (2.1) ^ Some patients were taking more than one antihypertensive ABPM= ambulatory blood pressure monitoring, ACE-I=angiotensin converting enzyme inhibitors, ARBs= angiotensin II receptor blockers, BB=beta-adrenergic receptor blockers, CCB= calcium channel blockers, HCTZ = hydrochlorothiazide therapy, IBT = individualized behavioural therapy, SHT = self-help psychotherapy, BP = blood pressure, SE = standard error * p < 0.05 for SHT v. IBT. Continuous data (age, duration of hypertension, 24-h ABPM, resting blood pressure) are expressed as mean (SE); all other data are expressed as number (%).   166 4.3.2 Primary outcome: change in ambulatory blood pressure (24-h monitoring) Hydrochlorothiazide produced a statistically significant reduction in both systolic and diastolic blood pressure during 24-hour monitoring of ambulatory blood pressure, and this change was greater than the changes observed with either individualized behavioural or self-help psychological therapy (systolic mean reduction ± standard error: −11.03 ± 2.53 v. −0.08 ± 2.38 v. −1.23 ± 2.83 mm Hg, respectively, p = 0.006; diastolic: −6.06 ± 1.56 v. 0.29 ± 1.47 v. −0.71 ± 1.75 mm Hg, respectively, p = 0.01. Neither form of psychological therapy reduced ambulatory blood pressure, as measured by 24-hour monitoring, relative to baseline (Table 4-2). Table 4-2 Twenty-four-hour ambulatory blood pressure measurements at baseline and change from baseline at week 12. HCTZ IBT SHT 24-hour ambulatory blood pressure measurements Baseline (n = 21) Change from baseline (n = 15) Baseline (n = 23) Change from baseline (n = 17) Baseline (n = 21) Change from baseline (n = 12) Systolic, mm Hg, mean (SE) 146.66 (2.79) −11.03* (2.53) 143.08 (2.28) 0.08 (2.38) 153.42 (2.12) −1.23 (2.83) Diastolic, mm Hg, mean (SE) 88.48 (2.05) −6.06* (1.56) 89.18 (2.06) 0.29 (1.47) 91.92 (2.16) −0.71 (1.75) HCTZ = hydrochlorothiazide therapy, IBT = individualized behavioural therapy, SHT = self-help psychotherapy, SBP = systolic blood pressure,  DBP = diastolic blood pressure, SE = standard error. * p ≤ 0.01 v. baseline v. either psychological therapy  4.3.3 Secondary outcome: change in resting clinic blood pressure For this outcome, we included data from all patients with at least one blood pressure measurement after treatment and used the weighted average from all post-treatment blood pressure measurements for the analysis. As such, data were available for more participants: 19 in the hydrochlorothiazide group, 18 in the individualized behavioural therapy group, and 16 in the self-help therapy group. In this analysis, both  167 hydrochlorothiazide therapy and individualized behavioural psychotherapy were associated with a statistically significant reduction (relative to baseline) in systolic and diastolic blood pressure. The extent of reduction in blood pressure was numerically greater in the group receiving hydrochlorothiazide than in the other 2 groups, but the mean change in resting clinic systolic or diastolic blood pressure over 12 weeks showed no statistically significant difference among the 3 groups (Table 4-3). Table 4-3 Resting Clinic Blood pressure Measurements at baseline and change from baseline over 12 weeks HCTZ IBT SHT Resting blood pressure measurements Baseline n = 21 Change from baseline n = 19 Baseline n = 23 Change from baseline n = 18 Baseline n = 21 Change from baseline n = 16 Systolic, mm Hg, mean (SE) 154.42 (2.39) −15.13*(2.64) 147.22 (2.21) −10.79* (2.91) 154.38 (2.86) −8.54 (4.71) Diastolic, mm Hg, mean (SE) 89.23 (1.61) −6.00*(1.18) 89.43 (1.99) −5.02* (1.50) 88.62 (2.09) −0.23 (2.06) BP = blood pressure, HCTZ = hydrochlorothiazide therapy, IBT = individualized behavioural therapy, SHT = self-help psychotherapy, SBP = systolic blood pressure, DBP = diastolic blood pressure, SE = standard error * p < 0.01 v. baseline  4.3.4 Adverse events A total of five patients withdrew because of adverse events. Three participants experienced intractable headache (one patient in the hydrochlorothiazide group and two in the self-help therapy group). In all three cases, the headache subsided after withdrawal from the study. One patient who was receiving hydrochlorothiazide withdrew because of a suspected allergic reaction to the study medication (the patient stopped taking the drug at day 21 because of soreness in the tongue and lips). One patient in the self-help therapy group withdrew because of palpitations. In addition to these five withdrawals, one patient who was receiving 25mg of hydrochlorothiazide experienced hypokalemia, which was  168 corrected by the addition of spironolactone. There were no serious adverse events during the trial. 4.4 Discussion It has been hypothesized that psychological stress may contribute to the elevation of blood pressure in patients with primary hypertension, and that psychological therapy may lower blood pressure. However, these hypotheses have been called into question by the results of a recent Cochrane systematic review, in particular the results obtained when the analysis was limited to studies that used blinded outcome assessment5. In that review of relaxation therapies, 25 RCTs (n = 1198 patients) were evaluated. The authors concluded that the effect of these therapies in lowering blood pressure was questionable because of the poor quality of the studies. In fact, when only trials using blinded outcome assessment were included (9 RCTs, n = 498 patients), there was no significant reduction in either systolic or diastolic blood pressure. The current study is the first RCT to directly compare psychological therapy with a standard pharmacological antihypertensive treatment. The use of hydrochlorothiazide as a control worked well in this study. The drug lowered ambulatory blood pressure, as measured by 24-hour monitoring, by about 11/6 mm Hg, which is similar to the reduction reported in a meta-analysis of other studies of standard-dose thiazide given for a similar duration of therapy, 9/4 mm Hg14. This result shows that the patients in this trial were representative of patients in other trials studying mild to moderate hypertension. This study has shown that in a clinical setting where thiazide therapy lowered blood pressure by a magnitude similar to that expected, two psychological therapies did not have this effect. This difference in outcome was particularly evident from the blood  169 pressure data obtained with 24-hour monitoring. In particular, the individualized behavioural therapy and self-help psychotherapy had no effect on 24-hour ambulatory systolic or diastolic blood pressure. Hydrochlorothiazide also significantly lowered resting clinic blood pressure relative to baseline. In addition, individualized behavioural psychotherapy but not self-help psychotherapy produced a statistically significant change in resting clinic blood pressure from baseline. For this outcome, however, there was no statistically significant difference among the groups. This lack of difference may have been due in part to the “placebo effect” commonly observed in studies that used in-clinic measurements of blood pressure. The causes of this phenomenon are unknown, but participating in a study may offer the patient some reassurance (e.g., by having the doctor’s full attention, by meeting a psychological need), which could be enough to reduce anxiety and stress or to provoke changes in attitudes, which in turn might improve blood pressure readings in the clinic setting. It is also possible that the individualized behavioural psychotherapy helped patients to learn to relax in the clinic setting, which would have offset the “white-coat effect.” If so, this would be unlikely to have any clinical value, as there was no reduction in ambulatory blood pressure as measured by 24-hour monitoring. This study was a good demonstration of the value of such 24-hour monitoring. A previous study provided evidence for the lack of a placebo effect in patients with mild to moderate hypertension when blood pressure was measured by 24-hour monitoring17. The combination of a lack of the placebo effect and the large number of blood pressure measurements obtained increases the power of 24-hour monitoring to identify a treatment effect, as occurred in this trial.  170 One of the strengths of this study was the proper randomization as well as the foolproof method of concealing treatment allocation from the patients and the investigators. Two additional strengths were the use of an automated device for recording both ambulatory and clinic blood pressure, and the absence of the investigators at the time of measurement. The objective of this was to reduce subjective bias when measuring blood pressure. A further strength of this study was that all of the available results were used in the analysis, which prevented any reporting bias. One limitation of this study was the small sample size, which was caused by difficulties in recruiting patients with newly diagnosed hypertension and by excluding a large number of previously treated patients who did not meet the blood pressure criteria after the washout period (65 [58%] of the 112 patients who underwent washout). A second, related limitation was the high rate of patients unavailable for the primary outcome analysis (6/21 [29%] from the hydrochlorothiazide group, 6/23 [26%] from the individualized behavioural psychotherapy group and 9/21 [43%] from the self-help therapy group). Because we did not achieve the desired sample size and because many patients withdrew after randomization, the study’s power was lower than planned, and the probability of incorrectly accepting the null hypothesis when it is not true (i.e., type II or beta error) was increased. Our inability to find differences when we compared the three groups of clinic blood pressure measurements is an example of this type II error. This loss of power, however, did not prevent detection of a difference between hydrochlorothiazide and either psychological intervention by 24-hour ambulatory measurements. A third limitation was the chance finding that baseline blood pressure in the self-help psychotherapy group was higher than that in the individualized behavioural  171 psychotherapy group. This might have reduced the opportunity for the individualized behavioural psychotherapy intervention to lower blood pressure in that group. However, when we performed the post-hoc ANCOVA analysis using baseline values as a covariate, the p-values changed minimally for both ambulatory and resting clinic blood pressure outcomes; we therefore believe that the initial difference in blood pressure between these two groups probably had little effect. Nonetheless, caution is warranted in interpreting these results, as the trial had limited power to prove a lack of effect of the psychological interventions on the 24-hour blood pressure measurements. When we planned our study, no information was available on the effect of psychological therapy in lowering blood pressure relative to a pharmacological treatment. We chose hydrochlorothiazide because, in addition to the well-known ability of this drug to lower blood pressure, the thiazides in general have the most evidence for reductions in mortality and morbidity when used as first-line drugs18. The key finding of this study is that compared with hydrochlorothiazide, psychological therapies appeared to have no clinically important effect in lowering blood pressure over a 12-week period, as assessed by 24-hour ambulatory monitoring. These results apply to patients with mild uncomplicated hypertension (systolic ≥ 140 and/or diastolic ≥ 90 mm Hg). This new information needs to be put into context with other available RCT data. The best available evidence of the effect of relaxation therapies on blood pressure was provided by a recent Cochrane systematic review. In that review, Dickinson and colleagues5 found that when only RCTs with blinded blood pressure measurement were included, the psychological or relaxation techniques had no statistically significant effect in reducing blood pressure. This led the authors to conclude, “In view of the poor quality  172 of included trials and unexplained variation between trials, the evidence in favor of causal association between relaxation therapy and blood pressure reduction is weak. Some of the apparent benefit of relaxation was probably due to aspects of treatment unrelated to relaxation”5. The results of the RCT presented here are in agreement with that conclusion. If future trials of psychological interventions and other relaxation therapies are conducted, they must have rigorous designs to minimize bias. 4.5 Funding source The Canadian Institutes of Health Research (CIHR) was the funding source. The authors’ work was independent of CIHR. The funding source had no financial or other interest in the study outcome and had no role in the design of the study or the collection, analysis, interpretation or reporting of the data. 4.6 Trial registration Clinical trials.gov identifier: NCT00247910. 4.7 Additional information: Details of psychological interventions. 4.7.1 Individualized behavioural therapy The individualized behavioural therapy intervention was first developed for and used by patients with cardiac disease (in unpublished clinical work) and was then used in a randomized controlled trial involving hypertensive patients16. The intervention consisted of 10 1-hour psychological therapy sessions over a 10-week period. To guarantee a high level of quality and maximal treatment benefit, the intervention was delivered by experienced PhD-level psychotherapists with specific training in cognitive behavioural interventions. In this study, 2 therapists provided these sessions, each treating a similar  173 number of patients (13 and 10, respectively). The first session consisted of an assessment of risk factors (work stress, home stress, time urgency, hostility, absence of pleasurable activities, coping styles, depression and anxiety). On the basis of this assessment, the therapist and client together set the targets for the psychological intervention. To apply the psychological interventions, each therapist used a set of manual-based techniques (stress management, cognitive behavioural therapy, autogenic training, anxiety management training)19-22. The most frequent psychological therapies offered were anxiety reduction, treatment of depression, management of anger and hostility, and relaxation training. When more than one psychological treatment area was identified, the therapist might have used a combination of these techniques. The results of pretreatment 24-hour monitoring of blood pressure were available to the psychotherapists to allow them to tailor the techniques to individual clients. More details about this approach are described elsewhere23. 4.7.2 Self-help therapy The self-help therapy involved an initial 1.5-hour session with a Master’s-level psychotherapist. The patient was then instructed to follow a self-help manual over a 10- week period to be used on a daily basis. The manual consisted of material derived from Linden’s review of the scientific basis for stress management24, which was being prepared for publication at the time of the study. Topics covered in the self-help manual included: recognition of stressors; behavioural coping skills; cognitive restructuring; building a healthy, balanced lifestyle; strengthening social support; and adding enjoyable activities to one’s life. In the first session, the therapist instructed each participant on how to use the self-help manual and to record their relaxation practices. Patients were also  174 given an audiotape to assist with training and practice in breathing and relaxation techniques. Each patient was contacted by his or her therapist at the midpoint of the self-help intervention (five weeks) to discuss any problems that might have arisen. Each patient met with his or her therapist for one hour at the end of the treatment period to review progress and to determine whether the patient wanted to receive individualized psychological therapy in the future. 4.7.3 Assessment tools for all treatment arms: The following psychological scales were used:  the Cook–Medley Hostility Inventory25, the State–Trait Anxiety Inventory26, the Behavioral Anger Response Questionnaire27, the Perceived Stress Scale28, the Beck Depression Inventory29 and the Balanced Inventory of Desirable Responding30.  175  4.8 References   (1)  Svetkey LP, Simons-Morton D, Vollmer WM, Appel LJ, Conlin PR, Ryan DH et al. Effects of dietary patterns on blood pressure: subgroup analysis of the Dietary Approaches to Stop Hypertension (DASH) randomized clinical trial. Archives of Internal Medicine 1999; 159(3):285-293.  (2)  He FJ, MacGregor GA. Effect of longer-term modest salt reduction on blood pressure [Systematic Review]. Cochrane Database of Systematic Reviews 2004;(4).  (3)  Fagard RH, Cornelissen VA. Effect of exercise on blood pressure control in hypertensive patients. European Journal of Cardiovascular Prevention and Rehabilitation 2007; 14(1):12-17.  (4)  Staessen J, Fagard R, Amery A. The relationship between body weight and blood pressure. [Review] [110 refs]. Journal of Human Hypertension 1988; 2(4):207- 217.  (5)  Dickinson HO, Campbell F, Beyer FR, Donald JN, Julia VC, Gary AF et al. Relaxation therapies for the management of primary hypertension in adults. Cochrane Database of Systematic Reviews 2008; Art No.CD004935.DOI:10.100214651858(1).  (6)  Gerin W, Pickering TG, Glynn L, Christenfeld N, Schwartz A, Carroll D et al. An historical context for behavioral models of hypertension. Journal of Psychosomatic Research 2000; 48(4-5):369-377.  (7)  Linden W. Psychologic treatment for hypertension can be efficacious. Preventive Cardiology 2003; 6(1):48-53.  (8)  Grossman P, Watkins LL, Wilhelm FH, Manolakis D, Lown B. Cardiac vagal control and dynamic responses to psychological stress among patients with coronary artery disease. American Journal of Cardiology 1996; 78(12):1424- 1427.  (9)  Stetter F, Kupper S. Autogenic training: A meta-analysis of clinical outcome studies. Applied Psychophysiology Biofeedback 2002; 27(1):45-98.  (10)  Nakao M, Yano E, Nomura S, Kuboki T. Blood pressure-lowering effects of biofeedback treatment in hypertension: A meta-analysis of randomized controlled trials. Hypertension Research 2003; 26(1):37-46.  176  (11)  Linden W, Chambers L. Clinical effectiveness of non-drug treatment for hypertension: A meta- analysis. Annals of Behavioral Medicine 1994; 16(1):35- 45.  (12)  Eisenberg DM, Delbanco TL, Berkey CS, Kaptchuk TJ, Kupelnick B, Kuhl J et al. Cognitive behavioral techniques for hypertension: are they effective? Annals of Internal Medicine 1993; 118(12):964-972.  (13)  Ebrahim S, Davey SG. Lowering blood pressure: A systematic review of sustained effects of non-pharmacological interventions. Journal of Public Health Medicine 1998; 20(4):441-448.  (14)  Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ 2003; 326(7404):1427.  (15)  Mattu GS, Perry TL, Jr., Wright JM. Comparison of the oscillometric blood pressure monitor (BPM-100(Beta) ) with the auscultatory mercury sphygmomanometer. Blood Pressure Monitoring 2001; 6(3):153-159.  (16)  Linden W, Lenz JW, Con AH. Individualized stress management for primary hypertension: a randomized trial. Archives of Internal Medicine 2001; 161(8):1071-1080.  (17)  Mancia G, Omboni S, Parati G, Ravogli A, Villani A, Zanchetti A. Lack of placebo effect on ambulatory blood pressure. Am J Hypertens 1995; 8(3):311- 315.  (18)  Wright JM, Lee CH, Chambers GK. Systematic review of antihypertensive therapies: does the evidence assist in choosing a first-line drug? CMAJ 1999; 161(1):25-32.  (19)  DeRubeis R, BecK AT. Cognitive Therapy. In: Dobson KS, editor. Handbook of Cognitive Behavioral Therapy. New York, NY: Guilford Press; 1988. 273-287.  (20)  Linden W. Autogenic training: A Clinical guide. New York, NY: Guilford Press; 1990.  (21)  Roskies E. Stress Management for Healthy Type A. New York, NY: Guilford Press; 1987.  (22)  Suinn RM. Anxiety Management Training: A Behavior Therapy. New York, NY: Plenum Press; 1990.  (23)  Linden W. Treating Hypertension. In: A Kuczmiercyk & Nicevic, editor. A Case Formulation Approach to Behavioral Medicine. London England: Routledge & Brunner; 2006.  177  (24)  Linden W. Stress Management: From Basic Science to Better Practice. USA: Sage Thousand Oaks; 2005.  (25)  Cook WW, Medley DM. Proposed hostility and pharisaic-virtue scales for the MMPI. J Appl Psychol 1954; 38:414-418.  (26)  Spielberger CD, Gorsuch RL, Lushene RE. Manual for the State-trait Anxiety Inventory. Palo Alto, Calif: Consulting Psychologists Press; 1970.  (27)  Linden W, Hogan BE, Rutledge T, Chawla A, Lenz JW, Leung D. There is more to anger coping than "in" or "out". Emotion 2003; 3(1):12-29.  (28)  Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health Soc Behav 1983; 24(4):385-396.  (29)  BecK AT. Depression Inventory. Philadelphia Pa: Center for Cognitive Therapy; 1978.  (30)  Paulhus DL. BIDR Reference Manual for Version VI. Vancouver, BC: University of British Columbia; 1991.   178  5 CONCLUDING CHAPTER 5.1 Clinical and research focus 5.1.1 Acute-phase therapy Chapter 2 and 3 of this thesis establish the scientific evidence for antihypertensive drug therapy when given in the acute phase (within 24 hours of the onset) of a myocardial infarction, other acute cardiovascular event, or a hypertensive emergency (acute end organ damage with marked hypertension). Acute cardiovascular events are characterized by high mortality during the first few hours or days, and this is particularly true for acute myocardial infarction1. Therefore, determining which drugs to administer, and when is key to patient outcome. Other systematic reviews of antihypertensive therapy have focused very little attention on acute phase therapy2-6.  This thesis research distinguished two acute phase anti-hypertensive treatment strategies. In the first strategy, anti-hypertensive therapy was started within the first 24 hours of an acute cardiovascular event and given for a maximum of 48 hours. In the second, the anti- hypertensive drug was started within 24 hours and continued for up to 10 days. These are referred to herein as “immediate intervention” when given for 1-48 hours and “short-term intervention” when started within the first 24 hours and continued up to 10 days. The outcome sought for both strategies was all-cause mortality at 48 hours, 10 days and ≥ 30 days.   179 The immediate intervention, which sets a limit of 48 hours to the duration of therapy, is a novel question to ask for anti-hypertensive therapy. Typically, questions are raised about the time of initiation, not the duration of therapy. Few investigators have considered that anti-hypertensive therapy could have a “critical” early period in which benefit occurs; after which further therapy offers no benefit, and perhaps results in harm.  The rationale for including an “immediate intervention” (starting < 24 hours and maximum therapy 48 hours) follows what is found with other therapies that have been proven mortality benefits. For example, a meta-analysis of randomized controlled trials of fibrinolytic therapy in acute myocardial infarction found that there was significant mortality benefit at 35 days despite the fact that fibrinolytic therapies are only administered for a few hours in the early period after the event7.  Although the anti-hypertensive drugs are started early (<24 hours) and the duration is short (maximum 48 hours) mortality outcome is measured at 48 hours, 10 and ≥30 days. This approach also follows from fibrinolytics. Consider the example of a large double- blind placebo controlled trial [ISIS-2 19888] where 17,187 patients within 24 hours of the onset of a suspected acute myocardial infarction were randomized to receive a one-hour streptokinase IV infusion or placebo infusion. Streptokinase had no effect on mortality at 48 hours (RR= 1.04, 95%CI [0.89, 1.21] but reduced mortality at 10 days (RR= 0.82, 95%CI [0.74, 0.91] and at 35 days (RR= 0.77, 95%CI [0.70, 0.84]).  180 5.1.1.1 Findings for the immediate intervention (start < 24 h, maximum therapy 48 hours) The immediate use of nitrates in patients with suspected or definite acute myocardial infarction (N= 82,624) is the only class of drugs associated with reduction of mortality during the first 48 hours (RR=0.81, 95%CI [0.74, 0.89]). This represents 4 lives saved per 1000 treated (Chapter 3; see also table 5.1). Unfortunately, there were not enough trials that reported mortality at 10 days or at ≥30 days to draw any conclusions of the effect of this immediate intervention at those times. Neither the immediate (start <24 h, maximum therapy 48 h) use of ACE-inhibitors (N= 77,414), nor beta blockers (N= 68,007) in patients with suspected or definite acute myocardial infarction were associated with statistically significant mortality benefit at 2 days (Chapter 3). In both cases there were insufficient trials to assess the immediate intervention on mortality at 10 days or at ≥30 days. The immediate use of calcium channel blockers (CCB) could not be appropriately assessed in most trials as they did not reported mortality data at any of these times. In Table 5-1 the mortality benefit of immediate use of nitrates in patients with suspected or definite acute myocardial infarction is compared with the immediate use of fibrinolytics and aspirin in the same clinical setting.  181   Table 5-1 Effect of immediate drug therapies* on mortality at different times after acute myocardial infarction   Drug therapy Mortality,  at 2 days Mortality,  at 10 days                     at ≥30 days Nitrates (this review)   6 trials (N=82,624) RR= 0.81 ARR= 0.43 % NNT=233 10 trials (N=6,007) RR= 0.84 ARR= NS NNT=NS 7 trials (N=5,771) RR= 0.92 ARR= NS NNT=NS Streptokinase8  1 trial (N=17,187) RR= 1.04 ARI= NS NNH=NS 1 trial (N=17,187) RR= 0.82 ARR= 1.5% NNT= 66 1 trial (N=17,187) RR= 0.77 ARR= 2.8 % NNT= 36 All Fibrinolytic7 9 trials(N=58,600) RR= 1.06 ARI= NS NNH=NS 9 trials (N=58,600) RR= 0.91 ARR= 0.6% NNT= 166 9 trials(N=58,600) RR= 0.82 ARR= 1.8 % NNT= 56 Aspirin8^ 1 trial (N=17,187) RR= 0.93 ARI= NS NNH=NS Not applicable as treatment continued beyond day 2 Not applicable as treatment continued * Only those BP lowering drugs that had shown beneficial effect at any time are displayed in this table RR=relative risk, ARR= absolute risk reduction, ARI=absolute risk increase, NNT=number needed to treat, NNH= number needed to harm, NS= not significant ^ According to the ATC 20029 meta-analysis there are 15 trials (N=19,288) studying antiplatelets for patients with suspected acute myocardial infarction. This table shows the result of largest trial8 (N=17,187)   182   5.1.1.2 Findings for short-term intervention (start < 24 h, maximum therapy 10 days) The second research question asked whether there was a mortality advantage of continuing therapy, started in the first 24 hours to 10 days. The 10-day time period was based on the fact that about 75% of deaths following an acute myocardial infarction occur within the first 10 days8. It is thus an appropriate period to assess the effect of antihypertensive drugs on mortality. Nitrates started within 24 hours and used for a maximum of 10 days, were associated with a statistically significant reduction in mortality at 10 days (RR=0.91, 95%CI [0.86,0.97] ARR=0.49%, NNT=204) (Chapter 3; See also table 5.2). However, the absolute mortality benefit at 10 days was almost entirely accounted for by the absolute mortality benefit at 2 days (RR = 0.81, 95%CI [0.74, 0.89], ARR=0.43%, NNT=233), (See Table 5-1and Table 5-2). This suggested that nitrates administered longer than 2 days had little or no effect on mortality. It was fortunately possible to confirm this with an analysis of the effect on mortality for the time period beyond 2 days (See Chapter 3, and Figure 5-1). Nitrates, administered from 3 to 10 days had no effect on mortality (RR= 0.98, 95% CI [0.91, 1.06] and nitrates administered from 11 to ~30 days caused a trend toward an increase in mortality (RR=1.10, 95% CI [1.00, 1.22]).  183   Figure 5-1. Effects of Continuation of Nitrates on Mortality at Different Times.    ACE-inhibitors started within 24 hours of the onset of a myocardial infarction and given for a maximum of 10 days were associated with a statistically significant reduction in mortality at 10 days (RR=0.93, 95%CI [0.87,0.98]); representing approximately 4 lives saved per 1000 treated (Chapter 3; See also table 5.2). However, whether this benefit was due to starting therapy within 24 hours or to effect occurring beyond 2 days could not be established, as there was no statistically significant benefit at 2 days. In fact, a mortality analysis of the different time period using trials where the ACE-I was continued for ~30  184 days revealed a similar effect mortality during all periods: 1-2 days, RR=0.91 (95% CI [0.82, 1.00]); 3-10 days, RR= 0.93 (95% CI [0.86, 1.01]; and 11 to ~30 days, RR= 0.93 (95% CI [0.85, 1.03]). Beta-adrenergic antagonists and calcium channel blockers started within 24 hours and continued for a maximum of 10 days were both not associated with a statistically significant reduction in mortality at 10 days (RR=0.96, 95% CI [0.91,1.02] and RR=1.01 (95% CI [0.73,1.38]), respectively (Chapter 3). Beta-adrenergic antagonist (BB), were the only class of drugs that had sufficient data to assess the effect of short-term therapy on mortality at ≥ 30 days. In 5 RCTs, (N=18,373) beta-blockers started within 24 hours and given for 10 days were associated with a statistically significant reduction in mortality during an average of 12 months of follow- up (RR=0.91, 95%CI[0.84,0.99], p=0.03 ). However, as explained in detail in chapter 3 this was a chance finding and publication as well as performance bias were likely present. Therefore, it is inferred that this does not represent a true delayed mortality benefit of beta-blockers administered for 1 to 10 days after an acute myocardial infarction.  Table 5-2 presents the findings of the present systematic reviews as compared to aspirin, which has a proven mortality benefit when started within 24 hours of the symptom onset. These indirect comparisons assume that the patients are similar. This is a reasonable assumption, as they are all studying patients with suspected or definite acute myocardial infarction.   185   Table 5-2. Effect of Short-term Drug Therapies* on Mortality in Patients with Acute Myocardial Infarction, at Different Times  Trial or Meta-analysis  of a Drug Therapy Mortality,  At 10 days Mortality,  at ≥ 30 days Nitrates (this review)   6 trials, N= 78,178 RR= 0.91 ARR= 0.49 % NNT=204 3 trials, N=570 RR= 0.72 ARR= NS NNT=NS ACE-inhibitors (this review)   10 trials, N= 84,311 RR= 0.93 ARR=0.37 % NNT=270 Not applicable as treatment continued beyond day 10 Aspirin8^  1 trial, N= 17,187 RR= 0.80 ARR= 1.7% NNT=60 Not applicable as treatment continued beyond day 10 * Only those BP lowering drugs that had shown beneficial effect at any time are displayed in this table RR=relative risk, ARR= absolute risk reduction, ARI=absolute risk increase, NNT=number needed to treat, NNH= number needed to harm, NS= not significant ^ According to the ATC 20029 meta-analysis there are 15 trials (N=19,288) studying antiplatelets for patients with suspected acute myocardial infarction. This table shows the result of largest trial8 (N=17,187).   5.1.2 Discussion on timing and duration of therapy The systematic review in Chapter 3 showed that nitrates, started within the first 24 hours of a myocardial infarction and continued for 48 hours, reduced mortality at 2 days, but that continuation of nitrates beyond 2 days resulted in no further mortality benefit (Table 5-1and Table 5-2). The review does not provide any indication as to when the best time is to administer nitrates within the first 24 hours. Fortunately, the largest trial in the meta- analysis (ISIS-4 study)10 (N=58,050) provided subgroup data based on when the nitrates were started within the first 24-hour period.  In this trial, patients suspected of having a myocardial infarction were randomized to receive 35 days of nitrates or placebo. The  186 overall effect of nitrates on mortality was not significant at 35 days (RR= 0.97, 95%CI [0.92-1.03]). However, the subgroup of patients who were given nitrates within the first 6 hours of the onset of symptoms (N=23,323) had a significant mortality benefit at 35 days (RR 0.89, 95%CI [0.82-0.98], ARR=0.88%; 9 lives saved per 1000 treated). (See figure 4 of page 675 in the original publication10). The findings from the ISIS-4 study10 suggest that the time-of-initiation of nitrate therapy is critical as it has been shown for thrombolytics7. Unfortunately, the other RCTs in the present meta-analysis do not provide subgroup data according to the hour of onset of therapy. However, based on the ISIS-4 findings, the significant mortality benefit at 2 days reported in chapter 3 (RR=0.81) for patients who started therapy any time in the first 24 hours could be greater for the sub-group of patients starting nitrates within 6 hours.  The ISIS-4 study10 (N= 58,050; a factorial trial with 3 independent comparisons) also provided data according to hour of administration of ACE-inhibitor therapy. The overall effect on mortality was statistically significant at 35 days (RR 0.94, 95%CI [0.88-0.99]). However, in contrast to the nitrates, ACE-inhibitors administered within 6 hours of symptoms (N=23,323) had no effect on mortality at 35 days (RR 0.98, 95% CI [0.90- 1.07]) suggesting that early treatment with ACE-inhibitors may not be a good idea. The effect of ACE inhibitors was better (RR 0.90, 95% CI [0.84-0.97]) if they were administered later. In the case of beta-blockers, three small trials (N=840) studied therapy started within 6 hours and continued for up to 48 hours.  Sample sizes were too small to assess mortality at 2, 10 or ≥ 30 days. There were 5 trials (N=2,785) that started beta-blockers within 6  187 hours and continued treatment for more than 3 days and showed no suggestion of a mortality benefit at 10 days (RR 1.15, 95% CI [0.78-1.70]. The timing of administration of calcium channel blockers could not be assessed due to lack of data. 5.1.3 Post-acute phase therapy Chapter 3 focused on antihypertensive therapy that began within the first 24 hours. It showed that the therapeutic effects of anti-hypertensive drugs in stable clinical settings could not be extrapolated to the effects when these drugs are started in acute settings (eg, within 24 hours of an acute myocardial infarction). This thesis therefore challenges the approach and findings of other systematic reviews that pool anti-hypertensive therapy RCTs, regardless of time of initiation of therapy. Such an approach is simplistic and misses important therapeutic effects that are dependent on the time of initiation of therapy. For example, beta-blockers when started days or weeks after an MI and continued for months are known from other systematic reviews to have a significant mortality benefit3;6. In contrast, this review and a systematic review by another group11 show that beta-blockers started within 24 hours and continued for 2 days or up to 10 days following a myocardial infarction does not affect mortality measured at 2 days or at 10 days. 5.2 The focus on all-cause mortality All-cause mortality was chosen as the primary outcome in the systematic reviews because it is a measure of net health effect. Anti-hypertensive therapy in any setting, but particularly in acute settings, can cause both harm and benefit. Cause of death is often  188 difficult to ascertain. Thus, RCTs and systematic reviews measuring cardiovascular mortality are subject to inadvertent error and bias. In the hypertensive emergency review (Chapter 2) mortality data was sparse with only 6 deaths reported in 15 trials (N=869). These trials had a short duration of follow-up (6-24 hours), but despite that the small number of deaths is strikingly low for patients with a hypertensive emergency who have a high risk of death during the first hours or days. It is likely that complete mortality data was not reported in these RCTs. Despite the lack of outcome data in the emergency review it accurately reflects the best available evidence and has been commended by others as an important basis for future research in this clinical setting12. In contrast, the second systematic review (Chapter 3) of acute cardiovascular events was large enough and included ample mortality data to make strong conclusions. The overall mortality rate in the placebo or control group vs. anti-hypertensive therapy group was 2 % (1525 / 75,449) and 1.8% (1362 / 75,463), respectively, at 2 days; and 5.6% (4602 / 82,766) and 5.2 % (4330 / 83,015), respectively, at 10 days. The importance of using all-cause mortality as an outcome is shown by a recent systematic review that claims that beta-blockers given post MI decrease coronary heart disease (CHD) events, RR 0.69 (95% CI 0.62-0.76)13. This certainly conveys a different message from our review, which showed no reduction in mortality with beta-blockers. When the two reviews are compared it is clear that the differences in the results are explained by different methodology (including trials that start beta-blockers treatment days or weeks after the onset) as well as different outcomes ( measuring CHD events and excluding “mortality in the period immediately after infarction”) . However, we feel  189 confident that the outcome we have chosen has the lowest risk of bias (reporting, documenting, censoring), and is a measure of the net health effect (benefit minus harm). In fact, all-caused mortality is considered the optimal outcome to be measured in hospitalized critically ill patients where it is very difficult to identify and record all serious adverse events (total mortality and serious morbidity)14. This thesis shows the importance of determining all cause, as opposed to cardiovascular mortality or morbidity, when assessing the impact of drug therapy. This research also shows the importance of including all-cause mortality rates for the entire clinical period, particularly stressing inclusion of the first 24 hours. If data was not provided by the original publications this data was actively sought from the authors.  5.3 Hypertensive thresholds and anti-hypertensive therapy In the first systematic review, the hypertensive emergency review required that all patients had a blood pressure that exceeded specific limits of blood pressure. The second review, acute cardiovascular events review, had no limitation in terms of BP. In the first review that required patients to have a high blood pressure threshold for entry, only two placebo controlled trials  (N=144 patients) met the inclusion criteria, while in the second review 65 placebo or no treatment controlled trials (N=166,206 patients) met the inclusion criteria. The first review had no mortality data versus placebo.  As a result, most of the findings and conclusions derive from the second, larger review.  190 5.4 Do the findings of these systematic reviews support the currently approved indications for antihypertensive drugs in these acute settings? In the following subsections the approved indications for different anti-hypertensive drugs, by Health Canada or by the U.S. Food & Drug Administration (FDA), for the acute cardiovascular events are compared with the findings of the present systematic reviews of randomized controlled trials in which all-cause mortality was used to assess the net health effect. Following this comparison, I present how I would personally use the antihypertensive drugs in the acute cardiovascular settings based on the evidence. 5.4.1 Nitrates (including nitroprusside) Approved Indications: Nitroglycerine is indicated for selected patients with acute coronary syndromes. Nitroprusside is indicated for hypertensive emergencies. The time that these drugs should be started is not specified for these indications. Findings from the systematic reviews: In the hypertensive emergencies review, nitrates (including nitroprusside) were the most studied class of drugs (9 out of 15 trials). However, there was no useful information with regard the effect of these drugs on mortality for nitrates or for any of the other classes of drugs. The differences in systolic and diastolic blood pressure reduction between these drugs and the active comparators were minor and are not considered to be clinically significant. In the acute cardiovascular event review, nitrates were studied in 18 trials (N= 84,413) out of 65 included trials (N=166,206). Nitroprusside was studied in only 2 (N=1,140). All of these trials studied patients with acute myocardial infarction.  191 The overall effect of nitrates (including nitroprusside) administrated within 24 hours of the symptom onset was a significant mortality reduction at 2 days (RR 0.81, 95%CI [0.74 -0.89]); 4 to 8 deaths prevented per 1000 patients treated. Nitrates were also associated with a statistically significant reduction in mortality when administered daily for 10 days (RR 0.91, 95%CI [0.86-97]). However, this benefit was entirely accounted for by the reduction in mortality at 2 days. No benefit was seen for nitrates administered from day 3 to 10. When the effects of the different nitrates on mortality at 2 days were analyzed separately nitroprusside reduced mortality but not statistically significantly (RR 0.70, 95%CI [0.33- 1.47]). Nitroglycerine significantly reduced mortality at 2 days (RR 0.82, 95%CI [0.68- 0.99]). Oral isosorbide-5-mononitrate also significantly reduced mortality at 2 days (RR 0.82, 95%CI [0.73-0.92]). There is nothing to suggest that the effect is different for different nitrates.  Conclusions: I would administer nitrates routinely and as soon as possible within the first 24 hours of a suspected or definite myocardial infarction (as per inclusion criteria of the trials involved) because they decrease mortality at day 2. Because of lack of effect on mortality when administered after day 2, I would not be continued nitrate therapy beyond day 2 unless there was a specific indication e.g., angina pectoris. Since the data is most robust for isosorbide mononitrate and it has the advantage of being administered orally, I would use isosorbide mononitrate in this setting. This approach represents a deviation from the current guidelines.  192  5.4.2 Angiotensin converting enzyme inhibitors (ACE-I) Approved Indications: Lisinopril is indicated for administration within 24 hours of acute myocardial infarction. Captopril is also indicated for post-myocardial infarction, but the time of starting is not specified. Findings from the systematic reviews: In patients with an acute myocardial infarction, ACE-inhibitors administrated within 24 hours of symptom onset were not associated with statistically significant reduction in mortality at 2 days (N=77,414; RR 0.91, 95%CI [0.82-1.0], but when these drugs were continued for 10 days there was a significant reduction in mortality (N=84,311; RR 0.93, 95%CI [0.87-0.98]) at day 10 (3 to 5 deaths prevented for 1000 treated). When the different ACE-I drugs were analyzed individually captopril (6 trials, N= 58,635) showed a significant reduction in mortality at 10 days (RR 0.92, 95%CI [0.86- 0.99], but lisinopril (1 trial, N=19,318) did not (RR 0.90, 95%CI [0.79-1.02]. However, these results do not provide any suggestion of a different effect of these two ACE-I drugs in this setting. Conclusion: I would administer an ACE-inhibitor routinely to patients with suspected or definite myocardial infarction starting the day after admission and continue the drug daily after that. The optimal time of starting an ACE-inhibitor is unknown but the evidence suggests that in contrast to nitrates early administration is not beneficial.  193 5.4.3 Angiotensin II receptor blockers (ARBs) Approved Indications: Valsartan is indicated for patients within 12 hours of an acute myocardial infarction in clinically stable patients with signs or symptoms of left ventricular dysfunction. The other ARBs do not have this indication. Findings from the systematic reviews: No trial assessed the effect of any ARB versus placebo within 24 hours of an acute myocardial infarction or any other acute cardiovascular setting. 5.4.4 Beta-adrenergic receptor blockers (BBs) Approved Indications: Labetalol is the only BB indicated for hypertensive emergencies, whereas metoprolol is the only BB indicated for acute myocardial infarction. The time of administration of metoprolol is “as soon as possible”. Findings from the systematic reviews: for labetalol In the hypertensive emergencies systematic review there was no trial included that studied a beta-adrenergic blocker. Conclusion: The indication of labetalol for hypertensive emergencies is not supported by RCT evidence. Findings for metoprolol: The present systematic review shows that beta-blockers administrated to 72,600 patients within 24 hours of the onset of an acute myocardial infarction, and continued for 10 days,  194 do not reduce mortality at 2 days (RR 0.95, 95%CI [0.85-1.07]) or 10 days (RR 0.96, 95%CI [0.91-1.02]). Limiting the analysis to the 5 trials15-19 (N=53,915) that studied metoprolol vs. placebo or no treatment in patients with acute myocardial infarction similarly showed no reduction in mortality at 2 days (RR 1.05, 95%CI [0.92-1.20] or at 10 days (RR 0.99, 95%CI [0.93- 1.06]). Conclusion: I would not routinely administer metoprolol or any beta-blocker within 24 hours of the onset of an AMI and would only use a beta-blocker when there was a specific indication. 5.4.5 Calcium channel blockers (CCBs) Approved Indications: No CCB is officially indicated for a hypertensive emergency or an acute cardiovascular event. Findings in the systematic reviews: Although many large trials have been conducted assessing the use of CCB after acute myocardial infarction, there is very little mortality data because it was not reported in the majority of trials. Conclusions: I would not routinely administer a CCB within 24 hours of any acute cardiovascular event.    195 5.4.6 Diuretics Approved Indications: Furosemide and Ethacrynic acid are indicated for the treatment of acute pulmonary edema. Findings in the systematic reviews: In the hypertensive emergency review there were three included trials that involve diuretics20-22. The three trials compared furosemide vs. nitrates. No mortality data was reported for any of these trials. There were no differences in systolic or diastolic blood pressure reduction between the two classes. No trial was found involving ethacrynic acid. Conclusions Despite the lack of RCT evidence, I would administer furosemide as part of the early overall management of patients with acute pulmonary edema.  5.5 Study bias and limitations of systematic reviews 5.5.1 Recruitment bias Both systematic reviews excluded trials that had selected their patients on the basis of previous responsiveness to an anti-hypertensive drug. This type of exclusion was to avoid recruitment bias which can jeopardize the external validity of the trial’s results as the findings from these types of trials cannot be extrapolated to a broader population such as those with life-threatening conditions, e.g., hypertensive emergencies or acute cardiovascular events. There was one trial with this type of recruitment bias, Annane et al 199623, which was excluded from the hypertensive emergency review.  196 5.5.2 Randomization, concealment of allocation and blinding Both reviews excluded trials with pseudo or quasi randomization (i.e., allocation of patients according to the date of birth or admission). In addition, since many trials did not provide sufficient details about how allocation concealment was achieved, trials were downgraded in their quality according to a Cochrane Collaboration risk of bias table (See Chapter 2 and 3 for details). Blinding of treatment allocation was not required for study inclusion in these systematic reviews because the outcome all-cause mortality has the least risk of detection bias14. However, in the larger systematic review of antihypertensive drugs on acute cardiovascular events without blood pressure thresholds (Chapter 3), there was a trend towards greater mortality benefit in open-label (OL) trials as compared to double-blind (DB) trials for nitrates, ACE-inhibitors  and CCBs, but a significant difference for beta blockers.  Nitrates OL RR 0.86 [0.76, 0.97] vs. DB RR 0.92 [0.86, 0.98]  ACE inhibitors OL RR 0.89 [0.79,1.01] vs. DB RR 0.94 [0.88,1.0]  CCB OL RR 0.47 [0.07, 3.02] vs. DB RR 1.76 [0.99, 3.14]  BB OL RR 0.73 [0.58,0.91] vs. DB RR 1.04 [0.91,1.19]  For the beta-blockers, the confidence intervals do not overlap for the open-label (N=16,193) vs. double-blind (N=51,814) trials. This finding is discussed in detail in Chapter 3. The potential cause of these differences between open-label and double-blind trials is performance bias (See below section), which even hard outcomes, such as all- cause mortality, are subject to. Therefore, conclusions were based on the more conservative and methodologically stronger double-blind RCT evidence.  197  5.5.3 Performance bias Although proper randomization would theoretically balance the co-variants