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A systematic review of the blood pressure lowering efficacy of diuretics as second-line therapy for primary… Chen, Mei Hui 2009

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A SYSTEMATIC REVIEW OF THE BLOOD PRESSURE LOWERING EFFICACY OF DIURETICS AS SECOND-LINE THERAPY FOR PRIMARY HYPERTENSION by Mei Hui Chen B.Sc., The University of British Columbia, 2003  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in The Faculty of Graduate Studies (Pharmacology and Therapeutics)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  August 2009  © Mei Hui Chen, 2009  ABSTRACT Context: Although other factors independent of their blood pressure (BP) lowering effect may contribute to the reduction in morbidity and mortality associated with antihypertensive drugs, efficacy of an antihypertensive treatment is gauged by the magnitude of BP reduction. Diuretics are widely prescribed for hypertension not only as first-line monotherapy but also second-line in combination therapy. Therefore, it is essential to determine the effects of diuretics on BP, heart rate (HR) and withdrawals due to adverse effects (WDAEs) when used second-line for hypertension. Objectives: 1) To quantify the additional BP reduction of a diuretic as a second-line drug in combination therapy in patients with primary hypertension (systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg); 2) To determine the additional effects on HR and WDAEs. Methods: A systematic review of published, double-blind, randomized controlled trials (RCTs) evaluating the BP lowering efficacy of combination therapy (with a diuretic) compared with the respective monotherapy (without a diuretic) for a duration of 3 to 12 weeks in patients with primary hypertension was conducted. Electronic databases were searched for the relevant trials and data were analyzed using Review Manager 5.0.20. Results: Fifty-three double-blind RCTs evaluating a thiazide in 15129 hypertensive patients (baseline BP of 156/101 mmHg) were included. Hydrochlorothiazide was the thiazide used in 49/53 (92%) of the included studies. The additional BP reduction induced by the thiazide as a second drug was estimated by comparing the difference in BP reduction between the combination and monotherapy groups. Thiazides as a secondline drug reduced BP reduction by 6/3 and 8/4 mmHg at doses of 1 and 2 times the  ii  manufacturer's recommended starting dose respectively. The BP lowering effect was dose related. The effect was similar to that obtained when thiazides are used as a single agent. Only 3 double-blind RCTs evaluating loop diuretics were identified; however, at one times the manufacturer’s recommended dose, the BP lowering effect is similar to thiazides. Conclusion: Thiazides when given as a second-line drug have a dose related effect to lower blood pressure that is similar to when they are used as a first-line drug.  iii  TABLE OF CONTENTS ABSTRACT........................................................................................................................ ii TABLE OF CONTENTS................................................................................................... iv LIST OF TABLES............................................................................................................. ix LIST OF FIGURES ........................................................................................................... xi 1  INTRODUCTION ...................................................................................................... 1 1.1  Hypertension ....................................................................................................... 1  1.1.1  Definition of hypertension .............................................................................. 1  1.1.2  Cardiovascular risk measures ......................................................................... 2  1.1.3  BP reduction and its relation to cardiovascular events ................................... 4  1.1.4  Management of hypertension.......................................................................... 4  1.1.4.1  Non pharmacological treatment.............................................................. 5  1.1.4.2  Pharmacological treatment...................................................................... 5  1.1.5 1.2  Combination therapy........................................................................................... 9  1.2.1  Achieving blood pressure reduction (surrogate outcome) .............................. 9  1.2.2  Importance of combination therapy .............................................................. 10  1.2.3  Pharmacological rationale for drug combinations in hypertension .............. 11  1.2.4  Use of combination therapy .......................................................................... 12  1.2.5  Clinical evidence of combination therapy for treatment of hypertension..... 12  1.3 2  Classes of commonly used anti-hypertensive drugs ....................................... 6  References......................................................................................................... 14  SYSTEMATIC REVIEW......................................................................................... 18  iv  2.1  What are systematic reviews and why do we need systematic reviews?.......... 18  2.2  The Cochrane collaboration.............................................................................. 19  2.3  Aim of this systematic review........................................................................... 20  2.4  Protocol ............................................................................................................. 21  2.4.1  Objectives ..................................................................................................... 22  2.4.2  Methodology ................................................................................................. 22  2.4.2.1  Types of studies .................................................................................... 22  2.4.2.1.1 Why are only randomized controlled trials included? ...................... 22 2.4.2.1.2 Why is blinding (masking) necessary? ............................................. 23 2.4.2.1.3 Why is a baseline measurement subsequent to a washout/placebo runin period important?.......................................................................................... 23 2.4.2.1.4 Why is the 3 to 12 week window selected? ...................................... 24 2.4.3  Types of participants..................................................................................... 24  2.4.4  Types of interventions................................................................................... 24  2.4.5 Types of outcome measures.......................................................................... 25 2.4.6  Search methods for identification of studies................................................. 26  2.4.7  Study selection .............................................................................................. 26  2.4.8  Data extraction .............................................................................................. 27  2.4.9  Risk of bias assessment................................................................................. 27  2.4.10  Data analysis and statistical consideration................................................ 28  2.4.11  Direct and indirect comparisons ............................................................... 28  2.5 3  References......................................................................................................... 30  RESULTS ................................................................................................................. 31  v  3.1  Search findings.................................................................................................. 31  3.1.1  Characteristics of included studies................................................................ 32  3.1.2  Characteristics of excluded studies............................................................... 67  3.2  Imputation of missing variance data ................................................................. 71  3.3  Pooling of trials................................................................................................. 72  3.4  Blood pressure lowering efficacy ..................................................................... 73  3.4.1 Thiazide plus other drug vs other drug alone................................................ 73 3.4.1.1  Thiazide plus ACEI vs ACEI alone ...................................................... 73  3.4.1.2  Thiazide plus ARB vs ARB alone ........................................................ 76  3.4.1.3  Thiazide plus renin inhibitor vs renin inhibitor alone........................... 77  3.4.1.4  Thiazide plus BB vs BB alone .............................................................. 77  3.4.1.5  Thiazide plus CCB vs CCB alone......................................................... 79  3.4.1.6  Thiazide plus centrally acting drug vs centrally acting drug alone ...... 80  3.4.1.7  Summary of the additional BP reduction induced by adding a thiazide to  drug classes ........................................................................................................... 80 3.4.1.8  Subgroup analysis ................................................................................. 81  3.4.1.9  Comparison of BP reduction achieved by HCTZ in combination therapy  and in monotherapy............................................................................................... 83 3.4.2  Loop diuretic plus other drug vs other drug alone........................................ 84  3.4.2.1  Loop diuretic plus ACEI vs ACEI alone .............................................. 85  3.4.2.2  Loop diuretic plus BB vs BB alone ...................................................... 85  3.5 3.5.1  Pulse pressure.................................................................................................... 86 Thiazides ....................................................................................................... 86  vi  3.5.2 3.6  Loop diuretics ............................................................................................... 87 Blood pressure variability ................................................................................. 87  3.6.1  Thiazides ....................................................................................................... 87  3.6.1.1  Baseline variability ............................................................................... 87  3.6.1.2  Baseline vs endpoint variability............................................................ 87  3.6.1.3  Combination vs monotherapy ............................................................... 88  3.6.2 3.7  Loop diuretics ............................................................................................... 88 Heart rate........................................................................................................... 89  3.7.1  Thiazides ....................................................................................................... 89  3.7.2  Loop diuretics ............................................................................................... 89  3.8 3.8.1  Thiazides ....................................................................................................... 89  3.8.2  Loop diuretics ............................................................................................... 90  3.9 4  Withdrawals due to adverse effects .................................................................. 89  References......................................................................................................... 91  DISCUSSION......................................................................................................... 103 4.1  What are some issues encountered in the search strategy?............................. 103  4.2  What is the additional BP reduction of thiazide and thiazide-like diuretics when  added to other classes of antihypertensive drugs? ...................................................... 104 4.3  What is the additional BP reduction of loop diuretics when given in addition to  another class of antihypertensive drugs? .................................................................... 105 4.4  Is there a difference in the reduction of blood pressure between adding a  thiazide to different classes of drugs?......................................................................... 105  vii  4.5  Is there a difference in the blood pressure lowering efficacy of diuretics given  as initial therapy or as a second line drug in combination therapy? ........................... 106 4.6  Does age have an effect on BP lowering of diuretics? ................................... 107  4.7  Does co-morbidity have an effect on BP lowering of diuretics? .................... 107  4.8  What is the effect of second-line diuretics on BP variability?........................ 107  4.9  What is the effect of second-line diuretics on pulse pressure? ....................... 108  4.10  What is the effect of second-line diuretics on heart rate?............................... 109  4.11  What is the effect of second-line diuretics on withdrawals due to adverse  effects? ........................................................................................................................ 110 4.12  What are the potential sources of bias in this systematic review?.................. 110  4.12.1  Sequence generation and allocation concealment................................... 111  4.12.2  Blinding................................................................................................... 111  4.12.3  Incomplete outcome data ........................................................................ 111  4.12.4  Selective outcome reporting ................................................................... 112  4.12.5  Other potential sources of bias................................................................ 112  4.12.5.1 Publication Bias .................................................................................. 112 4.12.5.2 Selection Bias...................................................................................... 112 4.12.5.3 Funding ............................................................................................... 113 4.12.5.4 Other factors........................................................................................ 113 4.13  References....................................................................................................... 114  5  C LINICAL IMPLICATIONS................................................................................ 116  6  RESEARCH IMPLICATIONS .............................................................................. 118  APPENDICES ................................................................................................................ 120  viii  LIST OF TABLES  Table 1.1: Classification of blood pressure for adults ........................................................ 2 Table 1.2 : Blood pressure targets of antihypertensive therapy according to several hypertension guidelines ...................................................................................................... 5 Table 3.1 : Characteristics of included studies ................................................................. 33 Table 3.2 : Reasons for exclusion of trials that met inclusion criteria for this review ..... 68 Table 3.3 : Starting doses of diuretics analyzed in the review.......................................... 73 Table 3.4 : Additional BP reduction by adding a thiazide to ACEI. Fixed effect model (95%CI)............................................................................................................................. 74 Table 3.5 : Additional BP reduction by adding a thiazide to ARB. Fixed effect model (95%CI)............................................................................................................................. 76 Table 3.6 : Additional BP reduction by adding a thiazide to a renin inhibitor. Fixed effect model (95%CI).................................................................................................................. 77 Table 3.7 : Additional BP reduction by adding a thiazide to a beta-blocker. Fixed effect model (95%CI).................................................................................................................. 78 Table 3.8: Additional BP reduction by adding a thiazide to CCB. Fixed effect model (95%CI)............................................................................................................................. 79 Table 3.9 : Summary of the additional BP reduction of thiazide as a second drug in combination therapy.......................................................................................................... 80 Table 3.10 : SBP reduction contributed to HCTZ added in combination with other drugs or as a single drug. Fixed effect model (95%CI). ............................................................. 84  ix  Table 3.11 : DBP reduction contributed to HCTZ added in combination with other drugs or as a single drug. Fixed effect model (95%CI). ............................................................. 84 Table 3.12 : Additional BP reduction by adding a loop diuretic to ACEI. Fixed effect model (95%CI).................................................................................................................. 85 Table 3.13 : Pulse pressure reduction at end of treatment. Combination therapy versus monotherapy: Hydrochlorothiazide as a second drug....................................................... 86 Table 3.14 : Difference in pulse pressure reduction at end of treatment. Combination therapy versus monotherapy: Thiazides as a second drug class. ...................................... 87 Table 3.15 : Variability of SBP and DBP at baseline ....................................................... 87 Table 3.16 : Standard deviations of BP at baseline vs. endpoint in trials with DBP entry criteria ............................................................................................................................... 88 Table 3.17 : The additional heart rate effects of adding a thiazide as the second drug. Fixed effect model (95%CI) ............................................................................................. 89 Table 3.18 : Withdrawals due to adverse effects: drug/thiazide vs drug alone ................ 89 Table 3.19 : Withdrawals due to adverse effects: drug/loop diuretic vs drug alone......... 90  x  LIST OF FIGURES  Figure 3.1: QUOROM flow diagram................................................................................ 32 Figure 3.2 Additional BP change (±95% CI) induced by adding thiazide as a second drug to other classes of anti-hypertensive drugs. ...................................................................... 81 Figure 3.3. Additional BP change (± 95% CI) induced by HCTZ 12.5mg/day in combination therapy with the following drugs. . .............................................................. 82 Figure 3.4. Additional BP change (± 95% CI) induced by HCTZ 25mg/day in combination therapy with the following drugs. ................................................................ 83  xi  1  INTRODUCTION 1.1  Hypertension Elevated blood pressure (BP), commonly called hypertension, is an important  health care problem, both in Canada and internationally. The worldwide prevalence of elevated BP is about 26% of the adult population, and the prevalence increases with age [1]. Elevated blood pressure is a major contributor to many cardiovascular diseases (CVD) and has been estimated to contribute 4.5% to the global disease burden [2]. 1.1.1  Definition of hypertension Hypertension has been subdivided into two forms: primary (essential) and  secondary hypertension. Primary hypertension accounts for 95-99% of cases and, as the name implies, the cause or causes are unknown (but includes both environmental and genetic factors). On the other hand, hypertension is called secondary when it is a consequence of some biochemical or mechanical pathology that is potentially reversible. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood pressure describes the relationship between BP and risk of CVD as “continuous, consistent, and independent of other risk factors” [3]. The chances of heart attack, heart failure, stroke, and kidney diseases increase with BP increments. Meta-analysis of observational studies showed that the risk of cardiovascular death increases continuously from BP levels of 115 mmHg systolic and 75 mmHg diastolic. At ages 40-69 years, each increment of 20 mmHg in SBP or 10 mmHg in DBP doubles the risk of cardiovascular (coronary heart disease and stroke) morbidity across the entire BP range [4].  1  However, there is no dividing line between high and normal BP. Arbitrary numerical values have defined hypertension as systolic BP (SBP) of 140 mmHg or greater, and/or diastolic BP (DBP) of 90 mmHg or greater. In 2003, JNC-7 introduced new classification scheme of BP for adults aged 18 years and older [3] (see Table 1.1). Table 1.1: Classification of blood pressure for adults [3] BP Classification Normal Prehypertension Stage 1 hypertension Stage 2 hypertension  SBP (mmHg) <120 120-139 140-159 ≥160  DBP (mmHg) and <80 or 80-89 or 90-99 or ≥100  JNC-7 suggests that individuals classified as hypertensive (stage1 and stage2) be treated. However, there are disagreements as to the minimum BP level to initiate treatment. As previously defined by Geoffrey Rose, the most appropriate definition of hypertension is “the level at which the benefits of action exceed those of inaction” [5]. Unfortunately, the available data does not allow us to precisely define hypertension using this definition. 1.1.2  Cardiovascular risk measures Both SBP and DBP provide independent clinical information about  cardiovascular risk. Data from the long-term Framingham cohort study shows that SBP rises throughout life, while DBP rises until the fifth decade when it starts to fall [6]. This observation has been thought to be due to age-related increase in stiffness of the large arteries. There is still some controversy over whether SBP or DBP is the best predictor of future CVD events. Pulse pressure (PP), the difference between systolic and diastolic pressure, has become increasingly recognized as an independent risk factor for cardiovascular events. Pulse pressure increases progressively with age and the rate of rise of PP accelerates after age 50 years. Analysis of the Framingham Heart Study found that  2  PP and SBP conferred greater risk of congestive heart failure (CHF) than DBP [7] and neither SBP nor DBP was superior to PP in predicting CHD risk [8]. In a 15 years follow up cohort study, PP was found to be a risk factor for CHD, CVD, stroke, and all-cause mortality [9]. However, the risk disappeared after adjusting for SBP. Nonetheless, the relative value of SBP, DBP and PP in hypertension treatment is still not clear. One of the most important characteristics of BP is that it is highly variable between individuals and within individuals. Thus BP fluctuates widely from minute to minute and from hour to hour within an individual. This variability can be assessed in an individual by machines designed to measure BP every 20 minutes over a 24-hour period. Variability using this technique has been shown to independently contribute to the development of end organ damage and cardiovascular events in hypertension [10]. A steep rise in BP around the time of awakening has been associated with a higher risk of acute myocardial infarction (MI) [11]. Daytime SBP variability has been shown to predict progression of early carotid atherosclerosis [12]. Furthermore, larger office BP variability has been found to be associated with a higher risk of stroke as well as MI in elderly patients [13,14]. In the Framingham Heart Study, it was found that heart rate (HR) may be an independent risk factor for CVD in hypertensive patients. Heart rate was found to be a predictor of sudden deaths with average resting HR of 83 beats/min or higher associated with a higher risk of death [15]. Other recent studies have also found significant association between HR and cardiovascular mortality [16, 17]. However, no trial has been designed to specifically evaluate the benefits of lowering HR in terms of cardiovascular outcomes.  3  1.1.3  BP reduction and its relation to cardiovascular events Hypertension contributes substantially to the development of cerebrovascular  disease, ischemic heart disease, cardiac and renal failure. The main goal of treatment is to reduce the risk of strokes, CVD and death that are associated with elevated BP. Reductions in BP with the use of BP lowering drugs have been associated with reductions in cardiovascular events. A meta-analysis of randomized controlled trials (RCT) using low-dose thiazides (<50mg/day equivalent of hydrochlorothiazide) as compared to placebo reduced SBP/DBP by 13/5 mmHg over a mean duration of 4.1 years resulted in a 11% reduction in mortality, 32% reduction in stroke and 28% reduction in coronary events [18]. The benefit of BP reduction with BP lowering drugs also has been shown to decrease all-cause mortality, as well as cardiovascular morbidity and with greater absolute benefits in older patients [19]. However, there is still no evidence to assess how much BP should be lowered. Excessive lowering can be related to a potential increase in cardiovascular events, referred to as the “J-curve phenomenon”. The critical point of inflection is not yet determined. A recent systematic review has demonstrated that for the general population of patients with elevated BP, treating patients to targets ≤85mmHg or ≤80mmHg as compared to the traditional target of ≤90mmHg is not associated with a reduction in morbidity and mortality [20]. 1.1.4  Management of hypertension When treating hypertension, guidelines recommend that clinicians attempt to  achieve a target BP. These BP targets differ in the general population and in patients with  4  diabetes mellitus or renal disease, but they have not been proven in randomized controlled trials (see Table 1.2). Table 1.2 : Blood pressure targets of antihypertensive therapy according to several hypertension guidelines Guidelines  General population  With diabetes mellitus or renal disease  JNC 7 2003 [3] British Hypertension Society 2004 [21] 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) [2] 2004 CHEP [22, 23] 2007 European Society of Hypertension-European Society of Cardiology [24]  <140/90 mmHg <140/85 mmHg  <130/80 mmHg <130/80 mmHg  <140/90 mmHg  <130/80 mmHg  <140/90 mmHg <140/90 mmHg  <130/80 mmHg <130/80 mmHg  1.1.4.1 Non pharmacological treatment In the algorithm for the treatment of hypertension, therapy begins with lifestyle modification. Some examples of these lifestyles modifications include weight reduction in those individuals who are overweight or obese, reduced total fat and saturated fat intake, reduced dietary sodium intake, increased physical exercise and smoking cessation. Non-pharmacological treatment may preclude or reduce the need for drug treatment in some patients. However, pharmacological treatment is frequently required to achieve and maintain adequate BP control, and a large number of patients will need more than one drug to achieve BP control. 1.1.4.2 Pharmacological treatment The first antihypertensive drugs that were used were the veratrum alkaloids in the 1930’s followed by Thiocyanates and ganglion-blocking agents in the 1940’s. Rauwolfia compounds such as reserpine were introduced in the early 1950’s, followed by the vasodilator hydralazine, peripheral sympathetic inhibitors such as guanethidine and the  5  thiazide diuretics. In the 1960’s, central sympathetic inhibitors and beta-adrenergic blocking agents (BB) were introduced. In the 1970’s alpha-adrenergic blocking agents such as prazosin and the angiotensin-converting enzyme inhibitors (ACEI) began to be used and in the 1980’s the calcium channel blockers (CCB) were introduced. The 1990’s saw the addition of the angiotensin II receptor blockers (ARB). The newest class of agents as of this date is the oral renin inhibitor aliskiren, which was approved for treatment of hypertension by US Food and Drug Administration in 2007. There are a large number of antihypertensive drugs on the market today that lower BP. In general, decisions about which agent or class to use as first-line or second-line in the management of elevated BP should be based on the best available RCT evidence of effectiveness assessing mortality and morbidity outcomes as compared to placebo or no treatment. Four systematic reviews using this evidence to assess the evidence for the five major classes of drugs (thiazide diuretics, ACEI, ARB, CCB and BB) have concluded that the evidence is best for low-dose thiazide therapy [25-28]. No other classes of drugs (ACEI, ARB, BB, CCB and α- blocker) were significantly better than low-dose thiazide diuretics for any of the cardiovascular outcomes. 1.1.5 Classes of commonly used anti-hypertensive drugs Diuretics lower sodium load in the body resulting in reduction of plasma and extracellular fluid volume and BP. Thiazides, such as hydrochlorothiazide or thiazide-like drugs such as chlorthalidone, act primarily on the distal convoluted tubule to block the sodium-chloride co-transporter, inhibiting sodium reabsoprtion. They have also been shown to decrease peripheral vascular resistance with long term therapy [29]. The BP lowering effect has been suggested to be due to a direct vasodilatory effect independent  6  of sodium-chloride co-transporter inhibition [30]. Loop diuretics inhibit sodium reabsorption in the ascending limb of the loop of Henle by inhibiting the sodiumpotassium-chloride co-transporter. They are the most powerful of the diuretics because they act on the thick ascending limb, which handles the largest fraction of sodium reabsorption. Potassium-sparing diuretics such as amiloride and triamterene inhibit reabsorption at the distal site of the renal tubule and are usually used in combination with other diuretics to reduce the risk of hypokalemia rather than for their BP lowering effect. The mechanism by which ACEI reduce BP is by blocking the conversion of angiotensin I to angiotensin II which is enzymatically mediated by ACE. Angiotensin II (AII) is a potent vasoconstrictor and also stimulates aldosterone secretion. The administration of ACEI results in vasodilation and dilation of efferent arteriole. Administration of ACEI has also been associated with an increase in bradykinin levels which may contribute to the vasodilatory effect. The production of AII is not completely blocked by ACEI because other enzymes such as tissue-based chymases may facilitate the formation of AII from its precursors. ARBs were introduced to inhibit the binding of AII to the angiotensin II type 1 (AT1) receptor thereby selectively inhibiting the vasoactive properties of AII. A newer class of agent that also blocks the renin-angiotensin-aldosterone system (RAAS) is the renin inhibitor, aliskiren, which directly inhibits plasma renin activity. The exact mechanism by which beta-blockers (BB) lower BP has not been established. Blockade of beta receptors (specifically, beta-1 receptors) in the heart reduces heart rate, myocardial contractility and conductivity. Beta-blockers cause a reduction in total peripheral resistance, and inhibit renin release by the kidneys.  7  Additional vasodilatory effects can be induced by drugs with beta-2 sympathomimetic activity such as pindolol or with combined beta and alpha adrenergic blockade such as labetolol or carvedilol Calcium-Channel Blockers (CCB) inhibit calcium entry into vascular smooth muscles by preventing opening of voltage-gated L-type channels. The 3 chemically distinct classes of CCBs are the dihydropyridines (eg nifedipine), phenyalkylamines (eg verapamil) and benzothiazepines (eg diltiazem). The predominant feature of dihydropyridines is arterial dilatation. They are strong vasodilators, acting via relaxation of vascular smooth muscle cells. They have a small negative inotropic effect which is usually overcome by a reflex increase in sympathetic activity. Phenylalkylamines have the most cardiac effect with negative chronotropic and dromotropic effects and the least vasodilatory effects in the group. Benzothiazepines have both cardiac depressant and vasodilator actions and are intermediate between the other two groups. Centrally-acting drugs inhibit sympathetic outflow via stimulation of central alpha-2 adrenergic receptors or type-1 imidazoline (I-1) receptors located in the nucleus tractus solitarii and the rostral ventrolateral medulla respectively. Methyldopa is the classic example of an alpha-2 agonist and act by stimulating central alpha receptors in the central nervous system, activating inhibitory neurons to produce a decrease in sympathetic outflow, resulting in a decrease in BP. Other drugs such as moxonidine and rilmenidine primarily activate I-2 receptors to inhibit central sympathetic activity. Clonidine shows equal affinity for both receptors.  8  1.2 1.2.1  Combination therapy Achieving blood pressure reduction (surrogate outcome) As mentioned earlier, morbidity and mortality from CVD have been shown to  correlate with the level of BP. Another important goal of treating high BP is to prevent further increases in BP. From large RCTs it has become clear that it is a challenge to reach and maintain BP targets in many patients. BP goals are not likely to be achieved at the starting dose of the first drug used. In fact, monotherapy, even when titrated to high doses, is effective in achieving the standard target BP of ≤140/90 mmHg in only 50% of a population with a baseline DBP of 95-109 mmHg [31]. Low-dose monotherapy, however, remains the accepted initial treatment. If BP is inadequately controlled with the low-dose monotherapy, 3 options are available. The first is to increase the daily dosage of the first drug to the maximum indicated or tolerated dose. The second option is to stop the first drug and do a trial of sequential monotherapy with different classes of drugs in the hopes of finding the drug that lowers BP to the greatest degree in that particular patient. This option would take a considerable length of time. The third option is to add a second drug from another class and at a low dose. JNC guidelines, which have been published since 1977, first recommended low dose combinations as initial treatment in 1997 [32]. In the most recent publication, JNC7, the guideline states “when BP is more than 20/10mmHg above goal, consideration should be given to initiating therapy with 2 drugs, either as separate prescriptions or in fixeddose combinations” since monotherapy is unlikely to be adequate in such people [3]. As stated in the WHO/ISH guidelines, “It is often preferable to add a small dose of a second  9  drug rather than increasing the dose of the original drug. This allows both the first and second drugs to be used in a low dose range, which is more likely to be free of side effects [2]. 1.2.2  Importance of combination therapy Hypertension is a multifactorial condition with more than one mechanism  involved in its pathogenesis. Modification of one physiologic system by monotherapy usually triggers a compensatory response from another system, limiting the fall in BP. Multiple inhibitory mechanisms are therefore likely to be more effective than a single one. The pharmacological rationale for combining 2 drugs of different classes is that by working at a separate site, different effector pathways can be interfered with. Also, the antihypertensive effectiveness of administration of a single drug might be lessened by counter-regulatory mechanisms in the body which tends to return BP values towards pretreatment values. By combining antihypertensive agents that possess different mechanisms of action, each component can potentially neutralize or minimize counterregulatory mechanisms triggered by the other, and thus help to further lower the BP. As well, low doses are generally used in combination therapy, which can minimize both the clinical and metabolic adverse effects seen with higher doses of the individual components. It has also been shown that one component of a fixed-dose combination therapy can effectively counterbalance the tendency of the other to produce adverse effects. For example, the peripheral edema that is associated with CCB occurs less frequently when an ACEI is co-administered [33, 34] However, there are some potential disadvantages to initiating treatment with fixed-dose combination therapy. If side effects occur, it will not be clear which drug is  10  responsible. In the event of a side effect both drugs would likely have to be discontinued. Moreover, BP can be controlled with only one drug in some patients even in Stage 2 hypertension; therefore, starting with 2 drugs will lead to unnecessary long-term treatment with the second drug. Finally, by starting with fixed-dose combination therapy, the risk of excessive hypotension is likely increased. 1.2.3  Pharmacological rationale for drug combinations in hypertension Many choices are available when considering combination therapy for  hypertension. The concept is to provide unique complementary benefits for both efficacy and safety or tolerability. Below are described some of the possible advantages of adding diuretic as a second-line drug in combination with other classes of antihypertensive drugs. By inducing salt excretion and reducing plasma volume, diuretics stimulate the renin-aldosterone-angiotensin system (RAAS). This results in an increased production of renin and angiotensin, thus potentially enhancing the BP lowering effect of ACEI, as these agents directly inhibit the diuretic induced RAAS activity. Thus diuretics added to any of the drugs that block the RAAS system including ACEI, ARB and renin inhibitors is likely a good combination. Diuretics can minimize the risk of hyperkalemia in patients treated with ACEI. The advantages of adding a diuretic to a BB or CCB are less obvious, however, in each case the drugs are probably working by different mechanisms. Some authors have suggested that the combination of a diuretic and CCB is not rational. These controversies enhance the interest of the proposed systematic review as if they were true, one would  11  expect the BP lowering effect of the diuretic as second-line drug to be different depending on the first-line drug. 1.2.4  Use of combination therapy Monotherapy remains the preferred way to initiate drug therapy, and therapy  should be individualized according to the individual’s response. A few fixed-dose combinations are available in Canada. However, they are not indicated for initial therapy in patients with mild to moderate hypertension. Dosage must be individualized and each component should be titrated separately. For example, thiazide diuretic should be introduced at a low dose and then progressively increased. It is recommended to use individual drugs (prescribed as separate drugs). Fixed combination tablets would only be an advantage when they supply the particular dose that has been determined to work in an individual [35]. 1.2.5  Clinical evidence of combination therapy for treatment of hypertension It has been shown in many clinical trials that for the majority of hypertensive  patients, one drug therapy is insufficient to attain and/or maintain BP goals. Recent studies have shown that most patients require a combination of antihypertensive medications to reach the BP goal. The HOT study randomized 18790 patients (mean BL 170/105mmHg) to 3 different diastolic BP target groups: ≤90mmhg, ≤85mmHg and ≤80mmHg [36]. At the end of the study (average follow-up time of 3.8years), 78% of the patients were still taking felodipine as baseline therapy, usually together with an ACEI (41%), BB (28%) or diuretics (22%), which reflects the need for combination therapy. In the UKPDS trial, type II diabetic patients randomized to tighter BP control (<150/85mmHg) required an  12  increased number of antihypertensive agents than did the control group (<180/105mmHg) [37]. At 9 years follow up, about 60% of the patients required 2 or more drugs to maintain BP lower than 150/85mmHg from a baseline pressure of 159/94mmHg. It was also shown in the SHEP trial that a large percentage of participants (elderly with isolated systolic hypertension) required multi-drug therapy to reach goal SBP of a least 20 mmHg reduction from an average baseline BP value of 170/77mmHg [38]. Only 46% of the patients were receiving step 1 monotherapy at the end of 5 years. Similarly, in the SYSEUR trial (174/86 mmHg), only about 40% of patients reached target BP (reduction of SBP by at least 20 mmHg or to less than 150 mmHg) on monotherapy at the end of 4 years follow-up [39]. These trials confirmed that less than 50% of patients can be controlled by monotherapy and the rest will eventually require additional drugs added to their treatment regimen. At least one second- or third- line drug was necessary to achieve modern treatment targets and the necessity of combination therapy has also been shown in many other trials as well [40, 41, 42]. Although patients were usually started on a onedrug therapy, none of these trials were strictly a trial of monotherapy because add-on was permitted and a substantial proportion of patients received more than one drug at the end of the trial.  13  1.3  References  1. Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide data. Lancet 2005;365:217-23 2. World Health Organization, International Society of Hypertension Writing Group. 2003 World Health Organization/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertension 2003; 21:1983-1992. 3. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003 Dec;42(6):1206-52 4. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality. Lancet. 2002;360:1903-1913 5. Rose G. Epidemiology. In: Marshall AJ, Barritt DW, eds. The Hypertensive Patient. Kent, UK: Pitman Medical, 1980:1–21. 6. Franklin SS, Larson MG, Khan SA, et al. Does the relation of blood pressure to coronary heart disease risk change with again? The Framingham Heart Study. Circulation. 2001; 103: 1245-49 7. Haider AW, Larson MG, Franklin SS, Levy D; Framingham Heart Study. Systolic blood pressure, diastolic blood pressure, and pulse pressure as predictors of risk for congestive heart failure in the Framingham Heart Study. Ann Intern Med. 2003; 138(1):10-6. 8. Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Is Pulse Pressure Useful in Predicting Risk for Coronary Heart Disease?: The Framingham Heart Study. Circulation 1999; 100:354-360 9. Antikainen RL, Jousilahti P, Vanhanen H, Tuomilehto J. Excess mortality associated with increased pulse pressure among middle-aged men and women is explained by high systolic blood pressure. J Hypertens. 2000; 18: 417–423 10. Frattola A, Parati G, Cuspidi C, Albini F, Mancia G. Prognostic value of 24-hour blood pressure variability. J Hypertens 1993; 11:1133-1137. 11. Kuwajima et al. Cardiac implications of the morning surge in blood pressure in elderly hypertensive patients: relation to arising time. Am J Hypertens 1995; 8: 29-33.  14  12. Sander D, Kukla C, Klingelhofer J, Winbeck K, Conrad. Relationship Between Circadian Blood Pressure Patterns and Progression of Early Carotid Atherosclerosis. Circulation. 102:1536:1541, 2000. 13. Eto M, Toba K, Akishita, M et al. Impact of blood pressure variability on cardiovascular events in elderly patients with hypertension. Hypertens Res 2005; 28:1-7. 14. Hata Y, Muratani H, Kimura Y et al. Office blood pressure variability as a predictor of acute myocardial infarction in elderly patients receiving antihypertensive therapy. Journal of Human Hypertension. 2002; 16:141-146 15. Gillman MW, Kannel WB, Belanger A, D’Agostino RB. Influence of heart rate on mortality among person with hypertension: The Framngham Study. Am Heart J. 1993; 125:1148-1154. 16. Mensink GBM, Hoffmeister H. The relationship between resting heart rate and allcause, cardiovascular and cancer mortality. European Heart Journal 1997;18:1404-1410 17. Greenland P, Daviglus ML, Dyer AR et al. Resting Heart Rate is a Risk Factor for Cardiovascular and Noncardiovascular Mortality. Am J Epidemiol. 1999; 149:853-62 18. Wright JM, Musini VM. First-line drugs for hypertension. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD001841. DOI: 10.1002/14651858.CD001841.pub2. 19. Staessen JA, Gasowski J, Wang JG, Thijs L, et al. Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet 2000; 355: 865-872. 20. Arguedas JAQ, Perez MI, Wright JM. Treatment blood pressure targets for hypertension. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD004349. DOI: 10.1002/14651858.CD004349.pub2. 21. Williams B, Poulter NR, Brown MJ, Davis M, McInnes GT, Potter JP, Sever PS and Thom S McG; The BHS Guidelines Working Party Guidelines for Management of Hypertension: Report of the Fourth Working Party of the British Hypertension Society, 2004 - BHS IV. Journal of Human Hypertension 2004; 18: 139-185 22. Hemmelgarn B, Zarnke KB, Campbell NRC, Feldman RD, McKay DW, McAlister FA, Khan NA, Schiffrin EL, Myers MG, Bolli P, Honos G, Lebel M, Levine M, Padwal R, for the Canadian Hypertension Education Program. The 2004 Canadian Hypertension Education Program recommendations for the management of hypertension: Part I: Blood pressure measurement, diagnosis and assessment of risk. Can J Cardiol 2004;20(1):31-40. 23. Khan NA, McAlister FA, Campbell NRC, Feldman RD, Rabkin S, Mahon J, Lewanczuk R, Zarnke KB, Hemmelgarn B, Lebel M, Levine M, Herbert C, for the  15  Canadian Hypertension Education Program. The 2004 Canadian recommendations for the management of hypertension: Part II: Therapy. Can J Cardiol 2004;20(1):41-54. 24. Mancia, G, De Backer, G, Dominiczak, A, et al. 2007 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). J Hypertens 2007; 25:1105. 25. 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 26. Psaty BM, Lumley T, Furberg CD, Schellenbaum G, Pahor M, Alderman MH, Weiss NS. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA 2003; 289(19):2534-44. 27. Psaty BM. Smith NL. Siscovick DS. Koepsell TD, et al.Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and metaanalysis.. JAMA 1997;277:739-745. [MEDLINE: 97195474] 28. Wright JM, Musini VM. First-line drugs for hypertension. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD001841. DOI: 10.1002/14651858.CD001841.pub2. 29. Van Brummelen P, Man in t’Veld AJ, Schalekamp MA. Hemodynamic changes during long-term thiazide treatment of essential hypertension in responders and nonresponders. Clin Pharmacol Ther 1980; 279:328-336 30. Pickkers P, Hughes AD, Franse GM, et al. Thiazide-induced vasodilatation in humans is mediated by potassium channel activation. Hypertension 1998; 32:1071-76 31. Materson BJ, Reda DJ, Cushman WC, et al. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. N Engl J Med. 1993;328:914-921. Erratum in: N Engl J Med. 1994;330:1689. 32. The Sixth Report of the Joint National Committee on Detection, Evaluation, and Diagnosis of High Blood Pressure (JNC VI). Arch Intern Med 1997; 157:2413. 33. Gradman AH, Cutler NR, Davis PJ, et al. Combined enalapril and felodipine extended release (ER) for systemic hypertension. Am J Cardiol. 1997;79:431–435. 34. Messerli FH, Oparil S, Feng Z. Comparison of Efficacy and Side Effects of Combination Therapy of Angiotensin-Converting Enzyme Inhibitor (Benazepril) With Calcium Antagonist (Either Nifedipine or Amlodipine) Versus High-Dose Calcium Antagonist Monotherapy for Systemic Hypertension. Am J Cardiol 2000;86:1182–1187  16  35. Canadian Pharmacists Association. Compendium of Pharmaceuticals and Specialties. [Accessed on July 2008]. Available Online from: URL: https://www.e-therapeutics.ca 36. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J,Rahn KH, Wedel H, Westerling S. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. HOT Study Group. Lancet 1998; 351(9118):1755-62. 37. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317:703-713 38. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991;265:3255-64. 39. Staessen JA, Fagard R, Thijs L et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997; 350: 757–64 40. Agodoa LY, Appel L, Bakris GL , et al, and the African American Study of Kidney Disease and Hypertension (AASK) Study Group. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA 2001; 285: 2719 –2728. 41. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med 1998;338:645-52. 42. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensinconverting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288:2981-2997.  17  2  SYSTEMATIC REVIEW 2.1  What are systematic reviews and why do we need systematic reviews? One of the methods to incorporate research evidence into clinical decision making  is the systematic review [1]. A systematic review is a literature review that addresses a specific research or clinical question, and in which evidence is systematically identified, appraised, and summarized according to pre-defined, explicit methods. Because of the overwhelming and ever-increasing amount of research information, it is difficult for health professionals, policy makers and consumers to stay informed and up-to-date in making informed health-related decisions. Therefore, systematic reviews are needed to efficiently integrate existing information and provide data for rational decision making. Systematic reviews can assess consistency of study findings and whether the scientific findings can be generalized [2]. Systematic reviews can be qualitative or quantitative. It is called a meta-analysis when statistical methods are used to generate a pooled estimate of a treatment effect or other end points. Combining the data from individual studies quantitatively using statistical methods increases the statistical power of the analysis and the precision of the treatment effect size [3]. Most review articles are narrative rather than systematic, and generally cover a broader scope within a specific topic. Both narrative and systematic reviews are retrospective studies and, therefore, are subject to bias. Therefore, the process of conducting a review must be rigorous and according to a well-defined methodology. The main and most crucial difference between a narrative and systematic reviews is the extent to which review methods have been used to minimize errors and bias. Narrative reviews  18  are most often written by experts in a given field using partial selection of the literature that support their preconceived opinions and exclude those with conflicting views. A narrative review is unscientific because it lacks formal tools to identify, evaluate, and synthesize the research evidence, making it impossible to replicate and the validity of the conclusions and recommendations questionable. In contrast to traditional narrative reviews, systematic reviews are designed to minimize bias and random errors (and ensuring their reliability) by employing explicit methods which are clearly stated. The approach used to identify and critically appraise all relevant studies, and to extract and synthesize data is pre-specified and transparent to allow reproducibility by others. Nevertheless, all reviews are retrospective, and hence subject to bias. Meta-analysis of primary studies could produce an inflated effect size if publication bias is present where positive-results studies are more likely to be published (sometimes more than once) than negative-result studies. There have been numerous methods to detect publication bias and statistical and remodeling methods are available to correct for this type of bias and to provide a more accurate estimate of the true effect size [4, 5, 6]. Other bias such as selection and observer bias can be minimized by having multiple reviewers to select the studies and extract the data. 2.2  The Cochrane collaboration The Cochrane collaboration is an international organization that aims to produce,  maintain, and disseminate up-to-date systematic reviews on all areas of health care. Founded in 1993, it is named after the British epidemiologist, Archie Cochrane, and is based on 10 key principles: collaboration, building on the enthusiasm of individuals,  19  avoiding duplication, minimizing bias, keeping up to date, striving for relevance, promoting access, ensuring quality, continuity, and enabling wide participation [7]. Cochrane reviews are published in the Cochrane Database of Systematic Reviews section of the Cochrane Library (updated quarterly). Because they are published electronically, it allows reviews to be replaced with updated version in response to new evidence or comments and criticisms from readers. The standardized framework of preparing a systematic review within the Cochrane collaboration can be found in the Cochrane handbook [2]. 2.3  Aim of this systematic review The issue of which antihypertensive agent should be used in first-line treatment  has been controversial for almost decades. Not surprisingly, there are also controversies as to the optimal drug combinations in terms of long-term outcomes (taking into consideration BP control and/or specific effects of specific drugs). However, all these studies underpin the importance of combination therapy in hypertension treatment. Therefore it is important to assess the BP lowering efficacy of all possible combinations. A systematic review published by Law and Wald has attempted to determine the BP lowering efficacy of five classes of antihypertensive agents (thiazides, ACEI, ARB, BB, and CCB as monotherapy and of 2 or more drugs in combination [8]. The authors analysed data from 50 studies to assess whether the combined effect of two drugs of different classes was additive with respect to BP reduction. The placebo-corrected mean weighted BP reduction of the ‘first drug’ monotherapy group, the ‘second’ drug monotherapy group, and the combination group (‘first’ and ‘second’ drugs given together) were evaluated. The review demonstrated that there was no statistical  20  significant difference between the expected BP reduction (sum of the first and second drugs alone) and the observed BP reduction in the combination group, concluding that the combination of major groups of antihypertensives was strictly additive. The authors also suggested that the effect of three drugs in combination would also be additive based on no trial assessing the BP effect of 3 drugs in combination. The authors did not attempt to compare the dose-related additional BP lowering efficacy of each major drug class separately as second-line therapy. This thesis is a systematic review designed to determine the additional BP lowering efficacy of second-line diuretics in patients with primary hypertension. Unlike Law and Wald’s review, it is not limited to RCTs with a placebo arm. Focussing on diuretics as second-line alone, this review has included 56 trials, more than what was identified by Law and Wald’s review. This current review will be able to quantify the additional reduction in SBP/DBP one would expect to achieve with the addition of a diuretic as the second drug in combination. A well-formulated research question includes five basic components: 1) types of study design 2) types of participants 3) types of interventions (exposure) 4) types of outcomes, and 5) types of control (any comparators where relevant). In this present review, the research question is: “In double-blind randomized controlled trials, what is the magnitude of additional BP reduction induced by diuretic given as a second drug in combination therapy in primary hypertensive patients?” 2.4  Protocol The protocol of this systematic review was finalized on April 2008 and published  in Issue 2, 2008 of the Cochrane Library [9] to outline the predefined procedural methods that would be followed in conducting this review.  21  2.4.1  Objectives  Primary Objective To quantify the additional reduction in systolic blood pressure (SBP) and diastolic blood pressure (DBP) of a diuretic as second-line therapy in patients with primary hypertension. Secondary Objectives 1. To determine the effects of a second-line diuretic on variability of blood pressure. 2. To determine the effects of a second-line diuretic on pulse pressure (PP). 3. To quantify the effects of a second-line diuretic on heart rate (HR). 4. To quantify the effects of a second-line diuretic on withdrawals due to adverse effects (WDAE). 2.4.2  Methodology  2.4.2.1 Types of studies Only randomized controlled trials (RCTs) were included and the study must have met the following criteria: •  Double-blind  •  Parallel design with random allocation treatment groups  •  Washout period of at least 2 weeks prior to randomization  •  Office BP measurement at baseline (following washout) and at one or more time points between 3 to 12 weeks post-treatment  2.4.2.1.1 Why are only randomized controlled trials included? In RCTs, patients are randomly assigned to receive one of two or more clinical interventions. With random assignment, each patient has an equal probability of being assigned to any given group. This helps to eliminate selection bias and balance known  22  and unknown baseline confounding factors, minimizing their influence on the outcomes of the study. Using this approach, any differences in outcomes can be attributed to the differences in the intervention received (study treatments). However, selection bias can still be introduced in RCTs if the statistical analysis of the study is not based on an intention-to-treat analysis. If some patients are excluded from the analysis, the baseline prognostic factors between the groups at baseline might no longer be evenly distributed, which could lead to potential bias. 2.4.2.1.2 Why is blinding (masking) necessary? Blinding helps to reduce bias after the assignment of treatments. Studies that will be included in this review will be double-blind RCTs in which the patients and the investigators are unaware of which treatment each patient is receiving. Knowledge of treatment assignment could lead to alteration of the study results arising from the participants, care-provider or the people who assess the outcomes. Double-blinding ensures that their preconceived views cannot systematically bias the assessment of outcomes. Blood pressure, the primary outcome in this review, is highly subject to observer bias when the BP is measured by auscultation. 2.4.2.1.3 Why is a baseline measurement subsequent to a washout/placebo run-in period important? A washout period (single-blind placebo run-in) helps to eliminate carry-over effects from previous drug therapy before the clinical trial is commenced. In trials with cross-over design, a washout period would also be necessary between different treatment periods for the same reason. Before randomization, data at the end of the run-in are collected providing the baseline data for the patients (i.e. baseline BP and HR data). The  23  washout period also serves to screen out ineligible patients. Patients who did not meet the inclusion BP criteria at the end of the washout period are not entered into the study. 2.4.2.1.4 Why is the 3 to 12 week window selected? Data obtained within the 3 to 12 week treatment period will be used in the analysis for this systematic review. The window period was selected based on a previous systematic review. A minimum of 3 weeks was required for the maximum effect of the drugs to be observed. An upper duration limit of 12 weeks was chosen to maximize the number of patients included in the analysis as withdrawals rate increases with the duration of the therapy. Also, with longer duration trials, patients are more likely to receive additional drugs or dose titration if they continue to fail to achieve the target BP level. Trials meeting the inclusion criteria but with greater than 12 weeks duration will be included only if they provided data for the 3 to 12 week treatment period. 2.4.3  Types of participants Men and non-pregnant women at least 18 years old with an office baseline SBP of  at least 140 mmHg and/or DBP of at least 90 mmHg. Participants with significant renal failure or creatinine levels greater than 1.5 times the normal value were excluded because these patients usually require dose adjustments. Patients were not restricted by other baseline risks or co-morbid conditions. 2.4.4  Types of interventions Combination therapy with a diuretic plus other non-diuretic antihypertensive  drug(s) versus other non-diuretic antihypertensive drug(s) alone. The addition of a diuretic must have been the only difference between the combination and monotherapy groups. In the case of fixed-dose combination, the pill should be identical in appearance  24  and taste to the individual components; in other cases where drugs are administered separately in the combination group, the monotherapy group should receive a matching placebo (double-dummy design) The diuretics that were included in this review were the loop diuretics and the thiazides. Potassium-sparing diuretics and aldosterone antagonists were not included in this review. The non-diuretic component included pharmacological agents in the following drug classes: Angiotensin-converting enzyme inhibitor (ACEI); calcium channel blocker (CCB); beta-blocker (BB); angiotensin receptor blocker (ARB); renin inhibitor (RI); and centrally-acting drugs (CAD) (but limited to guanabenz, rilmenidine, clonidine, moxonidine, methyldopa and guanfacine). All dosages and combinations of these drugs were considered. Trials in which titration to a higher dose was based on BP response were excluded. For forced titration trials, data from the lowest dose given within 3 to 12 weeks period were extracted. 2.4.5  Types of outcome measures  Primary Outcome •  Additional reduction in SBP and DBP with second-line diuretics. This was the difference in change from baseline in trough SBP and DBP at 3 to 12 weeks between the combination and monotherapy groups. If BP measurements were available at more than one time during the 3 to 12 week treatment period, the weighted mean of the BP data were used in this review.  Secondary Outcomes •  Change in standard deviation of BP with combination therapy as compared to monotherapy  25  •  Incidence of withdrawals due to adverse effects with combination therapy as compared to monotherapy  •  Change in heart rate with combination therapy as compared to monotherapy  •  Change in pulse pressure with combination therapy as compared to monotherapy  2.4.6  Search methods for identification of studies The following electronic databases were searched for relevant RCTs: MEDLINE  (1966 to July 2008), EMBASE (1988 to July 2008), and the Cochrane Central Register of Controlled Trials (The Cochrane Library 2008, Issue 2). We also searched the bibliographic citations of included studies and review articles for relevant studies not already identified by our comprehensive search. Authors were contacted to retrieve missing information. No language restrictions were applied. The structure of the electronic search strategy was based on the standard search strategy of the Hypertension Review Group, and modified and expanded with additional terms to identify RCTs assessing a diuretic combined with other antihypertensive drug classes for the treatment of primary hypertension (see Appendix A). 2.4.7  Study selection The titles and/or abstracts obtained from the search strategies were screened by  one reviewer. During the initial abstract screening, those studies that were irrelevant to the review or clearly did not meet the inclusion criteria were rejected. The remaining trials were obtained in full text to assess whether they met the pre-specified inclusion criteria. Trials were then assessed for inclusion eligibility by two reviewers independently. Any discrepancies were resolved by a third reviewer. Trials with multiple publications were counted only once.  26  2.4.8  Data extraction Data were extracted independently by two reviewers using a standardized form,  and then cross-checked. All numeric calculations and graphic interpolations were confirmed by a second person. The position of the patient during BP measurement may affect the BP lowering affect. When measurements were reported in more than one position, the order of preference was: 1) sitting; 2) standing; and 3) supine. In the case of missing information in the included studies, investigators were contacted (by email, letter and/or fax) to obtain the missing information. In the case of missing standard deviation of the change in BP or heart rate (HR), the standard deviation was imputed based on the information in the same trial or from other trials using the same dose. The following hierarchy (listed from high to low preference) was used to impute standard deviation values: 1. Standard deviation of change in BP/HR from a different position than that of the BP/HR data used. 2. Standard deviation at the end of treatment. 3. Standard deviation at the end of treatment measured from a different position than that of the BP/HR data used. 4. Standard deviation at baseline (except if this measure was used for entry criteria). 5. Mean standard deviation of change from other trials using the same drug and dose. 2.4.9  Risk of bias assessment The risk of bias in included studies was assessed using the Cochrane  Collaboration's recommended tool, which is a domain-based critical evaluation of the  27  following domains: sequence generation; allocation concealment; blinding; incomplete outcome data; selective outcome reporting; and other sources of bias [2]. 2.4.10 Data analysis and statistical consideration Data synthesis and analyses was done using the Cochrane Review Manager software, RevMan 5.0.20. Data for changes in BP and HR were combined using a weighted mean difference method. WDAE was analyzed using relative risk, risk difference, and number needed to harm. If possible, subgroup analyses were used to assess the results for specific categories of participants: 1) Age: adults (18-69 yrs), older people (70 years and older) 2) Race: White; Black; other 3) Baseline severity of hypertension: mild; moderate; severe 4) Drug classes: The different classes of drug used in combination with a diuretic 2.4.11 Direct and indirect comparisons When possible, direct and indirect comparisons of effect sizes were performed between different doses of diuretics. In the direct method, only trials that randomized patients to various doses of diuretics in combination therapy were included in the analysis. In the indirect method, an "adjusted indirect comparison" and the associated standard error were calculated using the methods previously described by Bucher 1997 and Song 2003 [10, 11]. A p-value less than 0.05 was considered statistically significant for all comparisons. Tests for heterogeneity of the treatment effect between trials were made using a standard chi-square statistic for heterogeneity. The fixed effect model was applied  28  to obtain summary statistics of pooled trials, unless significant between-study heterogeneity was present, in which case the random effects model was used. This model provides a more conservative statistical comparison of the difference between combination therapy group and monotherapy group because a confidence interval around the effect estimate is wider than a confidence interval around a fixed effect estimate. If a statistically significant difference was still present using the random effects model, the fixed effect pooled estimate and confidence interval were used as the best estimate because of the tendency of smaller trials, which are more susceptible to publication bias, to be over-weighted with a random effects analysis.  29  2.5  References  1. Cook DJ, Mulrow CD, Haynes RB. Systematic reviews: synthesis of best evidence for Clinical Decisions. Annals of Internal Medicine 1997; 126: 376-380. 2. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 [updated September 2008]. The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org. 3. Mulrow CD. Systematic Reviews: Rationale for systematic reviews. BMJ 1994; 309: 597-599. 4. Sutton AJ, Duval SJ, Tweedie RL, Abrams KR, Jones DR. Empirical assessment of effect of publication bias on meta-analyses. BMJ 2000;320:1574–7 5. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088-101. 6. Egger M, Smith GD, Schneider M, Minder C. Bias in detected by a simple, graphical test. BMJ 1997;315:629-34. 7. The Principles of the Cochrane Collaboration. [Cited on July 2009]. Available Online from: URL:http://www.cochrane.org/docs/tenprinciples.htm 8. 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 9. Chen JMH, Heran BS, Perez MI, Wright JM. Blood pressure lowering efficacy of diuretics as second-line therapy for primary hypertension (Protocol). Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD007187. DOI: 10.1002/14651858.CD007187. 10. Bucher HC, Guyatt GH, Griffith LE, Walker SD. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. Journal of Clinical Epidemiology 1997;50(6):683-691. 11. Song F, Altman DG, Glenny A-M, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published metaanalyses. BMJ 2003;325 : 472-476.  30  3  RESULTS 3.1  Search findings The search strategy was developed to identify all double-blind, RCTs that assess  the BP lowering efficacy of combination therapy versus their individual components in hypertensive patients. A search was performed to identify relevant trials for this review, and also for 3 other reviews which addressed similar research questions but focused on ACE inhibitors [1], angiotensin receptor blockers [1], renin inhibitors [1], beta blockers [2] and calcium channel blockers [3] as second-line drugs in combination therapy. In total, this search strategy identified 25084 citations and only 56 (0.2%) trials met the inclusion criteria and had data suitable for analysis in this systematic review (Figure 3.1). Forty-four other studies that met the inclusion criteria of this review were excluded because they did not provide extractable data (see section 3.1.2).  31  Figure 3.1: QUOROM flow diagram  25084 citations identified by search strategy 24094 citations excluded upon reading titles and/or abstracts 990 citations retrieved for detailed reading  250 potentially relevant trials for all four systematic reviews evaluated in detail  740 reviews and studies excluded upon detailed readings. Bibliographies of review articles searched for relevant trials  150 trials excluded - Irrelevant to this systematic review 100 trials meeting inclusion criteria for this systematic review 44 “excluded trials” - Insufficient data for this review 56 “included trials” with data available  3.1.1  Characteristics of included studies All the included studies were of parallel design. Of all the 56 included studies, 53  (95%) were published in English, 1 in German, 1 in French, and 1 in Spanish. Funding sources were only reported in 28 (50%) of the included studies. All the studies that reported funding source were industry funded. Fifty-three of the included studies assessed thiazides (49 with hydrochlorothiazide, 2 with indapamide, 1 with clopamide, and 1 with  32  chlorthalidone) and 3 included studies assessed loop diuretics (2 with piretanide and 1 with frusemide). There were no studies found that assessed the effect of a diuretic as a third-line drug. There were 7 studies that assessed the effect of a thiazide and a potassium-sparing diuretic combination as second-line therapy but these studies were excluded from this review. Table 3.1 summarizes the characteristics of each included study. Each study was assigned a unique identifier consisting of either the surname of the first author followed by the year of publication or the acronym of the trial name. Table 3.1 : Characteristics of included studies Study Study Description Asplund 1981 [4]  Design: 12 weeks double-blind, parallel study after 4 weeks run-in period with placebo. Randomized (methods not described) Participants: 75 patients with supine BP >160/95 mmHg at end of run-in period. Age range : 21-71 (mean: 48 yrs) Interventions: 3 treatment groups (bid): Monotherapy: Metoprolol 100mg (M100); HCTZ 12.5mg (H12.5) Combination: Fixed-ratio M100/H12.5 The dosage was 1 tablet morning and evening in all cases. Primary and Secondary Outcomes: Standing SBP and DBP and HR (timing of measurement not reported), WDAE Funding Source: Not reported  Benz 1998 [5]  Design: 8-week, double-blind, placebo-controlled parallel study after washout period of at least 2 weeks and single-blind placebo treatment for 2-4 weeks; randomized (methods not described) Participants: 871 adult out-patients with sitting diastolic BP 95-115 mm Hg. Difference between enrolment and randomization <=10mm Hg. Age: >18 (range 22-26, mean 52); 58% men. 75% white, 14%black, 11%other.  33  Study  Study Description Interventions: 9 treatment groups o.d.: Placebo Monotherapy: valsartan 80 or 160mg, Hydrochlorothiazide 12.5 or 25mg Combination therapy: valsartan 80mg/ hydrochlorothiazide 12.5mg (V80/H12.5), V160/H12.5, V80/H25, V160/H25. Primary and Secondary Outcomes: Sitting trough SBP and DBP; HR (no quantitative data), WDAE Notes: Efficacy analyses: 865 patients with post-randomization measurements 867 patients included in safety analysis 792/871 patients completed the trial 41 WDAE ( the number of WDAE in each group is not reported) "No statistically or clinically significant differences between groups in sitting or standing pulse rate" Funding Source: Novartis  Bermudez 1982 [6]  Design: 8 week comparative, double-blind, multi-center study after a 2-week placebo run-in period. Data extracted at week 4. Dose is doubled after week 4 if DBP > 90 mmHg. Participants: 76 ambulatory patients with DBP of 95 to 130 mmHg after 2 weeks of placebo run-in. Mean age: 47 years. 24% male. Interventions: 3 treatment groups (od): Monotherapy: Oxprenolol 160mg (O160); Chlorthalidone 20mg (C20) Combination: O160/C20 Primary and Secondary Outcomes: Trough supine SBP and DBP and HR; WDAE Notes: Efficacy analysis in 75 patients; Safety analysis in all 76 patients Language: Spanish Funding Source: Not reported  34  Study  Study Description Primary and Secondary Outcomes: Trough supine SBP and DBP and HR; WDAE Notes: Efficacy analysis in 75 patients Safety analysis in all 76 patients Language: Spanish Funding Source: Not reported  Brown 1990 [7]  Design: 4-week double-blind study after a 2 week placebo period. Randomized (methods not described) Participants: 40 patients, aged between 18 and 70 yrs with supine diastolic BP between 95 and 115mmHg after placebo phase. Mean age 58yrs. 19 male and 21 female. Interventions: 4 treatment groups: Placebo Monotherapy: Perindopril 4mg/day (P4); HCTZ 25mg/day (H25) Combination: P4/H25 (tablets were identical in appearance) Primary and Secondary Outcomes: Trough (24 hours post-dose) standing SBP and DBP; WDAE; HR (no quantitative data) Notes: No dropouts in study. “Heart rate was not influenced by any of the drug treatments used” Funding Source: Not reported  Camera 1995 [8, 9]  Design: 8-week double-blind active treatment following a 4-week single-blind placebo treatment. Randomized (methods not described). Participants: 149 patients, aged between 30 and 70 years, with uncomplicated mild to moderate hypertension (DBP 90-114 mmHg). 42% men. Mean age: 53 years.  35  Study  Study Description Interventions: 2 treatment groups (o.d.): Monotherapy: Lisinopril 20mg (L20) Combination: L20 plus HCTZ 12.5 Primary and Secondary Outcomes: Trough (24-28 hours post-dose) sitting SBP and DBP; WDAE Notes: 143/149 patients completed the study. Funding Source: Not reported  Chadha 1983 [10]  Design: 6 week double-blind trial after a 4-week placebo washout period. Randomized (methods not described). After 4 weeks of therapy, a second dose in the evening was added if DBP >95mmHg. On admission a low salt diet of 36g NaCl was prescribed. Data up to 4 weeks will be used in the review. Participants: 41 adult outpatients, aged 30-70 years, with DBP between 95 and 120mmHg at the end of placebo run-in. Interventions: 3 treatment groups (o.d.): Monotherapy: Penbutolol 40mg (P40); Frusemide 40mg (F40) Combination: P40/F40 Primary and Secondary Outcomes: Erect SBP and DBP and HR (timing of measurement not reported) Notes: Number of patients included in efficacy analysis was not reported. It was assumed in this review that all patients were included in the efficacy analysis Funding Source: Not reported  Chrysant 1994 [11]  Design: "randomization process failed to produce groups which were strictly comparable in terms of the level of hypertension" Participants: 505 patients whose sitting diastolic BP was 100-114mmHg after placebo period. 311 (62%) men. Mean age: 53 yrs. 67% white. 24% black.  36  Study  Study Description Interventions: 6 treatment groups (od): Placebo Monotherapy: Lisinopril 10mg (L10); HCTZ 12.5 mg (H12.5); H25 Combination: L10/H12.5; L10/H25 Primary and Secondary Outcomes: Trough (24±2 hours post-dose) sitting SBP and DBP Notes: 467 patients completed the study. Efficacy analysis: ITT (467 patients) Funding Source: ICI Pharmaceuticals Group  Chrysant 1996 [12]  Design: 6-week, double-blind, parallel multicenter study after a 1-4 week placebo run-in period. Randomized (methods not described). Participants: 334 outpatients, aged 18 years or older, with sitting diastolic BP between 95 and 114mmHg at two consecutive visits during the placebo phase, with a difference of 10mmHg or less at the two visits. 210 (63%) men. 26% black. 70% white. Mean age: 53.5yrs. Interventions: 8 treatment groups (o.d.): Placebo Monotherapy: Benazapril HCl 20mg (B20); HCTZ 25mg (H25) Combination: B5/H6.25; B10/H12.5; B20/H25; B20/H6.25; B5/H25 Study medication was provided in capsules of identical appearance. Primary and Secondary Outcomes: Trough (22 to 26 hrs post-dose) sitting SBP and DBP; HR (no quantitative data) Notes: Efficacy Analysis: all patients randomized to receive double-blind treatment with last post randomization measurement carried forward (n=328). 301/334 patients completed the study. Safety analysis in 334 patients “No clinically important changes from baseline were reported in mean pulse for any treatment group” Funding Source: Ciba Pharmaceuticals  37  Study  Study Description  Chrysant 2004 [13]  Design: 8-week double-blind factorial design study after a 4 week placebo runin period. Participants: 502 patients with average sitting DBP >=100mmHg and <=115mmHg at both week 3 and week 4 placebo run-in visits and a difference of <=7mmHg between the two measurements. 55.6% male and 74.1% white. Mean age: 53years. Interventions: 12 treatment groups (od): Placebo Monotherapy: Olmesartan 10, 20 or 40mg; Hydrochlorothiazide 12.5 or 25mg Combination: All possible combinations Primary and Secondary Outcomes: Trough sitting SBP and DBP; percentage of WDAE Notes: 451 patients completed the study. Percentage of WDAE was low (2%) Funding Source: Sankyo Pharma Inc.  Drayer 1995 [14]  Design: 8-week double-blind, multicenter, placebo-controlled, parallel group study after a 4-week placebo run-in phase. Randomized (methods not described) Participants: 413 ambulatory outpatients with sitting DBP between 95 and 114 mmHg after placebo period. Interventions: 9 treatment groups (od): Placebo Monotherapy: Hydrochlorothiazide 12.5mg (H12.5); Moexipril 3.75mg (M3.75); M7.5; M15; M30 Combination: H12.5/M3.75; H12.5/M7.5; H12.5/M15 Primary and Secondary Outcomes: Trough sitting SBP and DBP; WDAE; HR (no quantitative data)  38  Study  Study Description Notes: 391 patients completed the study "no significant changes in HR within any of the combination or monotherapy treatment groups" Funding Source: Not reported  Fernandez 1994 [15]  Design: 8-week double-blind. Randomized (method not described) Participants: 67 patients of either sex 18 to 75 yrs of age with seated diastolic BP >=95 and <=110 mm Hg. Mean age: 53 yrs. 23 (34%) male. Interventions: 4 treatment groups (o.d): -placebo -monotherapy: fosinopil 20mg (F20), hydrochlorothiazide 12.5mg (H12.5) -combination: F20/H12.5 Primary and Secondary Outcomes: Sitting trough SBP and DBP (24±3hrs after previous dose) Notes: Efficacy Analyses: ITT (blood pressure data at baseline and at least one follow-up visit) = 67 Assume WDAE = 2 (at week 6, two patients were withdrawn from the study due to adverse events) Funding Source: Not reported  Frei 1994 [16]  Design: 8-week multicenter, DB, placebo-controlled, parallel-group trial after a 4-week placebo run-in phase. Randomized (methods not described) Participants: 161 patients with DBP >=95 and <=114mmHg, and SBP <=240mmHg. Mean age 55.1yrs. Interventions: Treatment groups (od): Placebo Monotherapy: Moxonidine 0.4mg (M0.4); HCTZ 25mg (H25) Combination: M0.4/H25  39  Study  Study Description Primary and Secondary Outcomes: Sitting BP (timing of measurement not reported); WDAE Funding Source: Not reported  Frishman 1994 [17]  Design: 12-week double-blind, placebo-controlled, multicenter 3x4 factorial trial after a 4-6 week single-blind placebo phase. Randomized (methods not described). Participants: 512 patients aged 21 years or older with mild to moderate essential hypertension whose weight was within 35% of the ideal for height and frame were eligible for randomization. Mean sitting diastolic BP was stable and between 95 and 115 mmHg (inclusive). 364 (71%) male. 366 (71%) non-black. Interventions: 12 treatment groups (od): Placebo Monotherapy: HCTZ 6.25mg (H6.25); H25; Bisoprolol 2.5mg (B2.5); B10; B40 Combination: H6.25/B2.5; H6.25/B10; H6.25/B40; H25/B2.5; H25/B10; H25/B40 Primary and Secondary Outcomes: Trough (24 hours post-dose) sitting SBP and DBP; WDAE Notes: The primary efficacy variable was defined a priori as the change from baseline sitting diastolic BP in patients evaluable at weeks 3-4. (n=465) 403/512 patients completed the study. Funding Source: American Cyanamid Co.  Frishman 1995a [18]  Design: 4-week multicenter, double-blind, placebo-controlled, parallel-group study after 4- to 6-week single-blind placebo treatment. Participants: 547 patients, 21 years or older with sitting DBP between 95 and 115mmHg on 3 consecutive weekly visiting during placebo period.  40  Study  Study Description Interventions: 4 treatment groups (od): Placebo Monotherapy: Bisoprolol 5mg (B5); HCTZ 6.25mg (H6.25) Combination: B5/H25 Primary and Secondary Outcomes: Trough (24hours post-dose) sitting SBP and DBP and HR; WDAE Notes: 509/547 patients for efficacy analysis [310 (61%) male. 82% non-black, 18%black] Funding Source: American Cyanamid Company  Genthon 1994 [19]  Design: 8-week double-blind, multicentre, parallel-group trial following a 4week, single-blind, placebo run-in period. Randomized (methods not described) Participants: 660 patients of either sex, aged between 18 and 75 years, with supine DBP of more than 95mmHg but less than 115mmHg after placebo runin. Systolic BP <=200mmHg. Women of childbearing potential were excluded. Interventions: 3 treatment groups (o.d.): Monotherapy: Ramipril 2.5mg (R2.5); HCTZ 12.5mg (H12.5) Combination: R2.5/H12.5 Primary and Secondary Outcomes: Trough (22-26 hours post dose) supine SBP and DBP; WDAE; HR (no quantitative data) Notes: Efficacy Analysis: per-protocol analysis which excluded certain protocol violators (n=535 because 125/660 patients did not strictly fulfill the inclusion criteria for supine DBP during the placebo run-in). 624/660 patients completed the study. “Whilst heart rate was stable in all groups throughout the study, there was a slight decrease in all groups” Funding Source: Laboratoires Hoechst  41  Study  Study Description  Hart 1991 [20]  Design: 8-week double-blind, parallel-group multicentre study after a 2-week single-blind placebo run-in period. Randomized (methods not described) Participants: 299 patients aged 65-80 years with a sitting DBP of 100120mmHg (inclusive) during the placebo run-in period. 123 (41%) male. Mean age: 71 yrs Interventions: 3 treatment groups (od): Monotherapy: Lisinopril 20mg (L20); HCTZ 12.5mg (H12.5) Combination: L20/H12.5 Primary and Secondary Outcomes: Trough (24-28 hours) sitting SBP and DBP; WDAE Notes: 278/299 patients completed the study Efficacy analysis: Based on "per protocol analysis". Excluded were patients where the number of tablets returned was less or more than expected or if there was any deviation from the protocol during the interval between the last dose of medication and BP measurement (By 8 weeks of treatment 125 patients had complied with the protocol). “There was no statistically significant difference between the groups for HR” 2 patient died during the study "for reasons unrelated to the trial medication" Funding Source: Not reported  Homuth 1993 [21]  Design: 6-week multiclinic, double-blind, placebo-controlled trial after a 2week placebo run-in period. Randomized (methods not described) Participants: 480 patients, aged 21 to 65, with a diastolic BP between 100 and 115mmHg after run-in period. 295 (74%)men. Mean age: 47 years. Interventions: 12 groups (od): Placebo Monotherapy: Ramipril 2.5mg (R2.5); R5; R10; Piretanide 3mg (P3); P6 Combination: R2.5/P3; R2.5/P6; R5/P3; R5/6; R10/P3; R10/P6  42  Study  Study Description Primary and Secondary Outcomes: Trough (24hrs post-dose) SBP and DBP; WDAE Notes: Efficacy Analysis: ITT basis: Any randomized patient meeting the inclusion criteria with any post-randomization data during the double-blind treatment phase. 452/480 patients completed the study BP data obtained from fig 1 and fig 2 on page 669. The position of measurement was not mentioned. Funding Source: Cassella AG  Kayanakis 1987 [22]  Design: 8-week multicenter, double-blind, placebo-controlled parallel study after a 2 week placebo run-in period; randomized (method not described) Participants: 211 men and women aged 20-70 yrs with diastolic BP between 95 and 120 mm Hg and systolic BP between 160 and 200mmHg. Mean age: 53 yrs. 56% male Interventions: 4 groups (od): Placebo Monotherapy: Captopril 50mg (C50) ; HCTZ 25mg (H25) Combination: C50/H25 Primary and Secondary Outcomes: Supine trough SBP and DBP (20-24 h after the last medication); HR (data not shown); WDAE Notes: 205 completed the study; statistical analysis on 211 who entered doubleblind study “Heart rate did not change significantly with either treatment Funding Source: Not reported  Kellaway 1993 [23]  Design: 8-week multicenter, double-blind, parallel group study after a 2-week single blind placebo run-in period. Randomized (method not described). Non responders at week 4 received double dose of cilazapril. Data up to week 4 were used.  43  Study  Study Description Participants: 69 patients, aged 18 to 75 yrs, with sitting DBP 95-115 mmHg at end of placebo run-in. Interventions: 2 treatment groups (od): Monotherapy: Cilazapril 2.5mg (C2.5) Combination: C2.5/HCTZ12.5 Primary and Secondary Outcomes: Sitting SBP and DBP (timing of measurement not reported); WDAE; heart rate (data not shown) Notes: 87 patients entered run-in phase (51%male; mean age: 54.6yrs) Efficacy analysis not described (n=57) “Heart rate did not differ significantly at week 4 and 8” Funding Source: Not reported  Kochar 1999 [24]  Design: 8-week double-blind, placebo-controlled parallel study after a 4-5 week single-blind placebo phase (conducted at 46 sites in the US); randomized (method not described) Participants: 683 men and women (>=18yrs) with seated diastolic BP between 95 and 110 mm Hg at weeks 3 and 4 or optional week 4 and 5 of placebo lead in phase. Difference between weeks of <=8mm Hg. Mean age: 55yrs. 65% male, 85% white and 48 (14%) black. Interventions: 4x4 factorial design (od) Placebo Monotherapy: Irbesartan 37.5mg (I 37.5); I 100; I 300; Hydrochlorothiazide 6.25 (H 6.25); H 12.5; H 25 Combination: I 37.5/H 6.25; I 37.5/H 12.5; I 37.5/H 25; I 100/H 6.25; I 100/H 12.5; I 100/H 25; I 300/H 6.25; I 300/H 12.5; I 300/H 25 Primary and Secondary Outcomes: trough (24+-2h after the last dose) sitting SBP and DBP; WDAE Notes: Analyses of efficacy assessments included data for all patients who had  44  Study  Study Description a baseline evaluation and at least one on-therapy evaluation = 630 Safety analysis: patients with at least one dose of randomized therapy = 683 631 completed the study Funding Source: Bristol-Myers Squibb Pharmaceutical Research Institute  Lacourciere 1994 [25]  Design: 12-week double-blind, placebo-controlled, parallel 3 X 4 factorial design study after a 4-week single-blind placebo run-in period. Randomized (methods not described) Participants: 240 outpatients of both sexes, aged 18-70 yrs, with sitting DBP between 95 and 110mmHg, on the last visit during the run-in period. On average, the patients were aged in the early fifties and predominantly male. Interventions: 12 treatment groups (od): Placebo Monotherapy: Niebivolol 1mg (N1); N5; N10; HCTZ 12.5mg (H12.5); H25 Combination: N1H12.5; N1/H25; N5/H12.5; N5/H25; N10/H12.5; N10/H25 Primary and Secondary Outcomes: Trough (24hrs post dose) sitting SBP and DBP; HR (no extractable data provided for analysis) Notes: 226/240 patients completed the study. Efficacy analyses versus baseline and placebo were performed after four weeks on double-blind treatment and at the last available visit or end-point. All 240 patients were included. “No significant changes in HR in N1 or H monotherapies and combination groups. N5 and N10 monotherapies and in combination with H induced a significant reduction from baseline in seated HR (range 10.4-12.4bpm and 2.011.5bpm respectively)” Funding Source: Janssen Research Foundation and Le Centre Hospitalier de l'Universite Laval, Research Centre  Lacourciere 2005 [26]  Design: 8 week double-blind, parallel group study after a 2-week placebo runin period. Randomized by next available sequential number to receive doubleblind treatment.  45  Study  Study Description Participants: 774 patients with SBP >=160 and <=200mmHg after washout period. Mean age: 60years. Interventions: 3 treatment groups (od): Monotherapy: Valsartan 160mg Combination: Valsartan 160mg plus Hydrochlorothiazide 12.5mg or 25mg Drugs were forced titrated at week 4: Group 1: from valsartan 80mg to valsartan 160mg Group 2: from valsartan 160mg to valsartan 160mg plus H12.5 Group 3: from valsartan 160mg to valsartan 160mg plus H25 Primary and Secondary Outcomes: Trough sitting SBP and DBP; WDAEs Notes: ITT population: 767 patients; 411 (54%) men. Funding Source: Novartis Pharmaceuticals  Lenz 1994 [27]  Design: 8 week multicentre, double-blind, forced-titration parallel group study after 4-week placebo-baseline period. Randomized (methods not described). At week 4, doses are doubled. Only data up to 4 weeks are used. Participants: 368 men and women, at least 18yrs, with supine DBP >=105mmHg and <=120mmHg at two consecutive visits at end of placebo phase. 165 (45%) male. 364 (99%) white. Interventions: 3 treatment groups (od): Monotherapy: Quinapril 10mg (Q10); HCTZ 12.5mg (H12.5) Combination: Q10/H12.5 Primary and Secondary Outcomes: Trough standing BP; WDAE Notes: ITT analysis: all patients with data from placebo-baseline period and double-blind phase. Patients with only data within fewer than 19 days are excluded. (n=318) 346/369 patients completed the study All patients included in safety analysis.  46  Study  Study Description Funding Source: Parke-Davis GmbH  Li 2003 [28]  Design: 8-week double-blind, parallel-group study after a 2-week single-blind placebo phase. Randomized (methods not described). After 4 weeks, patients with uncontrolled sitting DBP (>=90mmHg) received double doses. Only data up to 4 weeks of treatment were used in this review. Participants: 179 patients aged 18-65 with sitting DBP 95-115mmHg and sitting SBP <180mmHg after placebo washout. Mean age: 46.6 yrs. 65%male. Interventions: 2 treatment groups (od): Monotherapy: Losartan 50mg Combination: Losartan 50mg plus HCTZ 12.5mg Primary and Secondary Outcomes: Trough (22-26 hours post dose) sitting SBP and DBP; WDAE Notes: Efficacy analysis: "all patients treated" approach - i.e. included all patients who received active treatment and who had valid BP measurements at baseline and on treatment. (n=175) Safety analysis: (n=179) Funding Source: Merck & Co Inc.  MacKay 1996 [29,  Design: 12-week double-blind, parallel group placebo-controlled multicenter  30]  study after a 4-week single blind placebo run-in. Stratified randomization. Participants: 703 men and women at least 18 years of age with sitting DBP >=95mmHg after first 2 weeks of placebo run-in, and sitting DBP of 95 to 115mmHg (not differed by more than 7mmHg) after last 2 weeks of placebo run-in. 420 (60%) male. Mean age: 53 yrs. 86% white, 12% black, 2% other. Interventions: 5 treatment groups (od): placebo monotherapy: losartan 50mg (L50), HCTZ 12.5mg (H 12.5) combination: L50/H6.25; L50/H12.5  47  Study  Study Description Primary and Secondary Outcomes: trough (22-26hr) sitting DBP and SBP; heart rate (data not shown), WDAE Notes: 604/703 patients completed the study. Efficacy analysis: included all randomized patients with at least one treatment period measurement (using last observation carried forward). “No clinically significant mean changes from baseline for heart rate in any groups.” Safety analysis: all patients for whom safety data were available Funding Source: Merck Research Laboratories, Clinical Research  Manning 1996 [31]  Design: 6-week multicentre, double-blind, placebo-controlled study after a 4-6 week run-in period. After the 6-week treatment, another 4-week treatment followed where patients could be titrated to 2x dosage depending on the response (data not retrieved). Randomized (methods not described). Participants: 63 patients, aged between 18 and 80 years, with supine resting diastolic BP between 95 and 115 mmHg on two occasions and the lower reading within 10% of the higher reading during the run-in period. Mean age: 53.3yrs. 64% male. Interventions: 3 treatment groups (od): Monotherapy: Controlled release diltiazem 150mg (D150); Normal release HCTZ 12.5mg (H12.5) Combination: D150/H12.5 Primary and Secondary Outcomes: Supine SBP and DBP (timing of measurement not reported); HR; WDAE Notes: Efficacy Analysis in 61 patients 61/63 patients completed the study Funding Source: Not reported  McGill 2001 [32, 33]  Design: 8-week multicenter, double-blind, double-dummy, placebo-controlled, parallel group, 4x5 factorial study after a 4-week, single-blind, placebo run-in  48  Study  Study Description period. Randomization was according to enrollment order and a computergenerated list, and was stratified by race (black/non-black) Participants: 818 men and women aged between 18 and 80 years with supine DBP between 95-114mmHg during the last 2 weeks of placebo run-in and SBP between 140 and 200mmHg immediately before randomization. Mean supine DBP could not vary by >7mmHg over last 2 weeks of run-in. Mean age: 53 yrs. 60% men. 27.1black and 72.9% non-black. Interventions: 4x5 treatment groups (o.d.): Placebo Monotherapy: Telmisartan 20mg (T20); T40; T80; T160; HCTZ 6.25mg (H6.25); H12.5; H25 Combination: T20/H6.25; T40/H6.25; T80/H6.25; T160/H6.25; T20/H12.5; T40/H612.5; T80/H12.5; T160/H12.5; T20/H25; T40/H25; T80/H25; T160/H25 Primary and Secondary Outcomes: Trough (24 hours post dose) supine SBP and DBP; HR (no extractable data); WDAE Notes: Of the 1293 patients screened, 818 were enrolled. 749/818 patients completed the trial. ITT: randomized patients with >=1 post randomization BP measurement (n=807 patients) (last observation carried forward) "No significant changes from baseline were seen in supine trough heart rate with any of the active treatments" Funding Source: Not reported  Merrill 1987 [34]  Design: 8-week multiclinic double-blind trial. Randomized (methods not described) Participants: 207 patients with a sitting DBP of 90-115mmHg after a 4week placebo baseline.  49  Study  Study Description Interventions: 5 treatment groups (o.d): Monotherapy: Lisinopril 20mg (L20); HCTZ 12.5mg (H12.5) Combination: L20/H6.25; L20/H12.5; L20/H25 Primary and Secondary Outcomes: Trough SBP and DBP (timing of measurement not reported); WDAE Notes: Source: Paper abstract Funding Source: Not reported  Mersey 1993 [35]  Design: 8-week double-blind placebo-controlled multicenter study after 4-6 week placebo period. Randomized (methods not described) Participants: 345 white men and women with sitting DBP of 92 to 109 on two occasions during the placebo period. Efficacy data in 322 patients (58% men; mean age: 50.8yrs) Interventions: 5 treatment groups (o.d): Placebo Monotherapy: Captopril 25mg (C25); HCTZ 12.5mg (H12.5) Combination: C25/H12.5; C50/H25 Primary and Secondary Outcomes: Trough (24+-3 hrs post dose) sitting SBP and DBP; HR (no extractable data); WDAE Notes: Efficacy analysis in 322 patients 296/345 patients completed the study “the only statistically significant change in HR was in C50/H25 group ” Funding Source: Bristol-Myers Squibb Company  Meyer 1994 [36]  Design: 16-week multicenter trial after 4-week single-blind placebo run-in. Randomized (methods not described) Participants: 205 patients with DBP of 95-115mmHg after placebo run-in. 63% male. Mean age: 51 yrs.  50  Study  Study Description Interventions: 3 treatment groups (od): Monotherapy: Trandolapril 2mg (T2); HCTZ 25mg (H25) Combination: T2/H25 Primary and Secondary Outcomes: Trough (24 hours post-dose) supine SBP and DBP; WDAE (treatment-related only); HR (no quantitative data) Notes: “No clinically significant changes in supine or standing heart rate” Efficacy analysis was done in the overall population. Funding Source: Not reported  Neutel 2007 [37]  Design: 12-week double-blind, parallel-group study after a 21-day single-blind placebo wash-out period. Randomized (methods not described) Participants: 538 patients aged 18 years or older with moderate hypertension that at enrolment was either untreated for at least 4 weeks or uncontrolled by monotherapy. Untreated patients were enrolled if seated SBP 160-179mmHg or seated DBP 100-109mmHg. Patients on monotherapy could be enrolled if seated SBP 150-179mmHg or DBP 95-109mmHg. Mean age 55yrs. 292 (55%) male. 84% white and 14% black/African-American. 228 (42.4%) had hyperlipidemia,. 74 (13.8%) had diabetes mellitus. Interventions: 3 treatment groups (od): Monotherapy: Hydrochlorothiazide - H12.5 for 2 weeks followed by forced titration to H25 for 10 weeks Irbesartan - I150 for 2 weeks followed by forced titration to I300 for 10 weeks Combination: I150/H12.5 for 2 weeks followed by forced titration to I300/H25 for 10 weeks Primary and Secondary Outcomes: Trough sitting SBP and DBP; WDAE Notes: 472 patients (87.7%) completed double-blind treatment. Efficacy analyses in all randomized subjects (ITT)  51  Study  Study Description Safety analyses in all randomized patients who took at least 1 dose of study medication (n=538) Funding Source: Bristol-Myers Squibb and Sanofi-Aventis  Oparil 1980 [38]  Design: 8-week double-blind study after 6 week placebo period; randomized study (methods not described) Participants: 97 outpatients, 21-65 yrs, with supine DBP between 100-120 mmHg. Difference between weeks 2 or 4 and week 6 of placebo phase <=10 mmHg. Mean age: 51 yrs. 34 (35%) male; 62 (64%) white Interventions: 3 treatment groups (bid): Monotherapy: Timolol maleate 10mg (T10); HCTZ 25mg (H25) Combination: T10/H25 Primary and Secondary Outcomes: Erect SBP and DBP; WDAE; supine HR (only range was given; not extracted for analysis) Notes: 90/97 patients completed the study Efficacy analysis not described (n=78 at week 8) For HR, "the decrease (bpm) ranged from 16 to 18 in the timolol/HCTZ group, 14 to 17 in the timolol group, and 5 to 6 in the HCTZ group" Funding Source: Merck Sharp & Dohme  Papademetriou 2000  Design: 8-week multicenter, double-blind, placebo controlled study after a 4-  [39]  5week placebo run-in phase. Randomized (methods not described). Participants: 275 patients with DBP between 95-114 mmHg on 2 separate occasions during clinic visits. 56% male, 21% black. Mean age: 52 years. Interventions: 4 treatment groups (od): Placebo Monotherapy: Hydrochlorothiazide 12.5mg (H12.5); Candesartan 32mg (C32) Combination: H12.5/C32  52  Study  Study Description Primary and Secondary Outcomes: Trough sitting SBP and DBP; WDAE; HR (no extractable data) Notes: “No clinically significant changes in HR” Funding Source: Not reported  Papademetriou 2006  Design: 8-week multicenter, double-blind, parallel group, unbalanced factorial  [40]  study after a 4- to 5-week single-blind placebo run-in period. A central, computer-generated randomization schedule using an interactive voice response system was used. Participants: 1571 patients aged 18 to 80 years with sitting DBP 95 to 114mmHg and SBP <180mmHg after placebo run-in. Mean age: 53 years. About half were men. 26% were African American. 10% had diabetes mellitus type 2. Interventions: 17 treatment groups (o.d.): Placebo Monotherapy: ER Metoprolol (M25, M50, M100, M200); Hydrochlorothiazide (H6.25, H12.5, H25) Combination: M25/H6.25; M25/H12.5; M50/H6.25; M50/H12.5; M100/H6.25; M100/H12.5, M100/H25; M200/H12.5; M200/H25 Primary and Secondary Outcomes: Trough sitting SBP and DBP; WDAE (not used; only total percentage of WDAE reported); HR (no extractable data) Notes: Efficacy analyses: ITT on all randomized patients taking at least one dose of study drug, and with at least one post baseline BP. 2.9% of patients had WDAE. There were no deaths. “Heart rate decreased with increasing doses of ER-metoprolol (maximal decrease of 10beats/min at 200mg) and did so independent of hydrochlorothiazide” Funding Source: AstraZeneca LP  53  Study  Study Description  Parati 2006 [41]  Design: 12-week multicenter, double-blind, parallel-group trial after a 2-week placebo run-in period. Participants: 353 patients aged between 18 and 75 years and a sitting DBP between 95 and 110mmHg placebo wash-out.. Mean age: 57 years. 56% male. Interventions: 10 treatment groups (o.d.): Monotherapy: Zofenopril (Z15, Z30, Z60); Hydrochlorothiazide (H12.5, H25) Combination: Z15/H12.5; Z30/H12.5; Z60/H12.5; Z15/H25; Z30/H25 Primary and Secondary Outcomes: Trough sitting SBP and DBP; WDAE (numbers of WDAE in each group not reported); HR (no extractable data) Notes: 330 patients completed the trial. Efficacy analyses: ITT - all randomized patients who received at least one dose of the treatment drug and who had at least one visit after baseline (n=353). 6 (1.7%) patients with WDAE. Safety analyses: all randomized patients. “No significant differences in heart rate between groups or from baseline” Funding Source: Menarini Industrie Farmaceutiche Riunite and Istituto Lusofarmaco d'Italia  Philipp 1997 [42]  Design: 8-week double-blind, factorial design, multicentre study after a 4-week placebo run-in period. Randomized (methods not described) Participants: 1096/1306 patients aged 18-75 years with sitting diastolic BP of 95-110mmHg. Mean age: 55.1 years. Interventions: 15 parallel groups (od): Placebo Candesartan Cilexetil 2, 4, 8 or 16mg, HCTZ 12.5 or 25mg Combination therapy with both agents at these respective doses  54  Study  Study Description Primary and Secondary Outcomes: Sitting SBP and DBP (timing of measurement not reported); HR (data not shown); WDAE (given as percentages; number of WDAE in each group not reported) Notes: ITT efficacy analysis in 1038 patients. 485 (47%) male. “No effects on heart rate” 2.4% of patients withdrew from the study due to adverse occurrences. Funding Source: Not reported  Pool 1987 [43]  Design: 12-week multicenter study after a placebo medication for 2-4 weeks. Randomized (methods not described). After week 4 or 8, the dosage could be double to achieve the target BP. Therefore, only data up to week 4 will be used in this review. Participants: 394 patients of either sex, aged >=18 years, with sitting DBP of 90-120mmHg inclusive after placebo period. Women of childbearing potential were actively practicing birth control. 75% male. Mean age: 73 years. 73% white; 21% black. Interventions: 3 treatment groups (o.d.) in 2:2:1 ratio: Monotherapy: lisinopril 20mg (L20); HCTZ 12.5mg (H12.5) Combination: L20/H12.5 Double-dummy technique Primary and Secondary Outcomes: Sitting SBP and DBP (timing of measurement not reported); HR Notes: Efficacy analysis: "per-protocol" methods with all completed patients but excluded protocol deviations and dropouts if dropout occurred prior to the time point being analyzed. (n=368) "all-patients-treated" method was also used but data not shown. Funding Source: Not reported  55  Study  Study Description  Pool 1993 [44]  Design: 6-week multicenter, double-blind, placebo-controlled, parallel group trial after a 4-6 week single-blind placebo run-in phase. Randomized (methods not described) Participants: 298 patients, aged 18-70 years, with 2 consecutive weekly mean supine DBP of 95-110mmHg, that varied ≤7mmHg after baseline phase. Interventions: 4 treatment groups (bid): Placebo Monotherapy: Diltiazem SR 120mg (D120); HCTZ 12.5mg (H12.5) Combination: D120/H12.5 Primary and Secondary Outcomes: Trough (+-2hours prior to the next scheduled dose) standing SBP and DBP; HR (not shown) Notes: 254/298 patients completed the study. 79% non-black. Mean age 54.4yrs. 66% men. Efficacy data set included only participants who were randomized and completed the enter study protocol without being discontinued or having a protocol violation (n=254) "no significant changes in supine HR from baseline to end of study for any of the treatment groups" "all active treatment were well tolerated, with essentially equivalent rates of drop-outs due to side effects" Funding Source: Marion Merrell Dow Inc.  1997 [45]  Design: 8-week multicenter 4 X 4 factorial, double blind, parallel group trial after a single-blind, placebo lead-in of 4-5 weeks. Randomized (methods not described). Participants: 550 white, Asian or black outpatients aged 1 to 75 years inclusive with seated DBP >=95mmHg and <=110mmHg at consecutive visits (3rd or 4th weeks, or 4th and 5th weeks) during placebo lead-in. Mean age: 51.5 yrs. 335 (61%) male. 461 (84%) white and 82 (15%) black.  56  Study  Study Description Interventions: 16 treatment groups (o.d.): Placebo Monotherapy: Fosinopril 2.5mg (F2.5); F10; F40; HCTZ 5mg (H5); H12.5; H37.5 Combination: F2.5/H5; F2.5/H12.5; F2.5/H37.5; F10/H5; F10/H12.5; F10/H37.5; F20/H12.5; F40/H5; F40/H12.5; F40/H37.5; Primary and Secondary Outcomes: Trough (24+-3hrs post dose) sitting SBP and DBP; HR (data not shown); WDAE Notes: Efficacy analysis: 1) using ITT population: patients having BP data at baseline and at least one follow-up visit and 2) using efficacy population: subset of the ITT population, made up of all patients who did not violate any of the terms in the protocol that might affect efficacy outcome. Only data on ITT population were presented (n=516). 506/550 patients completed the study Funding Source: Bristol-Myers Squibb Company  Pool 2007a [46]  Design: 8-week multicenter, double-blind, multifactorial study after a 3- to 4week single-blind placebo run-in period. Randomization by region was performed by interactive voice response system provider using a validated system that automates the random assignment of treatment groups to randomization numbers. Randomization codes were kept strictly confidential until the database was locked. Participants: 1123 men and non-pregnant women >= 18 years of age with mean sitting DBP >=95mmHg after a placebo run-in. Patients with mean sitting DBP >=110mHg or SBP >= 180mmHg were excluded. Mean age 56.1yrs. 56% male. 92% white; 7% African American. Interventions: 11 treatment arms (o.d.): Placebo Monotherapy: Aliskiren (A75, 150 or 300mg); Valsartan (V80, 160, 320mg) Combination: A75/V80; A150/V160; A300/V320; V160/HCTZ 12.5  57  Study  Study Description Primary and Secondary Outcomes: sitting (trough?) SBP and DBP; AEs, WDAE, Notes: ITT: all randomized patients with baseline and at least one post-baseline measurement (n=1117) safety analyses: all randomized patients who received at least one dose of study treatment (n=1123) Funding Source: Novartis Pharma AG  Pool 2007b [47]  Design: 8-week multicenter, double-blind parallel-group trial after a 2- to 4week, single-blind, placebo run-in period. Randomized (methods not described). Participants: 1346 patients aged >=18years with mean sitting DBP >=90 and <110mmHg after washout, and mean sitting DBP >=95 and <110mmHg at randomization. Mean age: 52.7years. 55%male; 69% white; 22% black.; 2% asian. Interventions: 8 treatment groups (o.d.): placebo Monotherapy: Valsartan (V160 or V320); Hydrochlorothiazide (H12.5 or H25) Combination: V160/H12.5; V320/H12.5; V320/H25 Primary and Secondary Outcomes: Trough sitting SBP and DBP; WDAE Notes: ITT: Efficacy analyses in all randomized patients who had a baseline and with post-baseline efficacy measurement (n=1329) Safety analyses: all randomized patients who received trial medication in a double-blind manner. Sex distribution in baseline characteristics (P=0.025) Funding Source: Novartis Pharmaceuticals Corporation  58  Study  Study Description  Prisant 2000 [48]  Design: 6-week double-blind, placebo-controlled, parallel-group, multicenter study after a 4-week single-blind placebo treatment. Randomized (methods not described). Participants: 429 men or women aged 18-80 years with supine DBP within the range of 95 to 114mmHg after 3 and 4 weeks of placebo treatment with a difference between measurements of 7mmHg or less. Interventions: 13 treatment groups (od): Placebo Monotherapy: Diltiazem XR (120, 180, 240, or 360mg); Indapamide (1.25 or 2.5mg) Combination: each of the combination of Diltiazem plus indapamide (excluding Diltiazem 360mg) Primary and Secondary Outcomes: Trough (before next morning dose) supine SBP and DBP; WDAE (only total was given; number of WDAE for each group not reported) Notes: The variability of indapamide 1.25mg was too large to demonstrate consistent effects and was not discussed in the article. Baseline demographics of all treated patients were similar (n=329): 60%male. Age: 50-54yrs. "no pattern was observed in the rate of discontinuations to adverse events or incidence of adverse events among patients who received any treatment" Funding Source: Not reported  Romero 1995 [49]  Design: 8-week multicenter, double-blind, active-controlled parallel study after 2-4 week placebo phase; randomized (method not described) Participants: 323 men and women, >==18yrs, with supine diastolic BP of >=105 and <=120 mm Hg at 2 consecutive visits during the placebo period. Mean age: 53yrs. 9 black, 1 Arabian, 313 white. 57% male.  59  Study  Study Description Interventions: 3 parallel treatment groups (o.d.) with placebo matching drugs: monotherapy: Quinapril 20mg (Q20); HCTZ 12.5mg (H12.5) combination: Q20/H12.5 Primary and Secondary Outcomes: Trough (24hr) supine DBP and SBP; HR (no quantitative data); WDAE Notes: Efficacy analysis using evaluable data analysis: all patients without protocol deviations with >= 26 days of double-blind treatment, with the data of the last visit as endpoint = 291 ( used) “Heart rate was not significantly modified in any of the groups” Funding Source: Parke Davis GmbH  Rosenthal 1990 [50]  Design: 4-week double-blind four-center study after a 2-week baseline placebo period. Randomized (methods not described). After 4 weeks, normotensives with DBP of 90-95mmHg continued the same dosage for 4 more weeks; the others took double dosages (data were not used in this review) Participants: 81 patients, aged 24 to 70, with supine diastolic BP of 100-120 after placebo period. Mean age: 52 years. 58 (72%) men. Interventions: 3 treatment groups (od): Monotherapy: Enalapril 20mg (E20); Hydrochlorothiazide 12.5 (H12.5) Combination: E20/H12.5 Primary and Secondary Outcomes: Trough supine SBP and DBP Notes: 69/81 patients completed the 8-week study. Funding Source: Not reported  Safar 1973 [51, 52]  Design: 45 days double-blind study after a 15 days placebo period. Randomized (methods not described). Participants: 30 men with DBP >=100mmHg. Mean age: 40years.  60  Study  Study Description Interventions: 2 treatment groups: Monotherapy: Pindolol 5mg tid Combination: Pindolol 5mg tid plus Clopamide 10mg od Primary and Secondary Outcomes: Standing SBP and DBP and HR (timing of measurement not reported); WDAE Notes: Language: French Funding Source: Not reported  Safar 1994 [53]  Design: 8-week double-blind study after 4-week single-blind placebo run-in period. (Randomized: methods not described). Participants: 465 patients, 19-72yrs, with supine DBP between 95 and 114mmHg. Interventions: 6 treatment groups (od) Placebo Monotherapy: Perindopril 4mg (P4); Indapamide 1.25mg (I1.25) Combination: P4/I0.625; P4/I1.25; P4/I2.5 Primary and Secondary Outcomes: Supine DBP (timing of measurement not reported); WDAEs (number of WDAE in each group not reported) Notes: Source: Poster In total, 25 patients discontinued from the study (14 due to AEs) Safety data: ITT analysis. Funding Source: Not reported  Saruta 2007 [54]  Design: 8-week double-blind, parallel group study after 4 to 6 weeks of placebo run-in period. Randomized (methods not described). Participants: 961 Japanese patients between 25 and 74 years of age with mean trough sitting DBP of 95 to 115mmHg and SBP <210mmHg at each visit throughout the placebo run-in period up to the day of randomization.  61  Study  Study Description Interventions: 6 treatment arms (o.d.): Placebo Monotherapy: Losartan 50mg (L50); hydrochlorothiazide 12.5mg (H12.5) Combination: L25/H6.25; L50/H6.25; L50/H12.5 Primary and Secondary Outcomes: Trough sitting SBP and DBP and HR; WDAE Notes: Efficacy analyses in 942 patients who took at least one dose of study medication and have data of trough DBP post-randomization Safety analyses: patients who had taken the study medication at least once (n=954) Funding Source: Banyu Pharmaceutical Co. Ltd.  Saul 1995 [55]  Design: 8-week double-blind treatment following a 4-week, single-blind, placebo run-in period. Randomized (methods not described). Participants: 256 patients, aged 18 to 80 years, with sitting DBP of 100-114 mmHg (inclusive) during placebo run-in. 142 (55%) men. Mean age: 57.6yrs. Interventions: 3 treatment groups (od): Monotherapy: Lisinopril 10mg (L10); HCTZ 25mg (H25) Combination: L10/H25 Ratio of 2:1:1 for L/H:L:H Primary and Secondary Outcomes: Trough (22-26 hours post-dose) sitting SBP and DBP; HR (no quantitative data); WDAE Notes: Efficacy analysis: Completed patients' analysis which included all randomized patients who completed the study. As no patients violated the study criteria, this is also an ITT analysis. “Only small mean changes in heart rate from baseline and there were no significant treatment differences” Funding Source: Not reported  62  Study  Study Description  Schoenberger 1986  Design: 16-week double-blind multicenter study after a 4-6week placebo lead-  [56]  in period. Randomized (methods not described). Captopril doses were double at the end of first 4 weeks of active treatment. Only data up to 4 weeks were used in this review. Participants: 382 Caucasian or Hispanic patients, aged >=18 yrs, with DBP 92-110mmHg on the last two visits of placebo period. Approximately 65% male. Mean age: 52 yrs. Interventions: 4 treatment groups: Placebo bid Monotherapy: Captopril 50mg (C50) o.d.; C50 bid Combination: C50 o.d. plus HCTZ 25mg o.d. Primary and Secondary Outcomes: Trough (24+-3 hours post dose) sitting SBP and DBP Notes: Efficacy analysis in 358 patients. Funding Source: Not reported  Thijs 1995 [57]  Design: 4-week double-blind multicenter trial after a 2-4 week single-blind placebo run-in phase. Randomized (methods not described). Treatment was discontinued if DBP <80 or >115mmHg. Participants: 611 men and women aged 21-70 years with supine DBP averaged 100-114mmHg. Supine SBP <220mmHg. 51% men. Mean age: 55 years. Interventions: 3 parallel groups (o.d.): Monotherapy: Ramipril 5mg (R5); Piretanide 6mg (P6) Combination: R5/P6 Primary and Secondary Outcomes: Trough (24 hours post-dose) standing SBP and DBP; WDAE  63  Study  Study Description Notes: Efficacy analysis: per-protocol analysis in patients who completed the one month follow-up. (for standing BP, n=583) “One patient died of myocardial infarction in the combination group” Funding Source: Not reported  Vaicaitis 1980 [58]  Design: 8-week multiclinic, double-blind study after 6 week baseline phase with placebo; randomized (method not described) Participants: 27 outpatients 21 to 65 years of age with supine diastolic BP between 100 and 120 mm Hg at end of baseline phase. Difference between week 2 or 4 and week 6 <=10mm Hg. Sitting systolic BP <160 mm Hg. Heart rate>=56beats/min. Mean age: 54yrs. 17 (63%) male. Interventions: 3 treatment groups (one tablet bid): Monotherapy: Timolol maleate 10mg (T10); HCTZ 25mg (H25) Combination: T10/H25 Primary and Secondary Outcomes: Erect SBP and DBP (timing of measurement not reported); supine pulse rate; WDAE Notes: Efficacy analysis not described (n=22) Funding Source: Merck Sharp & Dohme  Villamil 2007 [59]  Design: 8-week, multicenter, double-blind, multifactorial study trial after a 2week single-blind placebo run-in period. Randomized (methods not described) Participants: 2776 patients ≥18 years with mean sitting DBP ≥95mmHg after placebo run-in. Patients with mean DBP≥110mmHg and/or SBP≥180mmHg were excluded. Mean age: 55yrs. 55% male. 85% caucasian; 5% blacks. Interventions: 15 treatment groups (o.d.): placebo Monotherapy: Aliskiren (A75, A150 or A300mg); Hydrochlorothiazide (H6.25, H12.5 or H25mg)  64  Study  Study Description Combination: A75/H6.25, A75/H12.5, A75/H25, A150/H6.25, A150/H12.5, A150/H25, A300/H12.5, A300/H25 Primary and Secondary Outcomes: Trough sitting SBP and DBP; WDAE Notes: ITT: all randomized patients with a baseline measurement and at least on post-baseline measurement = 2752 patients Safety analyses: on all patients who received at least one dose of double-blind study medication = 2762 patients Funding Source: Not reported  von Manteuffel 1995  Design: 6 week double-blind parallel group study after a 4 week placebo  [60]  washout period. Block randomization was used. Participants: 173 patients with DBP of at least 100mgHg and not more than 114mmHg after placebo run-in. Interventions: 4 treatment groups (od): Placebo Monotherapy: Verapamil SR 240mg od (V240); Hydrochlorothiazide 12.5mg od (H12.5) Combination: V240/H12.5 Primary and Secondary Outcomes: Seating SBP and DBP (timing of measurement not reported) Notes: Language: German Funding Source: Not reported  Weinberger 1982 [61]  Design: 6-week double-blind multicentre trial after a 2-week placebo treatment. Randomized (methods not described). Participants: 207/255 patients with supine DBP of >=92mmHg and <110mmHg on 2 biweekly visits of placebo treatment. 58% men. Mean age: 49 yrs.  65  Study  Study Description Interventions: 3 treatment groups (tid): Monotherapy: Captopril 25mg (C25); HCTZ 15mg (H15) Combination: C25/H15 Primary and Secondary Outcomes: Supine SBP and DBP (examined 3-8 hours after the last dose of drug); HR (no extractable data for analysis); WDAE Notes: 198/207 patients completed the study. "Heart rate, both supine and standing, increased slightly (1.4-4.7%) but significantly in both groups receiving H but not the group receiving C alone, where slight (-1.7%-0.7%) but non-significant decreases in heart rate were observed" Funding Source: Not reported  Weir 1992 [62]  Design: 12-week double-blind, placebo controlled, multicentre study after a 4-6 week single-blind placebo run-in period. The 12 week period consists of three 4-week evaluation period with increasing fixed dose at each period. Randomized study (methods not described). Data on the first 4-week evaluation period was used in this review. Participants: 298 volunteers between 18 and 70 yrs of age with supine DBP >=95 and <=110 mmHg. Women of childbearing potential were excluded. Interventions: 4 treatment groups (bid): Placebo Monotherapy: Diltiazem SR 60mg (D60); HCTZ 6.25mg (H6.25) Combination: D60/H6.25 Primary and Secondary Outcomes: Trough (12+-2hrs post dose) supine SBP and DBP; supine HR (no quantitative data); WDAE Notes: Efficacy analysis: patients who completed a 4-week evaluation period without protocol violations (used) with n = 274 for period 1 (65%male; 86%non-black; mean age = 53.5 yrs) 14 patients discontinued period 1.  66  Study  Study Description “No significant differences between groups in HR in period 1” Funding Source: Marion Merrell Dow Inc.  Yodfat 1994 [63]  Design: 4-week parallel-group placebo-controlled multicentre study after 4week single-blind placebo period. Randomized (methods not described). Efficacy data up to 4 weeks of treatment were recorded. Participants: 377 patients of both sexes, between 20 and 68 yrs, with average sitting DBP >100mmHg and those who demonstrated at least 80% compliance after placebo period. 244 (65%) men. Mean age: 53 yrs. Interventions: 8 treatment groups (o.d.): Placebo Monotherapy: Cilazapril 2.5mg (C2.5); C5; HCTZ 12.5mg (H12.5); H25 Combination: C1.25/H6.25; C2.5/H12.5; C5/H25 Primary and Secondary Outcomes: Trough (22-24 hours post dose) sitting DBP; WDAE (number of WDAE for each group not reported) Notes: 363/377 patients completed the study Only efficacy data up to 4 weeks of treatment were recorded. ITT analysis: number of total patients is not explicitly reported. Assume 'N' for trough BP analysis is same as 'N' in Table 2 which report 'n' patients with normalized BP. (N=373) Funding Source: Not reported  3.1.2  Characteristics of excluded studies Forty-four of the studies that met the preliminary inclusion criteria were excluded  from this review. A majority of the excluded studies were crossover trials in which precrossover data were not provided. The reasons for exclusion of each trial are provided in Table 3.2.  67  Table 3.2 : Reasons for exclusion of trials that met inclusion criteria for this review Study Study Description Agrawal 1979 [64]  Crossover trial with no pre-crossover data for first 4 or 6 weeks of treatment (Propranolol 80mg bid vs bendrofluazide 2.5mg bid or their combination)  Agrawal 1987 [65]  Crossover trial with no pre-crossover data for first 4 weeks of treatment (propanolol 80mg od vs bendrofluazide 2.5mg od vs their combination)  Bateman 1979 [66]  Crossover trial with no pre-crossover data for first 4 weeks of treatment (atenolol 100mg od vs chlorthalidone 25mg od vs their combination vs placebo)  Bauer 1984 [67, 68]  Crossover trial with no pre-crossover data for first 4 weeks of treatment. 8 week treatment but titration in non-responders after 4 week treatment. (Enalapril 10mg bid vs Hydrochlorothiazide 25mg bid vs their combination)  Bertrand 1982 [69]  Chlortalidone given 3 times per week only.  Boike 1982 [70]  Crossover trial with no pre-crossover data for first 4 weeks of treatment (Atenolol 100mg od vs chlorthalidone 25mg od vs their combination vs placebo)  Bolzano 1984 [71]  Parallel group trial with 8-week treatment period. Hydrochlorothiazide was co-administered with amiloride. (Methyldopa 250mg (M250) vs Hydrochlorothiazide 25mg plus Amiloride 5mg (H25/A5) vs their combination)  Cajochen 1984 [72]  Crossover trial with BP data for the first 4 weeks of treatment. Number of patients per treatment arm for the first phase of study not mentioned. (Atenolol 100mg od vs Chlorthalidone 50mg od vs their combination)  Canter 1994 [73]  Parallel group trial with 8-week treatment period. Number of patients per treatment arm not reported (16 parallel arms: placebo; Quinapril 2.5, 10, 40mm/day; Hydrochlorothiazide 6.25, 12.5, 25mg/day; all possible combinations).  Chalmers 1982 [74]  Crossover trial with no pre-crossover data for first 8 weeks of treatment. (Indapamide 2.5mg od vs Pindolol 10mg od vs their combination vs placebo)  Chalmers 1986 [75]  Crossover trial with no pre-crossover data for first 4 weeks of treatment (Enalapril 10mg bid vs Hydrochlorothiazide 25mg bid vs their combination vs placebo)  Chrysant 1992 [76]  Parallel group trial with 4-week treatment period. Hydrochlorothiazide was co-administered with triamterene. (Atenolol 25mg vs HCTZ 25mg plus triamterene 50mg vs their combination)  68  Study  Study Description  Crowe 1987 [77]  Crossover trial with no pre-crossover data for first 4 weeks of treatment (Enalapril 10mg bid vs Hydrochlorothiazide 25mg bid vs their combination vs placebo)  De Divitiis 1981 [78]  Crossover trial with no pre-crossover data for first 4 weeks of treatment (Atenolol 100mg od vs chlorthalidone 50mg od vs their combination vs chlorthalidone 50mg od plus reserpine 0.25mg od)  De Divitiis 1983 [79]  Crossover trial with no pre-crossover data for first 4 weeks of treatment (indapamide 2.5mg od vs atenolol 100mg vs their combination)  Durel 1992 [80]  Crossover trial with no pre-crossover data for first 4 weeks of treatment (Atenolol 100mg od vs Chlorthalidone 50mg od vs their combination)  Erwteman 1984 [81]  Crossover trial with no pre-crossover data for first 4 weeks of treatment (chlorthalidone 25mg od vs metoprolol 200mg od vs their combination)  Fernandez 1980 [82]  Crossover trial with no pre-crossover data for first 4 weeks of treatment (alpha-methyldopa 750mg/day vs chlorothiazide 340mg/day vs their combination vs placebo)  Forette 1979 [83]  Crossover trial with no pre-crossover data for first 8 weeks of treatment. Clorexolone administered with canrenone. (acebutolol 400mg/day vs clorexolone 3mg/day+canrenone 25mg/day vs their combination).  Frishman 1987 [84]  Parallel group trial with 48 week treatment period, titration based on response starting at week 4. Pre-titration data not reported. (enalapril 10mg bid vs hydrochlorothiazide 25mg bid vs combination)  Hart 1985 [85]  Parallel group trial with 4-week treatment period. Hydrochlorothiazide was co-administered with triamterene. (Atenolol 100mg vs HCTZ 25mg plus Triamterene 50mg vs their combination)  Hunter 1999 [86]  Crossover trial with no pre-crossover data for first 12 weeks of treatment (captopril 50mg bid vs bendrofluazide 2.5mg od vs their combination)  Jaattela 1979 [87]  Crossover trial with no pre-crossover data for first 4 weeks of treatment (Propanolol 80mg bid vs bendrofluazide 2.5mgbid vs their combination)  Jackson 1986 [88]  Crossover trial with no pre-crossover data for first 4 weeks of treatment. However, HCTZ was co-administered with amiloride. (Atenolol 50mg vs HCTZ 25mg/amiloride 2.5mg od and their combination)  Khalil 1982 [89]  Crossover trial with pre-crossover data for the first 6 weeks of treatment. However, HCTZ was co-administered with amiloride. (Acebutolol 400mg vs Acebutolol 400mg plus HCTZ 50mg plus Amiloride 5mg)  69  Study  Study Description  Kieso 1983 [90]  Crossover trial with no pre-crossover data for first 4 weeks of treatment (Metoprolol 200mg od vs Metoprolol 200mg/chlorthalidone 25mg od)  Kubik 1979 [91]  Crossover trial with pre-crossover data for first 8 weeks of treatment. However, number of patients in each group not reported. [Metoprolol 100mg bid (M100) vs M100 bid plus 2 x chlorthalidone-K 25mg od (ChlorthalidoneK tablets each containing 6.7mmol potassium)]  Lang 1991 [92]  Parallel group with 8 week treatment . Number of patients per treatment arm for analysis not included. (Lisinopril 10mg od vs hydrochlorothiazide 12.5mg od vs their combination)  Lechi 1982 [93]  Crossover trial with no pre-crossover data for first 3 weeks of treatment (Labetalol 300mg od vs chlorthalidone 30mg od vs their combination vs placebo)  Leonetti 1986 [94]  Crossover trial with no pre-crossover data for first 4 weeks of treatment. (Atenolol 50mg od vs Chlorthalidone 12.5mg od vs their combination)  Magee 1986 [95]  Crossover trial with no pre-crossover data for first 3 weeks of treatment (Nadolol 80mg od and the combination of Nadolol 80mg od with hydrochlorothiazide 12.5, 25 or 50mg od)  Mehta 1988 [96]  Parallel group trial with 24 week treatment period, titration based on response starting at week 4. Pre-titration data not reported (Lisinopril 20mg od vs Lisinopril 20mg/Hydrochlorothiazide 12.5mg od)  Middlemost 1994  Parallel group trial with 8 week treatment period. Only ABPM data given.  [97]  (Enalapril 20mg od vs enalapril 20mg plus hydrochlorothiazide 12.5mg od)  Moncloa 1980 [98]  Parallel group treatment with 4 week treatment period. Hydrochlorothiazide was co-administered with amiloride. (Methyldopa 250mg bid vs HCTZ 25mg/Amiloride 2.5mg bid vs their combination)  Muiesan 1976 [99]  Parallel group treatment with 6 week treatment period. Hydrochlorothiazide was co-administered with amiloride. (Timolol 10mg bid vs HCTZ/Amiloride 25/2.5mg bid vs their combination)  Petrie 1975 [100]  Crossover trial with no pre-crossover data for first 4 weeks of treatment (Atenolol 100 bid vs bendrofluazide 2.5mg bid vs their combination)  Ricciardelli 1985  Crossover trial with no pre-crossover data for first 4 weeks of treatment  [101]  (atenolol 100mg od vs chlorthalidone 25mg plus atenolol 100mg od)  Rosenthal 1989 [102]  Parallel group trial after a 3 week treatment period. Hydrochlorothiazide was co-administered with triamterene. [Verapamil 80mg or 160mg vs  70  Study  Study Description Triamterene 25mg/HCTZ 12.5mg vs Triamterene 50mg/HCTZ 25mg vs all possible combinations)  Salako 1990 [103]  Crossover trial with no pre-crossover data for first 4 weeks of treatment (Atenolol 100mg od vs Chlorthalidone 25mg od vs their combination)  Salvetti 1989 [104,  Crossover trial with no pre-crossover data for first 4 weeks of treatment  105]  (Nifedipine 20mg bid vs chlorthalidone 25mg od vs their combination)  Scholze 1993 [106]  Parallel group trial with 6 weeks treatment period. Number of patient per treatment arm is not reported (placebo vs ramipril 2.5, 5 or10mg vs HCTZ 12.5 or 25mg vs all possible combinations)  VACSGAA 1977  Parallel group with 6months treatment, titration based on response starting at  [107]  week 4. Pre-titration data not reported. (Propanolol 40mg tid vs Propanolol in combination with hydrochlorothiazide 35mg or hydralazine 35mg tid vs the combination of 3 drugs)  Van Staden 19832  Crossover trial with no pre-crossover data for first 4 weeks of treatment  [108]  (Propanolol 80mg bid vs Bendrofluazide 2.5mg bid vs their combination)  Weinberger 1983  Study B: Parallel group with 12 week treatment period. BP measurements at  [109]  3-8hrs after the last drug dose. No properly defined "peak" or "trough" BP measurement. (captopril 52mg bid vs hydrochlorothiazide 25mg bid vs their combination vs placebo)  3.2  Imputation of missing variance data The weighted mean standard deviation (SD) of both SBP and DBP changes were  calculated from studies that provided the SD of SBP and DBP changes, respectively. Thirty-two (57%) of the included studies reported the SD of SBP change and thirty-four (61%) included studies reported the SD of DBP change. Eleven studies included in the other three reviews mentioned previously [110-119] also provided the SD of the changes in SBP and DBP. The values from all these studies were pooled in order to calculate the weighted mean estimates of the SD of the change in SBP and DBP for the combination and monotherapy groups. This was based on the assumption that the effect on BP variability is similar across drug classes. Eight studies [14, 16, 17, 23, 31, 111, 112, 116] 71  were ultimately excluded from the calculation because their SD values were not within three standard deviations of the estimated weighted mean SD of SBP change. For the same reason, five studies [14, 25, 17, 111, 112] were excluded from the calculation of the weighted mean SD of DBP change. After these adjustments, the weighted mean SD of SBP and DBP change values for the combination group were 13.2 (SD 1.5) mmHg and 8.1 (SD 0.8) mmHg, respectively. For the monotherapy group, the weighted mean SD of SBP and DBP change values were 13.6 (SD 1.8) mmHg and 8.3 (SD 1.1) mmHg, respectively. There were no statistically significant differences in the SD of SBP change or the SD of DBP change between the combination and monotherapy groups. These values were used according to the imputation hierarchy for trials that did not report the SD of the BP change value and in the nine included trials that reported outlier SD of the BP change values. The SD of BP change was imputed for 32/56 (57%) of the included studies. Of these studies, 4 (7%) were imputed using the SD of baseline SBP, 2 (4%) imputed using the SD of endpoint SBP, 5 (9%) imputed using the SD of endpoint DBP, 21 (38%) imputed using the weighted mean SD of SBP change from other trials, and 24 (43%) using the weighted mean SD of DBP change from other trials. 3.3  Pooling of trials  The diuretics were classified into two groups: 1) loop diuretics; and 2) thiazide and thiazide-like diuretics. The thiazide group was analyzed as a sub-class by pooling all trials that reported trough BP measurements. The loop diuretic group was analyzed separately. The doses of the individual diuretics were categorized as proportions of the manufacturer’s recommended starting dose (Table 3.3). This assumes that the starting dose recommended is effective in reducing BP and that all starting doses have a similar  72  BP lowering efficacy. In the case where a range of starting doses is recommended by the manufacturer, the lowest dose is considered to be the starting dose (1x). Table 3.3 : Starting doses of diuretics analyzed in the review Drug  Type of Diuretic  Furosemide Piretanide Hydrochlorothiazide Indapamide Chlorthalidone Clopamide  Loop Loop Thiazide Thiazide Thiazide Thiazide  3.4  Starting dose/day for hypertension 40-80mg/day 6-12mg/day 12.5mg/day 1.25mg/day 12.5mg/day 5-10mg/day  Available in Canada? Yes No Yes Yes Yes No  Blood pressure lowering efficacy  The additional BP lowering efficacy of adding a diuretic as second-line therapy to a non-diuretic (“other”) antihypertensive drug is summarized below. The outcome assessed is the difference in BP reduction between the combination (thiazide + other drug) and monotherapy (other drug alone) groups in parallel, double-blind RCTs. Using this approach, the difference is specified as the additional BP reduction induced by adding a diuretic as the second drug. 3.4.1  Thiazide plus other drug vs other drug alone By comparing the difference in BP reduction between the combination (a thiazide  + 1 other drug) and monotherapy (placebo or no treatment + 1 other drug) groups, the additional BP reduction resulting from adding a thiazide as the second drug was estimated. 3.4.1.1 Thiazide plus ACEI vs ACEI alone Twenty-four included studies assessed the BP lowering efficacy of thiazide plus ACEI combination and ACEI alone. DBP data, which was the primary outcome assessed in all these studies, was provided in all 24 studies, whereas SBP data was provided in only 20 of these studies. HCTZ was the thiazide that was given in all except one study  73  [53] which assessed indapamide at 0.625mg/day to 2.5mg/day. Although the dose of HCTZ was studied over a wide range (5mg/day to 45mg/day), a majority of the trials evaluated doses of 12.5mg/day and 25mg/day, which correspond to 1x and 2x the manufacturer’s recommended starting dose. In these studies, the drugs were given once daily except for one trial [109] in which the drugs were given three times daily (TID). Table 3.4 : Additional BP reduction by adding a thiazide to ACEI. Fixed effect model (95%CI). Dose of Thiazide in multiples of starting dose 0.4x 0.5x 1x 2x 3x 3.6x  # of studies (SBP/DBP)  Total # of patients in combination group (SBP/DBP)  Change in SBP (95% CI) mmHg  Change in DBP (95% CI) mmHg  1/1 1/3 14/17 7/11 1/1 1/1  93/93 42/156 1112/1274 433/680 92/92 62/62  -4.8 (-9.4, -0.2) -4.9 (-10.8, +1) -5.2 (-6.3, -4.1) -7.5 (-9.4, -5.7) -9.0 (-13.6, -4.4) -18.5 (-23.1, -13.9)  -0.8 (-3.2, +1.6) -1.4 (-3.3, +0.4) -3.1 (-3.7, -2.5) -3.8 (-4.7, -2.9) -3.5 (-5.9, -1.1) -9.2 (-12.0, -6.4)  Two studies provided SBP data for the addition of a thiazide ≤0.5x to an ACEI and the pooled result showed an additional reduction of -4.8 (95% CI -8.4, -1.2) mmHg. There were 4 studies with DBP data that showed the average additional effect on DBP reduction was not statistically significant [-1.2 (95% CI -2.7, +0.3) mmHg]. The combination of thiazide plus ACEI was superior to ACEI alone in lowering both mean SBP and DBP when the dose of thiazide was 1x or greater the manufacturer's recommended starting dose (see Table 3.4). Based on an indirect comparison, the additional SBP reduction achieved by thiazides 2x was statistically greater than by thiazides 1x. However, when 3 of the studies (19, 20, 23) that were judged to have a high risk of incomplete outcome data bias were removed, the difference was no longer statistically significant. A direct comparison of the 2 doses was performed with 3 studies [11, 41, 63] which included HCTZ at both 12.5mg/day and 25mg/day. From the pooled  74  analysis of these 3 trials, adding HCTZ at 25mg/day also did not show a statistically significant difference in the magnitude of BP reduction compared to adding HCTZ 12.5mg/day [SBP -1.6 (95% CI -4.3, +1.2) mmHg; DBP -1.1 (95% CI (-2.4, +0.3) mmHg]. There is only one study assessing thiazide 3x [45]. Based on the available evidence, the magnitude of additional reduction achieved with this dose was not significantly greater than those achieved with HCTZ 12.5mg/day or HCTZ 25mg/day. There is also only one study assessing thiazide 3.6x [61]. In this study, HCTZ was given at 15mg TID (45mg total daily dose). The addition of HCTZ 15mg TID resulted in a further SBP and DBP reduction that were statistically greater than those achieved with HCTZ at lower doses (see Table 3.4). The data showed that there is a possibility of greater BP reduction with higher HCTZ doses and with TID dosing. However, more studies are needed before conclusions can be made about thiazide doses greater than 2x the starting dose and different dosing schedules. A sensitivity analysis, where trials that measured BP in standing or supine positions were removed, was performed and showed that our effect estimate was not affected by the position of BP measurement. Removing the single study that assessed indapamide [53] in sensitivity analysis also did not statistically change the overall result. BP was measured before the next dosing schedule in all but four studies [23,43,53,61] 4  which did not mention the timing of BP measurement. Removing these 4 studies in sensitivity analysis also did not statistically change the BP lowering effect size. Eight of the 24 included studies were industry sponsored; the other 16 trials did not report funding sources. Therefore, it was not possible to investigate if funding source  75  affected the results. The mean age of patients in the included studies ranged from 47-58 years and only one study had a study population of mean age >70 years [20]. A subgroup analysis based on age and gender was not performed due to insufficient data. 3.4.1.2 Thiazide plus ARB vs ARB alone Thirteen studies assessed the combination of thiazides plus ARB and ARB alone. HCTZ administered once daily was the only thiazide studied in all 13 trials. Addition of HCTZ (6.25mg/day to 25mg/day) to an ARB significantly reduced both SBP and DBP (Table 3.5). Table 3.5 : Additional BP reduction by adding a thiazide to ARB. Fixed effect model (95%CI). Dose of Thiazide in multiples of starting dose  # of studies  0.5x 1x 2x  4 12 8  Total # of patients in combination group 511 1911 1557  Change in SBP (95% CI) mmHg  Change in DBP (95% CI) mmHg  -3.4 (-4.9, -1.8) -7.1 (-8.0, -6.3) -8.4 (-9.4, -7.5)  -1.6 (-2.5, -0.7) -3.3 (-3.8, -2.8) -4.2 (-4.8, -3.6)  A dose-response was observed, with a statistically significantly greater reduction in BP with the addition of HCTZ 12.5mg/day as compared to HCTZ 6.25mg/day. Furthermore, there was a significantly greater reduction in BP with HCTZ 25mg/day compared with HCTZ 12.5mg/day, based on an indirect comparison. This observation was confirmed by performing a direct comparison between the doses from 7 of the studies. The pooled analysis showed that the combination of HCTZ 25mg/day plus ARB resulted in a significantly greater reduction in both SBP and DBP compared to the combination of HCTZ 12.5mg/day plus ARB [SBP -1.6 (95% CI -2.6, -0.5) mmHg; DBP -1.2 (95% CI -1.8, -0.5) mmHg]. A sensitivity analysis showed that the position of BP measurement did not significantly affect the results. Two of the trials [42,46] did not record the timing of BP  76  measurement. Removal of these trials also did not change the results. Ten of the studies were industry sponsored and the source of funding was not reported for the other 3 studies so a sensitivity analysis could not be conducted. 3.4.1.3 Thiazide plus renin inhibitor vs renin inhibitor alone Only one included study [59] was identified assessing the BP lowering efficacy of HCTZ plus renin inhibitor and the renin inhibitor alone. Three different doses of HCTZ were assessed (6.25mg/day, 12.5mg/day, and 25mg/day). Addition of HCTZ at each dose resulted in a significantly greater reduction in both SBP and DBP (Table 3.6). However, due to the lack of studies, there is insufficient data to conclude if there was a doseresponse relationship. Table 3.6 : Additional BP reduction by adding a thiazide to a renin inhibitor. Fixed effect model (95%CI). Dose of Thiazide in multiples of starting dose  # of studies  0.5x 1x 2x  1 1 1  Total # of patients in combination group 360 553 546  Change in SBP (95% CI) mmHg  Change in DBP (95% CI) mmHg  -4.0 (-5.9, -2.2) -5.2 (-6.8, -3.7) -6.9 (-8.4, -5.4)  -1.8 (-3.0, -0.6) -3.0 (-4.0, -2.1) -3.5 (-4.5, -2.6)  3.4.1.4 Thiazide plus BB vs BB alone Nine included studies assessing the BP lowering efficacy of thiazide plus betablocker and beta-blocker alone were identified. HCTZ 6.25 to 50mg/day was assessed in 7 studies, chlorthalidone 20mg/day in 1 study [6] and clopamide 10mg/day another study [51].  77  Table 3.7 : Additional BP reduction by adding a thiazide to a beta-blocker. Fixed effect model (95%CI). Dose of Thiazide in multiples of starting dose 0.5x 1x 1.6x 2x 4x  # of studies 3 2 1 5 2  Total # of patients in combination group 557 485 24 283 31  Change in SBP (95% CI) mmHg  Change in DBP (95% CI) mmHg  -3.6 (-5.1, -2.1) -4.7 (-6.5, -3.0) -6.0 (-13.5, +1.5) -8.2 (-10.3, -6.2) -16.1 (-23.1, -9.2)  -1.8 (-2.7, -0.9) -2.3 (-3.4, -1.2) -4.0 (-8.6, +0.6) -4.0 (-5.3, -2.8) -6.3 (-10.6, -2.1)  Based on the best available evidence, adding a thiazide at doses as low as 0.5x to 1x the manufacturer's recommended starting dose to a beta-blocker significantly reduced both SBP and DBP (see Table 3.7). Addition of thiazide 1.6x did not show a statistically significant additional BP reduction. However, this observation was based on only one small trial evaluating the BP lowering efficacy of chlorthalidone 20mg/day added to a beta-blocker, which included only 24 patients in the combination group for the efficacy analysis [6]. There was a trend towards greater BP reduction with higher doses of thiazides added. There were 5 studies evaluating the addition of a thiazide at 2x the starting dose. Pooling the data from these 5 studies showed an additional reduction of -8.2 (95% CI 10.3, -6.2) mmHg in SBP and -4.0 (95% CI -5.3, -2.8) mmHg in DBP. Three of the trials were measured at trough and the other two trials did not report when BP was measured. Removing these 2 studies did not significantly alter the overall BP effect size. The drugs were given once daily except in one trial [4] which HCTZ 12.5mg was given twice daily (BID). Four of the 5 studies evaluated HCTZ whereas the other study [51] evaluated clopamide 5mg given twice daily. A sensitivity analysis removing either of these studies did not change the overall additional BP effect size of thiazides added as a second drug to a beta-blocker.  78  A direct comparison of the BP lowering efficacy of adding HCTZ 12.5mg/day and 25mg/day to a beta-blocker could be performed in 2 of the included studies [25,40]. These studies were pooled and data showed that adding HCTZ 25mg/day resulted in a numerically greater systolic BP reduction than adding HCTZ 12.5mg/day, but this did not reach statistical significance. The additional BP reduction resulting from the addition of thiazide 4x to a BB was assessed in 2 included studies (Table 3.7). The studies were fairly small in size with a total number of 31 patients in the combination group. As reflected by the wide confidence intervals, the estimate of the BP lowering efficacy at this dosage is imprecise. 3.4.1.5 Thiazide plus CCB vs CCB alone There were 5 included studies assessing the BP lowering efficacy of thiazide plus CCB and CCB alone. Two of the studies assessed HCTZ given once daily [31, 60], another two studies assessed HCTZ given twice daily [44, 62], and one study assessed indapamide given once daily [48]. Due to the lack of studies for each of the different regimens, it was not possible to sufficiently analyze the effect of each regimen on BP (see Table 3.8). Table 3.8: Additional BP reduction by adding a thiazide to CCB. Fixed effect model (95%CI). Dose of # of studies Total # of Change in SBP Change in DBP Thiazides in (SBP/DBP) patients in (95% CI) mmHg (95% CI) mmHg multiples of combination starting dose group 1x 3 129 -3.7 (-6.7, -0.6) -4.5 (-6.0, -2.9) 2x 2 137 -9.5 (-12.3, -6.6) -5.9 (-7.6, -4.1) Based on an indirect comparison, the addition of a thiazide at 2x the manufacturer’s starting dose to CCB resulted in a significantly greater reduction in BP compared with adding a thiazide at 1x the starting dose.  79  3.4.1.6 Thiazide plus centrally acting drug vs centrally acting drug alone There is only one included study assessing the BP lowering efficacy of a thiazide plus a centrally acting drug versus a centrally acting drug alone. This was a fairly small trial with only 42 patients in the HCTZ 25mg/day plus moxonidine combination group and 37 patients in the moxonidine monotherapy group [16]. This trial showed that adding HCTZ 25mg/day resulted in an additional SBP reduction of -7.0 (95% CI -12.9, -1.1) mmHg and a DBP reduction of -4.0 (95% CI -7.8, -0.3) mmHg. However, as reflected by the wide confidence intervals, the precision of our estimate of the additional BP lowering efficacy of adding a thiazide to a centrally-acting drug is low. 3.4.1.7 Summary of the additional BP reduction induced by adding a thiazide to drug classes Table 3.9 provides an overview of the additional BP reduction that was observed when a thiazide was given in combination with another class of antihypertensive drug. A graphical representation of the data can be seen in Figure 3.2. The dose of thiazides reviewed ranged from 0.4x to 4x the manufacturer’s recommended starting dose. It is evident that the addition of a thiazide within this dose-range as the second-drug resulted in a statistically significant additional BP reduction. The magnitude of the additional SBP/DBP reduction ranged from 4/2 to 14/6 mmHg. Table 3.9 : Summary of the additional BP reduction of thiazide as a second drug in combination therapy Dose of Thiazides (multiples of starting dose)  # of studies (SBP/DBP)  ≤0.5x 1x 2x 3x-4x  10/12 33/36 25/29 4/4  Total # of patients in combination group (SBP/DBP) 1563/1677 4190/4352 3022/3269 185/185  Change in SBP (95% CI) mmHg  Change in DBP (95% CI) mmHg  -3.7 (-4.6, -2.8) -6.0 (-6.5, -5.4) -8.0 (-8.7, -7.3) -14.2 (-17.2, -11.3)  -1.7 (-2.2, -1.2) -3.1 (-3.4, -2.8) -4.1 (-4.5, -3.7) -6.0 (-7.7, -4.3)  80  Blood Pressure Change (mmHg)  Figure 3.2 Additional BP change (±95% CI) induced by adding thiazide as a second drug to other classes of anti-hypertensive drugs. 0  SBP DBP  -10  -20  ≤ 0.5x  1x  2x  3x-4x  Thiazides (multiples of starting dose)  A dose-response relationship can be established in which higher doses of thiazides resulted in a statistically significant greater reduction in BP. However, data were limited for thiazides greater than 2x the starting dose. There is one study assessing thiazide 3x (OD dosing), one study assessing thiazide 3.6x (TID dosing), and 2 studies assessing thiazide 4x (TID dosing). Pooled analysis of these 4 studies showed that the additional reduction in SBP and DBP with thiazides 3x-4x was -14.2 (95% CI -17.2, -11.3) mmHg and -6.0 (95% CI -7.7, -4.3) mmHg, respectively. Although indirect comparisons  showed that thiazide 3x-4x resulted an additional BP reduction that was statistically higher than those achieved with thiazides 2x, no solid conclusions could be made about the difference because of the lack of studies and the difference in dosing schedules. Moreover, both of the studies assessing thiazides 4x were judged to have a high risk of incomplete outcome data bias (38, 58). 3.4.1.8 Subgroup analysis A majority of the data were for HCTZ 12.5mg/day and HCTZ 25mg/day. A subgroup analysis was done to determine whether the first drug has a significant effect on the  81  BP lowering of thiazide given as a second drug. As shown in Figure 3.3, the additional BP reductions induced by adding HCTZ 12.5mg/day to another class of anti-hypertensive drugs were similar with overlapping 95% confidence intervals. However, based on indirect comparisons, the additional systolic BP reduction with HCTZ 12.5mg/day was significantly greater when added to an ARB as compared to an ACEI or a renin inhibitor. Since these 3 classes of drugs are believed to lower BP by inhibiting the renin-angiotensin-aldosterone system (RAAS), albeit at different levels, one would not expect that adding HCTZ to one class would be different from adding it to the other in terms of magnitude of BP reduction. Furthermore, when HCTZ 25mg/day was added to the other antihypertensive drugs, the class of drugs to which HCTZ was added to did not have a statistically significant effect on the magnitude of the additional BP reduction (Figure 3.4). Therefore, the difference that was found between adding HCTZ 12.5mg/day to ARB and to the other drug classes is likely to be due to chance.  Blood Pressure Change (mmHg)  Figure 3.3. Additional BP change (± 95% CI) induced by HCTZ 12.5mg/day in combination therapy with the following drugs. 0  SBP DBP  -2 -4 -6 -8 -10 ACEI  ARB  RI  BB  CCB  82  Blood Pressure Change (mmHg)  Figure 3.4. Additional BP change (± 95% CI) induced by HCTZ 25mg/day in combination therapy with the following drugs. 0  SBP DBP  -10  ACEI  ARB  RI  BB  CCB  CAD  3.4.1.9 Comparison of BP reduction achieved by HCTZ in combination therapy and in monotherapy The BP lowering efficacy of HCTZ monotherapy versus placebo in patients with mild to moderate primary hypertension has been determined in a systematic review by Musini 2000 [120]. By performing an indirect comparison of the results between this current review and that of Musini 2000, we can investigate whether the additional BP achieved by adding HCTZ as the second drug in combination therapy differs from that achieved by administering HCTZ alone as monotherapy. Based on the best available evidence, the estimated additional BP that can be expected when HCTZ 12.5mg/day is added as a second drug is -6.0 (95% CI -6.5, -5.4) mmHg for SBP and -3.1 (95% CI -3.4, -2.8) mmHg for DBP. The estimated additional BP reduction that can be expected with the addition of HCTZ 25mg/day as a second-line drug is -8.0 (95% CI -8.7, -7.3) mmHg for SBP and -4.0 (95% CI -4.4, -3.6) mmHg for DBP. The results from Musini 2000 showed that BP lowering efficacy of HCTZ as a first-line agent versus placebo is a reduction of -5.7 (-7.0, -4.5) mmHg in SBP and -3.9 (-  83  4.7, -3.0) mmHg in DBP for HCTZ 12.5mg/day and -8.5 (-10.4, -6.6) mmHg in SBP and -4.7 (-5.8, -3.5) mmHg in DBP for 25mg/day (see Table 3.10 and Table 3.11). Table 3.10 : SBP reduction contributed to HCTZ added in combination with other drugs or as a single drug. Fixed effect model (95%CI). Drug Dose  HCTZ in combination SBP reduction # patients in (mmHg) combination group HCTZ 12.5 mg/day -6.0 (-6.5, -5.4) 4190 HCTZ 25 mg/day -8.0 (-8.7, -7.3) 2913 *adopted from Musini 2000 [120]  HCTZ as monotherapy* SBP reduction # patients in (mmHg) HCTZ group  Significance  -5.7 (-7.0, -4.5) -8.5 (-10.4, -6.6)  NS NS  579 368  Indirect comparison showed that the additional SBP reduction that resulted from the addition of HCTZ 12.5mg/day or HCTZ 25mg/day to another class of drugs was not statistically different from the SBP reduction induced by HCTZ 12.5mg/day or HCTZ 25mg/day monotherapy, respectively (Table 3.10). Table 3.11 : DBP reduction contributed to HCTZ added in combination with other drugs or as a single drug. Fixed effect model (95%CI). Drug Dose  HCTZ in combination DBP reduction # patients in (mmHg) combination group HCTZ12.5mg/day -3.1 (-3.4, -2.8) 4279 HCTZ25mg/day -4.0 (-4.4, -3.6) 3093 *adopted from Musini 2000 [120]  HCTZ as monotherapy* DBP reduction # patients in (mmHg) HCTZ group  Significance  -3.9 (-4.7, -3.0) -4.7 (-5.8, -3.5)  NS NS  579 368  The same conclusion was made for DBP reductions (Table 3.11). The additional SBP reduction that resulted from the addition of HCTZ 12.5mg/day or HCTZ 25mg/day to another class of drugs was not statistically different from the DBP reduction induced by HCTZ 12.5mg/day or HCTZ 25mg/day monotherapy, respectively. 3.4.2  Loop diuretic plus other drug vs other drug alone By comparing the difference in BP reduction between combination therapy (a  loop diuretic + 1 other drug) and monotherapy (placebo or no treatment + 1 other drug)  84  groups, the additional BP reduction resulting from adding a loop diuretic as the second drug was estimated. 3.4.2.1 Loop diuretic plus ACEI vs ACEI alone There are two included studies assessing the BP lowering efficacy of the combination of piretanide and ACEI versus ACEI alone [21, 57]. The first study (Homuth 1993) [21] assessed two different doses of piretanide (3mg/day and 6mg/day) whereas the other study [57] included only one dose (6mg/day). No included studies assessed piretanide at any other doses in combination with an ACEI. Homuth 1993 showed that the addition of piretanide 3mg/day, which corresponds to 0.5x the manufacturer's recommended starting dose, to ACEI did not result in a significant additional BP reduction. At 1x the starting dose, a statistically significant additional BP reduction was observed when the results from both studies were pooled (see Table 3.12) Table 3.12 : Additional BP reduction by adding a loop diuretic to ACEI. Fixed effect model (95%CI). Dose of loop diuretic (multiples of starting dose) 0.5x 1x  # of studies  Total # of patients in combination group  Change in SBP (95% CI) mmHg  Change in DBP (95% CI) mmHg  1 2  120 312  -1.8 (-5.2, +1.6) -6.5 (-8.7, -4.2)  -0.4 (-2.5, +1.7) -3.1 (-4.5, -1.7)  3.4.2.2 Loop diuretic plus BB vs BB alone Only one included study [10] compared the BP lowering efficacy of a loop diuretic plus a beta-blocker versus a beta-blocker alone. In this study, the combination group was given frusemide 20mg/day plus a beta blocker. There were only 16 patients in the combination group and 11 patients in the beta-blocker monotherapy group. Therefore, due to the lack of data for this combination, our effect estimates have extremely wide  85  confidence intervals, and is therefore imprecise [-13.0 (95% CI -33.0, -7.0) mmHg SBP; 8.0 (95% CI -19.0, +3.0) mmHg DBP]. 3.5  Pulse pressure  Pulse Pressure (PP) was not reported as an outcome in any of the included studies. Therefore, the value of change in PP was calculated by subtracting DBP change from SBP change for each treatment arm in the trial. Using this approach, the change in PP can only be calculated from trials that provided data for both SBP and DBP. 3.5.1  Thiazides Both SBP and DBP data was provided in 47/49 (96%) included studies assessing  HCTZ. The data demonstrated a trend towards higher PP reduction with increasing doses of HCTZ in the combination group (Table 3.13). Table 3.13 : Pulse pressure reduction at end of treatment. Combination therapy versus monotherapy: Hydrochlorothiazide as a second drug. Hydrochlorothiazide (multiples of starting dose)  # of studies  # of patients (combo/mono)  ≤0.5x 1x 2x 3x-4x  10 30 22 4  1563/1720 3974/4072 2913/2886 185/182  Weighted mean change in pulse pressure (95% CI) – combination group (with HCTZ) -3.1 (-4.4, -1.9) -5.9 (-7.6, -3.8) -8.6 (-11.4, -5.9) -6.8 (-12.2, -1.4)  Weighted mean change in pulse pressure (95% CI) - monotherapy group (no HCTZ) -1.3 (-2.3, -0.3) -3.0 (-4.4, -1.6) -4.0 (-6.2, -1.8) +0.7 (-0.7, +2.2)  An estimate of the reduction in PP achieved by indapamide, clopamide or chlorthalidone (as a second drug) cannot be estimated separately because data was obtained from 1 study each. Pooling of data from all thiazides did not significantly alter the results. However, pooling of data for all thiazides did not significantly alter the results. To determine the additional effect of all thiazides as a second drug on PP, the data for indapamide, clopamide and chlorthalidone were combined with HCTZ (Table 3.14).  86  There was a trend towards a greater PP reduction with higher doses of thiazides with an additional reduction in PP of -7.5 (95% CI -11.9, -3.2) mmHg with thiazide 3-4x. Table 3.14 : Difference in pulse pressure reduction at end of treatment. Combination therapy versus monotherapy: Thiazides as a second drug class. Thiazides (multiples of starting dose) ≤0.5x 1x 2x 3x-4x  3.5.2  # studies 10 30 25 4  Difference in PP between combination and monotherapy (95% CI) -1.7 (-3.2, -0.1) -2.8 (-5.0, -0.7) -4.7 (-6.9, -2.4) -7.5 (-11.9, -3.2)  Loop diuretics Due to the lack of studies with the loop diuretics, the reduction in pulse pressure  (PP) cannot be estimated. 3.6 3.6.1  Blood pressure variability Thiazides  3.6.1.1 Baseline variability The standard deviation (variability) of BP at baseline was reported in 27/53 (51%) included studies. There was no statistically significant difference between the variability of SBP (p=0.6) or of DBP (P=0.5) at baseline between the combination and monotherapy groups (Table 3.15). Table 3.15 : Variability of SBP and DBP at baseline SBP DBP  Weighted mean SD SD of weighted mean SD Weighted mean SD SD of weighted mean SD  Combo group 14.1 2.8 4.7 1.1  Mono group 13.8 1.8 4.5 0.9  3.6.1.2 Baseline vs endpoint variability The standard deviations of BP at baseline (after the run-in period) and the standard deviations of BP at endpoint were compared in 9 included studies. As shown in Table 3.16, there was no statistically significant difference between the SBP variability at  87  baseline and endpoint in the combination group or in the monotherapy group. For DBP variability, the baseline SDs were statistically significantly lower than the endpoint values in both the combination and monotherapy groups, an effect likely due to the fact that all studies had DBP entry criteria [121]. Table 3.16 : Standard deviations of BP at baseline vs. endpoint in trials with DBP entry criteria Weighted mean SD of SBP Weighted mean SD of DBP  At baseline (SD) At endpoint (SD) t-test baseline vs. Endpoint At baseline (SD) At endpoint (SD) t-test baseline vs. endpoint  combination group 14.1 (2.2) 15.7 (1.9) p = 0.1 5.0 (0.9) 8.6 (1.1) P<0.0001  Monotherapy group 14.3 (2.5) 16.0 (2.2) p = 0.3 4.9 (0.9) 8.4 (1.0) P<0.0001  3.6.1.3 Combination vs monotherapy To determine if the addition of thiazides affects the BP variability, the standard deviations of BP at the end of treatment were compared between the combination therapy and monotherapy groups. The standard deviation (variability) of BP at endpoint was reported in 9 included studies. As shown in Table 3.16, the weighted mean SD of SBP at the end of treatment was 15.7 mm Hg for the combination group, and 16.0 mm Hg for the monotherapy group. The weighted mean SD of DBP at the end of treatment was 8.6 mm Hg for the combination group, and 8.4 mm Hg for the monotherapy group. Variability of BP was not significantly different between the combination group and monotherapy group for both SBP (p=0.8) and DBP (p=0.7). 3.6.2  Loop diuretics Due to the lack of studies with the loop diuretics, their effects on BP variability  could not be estimated.  88  3.7  Heart rate  3.7.1  Thiazides Heart data are shown in Table 3.17. Heart rate data were extracted from 6 (11%)  included studies of which 4 studies involved the combination with a HCTZ [4,18,31,58]. The addition of HCTZ to another antihypertensive drug class did not show a statistically significant change in heart rate [+0.5 (95%CI -1.1, 2.1) beats/min]. There was one trial each for clopamide [51] and chlorthalidone [6] so no conclusions could be drawn about their effect on heart rate. Table 3.17 : The additional heart rate effects of adding a thiazide as the second drug. Fixed effect model (95%CI) Thiazides  # of trials  Total # of patients in combination group  HCTZ Clopamide Chlorthalidone  5 1 1  229 15 24  3.7.2  Change in HR, beats/minute (95% CI) +0.5 (-1.1, +2.1) +7.8 (-2.7, +18.3) -3.0 (-9.7, +3.7)  Loop diuretics None of the included studies assessing loop diuretics provided heart rate data.  3.8 3.8.1  Withdrawals due to adverse effects Thiazides Data on WDAEs during the 3 to 12 weeks of treatment were extracted from 35/53  (66%) of the included studies for analysis. Table 3.18 : Withdrawals due to adverse effects: drug/thiazide vs drug alone Drug comparisons  # of trials  ACEI/Thiazide vs ACEI ARB/Thiazide vs ARB BB/Thiazide vs BB CCB/Thiazide vs CCB CAD/Thiazide vs CAD Renin/thiazide vs Renin  13 9 5 2 1 1  # of WDAE in combination vs monotherapy groups 53/1508 vs 36/1097 82/2456 vs 33/1222 4/215 vs 3/153 2/97 vs 1/94 1/42 vs 2/37 36/1459 vs 9/546  RR (95% CI) 0.94 (0.62, 1.44) 1.14 (0.62, 1.71) 1.02 (0.33, 3.16) 1.63 (0.22, 11.98) 0.44 (0.04, 4.91) 1.5 (0.73, 3.09)  89  Of the 35 trials that reported WDAE, 4 studies reported no WDAE in both combination and monotherapy groups. Overall, 178/5944 (3%) of the patients in the combination group withdrew due to adverse effects compared with 84/3314 (2.5%) of the patients in the monotherapy group. There was no statistically significant difference in WDAE between the combination and monotherapy groups [RR 1.09 (95% CI 0.84, 1.42)]. 3.8.2  Loop diuretics Based on 2 included studies, adding a loop diuretic as the second drug was not  shown to have any significant impact on the number of withdrawals due to adverse effects (see Table 3.19). Table 3.19 : Withdrawals due to adverse effects: drug/loop diuretic vs drug alone Drug comparisons BB/Loop diuretic vs BB ACEI/Loop diuretic vs ACEI  # of trials 0 2  # of WDAE in combination vs monotherapy groups -6/441 vs 3/329  RR (95% CI) -0.94 (0.25, 3.5)  90  3.9  References  1. Chen JMH, Heran BS, Perez MI, Wright JM. Blood pressure lowering efficacy of drugs inhibiting the renin-angiotensin system as second-line therapy for primary hypertension [Protocol]. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD007188. DOI: 10.1002/14651858.CD007188. 2. Chen JMH, Heran BS, Perez MI, Wright JM.. 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The British Journal of Clinical Practice 1987;41(10):967-970. 78. De Divitiis O, Petitto M, Di Somma S, et al. Atenolol, chlorthalidone, and reserpine in mild-moderate hypertension: Double-blind comparison. Drugs Under Experimental & Clinical Research 1981;7(6):773-779. 79. De Divitiis O, Di Somma S, Petitto M, Fazio S, Ligouri V. Indapamide and Atenolol in the Treatment of Hypertension: Double-blind Comparative and Combination Study. Current Medical Research Opinion 1983;8(7):493-500. 80. Durel LA, Hayashi PJ, Weidler DJ, Schneiderman N. Effectiveness of Antihypertensive Medications in Office and Ambulatory Settings: A Placebo-Controlled Comparison of Atenolol, Metroprolol, Chlorthalidone, Verapamil, and an AtenololChlorthalidone Combination. J Clin Pharmacol 1992;32:564-570.  98  81. Erwteman TM, Nagelkerke N, Lubsen J, Koster M, Dunning AJ. Beta blockade, diuretics, and salt restriction for the management of mild hypertension: a randomised double blind trial. 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[Other: CN00175975; EMBASE 1986040698] 86. Hunter SJ, Wiggam MI, Ennis CN, Whitehead HM, Sheridan B, Atkinson AB, Bell PM. Comparison of effects of captopril used either alone or in combination with a thiazide diuretic on insulin action in hypertensive Type 2 diabetic patients: a double-blind crossover study.[see comment].. Diabetic Medicine 1999;16(6):482-7. 87. Jaattela A. The Fixed Combination of Propanolol and Bendrofluazide in the Treatment of Hypertension. Annals of Clinical Research 1979;11:80-82. 88. Jackson G, Rowland M, Adam G, MacFarlane E, Jackson PG. Placebo Controlled Double-blind Randomised Cross-over Trial of Atenolol, Hydrochlorothiazide and Amiloride, and the Combination (Kalten) in Patients Over 60 Years of Age. The British Journal of Clinical Practice 1986;40(6):230-234. 89. Khalil SI, El Zein O, El Mahadi Bella M. A double-blind, crossover study of acebutolol and hydrochlorothiazide/amiloride diuretic in Sudanese patients with essential hypertension.. Current medical research and opinion 1982;1(39-43). 90. Kieso HA, Gould BA, Mann S, Hornung RS, Altman DG, Raftery EB. Effect on Intra-aterial Blood Pressure of Slow Release Metoprolol Combined with Placebo or Chlorthalidone. British Medical Journal 1983;287:717-720.  99  91. Kubik M, Kendall M, Ebbutt A, John V. Metoprolol with and without chlorthalidone in hypertension. Clinical pharmacology and therapeutics 1979;25(1):25-32. 92. Lang H. The results of a large multicentre study comparing low-dose lisinoprilhydrochlorothiazide with the monocomponents.. Journal of Human Hypertension 1991;5 Suppl 2:73-6. 93. Lechi A, Pomari S, Berto R et al. Clinical Evaluation of Labetolol Alone and Combined with Chlorthalidone in Essential Hypertension: A Double-blind Multicentre Controlled Study. European Journal of Clinical Pharmacology 1982;22:289-93. 94. Leonetti G, Pasotti C, Capra A. Low-dose atenolol-chlorthalidone combination for treatment of mild hypertension.. International journal of clinical pharmacology, therapy, and toxicology 1986 Jan;24(1):43-7. 95. Magee PFA, Freis ED. Is Low-Dose Hydrochlorothiazide Effective? Hypertension 1986;8 (suppl II). 96. Mehta J, Lopez LM, Thorman AD. Lisinopril Versus Lisinopril plus Phydrochlorothiazide in Essential Hypertension. Am J Cardiol 1988;61:803-6. 97. Middlemost SJ, Tager R, Davis J, Sareli P. Effectiveness of enalapril in combination with low-dose hydrochlorothiazide versus enalapril alone for mild to moderate systemic hypertension in black patients. American Journal of Cardiology 1994;73(15):1092-7. 98. Moncloa F, Hwang IK, Muccilli AC. Multiclinic evaluation of the antihypertensive effect of a methyldopa, hydrochlorothiazine, and amiloride combination.. Clinical Therapeutics 1980;3(3):168-75. 99. Muiesan G, Magnani B, Agabiti-Rosei E, Alicandri C, Ambrosioni E, Miele N. Evaluation of the effect of timolol alone and in combination with hydrochlorothiazide and amiloride in the treatment of mild to moderate arterial hypertension: a double-blind, controlled study. Clinical Science & Molecular Medicine - Supplement 1976;3:529s531s. 100. Petrie JC, Galloway DB, Webster J, Simpson WT, Lewis JA. Atenolol and Bendrofluazide in Hypertension. British Medical Journal 1975;4:133-5. 101. Hemodynamic effects of the antihypertensive treatment with atenolol plus chlortalidone in fixed combination: A double-blind crossover comparison with atenolol.. Ricciardelli B, Cuocolo A, De LN, et al. Current Therapeutic Resesarch 1985;37(5):90111. 102. Rosenthal J, Letzel H, Blumner E, Volger K-D. Antihypertensive Therapy - DoseEffect Relationship Between a Combination of Triamterene/Hydrochlorothiazide and Verapamil. Munch. med. Wschr 1989;131(16):319-22.  100  103. Salako LA, Falase AO, Aderounmu AF, Walker O. Assessment of a Fixed-dosage Combination of Atenolol and Chlorthalidone (Tenoretic) in Hypertensive Nigerians. Afr. J. Med. Sci 1990;19:57-61. 104. Salvetti A, Magagna A, Innocenti et al. Chlorthalidone does not increase the hypotensive effect of nifedipine in essential hypertensives: a crossover multicentre study. Journal of hypertension 1989;7 (suppl 6):S250-1. 105. Salvetti A, Magagna A, Innocenti et al. The Combination of Chlorthalidone with Nifedipine Does Not Exert an Additive Antiypertensive Effect in Essential Hypertensives: A Crossover Multicenter Study. Journal of Cardiovascular Pharmacology 1991;17:332-335. 106. Scholze J, Breitstadt A, Cairns V, Bauer B, Bender N, Priestley C, Moreadith C, Phillips J, Vander Elst E, Koch G. Short report: ramipril and hydrochlorothiazide combination therapy in hypertension: a clinical trial of factorial design. The East Germany Collaborative Trial Group. Journal of hypertension 1993;11(2):217-21. 107. Veterans Administration Cooperative Study Group on Antihypertensive Aggents. Propanolol in the Treatment of Essential Hypertension. JAMA 1977;237(21):2303-10. 108. Van Staden DA, Van Gelder LW, Van Der Lingen RE. Trial of Bendrofluazide Compared to Propranolol plus Bendrofluazide (Inderetic) for the Treatment of Essential Hypertension in Blacks. Current Therapeutic Research 1983;34(4):620-626. 109. Weinberger MH. Influence of an angiotensin converting-enzyme inhibitor on diuretic-induced metabolic effects in hypertension. Hypertension 1983;5(5 Pt 2):III132-8. 110. Azizi M, Linhart A, Alexander J, Goldberg A, Menten J, Sweet C, Menard J. Pilot study of combined blockade of the renin-angiotensin system in essential hypertensive patients.. Journal of Hypertension 2000;18(8):1139-47. 111. Chan P, Lin CN, Tomlinson B, Lin TH, Lee YS. Additive effects of diltiazem and lisinopril in the treatment of elderly patients with mild-to-moderate hypertension. American Journal of Hypertension 1997;10(7 Pt 1):743-9. 112. Farsang, C. Kawecka-Jaszcz K. Langan J. Maritz F. Zannad F.. Antihypertensive effects and tolerability of candesartan cilexetil alone and in combination with amlodipine. Clinical Drug Investigation 2001;21(1):17-23. 113. Kuschnir E, Bendersky M, Resk J, Panart MS, Guzman L, Plotquin Y, Grassi G, Mancia G, Wagener G.. Effects of the combination of low-dose Nifedipine GITS 20mg and Losartan 50mg in patients with mild to moderate hypertension. Journal of cardiovascular pharmacology 2004;43:300-305.  101  114. Lessem JN, Barone EJ, Berl T, Detwiler J, Lewin AT, Lubash GD, Margolis R, McGowan RL, Ram CV, Vlachakis N, et al. Nicardipine and propranolol in the treatment of essential hypertension.. American Journal of Hypertension 1989;2(3 Pt 1):146-53. 115. Levine JH, Ferdinand KC, Cargo P, Laine H, Lefkowitz M. Additive effects of verapamil and enalapril in the treatment of mild to moderate hypertension. American Journal of Hypertension 1995;8(5 Pt 1):494-9. 116. Messerli F, Frishman WH, Elliott WJ. Effects of verapamil and trandolapril in the treatment of hypertension. American Journal of Hypertension 1998;11(3 Pt 1):322-7. 117. Pittrow DB. Antlsperger A. Welzel D. Wambach G. Schardt W. Weidinger G.. Evaluation of the efficacy and tolerability of a low-dose combination of isradipine and spirapril in the first-line treatment of mild to moderate essential hypertension. Cardiovascular Drugs & Therapy 1997;11(5):619-627. 118. Scholze J, Zilles P, Compagnone D. Verapamil SR and trandolapril combination therapy in hypertension - A clinical trial of factorial design. British Journal of Clinical Pharmacology 1998;45(5):491-495. 119. Scholze J, Bauer B, Massaro J. Antihypertensive profiles with ascending dose combinations of ramipril and felodipine ER. Clinical & Experimental Hypertension (New York) 1999;21(8):1447-62. 120. Musini VM. A systematic review of the blood pressure lowering efficacy of thiazide diuretics in the treatment of adult patients with primary hypertension. MSc Thesis. The University of British Columbia. 2000. 121. Musini VM, Wright JM. Factors Affecting Blood Pressure Variability: Lessons Learned from Two Systematic Reviews of Randomized ControlledTrials. PLoS ONE 2009;4(5):e5673. [DOI: 10.1371/journal.pone.0005673]  102  4  DISCUSSION Diuretics are widely prescribed for the treatment of hypertension. In the majority  of patients without a compelling indication for another class of drug, a low dose of diuretic should be considered as the first drug of choice in patients with mild to moderate hypertension [1]. It has been demonstrated that a low dose of thiazide, generally started with the equivalent of 12.5 mg to 25 mg per day of chlorthalidone or hydrochlorothiazide, reduces the risk of total mortality, strokes, and coronary artery disease compare to placebo or no treatment [2, 3]. In this review, giving a diuretic as second-line therapy in combination therapy to patients with primary essential hypertension has been shown to further reduce BP in a dose-related manner without increasing withdrawals due to adverse effects. 4.1  What are some issues encountered in the search strategy? The standard search strategy of the Cochrane Hypertension review group was  employed. However, it was not possible to modify the search strategy to identify only trials that involved both combination and monotherapy groups. The term “combination” cannot be used in the search to limit trials to those that involved at least a combination group because not all trials that used combination therapy were tagged with the keyword “combination”. To maintain high sensitivity and specificity, we included trials that had assessed as least 2 different drug classes. The result is that many irrelevant trials had to be excluded after reading the abstract. Of the studies that were methodologically acceptable, many did not provide the data required for meta-analysis. A number of studies initially thought to be eligible were excluded as the data needed was not available  103  in the publication. The majority excluded were crossover studies which did not report data from the first treatment period separately. 4.2  What is the additional BP reduction of thiazide and thiazide-like diuretics when added to other classes of antihypertensive drugs? Blood pressure efficacy data for the thiazide class was extracted from 53 included  studies. Since most of the studies included multiple comparison treatment arms, not all data were extracted for this review. Only data that addressed the comparisons relevant to this review were included. These data were taken from a total of 15129 hypertensive patients, 9483 treated with combination therapy and 5646 treated with monotherapy. These patients had a BP at baseline averaging 156/101 mmHg and a mean age of 54 years. These studies ranged from 3 to 12 weeks with an average 6-week double-blind treatment period. By comparing the difference in BP reduction between the combination (thiazide + 1 other drug) and monotherapy (placebo or no treatment + 1 other drug) groups, the additional BP reduction with a thiazide as second-line therapy was estimated. Hydrochlorothiazide was assessed in 49/53 (92%) of the included studies. The contribution of the thiazide component was statistically significant in terms of the magnitude of BP reduction. Participants who received combination therapy (with a thiazide) experienced greater reductions in both systolic and diastolic BP than participants receiving monotherapy (without thiazide). This is evident at all doses that were assessed in the review. The decrease in SBP/DBP ranged from an additional 4/2 mmHg for lower dose thiazides to 14/6 mmHg for higher dose thiazides.  104  In this review, the doses of thiazides have been categorized according to multiples of the manufacturer’s recommended starting dose ranging from 0.4x to 4x and data were pooled based on this categorization. A dose-response relationship was demonstrated at each increment of thiazide dose. This represents a very robust demonstration that the BP lowering effect of thiazides is dose-dependent. It is worth noting that the data are based primarily on white patients. Although non-white (blacks and others) patients were included in the efficacy analysis, they consisted of only a minority of the patients and most studies did not provide separate data for this subgroup. Therefore, our results are mostly generalizable to white hypertensive patients. 4.3  What is the additional BP reduction of loop diuretics when given in addition to another class of antihypertensive drugs? There are limited data available for the BP lowering efficacy of loop diuretic as a  second drug. Only three included studies provided these data. Adding a loop diuretic as a second drug was effective starting at 1x the manufacturer’s recommended dose, resulting in an additional reduction of -6.5 (95% CI -9.0, -4.0) mmHg in SBP and -3.1 (95% CI 4.5, -1.7) mmHg in DBP. There were no included studies assessing second-line loop diuretic at doses greater than 1x the manufacturer’s starting dose. 4.4  Is there a difference in the reduction of blood pressure between adding a thiazide to different classes of drugs? As described above, the available data have demonstrated a dose-related BP  lowering effect of thiazides as a second-line drug over the range of 0.4x to 4x the manufacturer’s recommended starting dose. In order to determine if there were a  105  difference in the additional BP reduction achieved between adding thiazides to different classes of first-line drugs, comparisons were made for the doses of HCTZ that had the most available data, 12.5mg/day and 25mg/day. Based on indirect comparisons, the choice of the first drug did not have a significant effect on the additional BP lowering of a thiazide when given as a second-line drug. A more direct way of assessing if the addition of a thiazide to different drug classes leads to differences in BP lowering would be by meta-analyzing head-to-head combination trials where the same dose of HCTZ was added to two different classes of drugs. The data here give a pretty good indication that the effect is independent of the first-line drug, a finding that was not expected. Based on their proposed mechanisms of action, most clinicians believe that adding a thiazide to an ACE inhibitor or ARB would have a greater effect than adding a thiazide to a CCB. 4.5  Is there a difference in the blood pressure lowering efficacy of diuretics given as initial therapy or as a second line drug in combination therapy? In order to determine whether there is a difference in the BP lowering efficacy of  HCTZ given as monotherapy or as a second drug in combination therapy, the magnitude of BP reduction was compared. The BP lowering efficacy of diuretics monotherapy (as a first-line drug) versus placebo in patients with mild to moderate primary hypertension was previously assessed in a systematic review by Musini 2000 [4]. Based on the available data, HCTZ demonstrated a dose-related reduction in BP compared to placebo. Results from that review showed that HCTZ 12.5mg/day and 25mg/day decreased SBP by -5.7 (95% CI -7.0, -4.5) mmHg and -8.5 (95% CI -10.4, -6.6) mmHg, respectively. The reduction in DBP were -3.9 (95% CI -4.7, -3.0) mmHg and -4.7 (95% CI -5.8, -3.5) mmHg, respectively. In our review, the BP lowering efficacy of HCTZ as a second drug  106  in the treatment of hypertension was estimated to be -6.0 (95% CI -6.5, -5.4) mmHg for SBP and -3.1 (95% CI -3.4, -2.8) mmHg for DBP at 12.5mg/day, and -8.0 (95% CI -8.7, 7.3) mmHg for SBP and -4.0 (95% CI -4.4, -3.6) mmHg for DBP at 25mg/day. As summarized in Table 3.10 and Table 3.11, the magnitude of BP lowering with HCTZ as a 5  first-line drug and as a second-line drug is remarkably similar and not statistically significantly different. Therefore, our review has demonstrated that HCTZ has a similar BP lowering efficacy as first-line and second-line therapy, and that the BP lowering effect of HCTZ as second-line therapy is additive. 4.6  Does age have an effect on BP lowering of diuretics? The age inclusion criteria for most studies ranged from 18 to 80 with an average  of 54 years. There was only one study that included only elderly patients [5] with a mean age of 71 yrs. Due to the lack of reporting and limited data, a subgroup analysis of older versus younger patients could not be performed. 4.7  Does co-morbidity have an effect on BP lowering of diuretics? It was not possible to perform a subgroup analysis of hypertensive patients with  other co-morbid diseases. None of the trials specifically selected for patients with comorbid conditions and the majority of the studies excluded patients with significant major diseases including renal, cardiovascular, hepatic and neurologic problems. Furthermore, data for these subgroups of patients, if included, have not been reported separately. 4.8  What is the effect of second-line diuretics on BP variability? The standard deviations (SD) of the BP at baseline and/or endpoint were reported  in 27/53 (51%) of the included studies. The endpoint variabilities of the combination and monotherapy groups were compared in order to determine the effect of adding diuretics  107  as a second drug on BP variability. The values used to determine endpoint variability were based on endpoint SDs. Analysis of the available data showed that adding diuretic as second-line therapy did not alter variability of resting SBP and DBP variability since there were no statistically differences between the combination and the monotherapy groups. Because mean values are used, both inter- and intra- individual variabilities were accounted for. To determine the effects on intra-individual variability, 24-hr blood pressure monitoring would be needed. BP criteria for entry into the trial was likely to affect the variability at baseline. The baseline variability in DBP has been shown in other reviews to be statistically lower than the endpoint values in trials with DBP entry criteria for both treated (monotherapy) and untreated (placebo) groups [6-9]. Consistent with these findings, the same trend was observed in this review. For both combination and monotherapy groups, baseline SD values for DBP were similar between both groups but were both significantly lower than endpoint values (p<0.0001). This effect is likely due to the inclusion of many patients near the DBP threshold level for entry into the trial and to the truncation of the distribution of blood pressures at this threshold. None of the trials which provided standard deviations had only SBP entry criteria and therefore it was not possible to determine the effect of SBP entry criteria on SBP variability at baseline. 4.9  What is the effect of second-line diuretics on pulse pressure? Pulse pressure (PP) has become increasingly recognized as an independent risk  factor for cardiovascular events [10,11]. Although PP has not been indicated as one of the primary or secondary endpoints in any of the included studies, we were able to calculate it from trials that provided both SBP and DBP data. Fifty-one (96%) of the studies  108  assessing a thiazide provided both SBP and DBP data whereas the other 2 studies only reported DBP data. By subtracting the change in DBP from the change in SBP for each of the 51 trials, it was found that PP was significantly reduced by adding a thiazide as a second drug at the dose range studied (0.4x to 4x the manufacturer’s recommended starting dose). There is a possibility of a dose-response relationship because there was a trend towards a greater reduction of PP with higher doses of thiazides (see Table 3.14). PP was further reduced by -1.7 (95% CI -3.2, -0.1) mmHg with the addition of thiazide ≤0.5x to as much as -7.5 (95% CI -11.9, -3.2) mmHg with thiazide 3x-4x. Hydrochlorothiazide was the thiazide used in all except 3 studies [12,13,14]. Removal of these 3 studies in sensitivity analysis did not significantly alter the results. Because there were only 3 studies assessing loop diuretics at various doses, their effects on pulse pressure could not be assessed in this review. 4.10 What is the effect of second-line diuretics on heart rate? The results for heart rate outcome were reported incompletely in many of the studies, where only p-values were given or changes were described as “not significantly different”. For the loop diuretics, there were no included studies providing heart rate data for analysis. Quantitative heart rate data could only be extracted from 6 (11%) of the included studies assessing thiazides. Pooled analysis of these 6 trials showed that addition of a thiazide to another antihypertensive drug did not significantly affect heart rate [+0.4 (95% CI -1.1, +2.0) beats/min].  109  4.11 What is the effect of second-line diuretics on withdrawals due to adverse effects? For the thiazides, the number of withdrawals due to adverse effects within 3-12 week treatment period was reported in 35/53 (66%) of the included studies. Consistent with the data for thiazides given as monotherapy [4], adding a thiazide as a second-line drug did not result in a significant increase or reduction in withdrawals due to adverse effects [RR 1.09 (95% CI 0.84, 1.42)]. The type of drug class to which thiazides was added also did not seem to significantly affect the results. Not all studies reported the reason for withdrawals, and the total adverse events in the studies were, on average, not statistically different between combination and monotherapy groups. It is worth noting that most studies excluded patients with previous known allergic reactions to diuretics or any of the drugs used in the studies. Therefore, this review is not a good assessment of adverse effects in a general population taking the drugs for long-term therapy. Because of the lack of identified trials, WDAE data for loop diuretics are very limited. Meta-analysis of 2 studies where a loop diuretic was added to ACEI shows that WDAE was not significantly changed [RR 0.94 (95CI 0.25, 3.5)] as compared to ACEI monotherapy. 4.12 What are the potential sources of bias in this systematic review? The risk of bias in the included studies was assessed individually using the Cochrane Collaboration's recommended tool. The criteria for judging risk of bias can be found in section 8.5 of the Cochrane Handbook for Systematic Review of Intervention [15]. (See Appendix B for the review author’s judgments about each methodological quality item presented as percentages across all included studies)  110  4.12.1 Sequence generation and allocation concealment There was an unclear risk of bias in all the included studies in terms of sequence generation and allocation concealment due to poor reporting. The authors merely stated “randomly assigned” or “using a randomized design” without defining the process or the approach used. Authors should report their methods of sequence generation and allocation concealment clearly. 4.12.2 Blinding Only double-blind, randomized, controlled trials were considered eligible for this review. Nearly all the trials merely stated that the trial was “double-blind” without providing further details about the blinding methods employed. Moreover, none of the studies tested whether the double-blind procedure was successful at the end of the study. Blinding of the patient to either diuretic treatment or non-diuretic treatment could have been broken as patients on diuretics might have noticed increased urine output in the first few days of active treatment. 4.12.3 Incomplete outcome data There was inconsistency in the methods of analysis and reporting of results. In a majority of the trials, not all patients randomized were included in the BP efficacy analysis as only those patients who did not violate the protocols or who completed the entire trial (i.e. per-protocol analysis and complete-patient analysis) were included. However, the number of randomized patients included in the efficacy analysis was greater than 80% in all except 6 studies [5, 13, 16, 17, 18, 19]. In Hart 1991 [5], 153/299 (51%) of the patients were included in the per-protocol analysis. In the other 5 studies, about 25-38% of the randomized patients were missing in the treatment arms in the  111  efficacy analysis. In this review, exclusion of more than 20% of the randomized patients was judged to have a high risk of bias. The majority of the other included studies were judged to have a low risk of bias in terms of incomplete outcome data 4.12.4 Selective outcome reporting All the included studies provided data on the change in BP, which was the primary outcome of this review. However, there were 4 studies that provided DBP without SBP data. There is a possibility of selective reporting bias for heart rate and withdrawals due to adverse effects since only 11% and 66% of the trials reported these outcomes, respectively. 4.12.5 Other potential sources of bias 4.12.5.1 Publication Bias Publication bias, defined in this review as the selective publication of studies with positive results, is another source of bias that may have skewed the results of this review. The most common way to investigate whether or not an effect estimate is subject to publication bias is to examine for funnel plot asymmetry. The funnel plots appeared reasonably symmetrical upon visual examination of the funnel plots. However, funnel plots cannot be investigated adequately in this review because each comparison in this review was set up according to treatment arms (i.e. the unit of analysis is treatment arm and not the entire study as a whole). 4.12.5.2 Selection Bias The method of recruitment of the participants for the trials may serve as another source of bias. Studies may have selected participants who are previously known to be responders to diuretics, either as a first-line drug or second-line drug. This may result in  112  an overestimation of the effect size of the BP lowering efficacy of the diuretics, as compared to the typical BP response observed in the general population taking diuretics. However, the degree of selection bias could not be assessed because the types of patients recruited were not described adequately. Also, in most studies, participants who were known to have allergic reactions to diuretics or any of the drugs used in the particular trial were excluded. Thus, these trials would have underestimated the incidence of adverse effects or withdrawals due to adverse effects associated with diuretics. 4.12.5.3 Funding 28/56 (50%) of the included studies were industry sponsored. The other 28 (50%) studies did not report any funding source. Therefore, it was not possible to compare the results between industry funded and non-industry funded trials because there were no trials that were reported as being non-industry funded. 4.12.5.4 Other factors Most BP measurements were taken just before the next dosing schedule (i.e. trough) in this review. However, 12/56 (21%) studies were included that did not mention the timing of the measurement. If these studies all measured peak BP, and diuretics have a greater BP lowering effect at peak as compared to trough, then including these 12 studies in the overall effect estimate may result in an overestimation of the trough BP lowering efficacy of diuretics. However, a sensitivity analysis excluding these 12 trials did not result in statistically significant difference in the effect estimate so including these trials and assuming they were taken at trough seems reasonable.  113  4.13 References 1. World Health Organization, International Society of Hypertension Writing Group. 2003 World Health Organization/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertension 2003; 21:1983-1992. 2. 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 3. Psaty BM, Lumley T, Furberg CD, Schellenbaum G, Pahor M, Alderman MH, Weiss NS. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA 2003; 289(19):2534-44. 4. Musini VM. A systematic review of the blood pressure lowering efficacy of thiazide diuretics in the treatment of adult patients with primary hypertension. MSc Thesis. The University of British Columbia. 2000. 5. Hart W. Lisinopril-hydrochlorothiazide combination compared with the monocomponents in elderly hypertensive patients. Journal of Human Hypertension 1991;5 Suppl 2:85-9. 6. Wong MMY. A systematic review of the blood pressure lowering efficacy of calcium channel blockers for primary hypertension. MSc Thesis. The Univeristy of British Columbia. 2007. 7. Heran BS, Wong MMY, Heran IK, Wright JM. Blood pressure lowering efficacy of angiotensin converting enzyme (ACE) inhibitors for primary hypertension. Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD003823. DOI: 10.1002/14651858.CD003823.pub2. 8. Heran BS, Wong MMY, Heran IK, Wright JM. Blood pressure lowering efficacy of angiotensin receptor blockers for primary hypertension. Cochrane Database of Systematic Reviews 20098, Issue 4. Art. No.: CD003822. DOI: 10.1002/14651858.CD003822.pub2. 9. Musini VM, Wright JM. Factors Affecting Blood Pressure Variability: Lessons Learned from Two Systematic Reviews of Randomized ControlledTrials. PLoS ONE 2009;4(5):e5673. [DOI: 10.1371/journal.pone.0005673] 10. Haider AW, Larson MG, Franklin SS, Levy D; Framingham Heart Study. Systolic blood pressure, diastolic blood pressure, and pulse pressure as predictors of risk for congestive heart failure in the Framingham Heart Study. Ann Intern Med. 2003; 138(1):10-6. 11. Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Is Pulse Pressure Useful in Predicting Risk for Coronary Heart Disease?: The Framingham Heart Study. Circulation 1999; 100:354-360  114  12. Bermudez J.A. Kornhauser Araujo C. Parra Carrillo J.Z. Paz Barahona M. Management of essential arterial hypertension with a single daily dose of a fixed combination of slow-release oxprenolol and chlorthalidone [Manejo de la hypertension arterial esencial con la combinacion fija de oxprenolol de liberacion lenta mas clorftalidone, en una dosis al dia. Ensayo comparative y multicentrico]. Investigacion Medica Internacional 1982;9(2):156-163 13. Prisant LM. Ambulatory Blood Pressure Profiles in Patients Treated with Once-Daily Diltiazem Extended-Release or Indapamide Alone or in Combination. American Journal of Therapeutics 2000;7:177-184. 14. Safar M, Maiz HB, Weiss Y, Lagrue G, Milliez P. [Antihypertensive action of a betablocker: value of a controlled therapeutic trial] [Action anti-hypertensive d'un bêtabloqueur: intérêt d'un essai thérapeutique contrôlé.]. Therapeutique (La Semaine des hôpitaux) 1973 Sep-Oct;49(7):459-62. 15. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 [updated September 2008]. The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org. 16. Genthon R, Andrieux LA, Arnaud J, Ballade M, Billou J, Bosredon A, Boutges B, Dubon T, Goigoux B, Lalanne G, Laurentjoye F, Lion A, Lorans P, Maurat X, Moulinet P, Ricard L, Roche A, Sdrigotti D, Rangoonwala B, et al. Study of the efficacy and safety of the combination ramipril 2.5 mg plus hydrochlorothiazide 12.5 mg in patients with mild-to-moderate hypertension. Int J Clin Pharmacol Res 1994;14(1):1-9 17. Kellaway GS. A comparison of the efficacy of cilazapril versus cilazapril plus hydrochlorothiazide in patients with mild to moderate essential hypertension. Inhibace General Practice Study Group.. European journal of clinical pharmacology 1993;44(4):377-9 18. Oparil S. Multiclinic double-blind evaluation of timolol combined with hydrochlorothiazide in essential hypertension. Current Therapeutic Research, Clinical & Experimental 1980;27(4):527-537. 19. Vaicaitis JS. VVaicaitis JS.. Evaluation of a beta-blocker, timolol maleate, combined with hydrochlorothiazide in essential hypertension. Current Therapeutic Research, Clinical & Experimental 1980;27(3):365-373  115  5  C LINICAL IMPLICATIONS This systematic review provides the best available evidence of the additional BP  lowering efficacy of diuretics as a second drug in combination therapy for the treatment of primary hypertension. Findings of this review 1. Adding a thiazide diuretic as second-line agent in combination therapy resulted in a greater reduction in BP as compared to monotherapy (without thiazide). 2. The additional BP reduction induced by thiazides was dose-dependent. The SBP/DBP decreased further from baseline with the addition of a thiazide by 4/2, 6/3, 8/4, 14/6 mmHg at doses ≤0.5x, 1x, 2x and 3x-4x respectively. 3. There was a trend towards a dose related pulse pressure reduction with thiazides. 4. Adding a thiazide diuretic as second-line therapy does not affect resting BP variability 5. Adding a thiazide diuretic as second-line therapy does not affect resting heart rate 6. Adding a thiazide diuretic as second-line therapy did not change the rate of withdrawals due to adverse events within 3-12 weeks treatment period. However, only 35/53 (66%) of the studies reported this outcome and there is a possibility for selective outcome reporting bias. 7. The magnitude of the BP reduction achieved by HCTZ given as a second-line drug is similar to the magnitude of BP lowering for HCTZ alone. Thus the BP lowering effect is additive. 8. The drug class to which thiazide was added did not appear to affect the additional BP lowering of the thiazide.  116  9. The evidence for loop diuretics is weak but they appear to reduce BP by 6/3 mmHg at the recommended starting dose. Implications of findings Thiazides produce a reproducible dose related additive blood pressure lowering effect when given as the second drug for hypertension.  117  6  RESEARCH IMPLICATIONS  1. Since systematic reviews are secondary analyses of the data obtain from primary research, the validity of the results are dependent on the quality of the primary trials. The quality of reporting of the clinical trials should be improved to provide complete information on the following parameters: A)  Methodological details: methods of randomization, blinding and allocation concealment.  B)  Complete baseline characteristic details of randomized patients: age, sex, race, baseline BP, other co-morbid illnesses, number of patients who were previously treated with the drug of interested and their response.  C)  Baseline BP and endpoint BP, the mean change from baseline for all treatment visits. The standard deviations of all of these parameters should also be reported. Values should be reported in tables and not in graphs/figures.  D)  The number of patients completing the trial and the number of patients assessed in the efficacy analysis for all randomized groups.  E)  The number of serious adverse events, deaths, number of withdrawals due to adverse events in each group, reasons for withdrawal for all randomized groups.  2. A systematic review of cross-over trials should be conducted to complement the findings of this systematic review.  118  3. Further systematic reviews can be conducted to answer other clinically relevant questions that are closely related to this review: 3.1  What is the additional BP lowering efficacy of thiazides in patients who did not respond to monotherapy with another class of antihypertensive drug? This question would be limited to non-responders to monotherapy.  3.2  What is the additional BP lowering efficacy of thiazides given in combination beyond 12 weeks of treatment?  3.3  Is there a difference in the BP lowering efficacy of different drug combinations involving diuretics? A systematic review of clinical trials with head-to-head comparisons of thiazides with different drug classes should be performed in order to determine if there is a difference in BP reduction achieved with different regimens.  4. A systematic review of the adverse effects of combination therapy should be performed to investigate the rate and severity of adverse events in long-term trials. 5. Long-term trials of head-to-head comparisons of different drug combinations must be performed in order to determine whether there are class-specific effects on morbidity and mortality, which are not dependent on their BP lowering effect.  119  APPENDICES Appendix A – Search strategy Search strategy used for MEDLINE 1. randomized controlled trial$.mp 2. randomized controlled trial.pt 3. controlled clinical trial.pt 4. controlled clinical trial$.mp 5. random allocation.mp 6. exp random allocation/ 7. exp double-blind method/ 8. double-blind.mp 9. exp single-blind method/ 10. single-blind.mp 11. or/1-10 12. (animals not human).sh 13. 11 not 12 14. clinical trial$.mp 15. clinical trial.pt 16. (clin$ adj25 trial$).mp 17. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).mp 18. random$.mp 19. exp research design/ 20. research design.mp  120  21. or/14-20 22. 21 not 12 23. 13 or 22 24. comparative stud$.mp 25. evaluation stud$.mp 26. follow up stud$.mp 27. prospective stud$.mp 28. (control$ or prospective$ or volunteer$).mp 29. or/24-28 30. 29 not 12 31. 23 or 30 32. blood pressure.mp 33. exp hypertension/ 34. hypertens$.mp 35. exp blood pressure/ 36. or/32-35 37. 31 and 36 38. amlodipine.mp 39. aranidipine.mp 40. azelnidipine.mp 41. barnidipine.mp 42. bencyclane.mp 43. benidipine.mp  121  44. bepridil.mp 45. cilnidipine.mp 46. cinnarizine.mp 47. clentiazem.mp 48. darodipine.mp 49. diltiazem.mp 50. efonidipine.mp 51. elgodipine.mp 52. etafenone.mp 53. fantofarone.mp 54. felodipine.mp 55. fendiline.mp 56. flunarizine.mp 57. gallopamil.mp 58. isradipine.mp 59. lacidipine.mp 60. lidoflazine.mp 61. lomerizine.mp 62. manidipine.mp 63. mibefradil.mp 64. nicardipine.mp 65. nifedipine.mp 66. niguldipine.mp  122  67. nilvadipine.mp 68. nimodipine.mp 69. nisoldipine.mp 70. nitrendipine.mp 71. perhexiline.mp 72. prenylamine.mp 73. semotiadil.mp 74. terodiline.mp 75. tiapamil.mp 76. verapamil.mp 77. calcium channel blocker$.mp 78. calcium channel antagonist$.mp 79. or/38-78 80. furosemide.mp 81. bumetanide.mp 82. piretanide.mp 83. torasemide.mp 84. azosemide.mp 85. ethacrynic acid.mp 86. ticrynafen.mp 87. tripamide.mp 88. phenoxybenzoic acid.mp 89. muzolimine.mp  123  90. indacrinone.mp 91. etozolin.mp 92. ozolinone.mp 93. cicletanine.mp 94. cicletanine.mp 95. tienilic acid.mp 96. tizolemide.mp 97. hydrochlorothiazide.mp 98. chlorothiazide.mp 99. buthiazide.mp 100. bendroflumethiazide.mp 101. hydroflumethiazide.mp 102. trichlormethiazide.mp 103. methylclothiazide.mp 104. polythiazide.mp 105. cyclothiazide.mp 106. cyclopenthiazide.mp 107. chlorthalidone.mp 108. metolazone.mp 109. quinethazone.mp 110. fenquizone.mp 111. clorexolone.mp 112. clopamide.mp  124  113. indapamide.mp 114. diapamide.mp 115. isodapamide.mp 116. mefruside.mp 117. xipamide.mp 118. diuretic$.mp. 119. or/80-118 120. ace inhibitor$.mp 121. angiotensin-converting enzyme inhibitor$.mp 122. exp angiotensin-converting enzyme inhibitor/ 123. exp ace inhibitor/ 124. alacepril.mp 125. altiopril.mp 126. benazepril.mp 127. captopril.mp 128. ceronapril.mp 129. cilazapril.mp 130. delapril.mp 131. derapril.mp 132. enalapril.mp 133. fosinopril.mp 134. idapril.mp 135. imidapril.mp  125  136. lisinopril.mp 137. moexipril.mp 138. moveltipril.mp 139. pentopril.mp 140. perindopril.mp 141. quinapril.mp 142. ramipril.mp 143. spirapril.mp 144. temocapril.mp 145. trandolapril.mp 146. zofenopril.mp 147. or/120-146 148. angiotensin receptor blocker$.mp 149. candesartan.mp 150. eprosartan.mp 151. irbesartan.mp 152. losartan.mp 153. telmisartan.mp 154. tasosartan.mp 155. valsartan.mp 156. or/148-155 157. exp beta-antagonist/ 158. exp beta-blocker/  126  159. beta blocker$.mp 160. beta-antagonist$.mp 161. acebutolol.mp 162. alprenolol.mp 163. amosulalol.mp 164. arotinolol.mp 165. atenolol.mp 166. befunolol.mp 167. betaxolol.mp 168. bevantolol.mp 169. bisoprolol.mp 170. bopindolol.mp 171. bocumolol.mp 172. bofetolol.mp 173. bofuralol.mp 174. bunitrolol.mp 175. bupranolol.mp 176. butofilolol.mp 177. carazolol.mp 178. carteolol.mp 179. carvedilol.mp 180. celiprolol.mp 181. cetamolol.mp  127  182. cloranolol.mp 183. dilevalol.mp 184. epanolol.mp 185. esmolol.mp 186. idenolol.mp 187. labetolol.mp 188. levobunolol.mp 189. mepindolol.mp 190. metipranolol.mp 191. metoprolol.mp 192. moprolol.mp 193. nadolol.mp 194. nadoxolol.mp 195. nebivalol.mp 196. nifenalol.mp 197. oxprenolol.mp 198. penbutolol.mp 199. pindolol.mp 200. practolol.mp 201. pronethalol.mp 202. propranolol.mp 203. sotalol.mp 204. sulfinalol.mp  128  205. talinolol.mp 206. tertatolol.mp 207. timolol.mp 208. toliprolol.mp 209. xibenolol.mp 210. or/157-209 211. guanabenz.mp 212. rilmemidine.mp 213. clonidine.mp 214. moxonidine.mp 215. methyldopa.mp 216. guanfacine.mp 217. or/211-216 218. renin inhibitor$.mp 219. aliskiren.mp 220. remikiren.mp 221. or/218-220 222. 79 and (119 or 147 or 156 or 210 or 217 or 221) 223. 119 and (147 or 156 or 210 or 217 or 221) 224. 147 and (156 or 210 or 217 or 221) 225. 156 and (210 or 217 or 221) 226. 210 and (217 or 221) 227. 217 and 221  129  228. or/222-227 229. 37 and 228 Search strategy used for EMBASE 1. randomized controlled trial$.mp 2. controlled clinical trials.mp 3. exp controlled clinical trial/ 4. random allocation.mp. 5. exp random allocation/ 6. double-blind.mp 7. single-blind.mp 8. or/1-7 9. exp animal/ 10. 8 not 9 11. clinical trial$.mp 12. exp clinical trials/ 13. (clin$ adj25 trial$).mp 14. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).mp 15. random$.mp 16. exp research design/ 17. research design.mp 18. or/11-17 19. 18 not 9  130  20. 10 or 19 21. comparative stud$.mp 22. exp comparative study/ 23. exp evaluation studies/ 24. evaluation stud$.mp 25. follow up stud$.mp 26. exp follow up studies/ 27. prospective stud$.mp 28. (control$ or prospective$ or volunteer$).mp 29. or/21-28 30. 29 not 9 31. 20 or 30 32. blood pressure.mp 33. exp hypertension/ 34. hypertens$.mp 35. exp blood pressure/ 36. or/32-35 37. 31 and 36 38. amlodipine.mp 39. aranidipine.mp 40. azelnidipine.mp 41. barnidipine.mp 42. bencyclane.mp  131  43. benidipine.mp 44. bepridil.mp 45. cilnidipine.mp 46. cinnarizine.mp 47. clentiazem.mp 48. darodipine.mp 49. diltiazem.mp 50. efonidipine.mp 51. elgodipine.mp 52. etafenone.mp 53. fantofarone.mp 54. felodipine.mp 55. fendiline.mp 56. flunarizine.mp 57. gallopamil.mp 58. isradipine.mp 59. lacidipine.mp 60. lidoflazine.mp 61. lomerizine.mp 62. manidipine.mp 63. mibefradil.mp 64. nicardipine.mp 65. nifedipine.mp  132  66. niguldipine.mp 67. nilvadipine.mp 68. nimodipine.mp 69. nisoldipine.mp 70. nitrendipine.mp 71. perhexiline.mp 72. prenylamine.mp 73. semotiadil.mp 74. terodiline.mp 75. tiapamil.mp 76. verapamil.mp 77. calcium channel blocker$.mp 78. exp calcium channel blocker/ 79. calcium channel antagonist$.mp 80. exp calcium channel antagonist/ 81. or/38-80 82. furosemide.mp 83. bumetanide.mp 84. piretanide.mp 85. torasemide.mp 86. azosemide.mp 87. ethacrynic acid.mp 88. ticrynafen.mp  133  89. tripamide.mp 90. phenoxybenzoic acid.mp 91. muzolimine.mp 92. indacrinone.mp 93. etozolin.mp 94. ozolinone.mp 95. cicletanine.mp 96. cicletanine.mp 97. tienilic acid.mp 98. tizolemide.mp 99. hydrochlorothiazide.mp 100. chlorothiazide.mp 101. buthiazide.mp 102. bendroflumethiazide.mp 103. hydroflumethiazide.mp 104. trichlormethiazide.mp 105. methylclothiazide.mp 106. polythiazide.mp 107. cyclothiazide.mp 108. cyclopenthiazide.mp 109. chlorthalidone.mp 110. metolazone.mp 111. quinethazone.mp  134  112. fenquizone.mp 113. clorexolone.mp 114. clopamide.mp 115. indapamide.mp 116. diapamide.mp 117. isodapamide.mp 118. mefruside.mp 119. xipamide.mp 120. diuretic$.mp. 121. exp diuretic/ 122. or/82-121 123. ace inhibitor$.mp 124. angiotensin-converting enzyme inhibitor$.mp 125. exp angiotensin-converting enzyme inhibitor/ 126. exp ace inhibitor/ 127. alacepril.mp 128. altiopril.mp 129. benazepril.mp 130. captopril.mp 131. ceronapril.mp 132. cilazapril.mp 133. delapril.mp 134. derapril.mp  135  135. enalapril.mp 136. fosinopril.mp 137. idapril.mp 138. imidapril.mp 139. lisinopril.mp 140. moexipril.mp 141. moveltipril.mp 142. pentopril.mp 143. perindopril.mp 144. quinapril.mp 145. ramipril.mp 146. spirapril.mp 147. temocapril.mp 148. trandolapril.mp 149. zofenopril.mp 150. or/123-149 151. angiotensin receptor blocker$.mp 152. candesartan.mp 153. eprosartan.mp 154. irbesartan.mp 155. losartan.mp 156. telmisartan.mp 157. tasosartan.mp  136  158. valsartan.mp 159. or/151-158 160. exp beta-antagonist/ 161. exp beta-blocker/ 162. beta blocker$.mp 163. beta-antagonist$.mp 164. acebutolol.mp 165. alprenolol.mp 166. amosulalol.mp 167. arotinolol.mp 168. atenolol.mp 169. befunolol.mp 170. betaxolol.mp 171. bevantolol.mp 172. bisoprolol.mp 173. bopindolol.mp 174. bocumolol.mp 175. bofetolol.mp 176. bofuralol.mp 177. bunitrolol.mp 178. bupranolol.mp 179. butofilolol.mp 180. carazolol.mp  137  181. carteolol.mp 182. carvedilol.mp 183. celiprolol.mp 184. cetamolol.mp 185. cloranolol.mp 186. dilevalol.mp 187. epanolol.mp 188. esmolol.mp 189. idenolol.mp 190. labetolol.mp 191. levobunolol.mp 192. mepindolol.mp 193. metipranolol.mp 194. metoprolol.mp 195. moprolol.mp 196. nadolol.mp 197. nadoxolol.mp 198. nebivalol.mp 199. nifenalol.mp 200. oxprenolol.mp 201. penbutolol.mp 202. pindolol.mp 203. practolol.mp  138  204. pronethalol.mp 205. propranolol.mp 206. sotalol.mp 207. sulfinalol.mp 208. talinolol.mp 209. tertatolol.mp 210. timolol.mp 211. toliprolol.mp 212. xibenolol.mp 213. or/160-212 214. guanabenz.mp 215. rilmemidine.mp 216. clonidine.mp 217. moxonidine.mp 218. methyldopa.mp 219. guanfacine.mp 220. or/214-219 221. renin inhibitor$.mp 222. exp renin inhibitor/ 223. aliskiren.mp 224. remikiren.mp 225. or/221-224 226. 81 and (122 or 150 or 159 or 213 or 220 or 225)  139  227. 122 and (150 or 159 or 213 or 220 or 225) 228. 150 and (159 or 213 or 220 or 225) 229. 159 and (213 or 220 or 225) 230. 213 and (220 or 225) 231. 220 and 225 232. or/226-231 233. 37 and 232  140  Appendix B – Methological graph  Adequate sequence generation? Allocation concealment? Blinding? Incomplete outcome data addressed? Free of selective reporting? 0% Yes (low risk of bias)  Unclear  25%  50%  75%  100%  No (high risk of bias)  141  

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