Medicine, Faculty of
Anesthesiology, Pharmacology and Therapeutics, Department of
DSpace
UBCV
Tasnim, Sara
Master of Science - MSc
University of British Columbia
Background: Alcohol is consumed by over 2 billion people worldwide. It is a common substance of abuse and can lead to more than 200 disorders including hypertension. Alcohol has both acute and chronic effects on blood pressure. This systematic review aimed to quantify the acute effect of different doses of alcohol on blood pressure (BP) and heart rate (HR) over time in the adult with both normal and raised blood pressure. We classified doses of alcohol into low (≤14 g alcohol), medium (>14g and ≤30g alcohol) and high (>30 g alcohol) based on the definition by Canadian Centre on Substance Use and Addiction. Objective: To quantify the magnitude of effect of acute alcohol consumption on blood pressure and heart rate in adults (≥18 years) during three different time periods: early, intermediate, and late. Method: We searched major databases (CENTRAL, MEDLINE, EMBASE) and other sources for randomized placebo-controlled trials (RCTs) comparing the effect of single-dose of alcohol with placebo on BP or HR in adults. Two authors independently extracted the data and assessed the quality of the studies. We used mean difference with 95% confidence interval to report effect size of outcome measures and a fixed effect model to combine the effect sizes across studies. Results: We included 32 RCTs involving 767 participants. Most of the study participants were healthy males (N=642) with a mean age of 33 years. Compared to placebo, low dose alcohol consumption had no significant early effect on BP but increased HR by 5 beats per minute (bpm). Effect of medium dose of alcohol on BP during the early period was -5.6/-4.0 mmHg and increase in HR was 4.6 bpm. The effect of high dose alcohol on mmHg BP was biphasic: early (-3.5/-1.9) intermediate (-3.7/-1.6) and late (3.7/2.4). HR in bpm was increased at all time periods: early 5.8, intermediate 6.2 and late 2.7. Conclusion: Compared to placebo alcohol causes a decrease in BP and increase in HR during the early and intermediate time periods (up to 12 hours) after alcohol consumption. Between 13 and 24 hours after consumption both blood pressure and heart rate are increased.
Effect of Alcohol on Blood Pressure: A Systematic Review and Meta-analysis by Sara Tasnim B. Pharm. Professional, University of Dhaka, 2016 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Science in The Faculty of Graduate and Postdoctoral Studies (Pharmacology and Therapeutics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) October 2019 ©Sara Tasnim, 2019 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, a thesis entitled: Effect of Alcohol on Blood Pressure: A Systematic Review and Meta-analysis submitted by Sara Tasnim in partial fulfillment of the requirements for the degree of Master of Science in Pharmacology and Therapeutics Examining Committee: James M. Wright, Anesthesiology, Pharmacology and Therapeutics Supervisor Kenneth Bassett, Anesthesiology, Pharmacology and Therapeutics Supervisory Committee Member Vijaya Musini, Anesthesiology, Pharmacology and Therapeutics Supervisory Committee Member iii Abstract Background: Alcohol is consumed by over 2 billion people worldwide. It is a common substance of abuse and can lead to more than 200 disorders including hypertension. Alcohol has both acute and chronic effects on blood pressure. This systematic review aimed to quantify the acute effect of different doses of alcohol on blood pressure (BP) and heart rate (HR) over time in the adult with both normal and raised blood pressure. We classified doses of alcohol into low (≤14 g alcohol), medium (>14g and ≤30g alcohol) and high (>30 g alcohol) based on the definition by Canadian Centre on Substance Use and Addiction. Objective: To quantify the magnitude of effect of acute alcohol consumption on blood pressure and heart rate in adults (≥18 years) during three different time periods: early, intermediate, and late. Method: We searched major databases (CENTRAL, MEDLINE, EMBASE) and other sources for randomized placebo-controlled trials (RCTs) comparing the effect of single-dose of alcohol with placebo on BP or HR in adults. Two authors independently extracted the data and assessed the quality of the studies. We used mean difference with 95% confidence interval to report effect size of outcome measures and a fixed effect model to combine the effect sizes across studies. Results: We included 32 RCTs involving 767 participants. Most of the study participants were healthy males (N=642) with a mean age of 33 years. Compared to placebo, low dose alcohol consumption had no significant early effect on BP but increased HR by 5 beats per minute (bpm). Effect of medium dose of alcohol on BP during the early period was -5.6/-4.0 mmHg and increase in HR was 4.6 bpm. The effect of high dose alcohol on mmHg BP was biphasic: early (-3.5/-1.9) intermediate (-3.7/-1.6) and late (3.7/2.4). HR in bpm was increased at all time periods: early 5.8, intermediate 6.2 and late 2.7. Conclusion: Compared to placebo alcohol causes a decrease in BP and increase in HR during the early and intermediate time periods (up to 12 hours) after alcohol consumption. Between 13 and 24 hours after consumption both blood pressure and heart rate are increased. iv Lay Summary Drinking excessive alcohol is considered one of the most common causes of raised blood pressure. We wanted to quantify the extent of alcohol's effect on blood pressure and heart rate following consumption. We reviewed the available evidence about the short-term effect of different doses of alcoholic drinks compared to non-alcoholic drinks on blood pressure and heart rate in adults with both normal and raised blood pressure. We included 32 randomized controlled trials involving 767 participants published up to March 2019. Though the trials included adults aged between 18-96 years with various health conditions, most of the participants were young healthy males. We found that alcohol decreases blood pressure during the first 12 hours and increases blood pressure after that. Alcohol increases heart rate up to 24 hours after consumption. The certainty of the evidence for the different doses of alcohol during three different time intervals was between moderate to low. v Preface Chapter 2 of this thesis has been published as part of methodology of the following Cochrane protocol in the Cochrane library: Tasnim S, Tang C, Wright JM. Effect of alcohol on blood pressure. Cochrane Database of Systematic Reviews. 2017(9). Dr. James M. Wright was the main contributor to this protocol’s idea. Dr. James M. Wright supervised Chantel Tang and Sara Tasnim in formulating the protocol’s design. This protocol was revised and edited by all co-authors. Chapter 3, 4 and 5 of this thesis are original and unpublished works of Sara Tasnim under the supervision of Dr. James M. Wright. No patient or animal contact occurred for the purpose of this thesis therefore ethical approval was not required. vi Table of Contents Abstract ......................................................................................................................................... iii Lay Summary ............................................................................................................................... iv Preface .............................................................................................................................................v Table of Contents ......................................................................................................................... vi List of Tables ................................................................................................................................ xi List of Figures .............................................................................................................................. xii Acknowledgements .................................................................................................................... xiv Dedication .....................................................................................................................................xv Chapter 1: Introduction ................................................................................................................1 1.1 Description of the condition............................................................................................ 1 1.2 Description of the intervention ....................................................................................... 1 1.3 How the intervention might work ................................................................................... 2 1.4 Why it is important to do this review.............................................................................. 4 1.5 Objectives ....................................................................................................................... 4 1.5.1 Primary objectives ...................................................................................................... 4 1.5.2 Secondary objective .................................................................................................... 4 Chapter 2: Methods .......................................................................................................................5 2.1 Criteria for considering studies for this review............................................................... 5 2.1.1 Types of studies .......................................................................................................... 5 2.1.2 Types of participants ................................................................................................... 5 2.1.3 Types of interventions................................................................................................. 5 vii 2.1.4 Types of outcome measures ........................................................................................ 6 2.1.4.1 Primary analyses ................................................................................................. 6 2.1.4.2 Secondary analyses ............................................................................................. 6 2.1.4.3 Additional analyses: ............................................................................................ 6 2.2 Search methods for identification of studies ................................................................... 6 2.2.1 Electronic searches...................................................................................................... 6 2.2.2 Searching other resources ........................................................................................... 7 2.3 Data collection and analysis............................................................................................ 7 2.3.1 Selection of studies ..................................................................................................... 7 2.3.2 Data extraction and management ................................................................................ 8 2.3.3 Assessment of risk of bias in included studies............................................................ 8 2.3.4 Measures of treatment effect ....................................................................................... 9 2.3.5 Unit of analysis issues ................................................................................................. 9 2.3.6 Dealing with missing data ........................................................................................... 9 2.3.6.1 General missing data ........................................................................................... 9 2.3.6.2 Missing statistics ................................................................................................. 9 2.3.7 Assessment of heterogeneity..................................................................................... 10 2.3.8 Assessment of reporting biases ................................................................................. 10 2.3.9 Data synthesis ........................................................................................................... 11 2.3.10 Subgroup analysis and investigation of heterogeneity.......................................... 11 2.3.11 Sensitivity analysis................................................................................................ 11 2.3.12 Overall grading of certainty of evidence - 'Summary of findings' tables ............. 12 Chapter 3: Results........................................................................................................................13 viii 3.1 Description of studies ................................................................................................... 13 3.1.1 Results of the search ................................................................................................. 13 3.1.2 Included studies ........................................................................................................ 13 3.1.3 Excluded studies ....................................................................................................... 14 3.2 Risk of bias in included studies .................................................................................... 15 3.2.1 Allocation (selection bias) ........................................................................................ 15 3.2.2 Blinding (performance bias and detection bias) ....................................................... 16 3.2.3 Incomplete outcome data (attrition bias) .................................................................. 17 3.2.4 Selective reporting (reporting bias) .......................................................................... 18 3.2.5 Other potential sources of bias .................................................................................. 19 3.2.6 Publication bias: ........................................................................................................ 20 3.3 Effects of interventions ................................................................................................. 22 3.3.1 Low dose alcohol: ..................................................................................................... 22 3.3.1.1 Effect of low dose of alcohol on SBP: .............................................................. 22 3.3.1.2 Effect of low dose of alcohol on DBP: ............................................................. 22 3.3.1.3 Effect of low dose of alcohol on MAP: ............................................................ 23 3.3.2 Medium dose:............................................................................................................ 24 3.3.2.1 Effect of medium dose of alcohol on SBP ........................................................ 24 3.3.2.2 Effect of medium dose of alcohol on DBP ....................................................... 24 Effect of medium dose of alcohol on MAP ...................................................................... 25 3.3.2.3 Effect of medium dose of alcohol on HR ......................................................... 26 3.3.3 High dose: ................................................................................................................. 27 3.3.3.1 Effect of high dose of alcohol on SBP .............................................................. 27 ix 3.3.3.2 Effect of high dose of alcohol on DBP ............................................................. 28 3.3.3.3 Effect of high dose of alcohol on MAP ............................................................ 28 3.3.3.4 Effect of high dose of alcohol on HR ............................................................... 29 3.4 Subgroup analysis and exploring heterogeneity ........................................................... 30 3.5 Sensitivity analysis........................................................................................................ 30 Chapter 4: Discussion ..................................................................................................................32 4.1 Summary of main results .............................................................................................. 32 4.1.1 Effect of low dose alcohol consumption: .................................................................. 32 4.1.2 Effect of medium-dose alcohol consumption: .......................................................... 32 4.1.3 Effect of high dose alcohol consumption: ................................................................ 32 4.1.4 Dose-dependent response .......................................................................................... 33 4.1.5 Possible mechanisms to explain the results .............................................................. 33 4.2 Clinical implications of the findings: ............................................................................ 34 4.3 Overall completeness and applicability of evidence ..................................................... 35 4.4 Certainty of the evidence .............................................................................................. 37 4.5 Potential biases in the review process ........................................................................... 42 4.6 Agreements and disagreements with other studies or reviews ..................................... 43 Chapter 5: Conclusion .................................................................................................................45 5.1 Implications for practice ............................................................................................... 45 5.2 Implications for research............................................................................................... 45 Bibliography .................................................................................................................................46 Appendices ....................................................................................................................................57 Appendix A : Search Strategies ................................................................................................ 57 x Appendix B : Data extraction form ........................................................................................... 61 Appendix C : Characteristics of included studies and their risk of bias assessment ................ 63 Appendix D : Baseline Characteristics of the included studies ................................................ 97 Appendix E : Funnel plots ...................................................................................................... 106 Appendix F : Results from sensitivity analysis....................................................................... 114 Appendix G : Forest plots ....................................................................................................... 116 Appendix H : Additional table ................................................................................................ 127 xi List of Tables Table 3-1: Effect estimates for low dose of alcohol compared to placebo ................................... 23 Table 3-2: Effect estimates for medium dose of alcohol compared to placebo ............................ 26 Table 3-3: Effect estimates for high dose of alcohol compared to placebo .................................. 29 Table 4-1: Summary of findings table for low dose of alcohol .................................................... 39 Table 4-2: Summary of findings table for medium dose of alcohol ............................................. 40 Table 4-3: Summary of findings table for high dose of alcohol ................................................... 41 Table B-1: Data extraction form…………………………………………………………………57 Table C-1: Characteristics of included studies and their risk of bias assessment………………..59 Table D 1: Baseline Characteristics of the included studies……………………………………..93 Table F-1: Comparison between the effect estimates by fixed-effect model and random-effect model........................................................................................................................................... 114 Table F-2: Effect estimates given by blinded studies compared to unblinded studies. .............. 115 Table H-1: Comparison between older participants and younger participants ........................... 127 Table H-2: Comparison between very high dose of alcohol compared to lower high dose alcohol..................................................................................................................................................... 128 xii List of Figures Figure 3-1: PRISMA diagram for included studies ...................................................................... 14 Figure E-1: Funnel plot: Medium dose Alcohol versus Placebo, outcome: 2.4 Heart rate. ....... 106 Figure E-2: Funnel plot: High dose alcohol versus Placebo, outcome SBP. .............................. 107 Figure E-3: Funnel plot: High dose alcohol versus Placebo, outcome DBP. ............................. 108 Figure E-4: Funnel plot: High dose alcohol versus Placebo, outcome MAP. ............................ 109 Figure E-5: Funnel plot: High dose alcohol versus Placebo, outcome HR. ............................... 110 Figure E-6: Funnel plot: Medium dose Alcohol versus Placebo, outcome SBP. ....................... 111 Figure E-7:Funnel plot: Medium dose Alcohol versus Placebo, outcome DBP. ........................ 112 Figure E-8: Funnel plot: Medium dose Alcohol versus Placebo, outcome MAP. ...................... 113 Figure G-1: Low dose of alcohol versus placebo, outcome: SBP .............................................. 116 Figure G-2: Low dose of alcohol versus placebo, outcome: DBP .............................................. 117 Figure G-3: Low dose of alcohol versus placebo, outcome: MAP ............................................. 117 Figure G-4: Low dose of alcohol versus placebo, outcome: HR ................................................ 118 Figure G-5: Medium dose of alcohol versus placebo, outcome: SBP ........................................ 119 Figure G-6: Medium dose of alcohol versus placebo, outcome DBP......................................... 120 Figure G-7: Medium dose of alcohol versus placebo, outcome MAP ........................................ 121 Figure G-8: Medium dose of alcohol versus placebo, outcomes HR ......................................... 122 Figure G-9: High dose of alcohol versus placebo, outcomes SBP ............................................. 123 Figure G-10: High dose of alcohol versus placebo, outcome DBP ............................................ 124 Figure G-11: High dose of alcohol versus placebo, outcome MAP ........................................... 125 Figure G-12: High dose of alcohol versus placebo, outcome HR .............................................. 126 xiii List of Abbreviations BP Blood pressure Bpm Beats per minutes DBP Diastolic blood pressure HR Heart rate MAP Mean arterial pressure MD Mean difference SBP Systolic blood pressure SD Standard deviation SEM Standard error of mean xiv Acknowledgements Looking back at this entire process I realize that there were a lot people that were involved and helped me to shape this work. Surely, though, the principle influence on any student is their supervisor and I would like to express my sincere gratitude to Dr. James M. Wright for his guidance and support which helped me to complete this work and look forward to new challenges. Many thanks as well for keeping that delicate balance of guidance and freedom which I believe is so important in this kind of research. I would especially like to thank Dr. Vijaya Musini, from whom I have always received support whenever I needed. I would also like to thank Dr. Kenneth Bassett for his constructive feedback. I would like to thank my colleagues at the Therapeutic Initiative and Cochrane Hypertension, Canada. Last but not the least, I would like to thank my husband, my parents, and my siblings for their unconditional love and support throughout the process. xv Dedication To my parents, my husband and my siblings. 1 Chapter 1: Introduction 1.1 Description of the condition Hypertension, or elevated blood pressure, is commonly defined as a resting systolic blood (SBP) pressure above 140 mmHg or a resting diastolic blood pressure (DBP) above 90 mmHg - or both - assuming that the person is not taking any antihypertensive medication [1]. It is one of the most common conditions with an increased prevalence with increasing age and affecting up to 31% of the world’s adult population [2]. Sustained hypertension is associated with an increased risk of stroke, myocardial infarction, heart failure, renal failure, blindness and cognitive impairment [3, 4]. In 2015, approximately 10.7 million deaths around the world were estimated to be attributable to hypertension related health complications [5]. Hypertension can be genetic or due to some environmental factors like poor diet, obesity, tobacco use, excessive alcohol consumption and sedentary lifestyle [5, 6]. A population-based study showed that incidence of hypertension is higher in African descendants (36%) than Caucasians (21%) [7]. Proper management of hypertension can lead to a reduction in cardiovascular complications and mortality [8, 9, 10]. While pharmacological interventions can effectively reduce blood pressure, multiple studies have shown that a healthy lifestyle alone without any pharmacological interventions can greatly reduce prevalence of hypertension [11, 12]. According to US guideline for the prevention, detection, evaluation and management of high blood pressure, adults were advised to reduce weight and sodium intake, increase physical activity and potassium intake, cease smoking, and moderate alcohol intake to manage hypertension non-pharmacologically [13]. 1.2 Description of the intervention Alcohol has been a part of almost every human culture for a very long time [14]. According to WHO, around 2.3 billion people globally drink alcohol and most of them are from European region. On average, drinkers consume 32.8 grams of pure alcohol per day and beer (34.3%) is the most consumed alcoholic beverage [15]. In United States, 14 grams of pure alcohol is considered as one standard drink or one unit and the maximum daily limit for men and women is 4 and 3 2 drinks, respectively [16]. Exceeding this limit increases the risk of cardiovascular, hepatic and nervous system disorders [17-23]. Also, multiple studies have found associations between consumption of alcoholic beverages and specific cancers [24, 25]. Abuse of alcohol resulted in approximately 3 million deaths worldwide and 132.6 million disability-adjusted life years (DALYs) in 2016 [15]. Alcohol is water soluble and can cross biological membranes by passive diffusion. It reaches equilibrium quickly if the body water content is higher. Presence of food in the stomach slows down alcohol absorption by retarding gastric emptying. Hence, it is recommended to not drink alcoholic beverages on an empty stomach. Alcohol is predominantly metabolized by alcohol dehydrogenase (ADH) enzyme system and to a lesser extent by cytochrome P-450 2E1 in the liver. Alcohol is first metabolized to acetaldehyde and then it is oxidized into acetyl CoA by aldehyde dehydrogenase (ALDH) [26]. While alcohol metabolism by the liver is well characterized, it's metabolism in the other parts of the body is not well defined. The enzyme catalase was found to be responsible for metabolizing alcohol in the brain to produce acetaldehyde [27]. Acetaldehyde is highly reactive, and it has been associated with a wide range of physiological adverse effects [28]. Despite the potential negative effects of alcohol consumption, systematic reviews based on cohort studies showed that light to moderate consumption of alcohol has a cardio-protective effect and may prolong survival in adult men and women [29-32]. 1.3 How the intervention might work The molecular mechanism through which alcohol raises blood pressure is still unclear. Alcohol can affect blood pressure through variety of possible mechanisms. Previous research suggests that acute alcohol consumption affects the renin–angiotensin–aldosterone system (RAAS) by increasing plasma renin activity [33]. The RAAS is responsible for maintaining the balancing of fluid and electrolytes. An increase in plasma renin results in increased production of angiotensin I (AI), which is converted to angiotensin II (AII) by angiotensin-converting enzyme (ACE). The hormone AII is a potent vasoconstrictor. It also stimulates aldosterone and vasopressin secretion 3 from the adrenal gland, promoting sodium and water retention [34]. As a result, peripheral resistance and blood volume increases leading to elevated arterial blood. Several clinical trials in humans and studies conducted on animal models reported the stimulation of sympathetic nervous system and increase in noradrenaline after the consumption of alcohol [35-39]. When noradrenaline stimulates the adrenergic receptors located in the heart muscles, heart rate and blood pressure increase. Alcohol has been reported to diminish baroreceptor sensitivity, which is a key factor in regulating blood pressure [40, 41]. Baroreceptors or stretch receptors are mechanoreceptors located on the arch of aorta and carotid sinus. They can detect the changes in blood pressure and maintain blood pressure by controlling heart rate, contractility and peripheral resistance. Acute administration of alcohol stimulates the release of histamine and endorphin, which interferes with baroreflex sensitivity [42]. Another possible mechanism is the increase in plasma cortisol levels following heavy alcohol consumption [43]. Several studies have suggested a role for cortisol in alcohol-induced hypertension [44, 45]. Cortisol is a type of steroid hormone. Presence of excess cortisol was associated in elevated blood pressure in normotensive participants [46, 47]. Alcohol can affect drinkers differently based of their age, sex, ethnicity, family history, and liver condition [26, 48-50]. Previous studies reported that women are affected more after drinking the same amount of alcohol than men because of their lower body weight and higher body fat. The blood alcohol concentration (BAC) rises faster in women because they have smaller volume of distribution [51]. In contrast, women eliminate alcohol from the body a little faster than men [52]. Different genetic variants of ADH and ALDH enzymes were found to show strikingly different metabolism rate of alcohol among different races. 4 1.4 Why it is important to do this review Several systematic reviews based on cohort studies concluded that alcohol intake has a considerable effect on blood pressure and the risk of hypertension [53, 54]. It was also shown that heavy alcohol consumption causes hypertension and leads to left ventricular dysfunction and dilated cardiomyopathy. On the other hand, there is abundant epidemiological and clinical evidence showing that light–moderate drinking is associated with a reduced risk of coronary heart disease (CHD), incidence of stroke and total mortality in middle-aged and elderly men and women [30-32, 55-57]. All these conclusions were based on findings from observational studies. There are several randomized controlled trials reporting the magnitude of effect of alcohol on blood pressure but because of the small size of those trials, they are not sufficient to draw a strong conclusion on their own. In 2005, McFadden and colleagues conducted a systematic review of RCTs, which investigated the hemodynamic effects of daily consumption of alcohol [58]. Based on nine RCTs where participants consumed alcohol repeatedly over days, they reported that alcohol increases SBP by 2.7 mmHg and DBP by 1.4 mmHg. However, they excluded articles where duration of BP observation was less than 24 hours and articles published in non- English languages. We believe inclusion of those studies will provide useful information about the dose-related magnitude and time-course effect of alcohol on blood pressure in people with both normal and elevated blood pressure. 1.5 Objectives 1.5.1 Primary objectives To determine the short-term dose-related effect of alcohol versus placebo on systolic blood pressure and diastolic blood pressure in healthy and hypertensive adults over 18 years of age. 1.5.2 Secondary objective To determine the short-term dose-related effect of alcohol versus placebo on heart rate in healthy and hypertensive adults over 18 years of age. 5 Chapter 2: Methods 2.1 Criteria for considering studies for this review 2.1.1 Types of studies All randomized controlled trials (RCT) that compared alcohol to placebo or similar tasting non-alcoholic beverages were included in this systematic review. 2.1.2 Types of participants We included adult (≥18) participants of both sexes with normal or elevated blood pressure without any restriction on the health condition. 2.1.3 Types of interventions We included any type of alcoholic beverages as the intervention arm. The dose of the alcohol needed to be reported by the authors to be included in the systematic review. Since there were no published standards for differentiating between low and medium dose of alcohol, we chose the alcohol content in one standard drink as the threshold between low and medium dose. Since the alcohol content in one standard drink varies in different countries (ranging from 8g-14g), we chose the Canadian standard of alcoholic beverage which is 14g of pure alcohol [59]. Accordingly, we considered up to 14g of alcohol as a low dose of alcohol. To differentiate between medium and high dose, the Canadian Centre on Substance Use and Addiction (CCSA) [59] identifies less than 30g of alcohol for men and 20g of alcohol for women as the threshold for low risk of alcohol intake. Thus, in our review we used up to 30g alcohol intake for men and 20g alcohol intake for women as moderate dose and above this limit as high dose. In studies where sex specific results were not provided, we categorized dose based on the dominating sex in terms of study participation. In conclusion, we categorized dose of alcohol as follows:  Low dose (≤14 g of alcohol/ ≤1 standard drink)  Medium dose (>14g and ≤30g of alcohol for men and >14g and ≤20g of alcohol for women)  High dose (>30 g of alcohol for men and >20 g of alcohol for women) 6 2.1.4 Types of outcome measures 2.1.4.1 Primary analyses Change in resting seated systolic and diastolic blood pressure at three different time periods after alcohol intake: early (< 6 hours); intermediate (7 to 12 hours); and late (≥ 13 hours). 2.1.4.2 Secondary analyses Change in resting heart rate at the same time periods as blood pressure outcomes above. 2.1.4.3 Additional analyses: Change in resting mean arterial pressure (MAP) at the same time periods as blood pressure outcomes above. 2.2 Search methods for identification of studies 2.2.1 Electronic searches The Cochrane Hypertension Information Specialist searched the following databases without language, publication year or publication status restrictions:  the Cochrane Hypertension Specialised Register via the Cochrane Register of Studies (CRS-Web) (searched 14 March 2019);  the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies (CRS-Web) (searched 14 March 2019);  MEDLINE Ovid (from 1946 onwards), MEDLINE Ovid Epub Ahead of Print, and MEDLINE Ovid In-Process & Other Non-Indexed Citations (searched 14 March 2019);  Embase Ovid (from 1974 onwards) (searched 14 March 2019);  ClinicalTrials.gov (www.clinicaltrials.gov) (searched 14 March 2019);  World Health Organization International Clinical Trials Registry Platform (www.who.it.trialsearch) (searched 14 March 2019). 7 The Information Specialist modelled subject strategies for databases on the search strategy designed for MEDLINE. Where appropriate, they were combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomised controlled (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.c. (Handbook 2011)). We present search strategies for major databases in appendix A. 2.2.2 Searching other resources  The Cochrane Hypertension Information Specialist searched the Hypertension Specialised Register segment (which includes searches of MEDLINE, Embase, and Epistemonikos for systematic reviews) to retrieve existing reviews relevant to this systematic review, so that we could scan their reference lists for additional trials. The Specialised Register also includes searches of CAB Abstracts & Global Health, CINAHL, ProQuest Dissertations & Theses and Web of Science for controlled trials.  We checked the bibliographies of included studies and any relevant systematic reviews identified for further references to relevant trials.  Where necessary, we contacted authors of key papers and abstracts to request additional information about their trials. 2.3 Data collection and analysis 2.3.1 Selection of studies We (ST and CT) independently screened the citations found from the database search result using Covidence software [60]. We excluded articles if the citation seemed completely irrelevant or was identified as a review or observational study after reading the title and abstract. For the rest of the studies, we (ST and CT) retrieved the full-text articles for further assessment. Any disagreements regarding inclusion or exclusion of studies were resolved by discussion between the authors. The reason for exclusion was documented for each citation at the full-text level. We also checked the list of references in the included studies and the articles that cited the included 8 studies in Google Scholar to identify relevant articles. We reported the flow of citation in figure 3-1. 2.3.2 Data extraction and management Two reviewers (ST and CT) performed data extraction independently using a standard data collection form (appendix B), followed by a cross-check. In the case of disagreement, the third reviewer (JMW) was involved to resolve the disagreement. When necessary, we contacted the authors of the studies for information about unclear study designs. We recorded the study design, type of masking, randomisation and allocation concealment method, details of intervention and comparator, duration of intervention, baseline characteristics of the participants, if food was consumed before or during the intervention, number of participants included in the final analysis, outcomes and results, method and position of BP measurement, declaration of conflict of interest, funding source and protocol registration number. All extracted data was entered and double-checked in RevMan 5.3 software [61]. 2.3.3 Assessment of risk of bias in included studies We (ST and CT) independently assessed the risk of bias of the included studies using the Cochrane risk of bias tool (version 1) following chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions [62] for the following domains:  Sequence generation (selection bias);  Allocation sequence concealment (selection bias);  Blinding of participants (performance bias);  Blinding of outcome assessors (detection bias);  Incomplete outcome data (attrition bias);  Selective outcome reporting (reporting bias); and  Other potential sources of bias (i.e. conflict of interest, funding source, registration of the study protocol) We assessed selective reporting bias for each of the outcomes separately. For the other domains, we grouped the outcomes together and provided only one judgement. We contacted the study 9 authors for missing or unclear information required for the risk of bias assessment and then reassessed the domains once the information was available. 2.3.4 Measures of treatment effect All the outcomes of interest in the review (SBP, DBP and HR) produced continuous data. We calculated and reported mean difference (MD), with corresponding 95% confidence interval (95% CI). 2.3.5 Unit of analysis issues Most of the included studies in the review had cross-over design. Carryover effect in a cross-over trial can confound the effect of subsequent treatment. We recorded the washout period of each included study reported by the authors to decide if there was a risk of carry over effect. If the cross-over trials were appropriate to combine with other trials, we used the recommended generic inverse variance approach of meta-analysis. For multi-arm trials, if a study reported more than one intervention arm, we identified the relevant intervention arm and included that in the review. If the studies reported more than one placebo group, we combined them into a single group when appropriate, using the formulae for combining groups reported in chapter 7 [62]. We followed the same formulae for combining groups if a study reported two different types of alcoholic beverages containing the same amount of alcohol. 2.3.6 Dealing with missing data 2.3.6.1 General missing data We contacted the study authors for missing or unclear information relevant for the review using the contact information provided in the respective articles. If the dose of the study was not reported in articles and the study author did not respond, we excluded it. 2.3.6.2 Missing statistics If a standard error (SE) is given instead of a standard deviation (SD), we used the formula SD = SE x square root of n (number of participants) to calculate the SD. 10 We also calculated SD if 95% CI, P-value or t value was reported in the included studies according to chapter 7 of the Cochrane Handbook [62]. If we were not able to get SD from the study authors or calculate from the values mentioned above, we imputed SD using the following hierarchy (listed from highest to lowest) [63]:  SD of change in blood pressure measured in a different position (e.g. lying down) than that of the blood pressure data used;  SD of blood pressure at the end of treatment;  SD of blood pressure at the end of treatment measured in a different position (e.g. lying down) than that of the blood pressure data used;  SD of blood pressure at baseline (unless this measure was used as an entry criterion);  Mean SD of change in blood pressure from other studies that studied the effect of alcohol. 2.3.7 Assessment of heterogeneity We conducted standard chi-square test using Review Manager Software 5.3 [61] to test for heterogeneity. A P-value of 0.1 or less was considered a statistically significant heterogeneity. I2 statistics was used to interpret the level of heterogeneity [62]. For the purposes of this review, if I2 value was more than 50%, it was considered a substantial level of heterogeneity. Furthermore, we visually inspected the forest plot to check if there were any non-overlapping confidence intervals indicating heterogeneity. Lastly, we attempted to explore the reason for heterogeneity by looking for clinical and methodological differences between trials. 2.3.8 Assessment of reporting biases Funnel plots were used if there were more than 10 studies that contributed to a meta-analysis in order to detect the extent of risk of reporting bias based on the symmetry of the plot [62]. We visually inspected the funnel plots. If the residual scatter plot resembles a symmetrical inverted funnel, publication bias was considered to be unlikely. Positive results are more likely to be published than negative results, which leads to potential publication bias. However, publication bias does not necessarily lead to asymmetry of funnel plots. Asymmetry in the funnel plot can also be due to inflated effects in smaller studies resulting from poor study design, heterogeneity, 11 sampling variation or chance. Therefore, we performed sensitivity analyses and searched for unpublished studies as outlined in the Cochrane Handbook for Systematic Reviews of Interventions chapter 10 [62]. 2.3.9 Data synthesis We used Cochrane review manager software [61] for all the data analyses. We conducted meta-analysis for the three dose groups (low dose, medium dose and high dose of alcohol) separately. We considered statistical, clinical and methodological heterogeneity between the study populations and only proceeded with meta-analysis if the interventions, comparisons and outcome measures were considered similar enough to pool. Where trials compared more than one dose of alcohol, we handled each comparison separately. Since all outcome of interest in this review provided continuous data, we used the inverse variance approach and fixed-effect model to combine effect sizes across studies. 2.3.10 Subgroup analysis and investigation of heterogeneity We planned on performing subgroup analysis based on the following:  Normotensive participants (defined as SBP < 140 mmHg and DBP < 90 mmHg) versus hypertensive participants (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg);  Sex of the participants. It is recommended that there should be at least 10 studies reporting each of the subgroups in question. Of the 32 included studies, there were only 4 studies that included hypertensive participants. So, it was not possible to conduct a subgroup analysis based on blood pressure. For the planned subgroup analysis based on sex, there was no study that reported male and female participant data separately, so it was not possible to conduct sub group analysis based on sex. 2.3.11 Sensitivity analysis The following sensitivity analyses were performed: 12  We checked if blinding of the participants and outcome assessors affected the effect estimate of BP and HR (blinded studies versus open label studies).  To check for the difference between the effect estimates of the outcomes derived by using the fixed-effect model and the random-effects model, we conducted sensitivity analysis. It was planned to be conducted only when there was substantial heterogeneity. 2.3.12 Overall grading of certainty of evidence - 'Summary of findings' tables We used the GRADE approach (Grading of Recommendations, Assessment, Development and Evaluation) [64] to assess the certainty of the body evidence as high, moderate, low or very low and provide review authors' comments to support our judgements as outlined in the Cochrane Handbook for Systematic Reviews of Interventions chapter 12 [62]. We included the outcomes SBP, DBP and HR for each comparison. Both reviewers (ST and CT) rated the certainty of evidence independently by examining risk of bias, indirectness, inconsistency, imprecision, and publication bias. To assess the risk of bias across studies, we rated the evidence as having no limitations, serious limitations, or very serious limitations while taking into account the extent that each trial contributes towards the magnitude of effect (weight) as based on their study sample size and mean difference. We used GRADEpro software [65] to construct a 'Summary of findings' table to compare outcomes including change in SBP and DBP and HR. In addition, we also included illustrative risks to present findings for the most important outcome (change in systolic blood pressure). 13 Chapter 3: Results 3.1 Description of studies 3.1.1 Results of the search The search was conducted up to March 2019 and resulted in 6869 citations. After de-duplication and screening of titles and abstracts, we were left with 482 citations for further assessment. We retrieved the full text articles of those these citations and 32 studies met the inclusion criteria (Figure 3-1). 3.1.2 Included studies Refer to appendix C for characteristics of included studies and appendix D for further details regarding the studies. Of the 32 included RCTs in 767 participants, 26 trials had cross-over designs and six had parallel group design. Three studies were single-blind, 12 studies were double-blind, and 17 studies were open-label studies. Most of the study participants were male (N=642). The age of the participants ranged between 18-96 years and the mean age was 33 years. Stott et al. [66] included relatively old participants (mean age 81; range between 70-96 years) compared to the other studies. Only 14 out of 34 studies reported the mean body weight of the participants. The mean body weight was 78 kg. Most of the studies included healthy participants with normal blood pressure. There were some studies that included participants with essential hypertension (10%) [67-71], type 1 diabetes (2.2%) [72], coronary heart disease (6.3%) [74-76] and regular user of methylenedioxymethamphetamine (MDMA) (2%) [73].Different types of alcoholic beverages (red wine, white wine, beer and vodka) were used in the 32 studies. 23 out of 32 studies used non-alcoholic beverage including juice as placebo [66-73, 75-89]. Seven studies [35, 44, 74, 90-93] used dealcoholized wine as placebo and two studies did not mention the type of control they used for alcohol [94, 95]. The dose of alcohol ranged between 0.35 mg/kg- 1.3 g/kg and the alcohol was consumed between 5 minutes to 1.5 hours. It is important to note that the dose of alcohol was comparatively higher (≥60g or ≥1g/kg) in nine studies [68, 75, 77, 85-89]. 14 Figure 3-1: PRISMA diagram for included studies 3.1.3 Excluded studies We excluded 450 articles after reviewing the full-text articles and the reasons for exclusion were recorded. Most of the articles were excluded for not being randomized controlled (195 articles) or placebo-controlled trials (150 articles). We also excluded 42 articles for not reporting the dose of the alcohol (see figure 3-1 for more reasons). 15 3.2 Risk of bias in included studies Refer to figure 2 for the overall 'Risk of bias' assessment. We (ST and CT) independently assessed the risk of bias following the methodology described in the Cochrane Handbook for Systematic Reviews of Interventions chapter 8 [62]. We assessed the risk of bias based on 11 domains: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias) for systolic blood pressure (SBP), selective reporting (reporting bias) for diastolic blood pressure (DBP), selective reporting (reporting bias) for mean arterial blood pressure (MAP), selective reporting (reporting bias) for heart rate (HR), other bias (conflict of interest, industry sponsorship) and other bias (was the study registered in clinical trials.gov and was the protocol available). We classified each domain as being at a low, high or uncertain risk of bias. In the case of disagreement, a third party (JMW) was involved in order to discuss and resolve the disagreement. In the case of uncertain information regarding the method of RCT, authors of studies were contacted via email in order to get clarification. 3.2.1 Allocation (selection bias) We (ST and CT) assessed selection bias based on two categories: random sequence generation and allocation concealment. For random sequence generation, 22 included studies [44, 66, 69, 70, 71, 73-76, 81, 82, 84, 85, 87-95] were classified as uncertain risk of bias. Even though these studies reported that participants were randomized to receive alcohol or placebo, the method of randomization was not mentioned. Although three studies [35, 79, 80] did not report the method of randomization but their reported baseline characteristics were well matched. We classified them as uncertain risk of bias. The remaining seven studies reported the method randomization; hence they were classified as low risk of bias. Random seed generation was used by Bau et al. [77, 78], computer-16 generated random selection of 4x4 Latin Squares was used by Cheyne et al. [72], a third person unaware of research objectives or protocol prepared sealed randomized envelops in blocks of 8 in Foppa et al. [67], randomized computer generated number table was used by Hering et al. [68], random sequence generator was used by Maufrais et al. [83] and random number allocator was used by Rosito et al. [86]. It is important to note that the information regarding to the method of randomization in two studies [67, 86] was provided by author via email. For allocation concealment, 28 included studies [44, 66, 68-70, 71, 73-79, 80, 81, 82-85, 87- 95] were classified as uncertain risk of bias because the method of allocation concealment was not reported. The remaining 4 studies were classified as low risk of bias. In the study by Barden et al. [35], treatment allocation was performed by a statistician who was not involved in the trial. Sealed randomized opaque envelops were used in two studies [67, 72]. Random number allocator was used by Rosito et al. [86]. It is important to note that the information regarding the method of allocation concealment in two studies [67, 86] was provided by author via email. Hering et al. [68] was also contacted but the author did not explicitly mention the method of allocation concealment in the email. Thus, this study was classified as uncertain risk of bias. 3.2.2 Blinding (performance bias and detection bias) In the case of performance bias, 6 studies were classified as low risk of bias, 19 studies were classified as high risk of bias and 7 studies were classified as unclear risk of bias. Six studies [44, 80, 85, 86, 88, 90] were classified as low risk of performance bias. The study Nishiwaki et al. [90] was a single-blinded study. In this study, all of the test drinks were poured into paper cups in order to achieve blinding of participants. Rosito et al. [86] was contacted for additional information regarding the method of blinding. The author explained the blinding method in the email in detail, so it was classified as low risk of bias. 19 studies were classified as high risk of performance bias. 17 out of 19 studies [35, 66-71, 75, 76, 79, 81, 83, 87, 89, 94, 95] were open-label, hence these studies were not blinded for participants and personnel. It is important to note that 2 out of 19 studies [91, 93] were single-17 blinded. Personnel was blinded instead of participants in the study by Karatzi et al. [93] and neither personnel nor participants was blinded in the study by Agewall et al. [91], so they were assessed as high risk of bias. 7 studies [72-74, 77, 78, 84, 92] were classified as unclear risk of performance bias. Bau et al [77, 78] only mentioned investigators and volunteers were blinded to the content of the drink, but the authors did not mention the method of blinding in the studies. Karatzi et al. [74] only mentioned the method of blinding of participants but it was not clear if the involved personnel were blinded as well. The method of blinding of participants and personnel was not mentioned in three studies [73, 84, 92]. In one study [72], subjects were blinded to the content of drink but some of them reported that they were able to detect the alcohol by taste at the end of the study. Hence, this study was classified as high risk of bias. In the case of detection bias, 9 studies [72, 77, 78, 80, 85, 86, 88, 91, 93] were classified as low risk of performance bias. They all included an independent individual that was blinded to the control and test groups to evaluate and analyse the data. 17 studies were classified as high risk of bias because they were described as open-label studies [35, 66, 67-71, 75, 76, 79, 81-83, 87, 89, 94, 95] and the outcome assessor was not blinded. One study [90], a single-blind study ensured participant blinding but not the outcome assessors. Five studies were classified as uncertain risk of detection bias. Four studies [44, 74, 92, 84] did not mention the method of blinding of outcome assessors. Even though Dumont et al. [73] mentioned the blinding of outcome assessors, it is not clear if the blinding of outcome assessment was maintained in the case of blood pressure and heart rate measurements. 3.2.3 Incomplete outcome data (attrition bias) 18 studies [35, 44, 66, 67, 69, 71, 73, 75-78, 80, 85, 87, 91- 93, 95] were classified as low risk of attrition bias. Four studies [69, 70, 73, 76] reported the reasons for participants withdrawal and excluded their data in the final analysis. The data was balanced across groups and hence, missing data did not affect the final results. 18 One study was classified as high risk of bias. Chen et al. [94] reported that two subjects in the alcohol group dropped from the study for unknown reason, so the data analyses were based on eight subjects in the alcohol group and 10 subjects in the control group. Since the reason behind withdrawal was not mentioned in this study, therefore, this study was considered as high risk of bias. 13 studies [68, 70, 72, 74, 79, 81-84, 86, 88-90] were classified as uncertain risk of attrition bias because the authors did not explicitly mention if all participants were included in the final analysis. 3.2.4 Selective reporting (reporting bias) We (ST and CT) assessed the reporting bias based on four categories: selective reporting of systolic blood pressure (SBP), selective reporting of diastolic blood pressure (DBP), selective reporting of mean arterial blood pressure (MAP) and selective reporting of heart rate (HR). In the case of selective reporting of systolic blood pressure (SBP), 25 studies [35, 44, 66-72, 74, 75, 76, 77, 79, 80, 82, 84-87, 89, 90, 92, 94, 95] were classified as low risk of bias because they recorded and reported the SBP either in the result section or in figure. 7 studies [73, 78, 81, 83, 88, 91, 93] were classified as high risk of bias. Agewall et al. [91] only measured blood pressure upon participant’s arrival and did not measure blood pressure after intervention. The aim of Bau et al. [78] was to determine the effect of alcohol on heart rate variability, so SBP was not measured in this study. Dumont et al. [73] measured blood pressure during the study period, but authors did not provide the before and after measurement of SBP. They only mentioned that change of blood pressure was not significant. The aim of Fazio et al. [81] was to determine the effect of alcohol on blood flow volume and velocity. Blood pressure was also measured but was not reported. Authors only mentioned that acute ethanol administration caused transitory increase in BP at 20 minutes. Three studies [83, 88, 93] measured blood pressure before and after treatment but did not report the measurements. In the case of selective reporting of diastolic blood pressure (DBP), 23 studies [35, 44, 66, 72, 80, 67-71, 74, 76, 77, 82, 84-87, 89, 90, 92, 94, 95] were classified as low risk of bias because 19 they measured and reported DBP in the results section or in figure. 9 studies [73, 75, 78, 79, 81, 83, 88, 91, 93] were classified as high risk of bias. Agewall et al. [91] only measured blood pressure upon participant’s arrival and did not measure blood pressure after intervention. The aim of Bau et al. [78] was to determine the effect of alcohol on heart rate variability, so DBP was not measured and reported in this study. Buckman et al. [79] reported that blood pressure was recorded beat to beat continuously, but DBP was not reported. Dumont et al. [73] measured blood pressure during the RCT, but authors did not provide the before and after measurement of DBP. They only mentioned change of blood pressure was not significant. The aim of Fazio et al. [81] was to determine the effect of alcohol on blood flow volume and velocity. Blood pressure was also measured but was not reported. Authors only mentioned acute ethanol administration caused transitory increase in BP at 20 minutes. Rossinen et al. [75] measured blood pressure but only selectively reported SBP instead of reporting both SBP and DBP. Three studies [83, 88, 93] measured blood pressure before and after treatment but did not report the measurements. For selective reporting of mean arterial blood pressure (MAP), 11 studies [67, 71, 73, 74, 79, 81, 83-85, 88, 93] were classified as low risk of bias because MAP was measured and reported. 21 studies [35, 44, 66, 68-70, 72, 75, 76, 77, 78, 80, 82, 86, 87, 89, 90- 92, 94, 95] were classified as high risk of bias because they did not report MAP. For selective reporting for heart rate (HR), only one study [82] was classified as high risk of bias because heart rate was not reported. The remaining 33 studies were classified as low risk of bias because heart rate was measured and reported. 3.2.5 Other potential sources of bias We divided other potential sources of bias into two main categories: conflict of interest/industry sponsorship and registration with clinical trials.gov. In the case of assessing conflict of interest and industry sponsorship, 21 studies [35, 44, 68-73, 77-79, 80, 83, 85, 88-91, 93, 95] were classified as low risk of bias because they reported industry sponsorship and had no conflict of interest. 11 studies [66, 67, 74, 75, 81, 82, 84, 86, 87, 20 92, 94] were classified as uncertain risk of bias due to unreported funding source or conflict of interest. In the case of registration with clinical trials.gov, only one study [35] was considered as low risk of bias. The trial was registered with the Australian New Zealand Clinical Trials Registry (ANZCTR). The remaining studies were classified as high risk of bias since the protocol was not registered and the study identifier was not reported. Therefore, it was difficult to determine apriori selection of primary and secondary outcome measures of the included studies. 3.2.6 Publication bias: There were not enough studies to construct a funnel plot for the outcomes under low dose of alcohol. We only interpreted the funnel plots which were constructed based on the studies reporting the outcomes under medium dose and high dose of alcohol versus placebo comparisons. We created a funnel plot using the mean difference (MD) from the studies reporting effect of medium dose and high dose of alcohol on SBP, DBP, MAP and HR against standard error (SE) of the MD to check for existence of publication bias. Visual inspection of the funnel plots showed that the effect estimate is equally distributed around the mean in figure D-1, D-2, D-3, D-4 and D-5 (See in appendix E). In figure D-6, D-7 and D-8, we observed slight asymmetry in the funnel plot that was probably due to heterogeneity rather than publication bias. There were some overlaps of data points in some funnel plots, indicating that some of the studies included here were of similar size. According to the chapter 10 of the Cochrane handbook [62], funnel plot asymmetry test should not be used if all the studies are of similar sizes. In this review, most of the studies included were of similar sizes. 21 Figure 3-2: Risk of bias summary of the included studies 22 3.3 Effects of interventions 3.3.1 Low dose alcohol: 14 gram of pure alcohol/ethanol or less was defined as low dose of alcohol (results summarized in table 3-1). 3.3.1.1 Effect of low dose of alcohol on SBP: ≤6 hours after alcohol consumption: Based on two studies [72, 90] in 28 participants, the mean decrease in SBP using fixed-effect model was 1.46 mmHg [95% CI -8.38 to 5.42, P value=0.67]. There was no heterogeneity, (I2=0%). 7-12 hours after alcohol consumption: Unfortunately, none of the included studies reported results at this time interval. ≥13 hours of alcohol consumption: Unfortunately, none of the included studies reported results at this time interval. 3.3.1.2 Effect of low dose of alcohol on DBP: ≤6 hours after alcohol consumption: Two studies [72, 90] reported the early effect of alcohol consumption on DBP and the decrease in DBP was 1.46 mmHg [95% CI from -6.91 to 3.99, P value= 0.36]. There was no heterogeneity, (I2=0%). 7-12 hours after alcohol consumption: Unfortunately, none of the included studies reported data at this time interval. 23 ≥13 hours of alcohol consumption: Unfortunately, none of the included studies reported data at this time interval. 3.3.1.3 Effect of low dose of alcohol on MAP: ≤6 hours after alcohol consumption: Based on the MAP data from two studies [72, 90] the mean effect estimate of low dose of alcohol on MAP was -1.45 mmHg [95% CI from -4.55 to 1.65, P value= 0.36]. There was no heterogeneity, (I2=0%). Table 3-1: Effect estimates for low dose of alcohol compared to placebo Outcomes or subgroup Number of studies Participants Effect estimate (mean difference with 95% CI) using fixed effect model 1.1 SBP ≤6 hours 2 28 -1.48 [-8.38, 5.42] 7-12 hours 0 0 Not estimable ≥13 hours 0 0 Not estimable 1.2 DBP ≤6 hours 2 28 -1.46 [-6.91, 3.99] 7-12 hours 0 0 Not estimable ≥13 hours 0 0 Not estimable 1.3 MAP ≤6 hours 2 28 -1.45 [-4.55, 1.65] 7-12 hours 0 0 Not estimable ≥13 hours 0 0 Not estimable 1.4 HR ≤6 hours 2 28 5.06 [1.88, 8.24] * 7-12 hours 0 0 Not estimable ≥13 hours 0 0 Not estimable *Statistically significant increase. 24 ≥ 13 hours after alcohol consumption: Unfortunately, none of the included studies reported data at this time interval. 3.3.2 Medium dose: 3.3.2.1 Effect of medium dose of alcohol on SBP ≤6 hours after alcohol consumption: Based on the data from nine studies [67, 69, 70, 71, 74, 86, 90, 94, 95] in 149 participants, a medium dose of alcohol decreased SBP by 5.63 mmHg [95% CI from -8.25 to -3.02, P-value <0.001]. The I2 statistic value was 63% and P-value for the chi2 test was 0.004, indicating substantial heterogeneity across studies. Due to the presence of substantial heterogeneity across the studies, we also conducted this analysis using random-effects model. Medium dose of alcohol decreased SBP by 6.15 mmHg [95% CI from -10.55 to -1.75, P-value 0.006]. 7-12 hours after consumption: Four studies [67, 69, 70, 95] (in 54 participants showed that a medium dose of alcohol decreased SBP by 3.22 mmHg [95% CI from -8.37 to 1.93, P value=0.22] 7-12 hours after the consumption of medium dose of alcohol. There was no heterogeneity (I2= 0). ≥ 13 hours after consumption: Based on the data in 66 participants from four studies [67, 69, 70, 86], the mean increase in SBP was 0.64 mmHg [95% CI from -3.90 to 5.18, P value=0.78]. There was no heterogeneity (I2= 0). 3.3.2.2 Effect of medium dose of alcohol on DBP ≤6 hours after alcohol consumption: Based on the data from nine studies [67, 69, 70, 71, 74, 86, 90, 94, 95] in 149 participants, medium dose alcohol decreased DBP by 4.01 mmHg [95% CI 25 from -6.02 to -2.00, P-value <0.001]. The I2 statistic value was 59%% and P-value for the chi2 test was 0.009, indicating substantial heterogeneity across studies. Due to the presence of substantial heterogeneity across the studies, we also conducted this analysis using random-effects model. Medium dose of alcohol decreased DBP by 3.76 mmHg [95% CI from -7.02 to -0.50, P-value 0.006]. 7-12 hours after alcohol consumption: Four studies [67, 69, 70, 95] in 54 participants, the mean decrease in DBP was 1.19 mmHg [95% CI from -4.29 to 1.90, P value=0.45] after 7-12 hours after the consumption of medium dose of alcohol. There was no heterogeneity (I2= 0). ≥ 13 hours after alcohol consumption: Based on the data from 66 participants from four studies [67, 69, 70, 86], the mean increase in DBP was 1.78 mmHg [95% CI from -0.95 to 4.51, P value=0.64]. There was no heterogeneity (I2= 0). Effect of medium dose of alcohol on MAP ≤6 hours after alcohol consumption: Based on the data from 13 studies in 199 participants [35, 44, 66, 68, 73, 75-77, 79, 80, 82, 84-87 89, 92], we found that high dose of alcohol decreased MAP by -2.92 mmHg [95% CI from -5.76 to -0.07, P-value=0.04]. There was evidence of low heterogeneity across the studies (I2=69%). Due to the presence of substantial heterogeneity across the studies, we also conducted this analysis using random-effects model. Medium dose of alcohol decreased MAP by 2.92 mmHg [95% CI from –5.76 to -0.07, P-value 0.04]. 7-12 hours after alcohol consumption: Based on the data from four studies [67, 69, 70, 95] in 54 participants, the mean decrease in MAP was 2.11 mmHg [95% CI from -4.69 to 0.48, P 26 value=0.11] after 7-12 hours after the consumption of medium dose of alcohol. There was no heterogeneity (I2= 0). ≥ 13 hours after alcohol consumption: Based on the data from 66 participants from four studies [67, 69, 70, 86], the mean increase in MAP was 1.43 mmHg [95% CI from -1.18 to 4.04, P value=0.28]. There was no heterogeneity (I2= 0). 3.3.2.3 Effect of medium dose of alcohol on HR ≤6 hours after alcohol consumption: 12 studies [67, 69, 70, 71, 74, 81, 83, 86, 90, 91, 93-95] reported the effect of alcohol consumption in 181 participants and the mean increase in HR was 4.62 bpm [95% CI from 3.14 to 6.11, P-value < 0.01]. There was no heterogeneity (I2= 0). Table 3-2: Effect estimates for medium dose of alcohol compared to placebo Outcomes or subgroup Number of studies Participants Effect estimate (mean difference with 95% CI) using fixed effect model 2.1 SBP ≤6 hours 10 149 -5.63 [-8.25, -3.02] ^ 7-12 hours 4 54 -3.22 [-8.37, 1.93] ≥13 hours 5 66 0.64 [-3.90, 5.18] 2.2 DBP ≤6 hours 10 149 -4.01 [-6.02, -2.00] ^ 7-12 hours 4 54 -1.19 [-4.29, 1.90] ≥13 hours 5 66 1.78 [-0.95, 4.51] 2.3 MAP ≤6 hours 13 199 -2.92 [-5.76, -0.07] ^ 7-12 hours 4 54 -2.11 [-4.69, 0.48] ≥13 hours 5 66 1.43 [-1.18, 4.04] 2.4 HR ≤6 hours 12 181 4.62 [3.14, 6.11] * 7-12 hours 4 54 1.22 [-1.88, 4.32] ≥13 hours 3 36 1.37 [-2.12, 4.86] ^ Statistically significant decrease * Statistically significant increase 27 7-12 hours after alcohol consumption: Based on the data from four studies [67, 69, 70, 95] in 54 participants, the mean increase in HR was 1.22 bpm [95% CI from –1.88 to 4.32, P value=0.44] after 7-12 hours after the consumption of medium dose of alcohol. There was no heterogeneity (I2= 0). ≥ 13 hours after alcohol consumption: Based on three studies [67, 69, 70] in 36 participants, the mean increase in HR was 1.37 bpm [95% CI from -2.12 to 4.86, P value=0.44]. The results of the effect of medium dose of alcohol on BP and HR is summarized in table 3-2 (analysis by fixed-effect model) and table F-1 (analysis by random effect model, under appendix F). 3.3.3 High dose: 3.3.3.1 Effect of high dose of alcohol on SBP ≤6 hours after alcohol consumption: Based on the data from 418 participants from 16 studies [35, 44, 66, 68, 75, 76, 77, 80, 82, 84, 85, 86, 87, 89, 92, 94] high doses of alcohol decreased SBP by 3.49 mmHg [95% CI from -6.03 to -0.95, P-value=0.007]. The I2 statistic value was 45% and P-value for the chi2 test was 0.02, indicating moderate heterogeneity across studies. 7-12 hours after alcohol consumption: Based on the data from 54 participants from three studies [35, 86, 87], high doses of alcohol decreased SBP by 3.72 mmHg [95% CI from -6.97 to -0.48, P-value= 0.02]. There was no heterogeneity (I2= 0). ≥ 13 hours after alcohol consumption: Based on the data from 154 participants from three studies [35, 86, 87], high dose of alcohol increased SBP by 3.69 mmHg [95% CI from 2.33 to 5.05, P-value= 0<0.001]. There was no heterogeneity (I2= 0). 28 3.3.3.2 Effect of high dose of alcohol on DBP ≤6 hours after alcohol consumption: Based on the data from 350 participants from 14 studies [35, 44, 66, 68, 76, 77, 80, 82, 84, 85, 87, 89, 92], high dose alcohol decreased DBP by 1.91 mmHg [95% CI from -3.86 to 0.04, P-value=0.05]. The I2 statistic value was 35% and P-value for the chi2 test was P<0.1 indicating low heterogeneity across studies. 7-12 hours after alcohol consumption: Based on the data from 54 participants from three studies [35, 86, 87], high dose alcohol decreased DBP by 1.71 mmHg [95% CI from –4.59 to 1.77, P-value=0.24]. There was no heterogeneity (I2= 0). ≥ 13 hours after alcohol consumption: Based on the data from 154 participants from 4 studies [35, 77, 86, 87], high dose alcohol increased DBP by 2.37 mmHg [95% CI from 0.24 to 4.49, P-value= 0.03] after 13 hours of consumption. There was no heterogeneity (I2= 0). 3.3.3.3 Effect of high dose of alcohol on MAP ≤6 hours after alcohol consumption: Based on the data from 16 studies in 418 participants [35, 44, 66, 68, 73, 75, 76, 77, 79, 80, 82, 84-87, 89, 92, 94], high dose of alcohol decreased MAP by 1.79 mmHg [95% CI from -3.72 to 0.13, P-value=0.07]. There was evidence of low heterogeneity across the studies (I2=30%). 7-12 hours after alcohol consumption: Three studies reported the effect of high dose of alcohol consumption in 54 participants [35, 86, 87], and the mean decrease in MAP was 2.47 mmHg [95% CI from -5.69 to 0.75, P-value=0.13]. There was no heterogeneity (I2= 0). ≥ 13 hours after alcohol consumption: Four studies [35, 77 86, 87], reported the effect of high dose of alcohol in 154 participants and the mean increase in MAP was 2.96 mmHg [95% CI 29 from 0.35 to 5.58, P-value=0.02] ≥ 13 hours after consumption. There was no heterogeneity (I2= 0). 3.3.3.4 Effect of high dose of alcohol on HR ≤6 hours after alcohol consumption: 17 studies [35, 44, 66, 68, 73, 75- 77, 79, 80, 82, 84-87, 89, 91, 92, 94]; reported effect of high dose of alcohol in 495 participants and the mean increase in HR was 5.75 bpm [95% CI from 3.99 to 7.51, P-value<0.001]. There was evidence of low heterogeneity across the studies (I2= 34%). Table 3-3: Effect estimates for high dose of alcohol compared to placebo Outcomes or subgroup Number of studies Participants Effect estimate (mean difference with 95% CI) using fixed effect model 3.1 SBP ≤6 hours 16 418 -3.49 [-6.03, -0.95] ^ 7-12 hours 3 54 -3.72 [-6.97, -0.48] ^ ≥13 hours 4 154 3.69 [2.33, 5.05] * 3.2 DBP ≤6 hours 14 350 -1.91 [-3.86, 0.04] 7-12 hours 3 54 -1.59 [-4.05, 0.88] ≥13 hours 4 154 2.37 [0.25, 4.49] * 3.3 MAP ≤6 hours 17 428 -1.53 [-3.34, 0.28] 7-12 hours 3 54 -2.47 [-5.69, 0.75] ≥13 hours 4 154 2.96 [0.35, 5.58] * 3.4 HR ≤6 hours 17 495 5.75 [3.99, 7.51] * 7-12 hours 5 144 6.16 [3.04, 9.28] * ≥13 hours 6 244 2.70 [0.80, 4.60] * ^ Statistically significant decrease * Statistically significant increase 30 7-12 hours after alcohol consumption: Five studies [35, 77 86, 87] reported the effect of high dose of alcohol in 144 participants and the mean increase in HR was 6.16 bpm [95% CI from 3.04 to 9.28, P-value<0.001]. There was moderate heterogeneity across studies (I2= 44%). ≥ 13 hours after alcohol consumption: Six studies [35, 75, 77, 78, 86, 87] reported effect of high dose of alcohol in 244 participants and the mean increase in HR was 2.70 bpm [95% CI from 0.80 to 4.60, P-value=0.005] ≥ 13 hours after consumption. There was no heterogeneity (I2= 0). The results of the effect of medium dose of alcohol on BP and HR are summarized in table 3-3. 3.4 Subgroup analysis and exploring heterogeneity It is recommended that there should be at least 10 studies reporting each of the subgroups in question. Among the 32 included studies, there were only 4 studies that included hypertensive participants [67, 69-71]. So, it was not appropriate to conduct a separate meta-analysis based on that population. For the planned subgroup analysis based on sex, there were no studies that reported male and female participant data separately. Therefore, we were unable to perform a subgroup analysis based on the sex of the participants. 3.5 Sensitivity analysis As planned, we conducted sensitivity analysis to see if there was any significant difference between the effect estimates of outcomes given by the fixed-effect model and the random-effects model, where there was a presence of substantial heterogeneity. The result is presented in table F-1 under appendix F and there was no significant difference between the results given by the two models. 31 We planned on conducting sensitivity analysis on the studies based on their level of risk of bias (high risk studies versus low risk studies). Most of the included studies had a similar risk of bias across all the domains except for performance bias and detection bias which arises from blinding of participants, personnel and outcome assessors. So, we decided to conduct a sensitivity analysis on the included studies based on blinding condition (table F-2, appendix F). We observed a greater reduction of blood pressure after a moderate dose of alcohol consumption for the unblinded studies, which was probably due to the presence of heterogeneous population. For, high dose alcohol studies, we did not find any significant difference between the blinded and unblinded studies. Overall, the blinding of the studies did not influence the outcomes. 32 Chapter 4: Discussion This review summarizes the acute effect of different doses of alcohol on blood pressure and heart rate in adults (≥18 years) during three different time intervals. 4.1 Summary of main results 4.1.1 Effect of low dose alcohol consumption: Low dose alcohol consumption had no effect on blood pressure within six hours, but we only found two trials studying this dose and no trials assessing blood pressure after 6 hours. Low dose alcohol increased heart rate within 6 hours suggesting that even one glass of wine increases heart rate. Unfortunately, we don't have any studies measuring heart rate more than 6 hours after the dose. 4.1.2 Effect of medium-dose alcohol consumption: Medium dose of alcohol decreased SBP by 5.6 mmHg and DBP by 4 mmHg within the first six hours of consumption. Though the hypotensive effect of alcohol seemed to last up to 12 hours after drinking alcohol and the effect is lost after 13 hours, the result was based on only four trials reporting the intermediate (7-12 hours) and late (after 13 hours) effect of alcohol on blood pressure. Heart rate was increased by 4.6 bpm six hours after drinking alcohol compared to the placebo group. The intermediate (7-12 hours) and late (after 13 hours) effect of the medium dose of alcohol on heart rate was based on only four trials and was not statistically different compared to placebo. 4.1.3 Effect of high dose alcohol consumption: High dose of alcohol decreased SBP by 3.49 mmHg within the first six hours and by 3.77 mmHg between 7-12 hours after consumption. After 13 hours, high dose of alcohol increased SBP by 3.7 mmHg compared to the placebo. DBP was not significantly affected up to 12 hours after 33 drinking a high dose of alcohol but there was a statistically significant increase in DBP during the ≥13 hours time interval after alcohol consumption. High dose of alcohol consumption increased heart rate by approximately 6 bpm in participants and the effect lasted up to 12 hours. After that, the heart rate was still raised in participants, but it averaged 2.7 bpm 4.1.4 Dose-dependent response There is likely a dose response effect of alcohol on BP as the effects of alcohol appeared to last longer with higher doses. However, we lacked data on the effect of low dose. We intended to find out the dose-dependent changes in SBP, DBP, MAP, and HR after consumption of a single dose of alcohol. Since the number of included studies that fell into our prespecified dose categories were not comparable, we were unable to conduct a comprehensive dose-dependent analysis. Rosito et al. [86] tested the effect of 15g, 30g, and 60g of alcohol on 40 young medical students. The decrease in SBP was greater with 30 g of alcohol 7 hours after consumption, compared to the placebo, 15 g, and 60g alcohol-consuming groups. In this study, alcohol did not haven't any significant effect on DBP in the four groups. 4.1.5 Possible mechanisms to explain the results There are multiple interrelated changes responsible for the biphasic effect of alcohol on blood pressure. Acute alcohol consumption was found to reduce 20-Hydroxyeicosatetraenoic acid (20-HETE) in study by Barden et al. [35]. 20-HETE is a signaling molecule with a wide range of effect on the cardiovascular system. It is a vasoconstrictor and inhibits sodium reabsorption in the proximal and distal tubules of the kidney. Reduction of 20-HETE was greatest when the blood alcohol level was highest [35, 96]. Increased production of nitric oxide (NO) was also associated with acute alcohol consumption [97, 98]. NO is released from endothelium and is a potent vasodilator. Also, there is an inverse relationship between nitric oxide (NO) and 20-HETE. Alcohol is often consumed mixed together with fruit juices and the combination was found to promote insulin 34 secretion [99]. Insulin is known to signal a phosphorylation-dependent mechanism resulting in the production of NO [100]. Moreover, alcohol's metabolic by-product acetaldehyde is another known vasodilator [101, 102]. Together, the reduction of the vasoconstrictors and the increase of vasodilators led to a drop in blood pressure which lasted for approximately 12 hours. The blood-alcohol level decreased over time and 20-HETE started to rise [35]. The hypertensive effect of alcohol after 13 hours of consumption was probably the result of the rise in vasoconstrictor level and the homeostatic response to restore blood pressure. The plasma renin activity was reported to be increased in the study by Kawano et al. [70] as a late effect of alcohol consumption. Heart rate was increased following alcohol consumption regardless of the dose of alcohol. It slows down the parasympathetic nerve activity and stimulates sympathetic nervous activity. Three studies [68, 103, 104] reported an increase in muscle sympathetic nervous activity (MSNA) which persists for at least 10 hours after consumption. Vagus nerve is a component of the parasympathetic nervous system and largely responsible for the regulation of the heart rate at rest. Two studies [75, 88] reported withdrawal of vagal tone and reduced heart rate variability within an hour after alcohol consumption which explains the increased heart rate. Two studies [79, 88, 105] also reported reduced baroreflex sensitivity following alcohol consumption. Impairment of baroreflex results in failure to sense the increase in heart rate and maintaining cardiovascular homeostasis. Kawano et al. [70] reported the reduction of plasma potassium level after alcohol consumption which might be another reason for the increase in heart rate. 4.2 Clinical implications of the findings: The systematic review provides us with a better understanding of the time-course of alcohol's acute effect on blood pressure and heart rate. This review only included short-term RCTs investigating alcohol's effect on blood pressure and heart rate. Acute alcohol consumption mimics the pattern of social drinking and the evidence indicates that even one glass of alcoholic drink can increase heart rate. The magnitude of the effect of alcohol on blood pressure and heart rate varies based on the genetic factors and the amount of alcohol consumed. 35 Alcohol impairs the autonomic nervous system and the cardiovascular system. Occasional drinking in healthy volunteers should not be harmful as the body recovers the next day. However, the constant temporary disruption of the cardiovascular system and the compensatory responses following the regular alcohol consumption may progress into permanent changes in the cardiovascular system and increase the risk of hypertension. Hypertensive individuals who takes antihypertensive drugs should be cautious about the timing of drinking alcohol because the combination of some antihypertensive drug and alcohol was found to act synergistically towards reducing blood pressure [70, 106, 107]. 4.3 Overall completeness and applicability of evidence The evidence synthesized in this review was collected from 32 RCTs in 767 participants. Of the 32 studies, two RCTs studied low dose alcohol, 12 RCTs studied medium-dose alcohol and 19 RCTs studied high-dose alcohol. Rosito et al. [86] studied both medium and high dose alcohol. The sample size in the meta-analysis for low dose comparison was not adequate to assess the effects of low dose of alcohol on BP and HR, however, we believe that the direction of the change in BP and HR was correct. For medium dose and high dose of alcohol, the participants represented a range in terms of age, sex and health condition. Since the participant population was predominantly young and healthy normotensive men, the overall evidence generated in this review cannot be extrapolated to women and older population with other co-morbidities. There was substantial heterogeneity in the meta-analysis for the effect of medium dose on SBP and DBP six hours after alcohol consumption (forest plots G-5 and G-6 under appendix G) due to the presence of three studies [69-71]. The participants of these studies were Japanese with a mean age of >50 years and essential hypertension. The mean reduction of SBP and DBP was greater in these participants compared to the participants from other studies ingesting medium doses of alcohol. The reason behind greater reduction of blood pressure after consuming alcohol is probably due to the presence of genetic variants of the hormones alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in the Japanese participants. Presence of these gene variants can increase blood acetaldehyde level more than 10 times the normal level [50, 36 108, 109]. Excess amount of acetaldehyde in blood is responsible for facial flushing, which was found to be a common adverse effect of alcohol consumption in East Asians. Acetaldehyde could be responsible for the hypotensive effect of alcohol [101, 102] and the excess amount of acetaldehyde could be the reason for the greater reduction of blood pressure in the aforementioned studies in Japanese population. To check if the age of the participants had any role in the effect of alcohol on blood pressure, we selected the studies with older participants (>50 years) from the forest plots G-5, G-6, G-9 and G-10 (Appendix G). The studies with older participants showed greater decrease in SBP and DBP compared to the studies with younger participants (<50 years) (result showed in table H-1 under appendix H). Though we do not have much confidence in the mean change of the blood pressure in older population due to having fewer number of studies compared to studies with younger participants and presence of heterogeneity, previous research suggests that age can affect the elimination rate of alcohol from the body [26, 110]. With increasing age, the amount of body water and liver mass decreases, leading to higher blood alcohol level. Also, the metabolizing enzymes such as cytochrome P-4502E1 and ALDH diminish with age. Older populations are more likely to take more drugs to treat existing co-morbidities and the drug-alcohol interaction can modify alcohol metabolism [111]. All these factors can lead to increased acetaldehyde in the body and greater reduction in blood pressure. Rosito et al. [86] reported the effect of 15, 30 and 60 g of alcohol compared to placebo on healthy male volunteers. According to our prespecified dose categories, both 15 and 30 g of alcohol fell under the medium dose category. Including both doses or deselecting either one of these doses from the forest plots G-5 and G-6 (medium dose of alcohol) resulted in the same statistically significant conclusion (Forest plots are shown under appendix G). We identified two studies [35, 87] from Figure G-9 and G-10 (Forest plots are shown under appendix G) to have considerably lower SE of MD compared to the other included studies. Assuming that these low SE of MD reported in these studies [35, 87] are errors and not reliable, 37 we replaced these measures with average SE of MD from the rest of the included studies. The statistically significant conclusions remained the same. Only seven studies (out of 32) used red wine as intervention, hence, we could not identify if there was any significant difference between red wine and other type of alcoholic beverages. Nine out of the 19 studies used comparatively high (≥60g or ≥1g/kg) dose of alcohol compared to the 10 other studies under high dose of alcohol category and the consumption of very high dose of alcohol in these nine trials over the reported short duration mimics the pattern of binge drinking. Hence, we conducted additional analyses to see if the very high dose of alcohol (≥60g or ≥1g/kg) had any dose-related effect compared to lower high dose of alcohol (31-59 g of alcohol) (see table H-2 under appendix H). The result suggested that the decrease in BP with very high dose of alcohol is more compared to lower high dose of alcohol. The change is heart rate was similar in both comparisons. However, the result was heterogenous and, therefore, we are unable to make any implications from that. This is the first systematic review on this topic based on RCTs. Much current literature on alcohol does not mention alcohol's hypotensive effect or the magnitude of change in BP or HR after alcohol consumption. The review will be useful for social and regular drinkers to appreciate the risks of low blood pressure within the first 12 hours after drinking. 4.4 Certainty of the evidence We graded the overall certainty of evidence using the GRADE approach in GRADEpro GDT software [65] and formulated summary of findings (SoF) table. We created three SoF tables to show the certainty of evidence and summary of the effects on the outcomes of interest (SBP, DBP and HR) for low (table 4-1), medium (table 4-2) and high dose (table 4-3) of alcohol. Ratings of the certainty of evidence ranged from moderate to low in the review which suggests that the effect estimates of alcohol might be slightly different than the true effect. For high dose 38 of alcohol, we found moderate certainty of evidence for decrease in SBP and low certainty of evidence for decrease in DBP within the first 6 hours and 7-12 hours after consumption. Moderate certainty of evidence suggests that SBP and DBP increases between 13 and 24 hours after alcohol ingestion. For medium dose of alcohol, moderate certainty of evidence showed decrease in SBP and DBP, 6 hours after alcohol consumption and low certainty of evidence showed decrease in SBP and DBP for 7-12 hours after alcohol consumption. After ≥13 hours of consumption, SBP and DBP increased and the certainty of evidence were low and medium respectively. For low dose of alcohol, we found low certainty of evidence that SBP, DBP and MAP falls within the first 6 hours after alcohol consumption. We also found moderate certainty of evidence that alcohol raises HR within the first 6 hours of consumption regardless of the dose of alcohol. Moderate certainty of evidence indicates increase in heart rate after 7-12 hours and ≥13 hours after high dose alcohol consumption whereas, low certainty of evidence was found for moderate dose of alcohol consumption. We did not consider the lack of blinding of the participants as a downgrading factor for certainty of evidence because we do not think that it affected the outcomes of this systematic review. Change in blood pressure and heart rate after alcohol consumption was not the primary outcome of interest in majority of the included studies. We do not think participants were anticipating any significant influence on blood pressure or heart rate after drinking. We also did not rate the certainty of evidence based on the funding source of the studies or the lack of registered protocol because we did not think it would affect the effect estimates of the outcomes. However, we noted the lack of description of randomization and allocation concealment method in most of the included studies was a reason for downgrading because of possibility of selection bias. 39 Table 4-1: Summary of findings table for low dose of alcohol Summary of findings table Population: Adult participants Setting: Ambulatory Intervention: Low dose of alcohol (≥14g) Comparison: Placebo Outcomes Number of participants (RCTs) Mean difference of alcohol compared to placebo [95% CI] Certainty of evidence (GRADE) Systolic blood pressure ≤6 hours 28 (2) -1.9 mmHg [-8.4 to 5.4] Low 1 2 Diastolic blood pressure ≤6 hours 28 (2) -1.5 mmHg [-6.9 to 4] Low 1 2 Heart rate ≤6 hours 28 (2) 5 bpm [1.9 to 8.2] Moderate 1 Acronyms and grades * The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect Footnotes 1 Unclear risk of selection bias 2 95% confidence interval around the best effect estimate includes both negligible effect and appreciable benefit. 40 Table 4-2: Summary of findings table for medium dose of alcohol Summary of findings table Population: Adult participants Settings: Ambulatory Intervention: Medium dose of alcohol (15-30g) Comparison: Placebo Outcomes Number of participants (RCTs) Mean difference of alcohol compared to placebo [95% CI] Certainty of evidence (GRADE) Systolic blood pressure ≤6 hours 149 (10) -5.6 mmHg [-8.3 to -3] Moderate 1 Systolic blood pressure 7-12 hours 54 (4) -3.2 mmHg [-8.37 to 1.93] Low 1 2 Systolic blood pressure ≥13 hours 66 (5) 0.6 mmHg [-3.9 to 5.2] Low 1 2 Diastolic blood pressure ≤6 hours 149 (10) -4 mmHg [-6 to -2] Moderate 3 Diastolic blood pressure 7-12 hours 54 (4) -1.2 mmHg [-4.3 to 1.9] Low 1 2 Diastolic blood pressure - ≥13 hours 66 (5) 1.8 mmHg [-0.9 to 4.5] Moderate 2 Heart rate ≤6 hours 181(12) 4.6 bpm [3.1 to 6.1] Moderate 3 Heart rate 7-12 hours 54 (4) 1.2 bpm [-1.9 to 4.3] Low 1 2 Heart rate ≥13 hours 36 (3) 1.4 bpm [-2.1 to 4.9] Low 1 2 Acronyms and grades * The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect Footnotes 1 Unclear risk of selection bias in more than one study. 2 95% confidence interval around the effect estimate includes both appreciable benefit and appreciable harm. 3 Unclear risk of selection bias and attrition bias in more than one study. 41 Table 4-3: Summary of findings table for high dose of alcohol Summary of findings table Population: Adult participants Setting: Ambulatory Intervention: High dose of alcohol (>30 g) Comparison: Placebo Outcomes Number of participants (RCTs) Mean difference of alcohol compared to placebo [95% CI] Certainty of evidence (GRADE) Systolic blood pressure ≤6 hours 418 (16) -3.5 mmHg [-6 to -0.5] Moderate1 Systolic blood pressure 7-12 hours 54 (3) -3.7 mmHg [-6.9 to -0.5] Moderate 1 Systolic blood pressure ≥13 hours 154 (4) 3.7 mmHg [2.3 to 5] Moderate 1 Diastolic blood pressure ≤6 hours 350 (14) -1.9 mmHg [-3.9 to 0.04] Low 1 2 Diastolic blood pressure 7-12 hours 54 (5) -1.6 mmHg [-4.1 to 0.9] Low 1 2 Diastolic blood pressure - ≥13 hours 154 (4) 2.4 mmHg [0.3 to 4.5] Moderate 1 Heart rate ≤6 hours 495 (17) 5.5 bpm [4.3 to 6.7] Moderate 1 Heart rate 7-12 hours 144 (7) 6.2 bpm [3 to 9.3] Moderate 1 Heart rate ≥13 hours 244 (8) 2.7 bpm [0.8 to 4.6] Moderate 1 Acronyms and grades * The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect Footnotes 1 Unclear risk of selection bias and attrition bias in more than one study. 2 95% confidence interval around the best effect estimate includes both negligible effect and appreciable benefit. 42 4.5 Potential biases in the review process We faced several limitations during the review process. First, there is the possibility of undesired bias and imprecision due to imputations of missing statistics. Most of the included studies did not report the SE/SD of the MD of the outcomes of interest. As described in our protocol when we were unable to calculate the required SE/SD from the study authors or by calculation from the reported P-value or 95% CI, we imputed the data according to the prespecified imputation hierarchy. We mostly used the reported endpoint SE/SD value to impute the SE/SD of MD. This is known to provide a good approximation of the SD of change in BP so is unlikely to lead to bias. Also, only 10 out of 32 studies [67, 71, 73, 74, 79, 83-85, 88, 93] reported changes in MAP after alcohol consumption along with their SE/SD. So, we had to calculate the missing MAP values from the reported SBP and DBP values using the formula mentioned in the protocol and impute the SE/SD for those. Secondly, the lack of representation of the female population was notable in the included studies. Only 16 out of 32 studies [66, 67, 68, 72, 73, 75, 79, 83-85, 87, 89, 91, 92, 94, 95] included total 129 (16% of the total participants) female participants, and the number was very low compared to 638 male participants, participating in the same studies. Only four studies [67, 79, 83, 89] included almost equal number of male and female participants. Moreover, none of the studies reported the male and female data separately. As a result, we were not able to quantify the magnitude of the effect of alcohol on men and women separately. This is unfortunate as we have reason to believe that the effects of alcohol on BP might be greater in women. Lastly, the methodological differences between the studies might have affected the measurement of the reported outcomes. Recent research suggests automated ambulatory blood pressure monitors are more reliable than manual sphygmomanometer, particularly because the automated monitors reduce white coat anxiety [112]. Of the 32 included studies, seven studies [44, 71, 74, 77, 80, 88] used manual mercury sphygmomanometer or semi-automated sphygmomanometer for BP measurement. The mixing of various measurements techniques (manual, semi-automated and fully automated) in the meta-analysis might have led to some of the heterogeneity. Another reason behind the heterogeneity was probably the variation of alcohol intake duration and time of 43 measurement of the outcomes across the included studies. Most of the studies gave participants 15-30 minutes to finish their drinks, started measuring the outcomes sometime after that and continued taking them for a certain period but there were some exceptions. Chen et al. [94] did not report the consumption duration and the time of measurement of BP and HR. Dai et al. [80] gave participants five minutes to consume high dose of alcohol and measured the outcomes immediately. On the other hand, Fantin et al. [95] allowed the participants to continue drinking during the period of outcome measurement. These difference in alcohol consumption duration and outcome measurement times probably contributed towards the wide variation in blood pressure in these studies and affected the overall result of the meta-analysis. We took several steps to minimize the risk of selection bias to identify eligible studies for inclusion in the review. We used highly sensitive search strategies. We also checked the list of references in the included studies and the articles that cited the included studies in Google Scholar to identify relevant articles. Furthermore, we contacted the study authors when there was insufficient or missing information in the included studies to obtain all relevant data. 4.6 Agreements and disagreements with other studies or reviews We are aware of one systematic review on effect of alcohol on blood pressure that was published in 2005 [58]. McFadden et al. [58] included both randomized and non-randomized studies with a minimum of 24-hours blood pressure observation after alcohol consumption. The systematic review only searched MEDLINE database for relevant studies, hence, it was not exhaustive. They included nine studies involving total 119 participants and the duration of the studies were between 4-7 days. The participants in those studies consumed alcohol regularly during the study period whereas, in our systematic review, we only included studies who consumed alcohol for a short period. Based on nine studies, McFadden at al. [58] reported that, the mean increase in SBP was by 2.7 mmHg and DBP was 1.4 mmHg. Only three out of these nine included studies measured BP at various time point and they found that alcohol has a hypotensive effect lasting up to 5 hours after alcohol consumption and a hypertensive effect 20 hours after alcohol consumption which lasts till next day. These are consistent with our results. However, the reported early reduction in BP was 11.6 mmHg of SBP and 7.9 mmHg DBP in the systematic 44 review [58]. These estimates are almost twice as large as our results. The inclusion of non-randomized studies in the systematic review [58], which are known to be at higher risk of bias is likely the reason for the discrepancy in the estimates of BP effects. 45 Chapter 5: Conclusion 5.1 Implications for practice The magnitude and direction of the effect of alcohol on blood pressure depend on the time after alcohol consumption. Moderate certainty of evidence shows that acute consumption of medium to high dose of alcohol decreases blood pressure within the first six hours and for up to 12 hours after alcohol consumption. For times greater than 13 hours of high doses of alcohol consumption increase blood pressure. Low, moderate and high alcohol consumption increased heart rate within the first 6 hours. High alcohol consumption also increased heart rate from 7 to 12 hours and after 13 hours. Most of the evidence from this review is relevant to healthy males as there were only small numbers of women (126 females compared to 638 males) in these trials. 5.2 Implications for research The review did not find any eligible RCTs that report effect of alcohol on women separately. Since women could be affected differently by alcohol than men, future RCTs in women are needed. If future RCTs include both men and women, it is important to report their blood pressure and heart rate readings separately. Though the eligible studies included East Asians, Latinos and Caucasian population, they lacked African, South Asian and Native Hawaiian / other Pacific Islander representation. More RCTs are needed studying the effect of low dose alcohol to better delineate the dose response effect of alcohol on BP and heart rate. RCTs with measurements more than 24 hours after alcohol consumption are needed to see how long the effect of high dose acute alcohol consumption lasts. 46 Bibliography 1. Poulter NR, Prabhakaran D, Caulfield M. Hypertension. Lancet. 2015 Aug; 386(9995):801-12. 2. Mills KT, Bundy JD, Kelly TN, Reed JE, Kearney PM, Reynolds K, Chen J, He J. Global disparities of hypertension prevalence and control: a systematic analysis of population-based studies from 90 countries. Circulation. 2016 Aug 9;134(6):441-50. 3. Kannel WB, Castelli WP, McNamara PM, McKee PA, Feinleib M. Role of blood pressure in the development of congestive heart failure: the Framingham study. New England Journal of Medicine. 1972 Oct 19;287(16):781-7. 4. World Health Organization. A global brief on hypertension: silent killer, global public health crisis: World Health Day 2013. World Health Organization; 2013. 5. GBD 2013 Risk Factors Collaborators. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016; 388: 1659–724 6. Weber MA, Schiffrin EL, White WB, Mann S, Lindholm LH, Kenerson JG, Flack JM, Carter BL, Materson BJ, Ram CV, Cohen DL. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. The journal of clinical hypertension. 2014 Jan;16(1):14-26. 7. Willey JZ, Moon YP, Kahn E, Rodriguez CJ, Rundek T, Cheung K, Sacco RL, Elkind MS. Population attributable risks of hypertension and diabetes for cardiovascular disease and stroke in the northern Manhattan study. Journal of the American Heart Association. 2014 Sep 16;3(5):e001106 8. 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: 3255–3264.RA 47 9. Kostis JB, Davis BR, Cutler J, Grimm RH Jr, Berge KG, Cohen JD, et al. Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group. JAMA. 1997; 278: 212–216.RA 10. Staessen JA, Thijs L, Fagard R, O’Brien ET, Clement D, de Leeuw PW, et al. Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension. Systolic Hypertension in Europe Trial Investigators. JAMA. 1999; 282: 539–546.RA 11. Guitteau M, Rosenberg M. Lifestyle recommendations plus the DASH diet reduced hypertension in patients with above-optimal blood pressure. ACP journal club. 2006;145(2):42. 12. Appel LJ, Champagne CM, Harsha DW, Cooper LS, Obarzanek E, Elmer PJ, Stevens VJ, Vollmer WM, Lin PH, Svetkey LP, Young DR. Effects of comprehensive lifestyle modification on blood pressure control: main results of the PREMIER clinical trial. JAMA: Journal of the American Medical Association. 2003 Apr. 13. Reboussin DM, Allen NB, Griswold ME, Guallar E, Hong Y, Lackland DT, Miller EP, Polonsky T, Thompson-Paul AM, Vupputuri S. Systematic review for the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology. 2018 May 7;71(19):2176-98. 14. McGovern PE. Uncorking the past: the quest for wine, beer, and other alcoholic beverages. Univ of California Press; 2009 Oct 30. 15. World Health Organization. Global status report on alcohol and health 2018. World Health Organization; 2018. 16. National Institute on Alcohol Abuse and Alcoholism (NIAAA). What Is A Standard Drink? Available at: https://www.niaaa.nih. gov/alcohol-health/overview-alcohol-consumption/what-standarddrink. Accessed: August 16, 2017 48 17. Bellentani S, Saccoccio G, Costa G, Tiribelli C, Manenti F, Sodde M, Croce LS, Sasso F, Pozzato G, Cristianini G, Brandi G. Drinking habits as cofactors of risk for alcohol induced liver damage. Gut. 1997 Dec 1;41(6):845-50. 18. Fuchs FD, Chambless LE, Whelton PK, Nieto FJ, Heiss G. Alcohol consumption and the incidence of hypertension: The Atherosclerosis Risk in Communities Study. Hypertension. 2001 May;37(5):1242-50. 19. Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology. 2011 Nov 1;141(5):1572-85. 20. Lieber CS. Hepatic and other medical disorders of alcoholism: from pathogenesis to treatment. Journal of studies on alcohol. 1998 Jan;59(1):9-25. 21. McCullough AJ, O'Shea RS, Dasarathy S. Diagnosis and management of alcoholic liver disease. Journal of Digestive Diseases. 2011 Aug;12(4):257-62. 22. Nutt D. Alcohol and the brain: pharmacological insights for psychiatrists. The British Journal of Psychiatry. 1999 Aug;175(2):114-9. 23. Welch KA. Neurological complications of alcohol and misuse of drugs. Practical Neurology. 2011 Aug 1;11(4):206-19. 24. Seitz HK, Stickel F. Molecular mechanisms of alcohol-mediated carcinogenesis. Nature Reviews Cancer. 2007 Aug;7(8):599. 25. Kushi LH, Doyle C, McCullough M, Rock CL, Demark‐Wahnefried W, Bandera EV, Gapstur S, Patel AV, Andrews K, Gansler T, American Cancer Society 2010 Nutrition and Physical Activity Guidelines Advisory Committee. American Cancer Society Guidelines on nutrition and physical activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity. CA: a cancer journal for clinicians. 2012 Jan;62(1):30-67. 26. Cederbaum AI. Alcohol metabolism. Clinics in liver disease. 2012 Nov 1;16(4):667-85. 27. Heit C, Dong H, Chen Y, Thompson DC, Deitrich RA, Vasiliou VK. The role of CYP2E1 in alcohol metabolism and sensitivity in the central nervous system. InCytochrome P450 2E1: Its Role in Disease and Drug Metabolism 2013 (pp. 235-247). Springer, Dordrecht. 49 28. Zimatkin SM, Pronko SP, Vasiliou V, Gonzalez FJ, Deitrich RA. Enzymatic mechanisms of ethanol oxidation in the brain. Alcoholism: clinical and experimental research. 2006 Sep;30(9):1500-5. 29. Di Castelnuovo A, Costanzo S, Bagnardi V, Donati MB, Iacoviello L, De Gaetano G. Alcohol dosing and total mortality in men and women: an updated meta-analysis of 34 prospective studies. Archives of internal medicine. 2006 Dec 11;166(22):2437-45. 30. Taylor B, Irving HM, Baliunas D, Roerecke M, Patra J, Mohapatra S, Rehm J. Alcohol and hypertension: gender differences in dose–response relationships determined through systematic review and meta‐analysis. Addiction. 2009 Dec;104(12):1981-90. 31. Briasoulis A, Agarwal V, Messerli FH. Alcohol consumption and the risk of hypertension in men and women: a systematic review and meta‐analysis. The Journal of Clinical Hypertension. 2012 Nov;14(11):792-8. 32. Plunk AD, Syed‐Mohammed H, Cavazos‐Rehg P, Bierut LJ, Grucza RA. Alcohol consumption, heavy drinking, and mortality: Rethinking the J‐Shaped curve. Alcoholism: Clinical and Experimental Research. 2014 Feb;38(2):471-8. 33. Puddey IB, Vandongen R, Beilin LJ, Rouse IL. Alcohol stimulation of renin release in man: its relation to the hemodynamic, electrolyte, and sympatho-adrenal responses to drinking. The Journal of Clinical Endocrinology & Metabolism. 1985 Jul 1;61(1):37-42. 34. Schrier RW, Abraham WT. Hormones and hemodynamics in heart failure. New England Journal of Medicine. 1999 Aug 19;341(8):577-85. 35. Barden AE, Croft KD, Beilin LJ, Phillips M, Ledowski T, Puddey IB. Acute effects of red wine on cytochrome P450 eicosanoids and blood pressure in men. Journal of hypertension. 2013 Nov 1;31(11):2195-202. 36. Zhang X, Abdel-Rahman AA, Wooles WR. Impairment of Baroreceptor Reflex Control of Heart Rate But Not Sympathetic Efferent Discharge By Central Neuroadministration of Ethanol. Hypertension. 1989;14:282-92. 37. Russ R, Abdel-Rahman AR, Wooles WR. Role of the sympathetic nervous system in ethanol-induced hypertension in rats. Alcohol. 1991 Jul 1;8(4):301-7. 38. Grassi GM, Somers VK, Renk WS, Abboud FM, Mark AL. Effects of alcohol intake on blood pressure and sympathetic nerve activity in normotensive humans: a preliminary 50 report. Journal of hypertension. Supplement: official journal of the International Society of Hypertension. 1989 Dec;7(6):S20-1. 39. Randin D, Vollenweider P, Tappy L, Jéquier E, Nicod P, Scherrer U. Suppression of alcohol-induced hypertension by dexamethasone. New England Journal of Medicine. 1995 Jun 29;332(26):1733-8. 40. Abdel-Rahman AR, Dar MS, Wooles WR. Effect of chronic ethanol administration on arterial baroreceptor function and pressor and depressor responsiveness in rats. Journal of Pharmacology and experimental Therapeutics. 1985 Jan 1;232(1):194-201. 41. Rupp H, Brilla CG, Maisch B. Hypertension and alcohol: central and peripheral mechanisms. Herz. 1996 Aug;21(4):258-64. 42. Carretta R, Fabris B, Bardelli M, Muiesan S, Fischetti F, Cesanelli R, Pizzolitto A, Bianchetti A, Campanacci L. Acute effects of intravenous infusions of alcohol on baroreceptor sensitivity in essential hypertension. Cardiovascular research. 1988 Mar 1;22(3):226-30. 43. Jenkins JS, Connolly J. Adrenocortical response to ethanol in man. British medical journal. 1968 Jun 29;2(5608):804. 44. Potter JF, Watson RD, Skan WE, Beevers DG. The pressor and metabolic effects of alcohol in normotensive subjects. Hypertension. 1986 Jul;8(7):625-31. 45. Husain K, Ansari RA, Ferder L. Alcohol-induced hypertension: Mechanism and prevention. World journal of cardiology. 2014 May 26;6(5):245. 46. Whitworth JA, Saines D, Scoggins BA. Blood pressure and metabolic effects of cortisol and deoxycorticosterone in man. Clinical and Experimental Hypertension. Part A: Theory and Practice. 1984 Jan 1;6(4):795-809. 47. Whitworth JA, Williamson PM, Mangos G, Kelly JJ. Cardiovascular consequences of cortisol excess. Vascular health and risk management. 2005 Dec;1(4):291. 48. Chen CC, Lu RB, Chen YC, Wang MF, Chang YC, Li TK, Yin SJ. Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism. The American Journal of Human Genetics. 1999 Sep 1;65(3):795-807. 49. Gentry RT. Effect of food on the pharmacokinetics of alcohol absorption. Alcoholism: Clinical and Experimental Research. 2000 Apr;24(4):403-4. 51 50. Thomasson HR, Beard JD, Li TK. ADH2 gene polymorphisms are determinants of alcohol pharmacokinetics. Alcoholism: Clinical and Experimental Research. 1995 Dec;19(6):1494-9. 51. Kwo PY, Ramchandani VA, O'Connor S, Amann D, Carr LG, Sandrasegaran K, Kopecky KK, Li TK. Gender differences in alcohol metabolism: relationship to liver volume and effect of adjusting for body mass. Gastroenterology. 1998 Dec 1;115(6):1552-7. 52. Thomasson H. Alcohol elimination: faster in women?. Alcoholism: Clinical and Experimental Research. 2000 Apr;24(4):419-20. 53. Worm N, Belz GG, Stein-Hammer C. Moderate wine consumption and prevention of coronary heart disease. Deutsche medizinische Wochenschrift (1946). 2013 Dec;138(51-52):2653-7. 54. Chen L, Smith GD, Harbord RM, Lewis SJ. Alcohol intake and blood pressure: a systematic review implementing a Mendelian randomization approach. PLoS medicine. 2008 Mar 4;5(3):e52. 55. Djoussé L, Gaziano JM. Alcohol consumption and risk of heart failure in the Physicians' Health Study I. Circulation. 2007 Jan 2;115(1):34. 56. Abramson JL, Williams SA, Krumholz HM, Vaccarino V. Moderate alcohol consumption and risk of heart failure among older persons. Jama. 2001 Apr 18;285(15):1971-7. 57. Jaubert MP, Jin Z, Russo C, Schwartz JE, Homma S, Elkind MS, Rundek T, Sacco RL, Di Tullio MR. Alcohol consumption and ambulatory blood pressure: a community-based study in an elderly cohort. American Journal of Hypertension. 2013 Dec 21;27(5):688-94. 58. McFadden CB, Brensinger CM, Berlin JA, Townsend RR. Systematic review of the effect of daily alcohol intake on blood pressure. 59. National Alcohol Strategy Advisory Committee Working Group. What Is a Drink? Communicating Drink Information to the Consumer. 2015. 60. Covidence. Covidence Systematic Review Software. 61. Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014. 52 62. Higgins JP, Green S, editors. Cochrane handbook for systematic reviews of interventions. John Wiley & Sons; 2011 Aug 24. 63. Musini VM, Nazer M, Bassett K, Wright JM. Blood pressure‐lowering efficacy of monotherapy with thiazide diuretics for primary hypertension. Cochrane Database of Systematic Reviews. 2014(5). 64. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, Norris S, Falck-Ytter Y, Glasziou P, Jaeschke R, Rind D. GRADE guidelines: 1. Introduction—GRADE evidence profiles and summary of findings tables. Journal of clinical epidemiology. 2011 Apr 1;64(4):383-94. 65. GRADEpro GDT: GRADEpro Guideline Development Tool [Software]. McMaster University, 2015 (developed by Evidence Prime, Inc.). Available from gradepro.org. 66. Stott DJ, Dutton M, Murray GD, Williams BO, McInnes GT. Hemodynamic effects of a single moderate dose of alcohol in elderly subjects. Journal of studies on alcohol. 1991 Jul;52(4):377-9. 67. Foppa M, Fuchs FD, Preissler L, Andrighetto A, Rosito GA, Duncan BB. Red wine with the noon meal lowers post-meal blood pressure: a randomized trial in centrally obese, hypertensive patients. Journal of studies on alcohol. 2002 Mar;63(2):247-51. 68. Hering D, Kucharska W, Kara T, Somers VK, Narkiewicz K. Potentiated sympathetic and hemodynamic responses to alcohol in hypertensive vs. normotensive individuals. Journal of hypertension. 2011 Mar 1;29(3):537-41. 69. Kawano Y, Abe H, Kojima S, Ashida T, Yoshida K, Imanishi M, Yoshimi H, Kimura G, Kuramochi M, Omae T. Acute depressor effect of alcohol in patients with essential hypertension. Hypertension. 1992 Aug;20(2):219-26. 70. Kawano Y, Abe H, Kojima S, Takishita S, Omae T. Interaction of alcohol and an α1-blocker on ambulatory blood pressure in patients with essential hypertension. American Journal of Hypertension. 2000 March:13(3) 307-312 71. Kojima S, Kawano Y, Abe H, Sanai T, Yoshida K, Imanishi M, Ashida T, Kimura G, Yoshimi H, Matsuoka H. Acute effects of alcohol ingestion on blood pressure and erythrocyte sodium concentration. Journal of Hypertension. 1993 Feb;11(2):185-90. 53 72. Cheyne EH, Sherwin RS, Lunt MJ, Cavan DA, Thomas PW, Kerr D. Influence of alcohol on cognitive performance during mild hypoglycaemia; implications for Type 1 diabetes. Diabetic Medicine. 2004 Mar;21(3):230-7. 73. Dumont GJ, Kramers C, Sweep FC, Willemsen JJ, Touw DJ, Schoemaker RC, Van Gerven JM, Buitelaar JK, Verkes RJ. Ethanol co-administration moderates 3, 4-methylenedioxymethamphetamine effects on human physiology. Journal of psychopharmacology. 2010 Feb;24(2):165-74. 74. Karatzi KN, Papamichael CM, Karatzis EN, Papaioannou TG, Aznaouridis KA, Katsichti PP, Stamatelopoulos KS, Zampelas A, Lekakis JP, Mavrikakis ME. Red wine acutely induces favorable effects on wave reflections and central pressures in coronary artery disease patients. American Journal of Hypertension. 2005 Sep 1;18(9):1161-7. 75. Rossinen J, Viitasalo M, Partanen J, Koskinen P, Kupari M, Nieminen MS. Effects of acute alcohol ingestion on heart rate variability in patients with documented coronary artery disease and stable angina pectoris. The American Journal of Cardiology. 1997 Feb 15;79(4):487-91. 76. Williams MJ, Sutherland WH, Whelan AP, McCormick MP, de Jong SA. Acute effect of drinking red and white wines on circulating levels of inflammation-sensitive molecules in men with coronary artery disease. Metabolism. 2004 Mar 1;53(3):318-23. 77. Bau PF, Bau CH, Naujorks AA, Rosito GA. Early and late effects of alcohol ingestion on blood pressure and endothelial function. Alcohol. 2005 Aug 1;37(1):53-8. 78. Bau PF, Moraes RS, Bau CH, Ferlin EL, Rosito GA, Fuchs FD. Acute ingestion of alcohol and cardiac autonomic modulation in healthy volunteers. Alcohol. 2011 Mar 1;45(2):123-9. 79. Buckman JF, Eddie D, Vaschillo EG, Vaschillo B, Garcia A, Bates ME. Immediate and complex cardiovascular adaptation to an acute alcohol dose. Alcoholism: Clinical and Experimental Research. 2015 Dec;39(12):2334-44. 80. Dai X, Thavundayil J, Gianoulakis C. Differences in the Responses of the Pituitary β‐Endorphin and Cardiovascular System to Ethanol and Stress as a Function of Family History. Alcoholism: Clinical and Experimental Research. 2002 Aug;26(8):1171-80. 54 81. Fazio M, Bardelli M, Fabris B, Macaluso L, Fiammengo F, Vran F, Bossi M, Candido R, Gerloni R, Carretta R. Large-artery hemodynamics after acute alcohol administration in young, healthy volunteers. Angiology. 2004 Mar;55(2):139-45. 82. Koenig D, Berg A, Plarr K, Grathwohl D, Halle M, Keul J. Acute Influence of Beer in Moderate Dosage on Blood Pressure Regulation and Electrolyte Concentrations. Aktuelle Ernahrungsmedizin. 1997 Jan 1;22(2):76-81. 83. Maufrais C, Charriere N, Montani JP. Cardiovascular and cutaneous responses to the combination of alcohol and soft drinks: the way to orthostatic intolerance?. Frontiers in Physiology. 2017 Nov 10;8:860. 84. Maule S, Chaudhuri KR, Thomaides T, Pavitt D, McCleery J, Mathias CJ. Effects of oral alcohol on superior mesenteric artery blood flow in normal man, horizontal and tilted. Clinical Science. 1993 Apr 1;84(4):419-25. 85. Narkiewicz K, Cooley RL, Somers VK. Alcohol potentiates orthostatic hypotension: implications for alcohol-related syncope. Circulation. 2000 Feb 1;101(4):398-402. 86. Aranha Rosito G, Danni Fuchs F, Duncan BB. Dose-dependent biphasic effect of ethanol on 24-h blood pressure in normotensive subjects. American journal of hypertension. 1999 Feb 1;12(2):236-40. 87. Stott DJ, Ball SG, Inglis GC, Davies DL, Fraser R, Murray GD, McInnes GT. Effects of a single moderate dose of alcohol on blood pressure, heart rate and associated metabolic and endocrine changes. Clinical Science. 1987 Oct 1;73(4):411-6. 88. Van De Borne P, Mark AL, Montano N, Mion D, Somers VK. Effects of alcohol on sympathetic activity, hemodynamics, and chemoreflex sensitivity. Hypertension. 1997 Jun;29(6):1278-83. 89. Zeichner A, Edwards P, Cohen E. Acute effects of alcohol on cardiovascular reactivity to stress in college-age Type A (coronary prone) individuals. Journal of Psychopathology and Behavioral Assessment. 1985 Mar 1;7(1):75-89. 90. Nishiwaki M, Kora N, Matsumoto N. Ingesting a small amount of beer reduces arterial stiffness in healthy humans. Physiological reports. 2017 Aug;5(15):e13381. 91. Agewall S, Wright S, Doughty RN, Whalley GA, Duxbury M, Sharpe N. Does a glass of red wine improve endothelial function?. European Heart Journal. 2000 Jan 1;21(1):74-8. 55 92. Mahmud A, Feely J. Divergent effect of acute and chronic alcohol on arterial stiffness. American Journal of Hypertension. 2002 Mar 1;15(3):240-3. 93. Karatzi K, Rontoyanni VG, Protogerou AD, Georgoulia A, Xenos K, Chrysou J, Sfikakis PP, Sidossis LS. Acute effects of beer on endothelial function and hemodynamics: a single-blind, crossover study in healthy volunteers. Nutrition. 2013 Sep 1;29(9):1122-6. 94. Chen W, Lockhart JO. Does Moderate Level of Alcohol Consumption Produce a Relaxation Effect?. ERIC. 1986 Sep; 1-16. 95. Fantin F, Bulpitt CJ, Zamboni M, Cheek E, Rajkumar C. Arterial compliance may be reduced by ingestion of red wine. Journal of human hypertension. 2016 Jan;30(1):68. 96. Collins XH, Harmon SD, Kaduce TL, Berst KB, Fang X, Moore SA, Raju TV, Falck JR, Weintraub NL, Duester G, Plapp BV. ω-Oxidation of 20-hydroxyeicosatetraenoic acid (20-HETE) in cerebral microvascular smooth muscle and endothelium by alcohol dehydrogenase 4. Journal of Biological Chemistry. 2005 Sep 30;280(39):33157-64. 97. Deng XS, Deitrich RA. Ethanol metabolism and effects: nitric oxide and its interaction. Current clinical pharmacology. 2007 May 1;2(2):145-53. 98. Rocha JT, Hipólito UV, Callera GE, Yogi A, dos Anjos Neto Filho M, Bendhack LM, Touyz RM, Tirapelli CR. Ethanol induces vascular relaxation via redox-sensitive and nitric oxide-dependent pathways. Vascular pharmacology. 2012 Jan 1;56(1-2):74-83. 99. Steiner J, Crowell K, Lang C. Impact of alcohol on glycemic control and insulin action. Biomolecules. 2015;5(4):2223-46. 100. Muniyappa R, Montagnani M, Koh KK, Quon MJ. Cardiovascular actions of insulin. Endocrine Reviews. 2007 Aug 1;28(5):463-91. 101. Altura BM, Carella A, Altura BT. Acetaldehyde on vascular smooth muscle: possible role in vasodilator action of ethanol. European journal of pharmacology. 1978 Nov 1;52(1):73-83. 102. Gillespie JA. Vasodilator properties of alcohol. British medical journal. 1967 Apr 29;2(5547):274. 103. Spaak J, Merlocco AC, Soleas GJ, Tomlinson G, Morris BL, Picton P, Notarius CF, Chan CT, Floras JS. Dose-related effects of red wine and alcohol on hemodynamics, 56 sympathetic nerve activity, and arterial diameter. American Journal of Physiology-Heart and Circulatory Physiology. 2008 Feb;294(2):H605-12. 104. Carter JR, Stream SF, Durocher JJ, Larson RA. Influence of acute alcohol ingestion on sympathetic neural responses to orthostatic stress in humans. American Journal of Physiology-Endocrinology and Metabolism. 2011 Feb 15;300(5):E771-8. 105. Fazio M, Bardelli M, Macaluso L, Fiammengo F, Mattei PL, Bossi M, Fabris B, Fischetti F, Pascazio L, Candido R, Carretta R. Mechanics of the carotid artery wall and baroreflex sensitivity after acute ethanol administration in young healthy volunteers. Clinical Science. 2001 Sep 1;101(3):253-60. 106. Kawano Y, HItoshi A, Kojima S, Takishita S, Omae T. Effects of propranolol on cardiovascular and neurohumoral actions of alcohol in hypertensive patients. Blood pressure. 1999 Jan 1;8(1):37-42. 107. Bailey DG, Spence JD, Edgar B, Bayliff CD, Arnold JM. Ethanol enhances the hemodynamic effects of felodipine. Clinical and investigative medicine. Medecine clinique et experimentale. 1989 Dec;12(6):357-62. 108. Enomoto N, Takase S, Yasuhara M, Takada A. Acetaldehyde metabolism in different aldehyde dehydrogenase‐2 genotypes. Alcoholism: Clinical and Experimental Research. 1991 Feb;15(1):141-4. 109. Peng Q, Gizer IR, Libiger O, Bizon C, Wilhelmsen KC, Schork NJ, Ehlers CL. Association and ancestry analysis of sequence variants in ADH and ALDH using alcohol‐related phenotypes in a Native American community sample. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2014 Dec;165(8):673-83. 110. Hahn HK, Burch RE. Impaired ethanol metabolism with advancing age. Alcoholism: Clinical and Experimental Research. 1983 Jun;7(3):299-301. 111. Meier P, Seitz HK. Age, alcohol metabolism and liver disease. Current Opinion in Clinical Nutrition & Metabolic Care. 2008 Jan 1;11(1):21-6. 112. Mirdamadi A, Etebari M. Comparison of manual versus automated blood pressure measurement in intensive care unit, coronary care unit, and emergency room. ARYA atherosclerosis. 2017 Jan;13(1):29. 57 Appendices Appendix A : Search Strategies Database: Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R) <1946 to March 06, 2019> Search Date: 7 March 2019 -------------------------------------------------------------------------------- 1 exp alcohol drinking/ (64712) 2 (alcohol$ or beer? or liquor? or spirit? or wine?).tw,kf. (345655) 3 or/1-2 (358718) 4 cardiovascular.mp. (521918) 5 hypertension/ (224504) 6 essential hypertension/ (2079) 7 hypertens$.tw,kf. (409139) 8 exp blood pressure/ (280283) 9 (blood pressure or bp or dbp or sbp).mp. (549491) 10 exp heart rate/ (163137) 11 ((heart or pulse) adj2 rate?).tw,kf. (160194) 12 or/4-11 (1352506) 13 randomized controlled trial.pt. (477139) 14 controlled clinical trial.pt. (92944) 15 randomized.ab. (436110) 16 placebo.ab. (195778) 17 clinical trials as topic/ (186161) 18 randomly.ab. (306525) 19 trial.ti. (195032) 20 or/13-19 (1201316) 21 animals/ not (humans/ and animals/) (4520864) 22 20 not 21 (1104968) 23 3 and 12 and 22 (2313) 58 -------------------------------------------------------------------------------- Database: Cochrane Central Register of Controlled Trials via Cochrane Register of Studies (CRS-Web) Search Date: 7 March 2019 -------------------------------------------------------------------------------- #1 MESH DESCRIPTOR Alcohol Drinking EXPLODE ALL AND CENTRAL:TARGET #2 (alcohol* OR beer* OR liquor* OR spirit* OR wine) NEAR5 (consum* OR drink* OR usage OR use*):ti,ab AND CENTRAL:TARGET #3 #1 OR #2 AND CENTRAL:TARGET #4 cardiovascular AND CENTRAL:TARGET #5 MESH DESCRIPTOR Hypertension AND CENTRAL:TARGET #6 MESH DESCRIPTOR Essential Hypertension AND CENTRAL:TARGET #7 hypertens* AND CENTRAL:TARGET #8 MESH DESCRIPTOR Blood Pressure EXPLODE ALL AND CENTRAL:TARGET #9 (blood pressure OR bp OR dbp OR sbp) AND CENTRAL:TARGET #10 MESH DESCRIPTOR Heart Rate EXPLODE ALL AND CENTRAL:TARGET #11 (heart OR pulse) NEAR2 rate* AND CENTRAL:TARGET #12 #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 AND CENTRAL:TARGET #13 #3 AND #12 AND CENTRAL:TARGET -------------------------------------------------------------------------------- Database: Cochrane Hypertension Specialised Register via Cochrane Register of Studies (CRS-Web) Search Date: 7 March 2019 -------------------------------------------------------------------------------- #1 MESH DESCRIPTOR Alcohol Drinking EXPLODE ALL AND INSEGMENT #2 (alcohol* OR beer* OR liquor* OR spirit* OR wine) AND INSEGMENT #3 #1 OR #2 AND INSEGMENT 59 #4 RCT:DE AND INSEGMENT #5 Review:ODE AND INSEGMENT #6 #4 OR #5 AND INSEGMENT #7 #3 AND #6 AND INSEGMENT -------------------------------------------------------------------------------- Database: Embase <1974 to 2019 March 06> Search Date: 7 March 2019 -------------------------------------------------------------------------------- 1 drinking behavior/ (45262) 2 ((alcohol$ or beer? or liquor? or spirit? or wine?) adj10 (consum$ or drink$ or usage or use?)).tw. (157940) 3 or/1-2 (176334) 4 cardiovascular.tw. (572671) 5 hypertens$.tw. (584744) 6 exp blood pressure/ (510351) 7 (blood pressure or bp or dbp or sbp).tw. (535996) 8 exp heart rate/ (228390) 9 ((heart or pulse) adj2 rate?).tw. (212286) 10 or/4-9 (1663331) 11 randomized controlled trial/ (534928) 12 crossover procedure/ (58141) 13 double-blind procedure/ (157592) 14 (randomi?ed or randomly).tw. (1113801) 15 (crossover$ or cross-over$).tw. (97819) 16 placebo.ab. (274941) 17 (doubl$ adj blind$).tw. (194854) 18 assign$.ab. (350521) 19 allocat$.ab. (132682) 60 20 or/11-19 (1630736) 21 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) (6056614) 22 20 not 21 (1421433) 23 3 and 10 and 22 (1778) -------------------------------------------------------------------------------- Database: ClinicalTrials.gov Search Date: 7 March 2019 -------------------------------------------------------------------------------- Other terms: randomized Intervention/treatment: alcohol OR beer OR liquor OR spirits OR wine Study type: Interventional Studies (Clinical Trials) Outcome Measures: blood pressure OR heart rate -------------------------------------------------------------------------------- Database: WHO International Clinical Trials Registry Platform (ICTRP) Search Date: 7 March 2019 -------------------------------------------------------------------------------- randomized AND blood pressure AND alcohol randomized AND blood pressure AND beer randomized AND blood pressure AND liquor randomized AND blood pressure AND spirits randomized AND blood pressure AND wine randomized AND heart rate AND alcohol randomized AND heart rate AND beer randomized AND heart rate AND liquor randomized AND heart rate AND spirits randomized AND heart rate AND wine 61 Appendix B : Data extraction form Table B-1: Data extraction form Reviewer name: Article name: Study identifier: Is the protocol available: Study design and duration Research question (PICO) Patient inclusion criteria Patient exclusion criteria Outcomes Participants baseline characteristics Total randomized, N Alcohol, n Placebo, n SBP (mean ±SD) Before ≤6 h 7-12 h ≥13 h Before ≤6 h 7-12 h ≥13 h P value in comparison to placebo DBP (mean ±SD) Before ≤6 h 7-12 h ≥13 h Before ≤6 h 7-12 h ≥13 h P value in comparison to placebo MAP (mean ±SD) Before ≤6 h 7-12 h ≥13 h Before ≤6 h 7-12 h ≥13 h P value in comparison to placebo HR (mean ±SD) Before ≤6 h 7-12 h ≥13 h Before ≤6 h 7-12 h ≥13 h P value in comparison to placebo Total withdrawal, n (%) 62 When was the BP measured? What instrument was used to measure BP When was HR measured? What instrument was used to measure HR? How was data of patients withdrawing from the trial accounted for? Additional note 63 Appendix C : Characteristics of included studies and their risk of bias assessment Table C-1: Characteristics of included studies and their risk of bias assessment Study ID Description Agewall 2000 Methods Randomized controlled trial, single blinded, cross-over design Participants Twelve adult volunteers (8 male and 4 female) with mean age of 31 years were included in the study Inclusion criteria:  Normotensive  less than 40 years of age  non-smokers,  non-diabetic,  normal serum cholesterol and  on no medications. Interventions  250 ml of a Cabernet Sauvignon/Merlot red wine containing 12·5% alcohol by volume (calculated dose:31.25 g)  De-alcoholised red wine containing less than 0.5% alcohol by volume consumed over 10 minutes. Outcomes  Brachial artery diameter  Arterial flow velocity measurements  Heart rate  Plasma–ethanol measured at baseline and 60 minutes after the consumption of drink. Notes  The subjects were served a standardized light lunch at noon. The lunch consisted of a baguette filled with 5 g of margarine, 2 leaves of lettuce, half of a sliced tomato, a slice of lean cheese and a little pepper, a low-fat yoghurt (150 g) and a banana 64 Study ID Description  The washout period was 1 week between the interventions. Barden 2013 Methods Randomised controlled trial, three period open-label crossover study Participants Twenty-five men with a mean age of 56 years were recruited for the study Inclusion criteria:  Male between 20-65 years  alcohol consumption >30g/day <110gm/day,  non-smokers,  not taking any medication Exclusion criteria:  Alcohol consumption <30g/day >110gm/day, smokers, taking medication  Women were excluded from the study because the protocol required that a relatively high dose of alcohol be consumed in a single session.  Smoking within the past 6 months,  BMI greater than 30kg/m2,  Chronic liver disease,  Cardiovascular disease,  Diabetes mellitus,  Blood pressure above 160/90mmHg or treatment with antihypertensive agents,  Total cholesterol above 7.5 mmol/l or use of lipid-lowering agents, aspirin or NSAIDs Interventions  375 ml of red wine with approximately 14% alcohol content (41 g of alcohol)  The equivalent volume of de-alcoholised red wine with approximately 0.6% alcohol content (DRW) 65 Study ID Description  Water Outcomes  Measurement of plasma 20- hydroxyeicosatrienoic acid  Measurement of plasma epoxyeicosatrienoic acids and dihyroxyeicosatetraenoic acid metabolites  Measurement of F2-isoprostanes and endothelin-1  Systolic blood pressure  Diastolic blood pressure  Heart rate Notes  The authors estimated that studying 20–25 men would give them at least 80% power to detect a 20% difference in plasma 20-HETE and a power to detect a 20% difference in plasma 20-HETE and a 5mmHg difference in SBP at a significance level of P less than 0.05.  The men were asked to maintain their usual drinking, dietary and exercise habits during the study, but to abstain from drinking alcohol for 48 h prior to each study visit and from taking any dietary supplements for 2 weeks prior to and during the study.  The washout period was 2 weeks between the interventions.  We calculated MAP from the reported SBP and DBP. SD for the MAP had to be imputed. Bau 2005 Methods Randomized controlled trial, double-blinded, parallel group assignment. Participants 100 males aged with a mean age of 20.74 ± 2.36 (SD) years (range 18-25 years) with no history of cardiovascular disease or medication use and non-smokers. Baseline characteristics:  Baseline systolic blood pressure (mean ± SEM) was 115.5 mmHg and diastolic blood pressure (mean ± SEM) was 66 Study ID Description 67.7 mmHg in the placebo group.  Baseline systolic blood pressure (mean ± SEM) was 114.2 mmHg and diastolic blood pressure (mean ± SEM) was 64.8 mmHg in the alcohol group.  Baseline heart rate (mean ± SEM) was 72.17 ± 1.54 bpm in the placebo group.  Baseline heart rate (mean ± SEM) was 72.43 ± 1.59 bpm in the alcohol group. Interventions  500 ml placebo beverage containing 2.6 g citric acid, 35.6 g glucose and distilled water was given to placebo group  500 ml alcohol beverage containing 2.6 g citric acid, 35.6 g glucose, 60 g of ethanol and distilled water was given to alcohol group Outcomes  The diameter of brachial artery (DBA)  Endothelium-dependent flow-mediated dilation.  Endothelium-independent nitroglycerin-mediated dilation  Systolic blood pressure (SBP),  Diastolic blood pressure (DBP)  Heart rate Measurements were made at 10p.m. (4 h after intervention) and 7a.m. (13 h after intervention). Notes  All volunteers were asked to abstain from alcohol and other psychoactive substances 48 h before the study.  Mean arterial pressure (MAP) was not given but can be calculated by using the formula: MAP = 1/3 (SBP - DBP) + DBP and SD was imputed.  Adverse events experienced by participants included dizziness and vomit. Bau 2011 Methods Randomized controlled trial, double-blinded, parallel group 67 Study ID Description assignment. Participants 70 healthy men with a mean age of 20.7 ± 2.4 (SD) years (range 18-25 years) without cardiovascular disease, not using drugs with cardiovascular effects and non-smokers were recruited from general population for the study. Baseline characteristics:  Baseline mean age was 20.9 ± 2.4 years in the placebo group and 20.6 ± 2.4 years in the alcohol group.  Baseline body mass index (BMI) was 23.2 ± 2.2 kg/m2 in the placebo group and 22.1 ± 2.0 kg/m2 in the alcohol group.  Baseline mean blood pressure (MAP) was 87.2 ± 7.8 mmHg in the placebo group and 86.6 ± 9.0 in the alcohol group.  Baseline heart rate (mean ± SD) was 75 ± 10 bpm in the placebo group and 77 ± 11 bpm in the alcohol group. Interventions  500 ml placebo beverage containing 2.6 g citric acid, 35.6 g glucose and distilled water was given to placebo group.  500 ml alcohol beverage containing 2.6 g citric acid, 35.6 g glucose, 60 g of ethanol and distilled water was given to alcohol group. Outcomes  Heart rate variability  Standard deviation of all normal R-R intervals (SDNN) - to evaluate vagal modulation to the sinus node.  Root mean square of successive difference (RMSSD) - to evaluate vagal modulation to the sinus node.  Percentage of pairs of adjacent R-R intervals differing by more than 50 ms (PNN50) - to evaluate vagal modulation to the sinus node. 68 Study ID Description measured during: pre-ingestion; 1-4 h after ingestion (high plasma levels of alcohol, with vasodilation and lower blood pressure); 4-10 h after ingestion (vanishing of alcohol), and between 10 and 17 h after ingestion (after elimination, when there is a late increase in blood pressure). Notes  All volunteers were asked to abstain from alcohol and other psychoactive substances 48 h before the stud Buckman 2015 Methods Randomized controlled trial, parallel group assignment, open-label study. Participants Seventy-two healthy participants with an average age of 21.7 years (SD=0.9). Among the participants 44% were females. Exclusion criteria:  under 21 years of age,  reported consuming less than 4 drinks (3 drinks for women) twice per month in the past year, or  were more than 20% overweight or underweight from the ideal for gender, height, and body frame based on the Metropolitan Life Height–Weight Table  regular (greater than monthly) drug use,  self-report of current learning disability,  lifetime history of bipolar disorder or psychosis diagnosis,  substance use treatment in the past year,  biological mother heavy substance use during pregnancy, and  for women, pregnancy Interventions  95% Ethanol with mixer (orange, cranberry, and lime juice) calculated based on body weight: (0.90 ml/kg for men, 0.78 ml/kg for women)  Physiologically inactive dose of alcohol (100 µl EtOH float 69 Study ID Description per each cup) with mixer  Placebo (100% mixer, no alcohol) Each beverage was divided into 3 equal drinks, and participants were instructed to consume each beverage evenly over a 5-minute period (total drinking time =15 minutes) Outcomes  Variability in cardiovascular function: Heart rate variability (HRV), high frequency HRV, Low frequency HRV, stoke volume variability (ml), Pulse transit Variability (ms), Systolic blood pressure variability (mmHg).  Average cardiovascular activity: Heart rate (bpm), stroke volume (ml), pulse transit time (ms), systolic blood pressure (mmHg), Mean arterial blood pressure (mmHg)  Sensitivities of cardiovascular function: Heart rate baroreflex sensitivity, Stroke volume baroreflex sensitivity, Vascular tone baroreflex sensitivity. Notes - Chen 1986 Methods Randomized controlled trial, parallel group assignment, open-label study. Participants Twenty college students, both male and females between the age of 19 and 32 years participated in the study. Inclusion criteria:  Non-smokers  Non-alcoholic or with no drinking problem  No blood pressure problem  Good general health Interventions  Sufficient quantities of beer or wine to achieve a blood level of 0.05%  No alcohol Outcomes  Heart rate 70 Study ID Description  Systolic blood pressure  Diastolic blood pressure  Respiratory rate  Subjective ratings of anxiety level Notes  All the tests were conducted in a group setting in the laboratory. Alcohol and control groups were tested separately at about the same time of the day to control possible variations due to biological rhythms' change. Cheyne 2004 Methods Randomized controlled trial, double-blinded, cross-over design. Participants Seventeen subjects (14 male, 3 female) with a mean age of 35 years (range 21–46 years) with Type 1 diabetes, HbA 1c 8.1% (1.4%) [mean (SD)], duration of diabetes 19 years (12 years) were studied. All were drivers and drank alcohol (between 1 and 14 units per week). They did not have a history of alcoholism or drug abuse and were not taking any other medication apart from insulin. Interventions  0.35 mg/kg of alcohol (vodka and sugar-free orange squash)  Placebo (similar volume of sugar-free orange squash only) Outcomes  Heart rate  Blood pressure  Cognitive function  Hazard perception test  Blood glucose and alcohol level Notes  All studies were done in the Diabetes and Endocrine Centre at the Royal Bournemouth Hospital.  Washout period between the sessions were 2 weeks.  16 patients the study had 80% power to detect effect sizes of 0.75 within-subject standard deviations for all outcomes. Dai 2002 Methods Randomized controlled trial, double-blinded, cross-over design. 71 Study ID Description Participants 20 subjects with high risk and 20 subjects with low risk of alcoholism (total 40 subjects) were included in the study. All subjects were men and between 19 and 25 years old. Inclusion criteria: Not reported Exclusion criteria:  A Michigan Alcoholism Screening Test score of 10 or higher (Selzer, 1971) and the presence of alcohol dependence or abuse diagnosis (DSM-IV) (American Psychiatric Association, 1994);  Medical problems, such as liver or kidney problems, diabetes, hypertension, or other chronic disease;  Mental health problems, such as depression or schizophrenia;  Use of prescribed psychotropic drugs;  Use of drugs of abuse other than alcohol, such as cocaine and cannabis; and  Smoking of more than 10 cigarettes per day.  Female subjects were not included in these studies because of the complexity of controlling for the phases of the reproductive cycle and the use of various contraceptive medication.  Subjects whose mother was, or had previously been, an alcoholic was excluded from the study to avoid including subjects exposed to ethanol during fetal life. Interventions  Ethanol (0.50 g/kg)  Placebo drink (1 part degassed tonic water and 2 parts unsweetened orange juice) The beverage was consumed as a single drink within 5 min. Outcomes  Heart rate 72 Study ID Description  Systolic blood pressure  Diastolic blood pressure  Estimation of the blood alcohol level (BAC)  Estimation of Plasma ß-Endorphin Levels HR, SBP and DBP measurements was taken at the baseline and at 5, 20, 35, 50, 65, 95, 125, 155, 185, 215, and 245 min after the ingestion of drink. Notes All subjects were requested to abstain from alcohol for 48 hr before each testing session Dumont 2010 Methods Randomized controlled trial, four-way, double blind, cross- over design. Participants Sixteen healthy volunteers (9 male and 7 female) with a mean age (SD) of 22.1 (2.9) years (range 18-29) Inclusion criteria:  Regular users of ecstasy (at least eight exposures in the last two years) and alcohol (at least one exposure per week) Exclusion criteria:  Pregnancy,  History of psychiatric illness,  Use of over-the-counter medication within 2 months prior to the study start,  (History of) treatment for addiction problems,  (Familial or personal history of) schizophrenia,  Excessive smoking (>10 cigarettes/day), and  Orthostatic dysregulation Interventions  Ethanol infusion (target blood alcohol concentration of 0.6‰),  Placebo infusion (glucose 5%) as placebo for ethanol infusion 73 Study ID Description  100 mg MDMA capsule  Placebo for MDMA Outcomes Cardiovascular function assessed by  heart rate,  systolic blood pressure  diastolic blood pressure Plasma concentration of  antidiuretic hormone (ADH),  sodium,  norepinephrine (NE), and  epinephrine (E) Notes  Washout of 7 days between each treatment.  A light breakfast was offered.  A 30 min lunch break was scheduled 210 min after drug administration.  Drug administration was scheduled at 10:30 h and the ethanol infusion was started at 11:00 h  outcomes were assessed before administration and at 30, 90, 150, 240, 300, and 360 mins after administration.  The alcohol clamp was targeted at 0.6‰, the equivalent of approximately 2–3 alcoholic beverages  Drug use was not allowed 14 days prior to the first study day until study completion Fantin 2016 Methods Randomized controlled trial, open-label with cross-over design. Participants 18 healthy adults (12 male and 6 female) with a mean age 34.2 years (range 25–53 years) Exclusion criteria:  Subjects >55 years  Subjects with hypertension or diabetes, any arrhythmia, 74 Study ID Description heart failure, valvular heart disease, malignancy, renal failure, body-mass index >30 kgm2 or on hormone-replacement therapy Interventions 250 ml of red wine (12% of ethanol) Outcomes Heart rate, BP and arterial stiffness, as assessed by QKD Notes  Subjects were asked not to drink for 24 h before the 24 h ambulatory readings of the first day.  The investigators did not record which type of food they ate during the study day  None of the subjects ingested caffeine during the study days.  None of the subjects indulged in binge drinking during the study.  None of the subjects was involved in intense physical activity during the study  Alcohol was ingested between 1830 hours to 0430 hours  We calculated MAP from SBP and DBP.  The readings were taken approximately at every half an hour with ambulatory BP monitor Fazio 2004 Methods Randomized controlled trial, open-label with cross-over design. Participants 10 young healthy and normotensive male volunteers with a mean age of 22 ±2.1 (SD) years (range 20–25 years) Interventions  95% ethanol infusion via arm vein (7.5 mg/kg/minute in 250 mL saline)  95% ethanol, 0.3 g/kg in 250 ml water, orally, within 5 minutes  250 ml Saline infusion alone in 40 minutes (6.25 mL/minute) Outcomes  Heart rate 75 Study ID Description  Mean blood pressure  Cardiac index  Total peripheral vascular resistance  Changes of diameter, mean blood velocity and mean blood flow of carotid artery in diameter  Changes of diameter, mean blood velocity and mean blood flow of branchial artery in diameter Notes  The subjects rested quietly in recumbent position for 30 minutes to allow blood pressure and heart rate to stabilize before measurement of baseline hemodynamic variables Foppa 2002 Methods Randomized controlled trial, open-label with cross-over design. Participants 13 hypertensive and centrally obese individuals (8 post- menopausal women and 5 men) Inclusion criteria:  Study subjects were required to have systolic blood pressure greater than 140 or diastolic blood pressure greater than 90 mmHg, in at least two separate measurements or be taking anti- hypertensive drugs.  Central obesity was defined for this specific study as one of the following: a body-mass index (BMI) greater than 30 kg/m2; BMI greater than 27.3 kg/m2 with waist-hip ratio greater than 0.95 for women; or BMI greater than 27.8 kg/m2 with waist-hip ratio greater than 1.05 for men  Men were between 35 and 65 years of age, women postmenopausal (last menses more than 1 year ago) and younger than 66 Exclusion criteria:  A history of heavy alcohol ingestion, defined as an average ethanol intake greater than 30g/day; 76 Study ID Description  Diagnosed diabetes mellitus; symptomatic ischemic heart disease; evidence of major target organ damage; or the presence of a disease or the use of a drug that could adversely influence blood pressure or metabolic control Interventions  250 ml of red wine (23 g ethanol)  Placebo equivalent (200 ml of water and 50 ml of grape juice) Outcomes  Systolic blood pressure  Diastolic blood pressure  Mean blood pressure  Heart rate Measured at the following time intervals: postprandial (3 hours from intervention), daytime (1200h-2200h), nighttime (2200h-0700h) and overall (19-hour interval, from intervention at 1200h to 0700h, Day 2). Notes  Hospital settings  Participants were instructed not to change diet, sleep, physical activity and smoking habits across the entire study. They were also instructed to fast for at least 12 hours, abstain from alcohol intake for 36 hours and not take antihypertensive drugs from 3 days prior to each study period.  Washout period was 1-3 weeks between the experimental periods  Wine and control solutions were administered at 1200h together with a standardized meal over a 15-minute interval. The meal was composed essentially of carbohydrates (pasta, tomato sauce and a jelly dessert), with total energy content of 650 Kcal. 77 Study ID Description  Participants were allowed to take their pre-study antihypertensives during the washout period and were told to stop them 3 days before the study day. Hering 2011 Methods Randomized controlled trial, open-label with cross-over design. Participants Total 24 participants; 13 patients (eight men and five women) with essential hypertension and 11 normotensive controls (six men and five women) matched for sex, age (44±2 vs. 43±2 years, respectively; mean±SEM), and BMI (29±1 vs. 28±1kg/m2, respectively) Inclusion criteria:  Hypertensive patients with stage 1 and 2 hypertension who were newly diagnosed, never treated for hypertension, and free of any other diseases  All participants consumed alcoholic beverages socially (between 100 and 200 g of alcohol a week, with the median of 150 g in both groups). Exclusion criteria:  Patients with white-coat hypertension and controls with masked hypertension Interventions  Alcohol (1.0 g/kg body weight, diluted in 500 ml low caloric orange juice) or  Vehicle (500 ml of low-caloric orange juice) Administered over a period of 20 minutes. Outcomes  Heart rate  Systolic blood pressure  Diastolic blood pressure  Muscle sympathetic nerve activity Notes  Standard light breakfast was provided before the experiment 78 Study ID Description  All participants were asked to abstain from alcohol for at least 36 h  Ten-minute recordings were performed 10 min after completion of drinking either alcohol or place  We calculated MAP from the reported SBP and DBP. SD was imputed. Karatzi 2005 Methods Randomized controlled trial, double-blinded, cross-over design. Participants 15 male participants with coronary artery disease with a mean age of 52.4±9.7 (SD) years and body mass index (BMI) of 28.3±1.8 kg/m2. Inclusion criteria:  The coronary angiography was performed within the past 6 months and no revascularization procedure was carried out the past 3 months. Exclusion criteria:  Presence of diabetes mellitus, obesity, any liver, kidney, or endocrine diseases, and administration of antioxidant vitamin supplementation. Interventions  250 mL of regular (12% ethanol, Grand Reserve 1996, Boutaris, Greece) or  250 mL of dealcoholized red wine (<1% ethanol) Outcomes  Central and peripheral blood pressures (BP)  Arterial stiffness  Heart rate assessed at fast and 30, 60, and 90 min postprandially. Notes  A sample size of 15 subjects was estimated as efficient (80% power) to demonstrate a change by 6% in Augmentation index (AIx) (α= 0.05 and β=0.20; two-tailed test) 79 Study ID Description  All patients were receiving nitrates, β-blockers, antiplatelets. Nine of them (60%) were taking angiotensin-converting enzyme inhibitors and 2 (13.3%), calcium channel blockers. Further- more, all participants were ex-smokers and their alcohol use was in accordance with the recommendations (20 to 30 g alcohol/d) Karatzi 2013 Methods Randomized controlled trial, single-blinded, cross-over design. Participants 17 healthy, non-smoking, male volunteers with 28.5±5.2 years and 24.4±2.5 BMI) Exclusion criteria were:  Medical history of coronary artery disease, diabetes mellitus, liver or endocrine diseases  Smoking, alcohol consumption more than the recommended amount (20-30 gr alcohol/day), vigorous exercise, antioxidant vitamin supplementation  Dieting at the time of the study. Interventions  400 ml of beer & 400 ml water (~20 g of ethanol and ~48 mg polyphenol)  800 ml of dealcoholized beer (same amount of polyphenols), and  67 ml of vodka & 733 ml water (same amount of alcohol) consumed within 15 minutes Outcomes  Endothelial function (brachial flow mediated dilatation)  Aortic and brachial pressure  Aortic stiffness (pulse wave velocity, pressure wave reflections (Aix) assessed at fast and 1 and 2 hours postprandial. Notes  All vascular and hemodynamic tests were performed at the Cardiovascular Research Laboratory (Laiko Hospital) in the 80 Study ID Description morning hours (at 8:00) and after 10-12 hours fast and absence of alcohol, coffee and caffeinated drinks since noon of the previous day.  Washout period was at least 1 week  The test drinks were accompanied with a sandwich (2 slices of white bread, 1 slice of turkey and 1 slice of low fat cheese)  The above mentioned drinks were matched for their antioxidant and alcohol content, namely 400 ml of beer had the same antioxidant concentration with 800 ml of dealcoholized beer (∼48mg polyphenols) and 400 ml of beer had the same alcohol concentration with 67 ml of vodka (∼ 20 g of ethanol).  All volunteers were instructed to avoid significant changes in their physical activity and their diet between the 3 visits.  They were also advised to consume the same quality and quantity of food one day before the study days Kawano 1992 Methods Randomized controlled trial, open label, crossover design. Participants Sixteen Japanese men (22-70 years old) with essential hypertension. Their mean age was 55.2±3.3 years (mean ± SEM) Interventions  1 ml/kg ethanol (vodka)  non-alcoholic beverage (lime juice and water) ingested at dinner Outcomes Ambulatory blood pressure and heart rate were measured every 30 minutes until noon the next day Notes  Alcohol was forbidden for at least 7 days before the study.  Patients were asked to discontinue their antihypertensive medication for at least 7 days before the study.  All the patients were admitted to the National 81 Study ID Description Cardiovascular Center Hospital where they consumed a standard daily diet of 6,300 kJ (1,500 kcal) that contained 7-9 g NaCl  All participants were habitual drinkers  All the patients were diagnosed as having mild-to-moderate essential hypertension (average diastolic blood pressure, 90-114 mm Hg)  No patient had serious cardiac, neurological, or hepatic disorders.  Interventions were given at dinner  All the patients were admitted to the National Cardiovascular Center Hospital where they consumed a standard daily diet of 6,300 kJ (1,500 kcal) that contained 7-9 g NaCl.  The two study periods were separated by a rest day.  We calculated MAP from the reported SBP and DBP. SD for MAP had to be imputed. Kawano 2000 Methods Randomized controlled trial, open label, crossover design. Participants 10 Japanese hypertensive patients with a mean age ± SEM of 54±3 years and body weight of 70±2 kg. Inclusion criteria:  Mild essential hypertension Interventions  1 ml/kg of alcohol (vodka with lime juice and water) or  Isocaloric control drink (Calorie Mate, Otsuka Pharmaceutical Co, Tokushima, Japan) consumed within 60 minutes  Prazosin 1 mg, 3 times daily plus alcohol Outcomes  Systolic blood pressure  Diastolic blood pressure 82 Study ID Description  Heart rate  Serum electrolyte level BP and HR were measured every 30 min for 24 hours Notes  Light meal was provided with interventions  All of the subjects had an average daily alcohol consumption of 30 to 120 mL (mean ±SEM:72 ±13 ml).  Antihypertensive medication was discontinued for ⱖ7 days before the study  We calculated MAP from the reported SBP and DBP. SD for MAP had to be imputed. Koenig 1997 Methods Randomized controlled trial, open label, crossover design. Participants 15 male subjects between the ages of 20 and 35 years (average gross height 184 cm, weight 76 kg) were enrolled in the study. Exclusion criteria:  Subjects with acute or chronic diseases. Interventions  10 ml / kg Body weight of Kölsch (beer) or  the same amount of Kolschbier brewing water was chosen as placebo consumed within 30 minutes Outcomes  Systolic blood pressure  Diastolic blood pressure  Serum electrolyte level measured at baseline, 2 and 3 hours after consumption. Notes  Washout period was 14 days between the interventions  The subjects were told abstain from alcohol for 5 days prior to the study Kojima 1993 Methods Randomized controlled trial, open label, crossover design. Participants 21 men with essential hypertension and mean (SD) age of 56.5(11.8) was enrolled in the study 83 Study ID Description Exclusion criteria:  Participants with serious heart, liver and kidney diseases Interventions  Alcohol in the form of vodka made up to 500 ml with lime juice  500 ml lime juice made isocaloric by addition of a candy (calorie mate, Otsuka Pharmaceutical Ltd, Japan) Outcomes  Heart rate  Systolic blood pressure  Diastolic blood pressure Measured 30 mins before and 2 hours after consumption. Notes  Washout period: 2 days  All the patients were admitted to the National Cardiovascular Center Hospital and ate a standard daily diet of 6300 kJ containing 7-9 g salt.  All the antihypertensives were discontinued.  The drinks were given with supper (1700-1730 h) to mimic usual drinking pattern. Mahmud 2002 Methods Randomized controlled trial, double-blinded, cross-over design. Participants 8 healthy normotensives (three men and five women) between the age of 21-40 years and mean ± SEM body weight of 70±3.9 kg. Interventions  500 mL of red wine (0.8 g/kg ethanol) or  500 mL of red wine without alcohol consumed within 10 min Outcomes  Branchial and aortic blood pressure  Heart rate  Pulse wave measured at baseline, 30, 60, and 90 min after ingestion of either drink. Notes  Subjects were not taking any medication or vitamin 84 Study ID Description supplements.  subjects had an average alcohol intake of 10 ±3.8 units/week.  Subjects were asked to abstain from all caffeine-containing beverages in the 12 h before each visit as well as alcohol in the 24 h before the visit.  Washout period was 1 week between the two visits  We calculated MAP from the reported SBP and DBP. SD for the MAP had to be imputed. Maufrais 2017 Methods Randomized controlled trial, open-label, cross-over design. Participants 24 healthy young subjects (12 men, 12 women) of European descent with a mean ± SD age of 23.3 ± 2.2 years and weight 62.9 ± 10.1 kg Exclusion criteria:  Subjects with a body mass index greater than 30 kg.m −2, competition athletes and individuals with a daily exercise workload exceeding 60 min per day. Interventions The subjects ingested one of the following four drinks at a temperature of around 10 ◦C (at a convenient pace over 5min):  390mL distilled water + 10mL lemon juice,  48 g sucrose + 10mL lemon juice, diluted in distilled water up to a total volume of 400mL,  Vodka (40% alcohol per volume, given at 1.28mL.kg −1 of body weight, providing 0.4 g alcohol.kg −1) + 10mL lemon juice, diluted in distilled water up to 400mL,  48 g sucrose + 40% vodka (at 1.28mL.kg −1) + 10mL lemon juice, diluted in distilled water up to 400mL. Outcomes  Heart rate  Mean blood pressure 85 Study ID Description  Skin temperature  Stroke volume  Cardiac output  Total peripheral resistance measured before drinking and at 15, 30, 60, 90, and 120 min post-drink. Notes  None of the subjects had any diseases or were taking any medication affecting cardiovascular or autonomic regulation.  All participants were requested to avoid alcohol or caffeine for at least 24 h prior to the test.  A light standardized breakfast provided by the investigators, consisting of one mini-pack of 33 cl of commercial light ice tea (33 kcal, 8 g carbohydrates/6.6 g sugar) and two cereal bars (total of 150 kcal, 39 g carbohydrates/12 g sugar), to avoid that consumption of alcohol in the same morning were done on an empty stomach.  The authors chose type I error (α) of 0.05 and a desired power (1-β) of 0.80, suggesting that a total number of12 subjects per gender would be required. Maule 1993 Methods Randomized controlled trial, single-blind, crossover design. Participants 10 healthy subjects (6 males, 4 females) with a mean age of 31 (range 22-51) and mean weight of 68.1 kg were included in the study. Interventions  40% vodka diluted in sugar-free orange juice with aspartame 0.8g/100 ml (dose:0.5 g/kg body weight) or,  Placebo consisted of sugar-free orange juice with aspartame 0.8g/100 ml 86 Study ID Description consumed within 10 minutes. Outcomes  Systolic blood pressure  Diastolic blood pressure  Mean arterial blood pressure  Heart rate  Total peripheral vascular resistance  Skin temperature  Digital skin blood flow blood pressure and heart rate were measured at baseline and every 5 mins till 45th minute. Notes  All subjects were off medication and had normal liver function tests.  Subjects had alcohol consumption less than 80g per week  Alcoholic drinks were not allowed 3 days before the study.  Subjects refrained from smoking and drinking caffeinated beverages from midnight before the study.  Subjects were studied after an overnight fast Narkiewicz 2000 Methods Randomized controlled trial, double-blind, crossover design. Participants 19 healthy young volunteers (18 men and 1 women) with a mean age ± SD of 26±2 years participated in the study. Interventions  Alcohol (1.0 g/kg body weight, diluted in 400 mL of water) or  Placebo (400 mL water) consumed over a 30-minute period. Outcomes  Lower-body negative pressure  Systolic blood pressure  Diastolic blood pressure  Mean arterial pressure  Heart rate 87 Study ID Description Notes  None was taking any medications.  All subjects were social drinkers only and had abstained from alcohol for minimum 48 hours before the study. Nishiwaki 2017 Methods Randomized controlled trial, single-blind, crossover design. Participants 11 healthy young men with mean age ± SD of 21.1 ± 0.2 years, body weight 62.6±2.6 kg Interventions  200 mL of beer;  350 mL of beer;  200 mL of alcohol-free beer;  350 mL of alcohol-free beer consumed within 5 minutes. Outcomes  Systolic blood pressure  Diastolic blood pressure  Heart rate  Pulse pressure measured at baseline, 30, 60 and 90 minutes after ingestion Notes  All subjects habitually consumed alcohol-containing beverages, but none exceeded the recommended amount of beverage  All experiments were conducted after a light meal.  No participants had chronic diseases that could affect cardiovascular health, metabolism, or daily physical activity; none had history of smoking; and none were taking any medications.  All participants were asked to abstain from alcohol- and caffeine-containing beverages and to avoid strenuous physical activity for 12 h prior to an experimental session.  In addition, participants were advised to eat the same meals (breakfast, lunch, and dinner) on the day before each 88 Study ID Description experimental session.  We calculated MAP from the reported SBP and DBP. SD for the MAP had to be imputed. Potter 1986 Methods Randomized controlled trial, double-blind, crossover design. Participants 16 normotensive male medical students (eight with a family history of hypertension) with a mean age of 22 years and mean body weight of 77 kg were included in the study. Interventions  0.75 g/kg bodyweight of alcohol in the form of beer or  600 ml of alcohol-free lager (Canada Dry Rawlings, Northants, UK) consumed within 15 minutes. Outcomes  Systolic blood pressure  Diastolic blood pressure  Pulse rate  Plasma catecholamines,  Plasma cortisol and plasma renin activity  Plasma norepinephrine and epinephrine Notes  Washout period was 1 week between the interventions  All subjects abstained from alcohol, caffeine, and tobacco for 24 hours (although diet was otherwise unrestricted), and all fasted for 12 hours before each part of the study  Subjects were considered to have a family history of hypertension if one or both parents had ever received treatment for hypertension or had a resting blood pressure of 160/95 mm Hg or more.  All subjects were healthy and taking no medication  We calculated MAP from the reported SBP and DBP. SD for the MAP had to be imputed. Rosito Methods Randomized controlled trial, double-blind, parallel group 89 Study ID Description 1999 assignment. Participants Forty male medical students with a mean age of 22.2 years were included in the trial. Interventions  Water or  15, 30, or 60 g of ethanol in solutions containing citric acid (2.6 g), glucose (35.6 g), with water to complete 500 mL and lunch was provided immediately. Outcomes  Systolic blood pressure  Diastolic blood pressure  Heart rate measured every hour for 24-hours. Notes  Subjects were instructed them to abstain from alcohol during the 3 days preceding the study.  They slept in the hospital the night before the study period and consumed a balanced diet.  They ate lunch immediately after the intervention.  We calculated MAP from the reported SBP and DBP. SD for the MAP had to be imputed Rossinen 1997 Methods Randomized controlled trial, open-label, crossover design. Participants Twenty patients (17 men and 3 women, aged 39 to 68 years) with angiographically verified and coronary heart disease and electrocardiographic evidence of myocardial ischemia were included in the study Inclusion criteria:  Patients with luminal diameter narrowing ≥50% in at least 1 of the major epicardial coronary arteries and ischemia verified by exercise test within 6 months were eligible for the study. Exclusion criteria: 90 Study ID Description  Subjects with acute myocardial infarction within 1 month, New York Heart Association class IV symptoms, luminal diameter narrowing ≥50% in the left main coronary artery or luminal diameter narrowing ≥80% in all 3 major epicardial vessels, ejection fraction ≤25% on left ventricular cineangiography,  previous sustained ventricular tachycardia or fibrillation, and  presence of other than sinus rhythm or  history of alcohol abuse Interventions  1.25 g of ethyl alcohol per body weight in kilograms diluted to 15% juice yielding volumes of 700 ±126 ml, or  an equivalent volume of juice Patients were instructed to drink at an even pace over the 1 and 1/ 2 hours. Outcomes  Heart Rate Variability  Systolic blood pressure Notes  Washout period: 7 ±3 days (range 4 to 14)  Regular daily medication was continued throughout the study.  Nineteen patients were taking beta blockers and long-acting nitrates, 17 aspirin, 7 calcium antagonists, and 4 angiotensin-converting enzyme inhibitors.  Nine patients had arterial hypertension,  12 had had at least 1 myocardial infarction;  none had diabetes mellitus.  Seven patients had New York Heart Association class II, and 13 patients class III symptoms.  Eight patients had 1- vessel, 8 patients had 2-vessel, and 4 91 Study ID Description patients had 3- vessel disease on coronary angiography. Stott 1987 Methods Randomized controlled trial, open-label, crossover design. Participants Ten healthy subjects (seven males, three females) aged 18-31 years and body weight of 56-101 kg Interventions  1.3 g of alcohol/kg body weight, in the form of vodka made up to 1 litre with orange juice  1 litre of orange juice made isocaloric with glucose Outcomes  Plasma noradrenaline and adrenalin  Systolic blood pressure  Diastolic blood pressure  Heart rate measured at baseline (13.00) and at 14.00, 15.00, 16.00, 17.00, 19.00 and 22.00 hours that day, 09.00 and 14.00 hours the next day, and at 14.00 hours for a further 5 days Notes  Subjects daily average alcohol consumption was 26g  Subjects had a light lunch at mid-day.  For 1 week before and during each study phase, subjects drank no other alcohol.  For 3 days before and throughout each study phase, diet was controlled within individuals by careful recording in study phase 1 and replication of dietary intake in phase 2 by each subject.  We calculated MAP from the reported SBP and DBP. SD for the MAP had to be imputed. Stott 1991 Methods Randomized controlled trial, open-label, crossover design. Participants Eight normotensive elderly subjects (6 male, 2 female) with a mean age of 81 years (range 70-96 years) and mean body weight of 68.4 kg were included in the study. Interventions  0.5 g of alcohol/kg of body weight, in the form of vodka 92 Study ID Description made up to 200 mL with unsweetened orange juice  200 mL of orange juice alone, each consumed over 15 minutes Outcomes  Systolic blood pressure  Diastolic blood pressure  Heart rate  Plasma sodium and potassium  Blood alcohol  Blood sugar baseline recording was taken at 1:00 and further recordings were taken at 1:30, 2:00, 3:00 and 4:00 PM Notes  All had sitting systolic and diastolic blood pressures of 110-180 and < 100 mmHg, respectively, and normal orthostatic responses with a reduction of systolic blood pressure of < 10 mmHg on standing  Subjects were moderate to occasional drinkers with a usual weekly alcohol intake of 2.0 - 1.1 (maximum 7) units (1 unit = 10 g)  Subjects were non-smokers.  Two subjects had a history of cerebrovascular disease, one had a chronic obstructive airways disease and one had a peripheral vascular disease.  All subjects had a normal resting electrocardiogram, and none were taking cardioactive drugs  Subjects drank no other alcohol for 24 hours before each study day.  No other food or drink was allowed between 12 noon and 4:00 PM on study days  Subjects had a standard light lunch at midday (12 noon) 93 Study ID Description  We calculated MAP from the reported SBP and DBP. SD for the MAP had to be imputed. Van De Borne 1997 Methods Randomized controlled trial, double-blinded, crossover design. Participants 16 normal male subjects with a mean age of 26±4 (SD) years Interventions  Alcohol (1.0g/kg body weight, diluted in 400 mL water)  400 mL of water consumed over 30 minutes Outcomes  Blood pressure  Heart rate  Heart rate variability  Muscle sympathetic nerve activity  Forearm vascular resistance  Minute ventilation measured at baseline and 45, 60 and 80 mins after the ingestion Notes  None was taking any medications  Subjects were fed and hospitalised in the Clinical Research Center for approximately 4 hours after alcohol intake, after which they were driven home.  All studies were performed with subjects in the fasting state to avoid changes in muscle SNA and in alcohol absorption induced by food intake. Williams 2004 Methods Randomized controlled trial, open-label, crossover design. Participants Fourteen men with a mean age of 59±7 (SD) years and body weight of 86± 13 (SD) kg were included in the study. Inclusion criteria:  Men with angiographic evidence of coronary artery disease (CAD). Exclusion criteria:  Men who had experienced an acute coronary event within 94 Study ID Description the preceding 60 days, had significant renal or hepatic disease, uncontrolled hypertension, diabetes mellitus, a recent history of smoking cigarettes, a history of alcohol dependence or abuse, or were receiving oral anticoagulant therapy. Interventions  Red wine (Stoneleigh Marlborough Pinot Noir, New Zealand, 1998) or white wine (Jackson Estate Marlborough Sauvignon Blanc, New Zealand, 1998) at a dose of 0.52 g alcohol/kg body weight  Isoenergetic, non-alcoholic beverage (raspberry cordial: Schweppes, Auckland, New Zealand) Outcomes  Plasma levels of IL-6  Systolic blood pressure  Diastolic blood pressure  Heart rate  Plasma concentrations of soluble cell adhesion molecules BP and HR were measured at baseline,1 hour and 6 hours after consumption Notes  The self- reported drinking habits of the subjects were recorded  Subjects were instructed to refrain from drinking alcohol for 1 week before each study visit.  On study days, the men were instructed to consume a light breakfast consisting of 2 slices of toast with jam at home before reporting to the study center at 9 AM. Tea, coffee, and fruit juices were not permitted.  Test beverages were consumed with a light meal that was low in antioxidants. This meal was designed to minimize the influence of nutrient and antioxidant intake on study 95 Study ID Description variables while complying with the dictum that alcoholic beverages should be consumed with food. The meal consisted of a small bread roll (58 g) filled with 5 g margarine, 2 leaves of lettuce, half a tomato sliced, a slice of low-fat cheese (25 g), a low-fat yogurt (200 g), and a banana (total energy, 2,222 kJ (513 kcal); carbohydrate, 62% energy; protein, 18% energy; fat, 20% energy).  During the following 6-hour test period, subjects did not consume any food and were permitted only bottled water to drink.  Washout period between the wine interventions was at least one week.  Three months after the wine study, the subjects ingested an isoenergetic, non-alcoholic beverage with the light meal in an identical protocol.  All men were receiving aspirin therapy, and most were also receiving treatment with statins and ß-blocking drugs. Approximately half of the men were taking angiotensin-converting enzyme (ACE) inhibitor drugs.  Nearly all the men were light to moderate consumers of alcohol.  We calculated MAP from the reported SBP and DBP. SD for the MAP had to be imputed. Zeichner 1985 Methods Randomized controlled trial, open-label, parallel group assignment. Participants 48 healthy psychology undergraduate students (24 males and 24 females) with mean age of 20.9±2.18 (SD) years (range 19-23) Interventions  1 g/kg body weight of 95% USP alcohol in a mixture of 1 part alcohol to 5 parts orange juice  Orange juice 96 Study ID Description all participants were told that they must consume the first drink within 10 min and the second drink within the subsequent 10 min. Outcomes  Systolic blood pressure  Diastolic blood pressure  Heart rate baseline and 40 mins after alcohol consumption Notes  Participants abstained from alcoholic beverages for a minimum of 24 hr and from coffee, tea, cigarettes and food for at least 4 hr prior to the experimental session.  We calculated MAP from the reported SBP and DBP. SD for the MAP had to be imputed. 97 Appendix D : Baseline Characteristics of the included studies Table D-1: Baseline Characteristics of the included studies Study ID Randomized Participants, N Mean age (range), years Mean body weight, kg Ethnicity/ Country Health condition Reported dose of alcohol Duration of intervention Baseline SBP (SD) Baseline DBP (SD) Baseline MAP (SD) Baseline HR (SD) Agewall 2000 12 31(less than 40 years old) Not reported New Zealand Healthy, normotensive and non-smokers 31.25 g 10 mins 121(6) 79(4) Not reported 61(7) Barden 2013 24 56(20-65) Not reported Australia Healthy 41 g 30 mins 115(11) 72(6) Not reported 62.7 Bau 2005 100 20.7 (18-25) Not reported Brazil Healthy, non-smokers 60 g 30 mins 114.2 64.8 Not reported 72.43 (10.9) Bau 2011 70 20.7 (18-25) Not reported Brazil Healthy 60 g 30 mins Not reported Not reported 87.2 ( 7.8) 75 (10) 98 Study ID Randomized Participants, N Mean age (range), years Mean body weight, kg Ethnicity/ Country Health condition Reported dose of alcohol Duration of intervention Baseline SBP (SD) Baseline DBP (SD) Baseline MAP (SD) Baseline HR (SD) Buckman 2015 72 21.5 Not reported White (57%), African American (9%), Asian (22%) Healthy 0.90 ml/kg for men, 0.78 ml/kg for women 15 mins 116.9 (13.5) Not reported 80.1 (8.7) 66.9 (9.9) Chen 1986 20 19-32 Not reported Not reported Healthy, normotensive and non-smokers Target to achieve blood level of 0.05% Not reported (mentioned that fairly fast rate) 118 (12.88) 62.25 (5.1) Not reported 63.13 (7.1) Cheyne 2004 17 35 (21-46) Not reported England Type 1 diabetes 0.35 mg/kg BW Not reported 116.2 (18.7) 66.8 (8.2) Not reported 70 (12) Dai 2002 40 19-25 years 81.35 Canada Healthy 0.5 g/kg 5 mins 114.1 72.6 Not reported 63.5 99 Study ID Randomized Participants, N Mean age (range), years Mean body weight, kg Ethnicity/ Country Health condition Reported dose of alcohol Duration of intervention Baseline SBP (SD) Baseline DBP (SD) Baseline MAP (SD) Baseline HR (SD) Dumont 2010 14 22.1 (18-29) Not reported Netherlands Regular user of MDMA otherwise healthy Target blood alcohol level 0.6%, equivalent of 2-3 alcoholic beverages. 3 hours to maintain the target BAC Not reported Not reported 95 66 Fantin 2016 18 34.2 (25-53) 70.2 (53-85.6) Not reported Healthy 30 g 10 hours 110.3 (12) 80 (8) Not reported 75.5 (11.5) Fazio 2004 10 22 (20-25) Not reported Italy Healthy 0.3 g/kg 5 mins Not reported Not reported 91 68 100 Study ID Randomized Participants, N Mean age (range), years Mean body weight, kg Ethnicity/ Country Health condition Reported dose of alcohol Duration of intervention Baseline SBP (SD) Baseline DBP (SD) Baseline MAP (SD) Baseline HR (SD) Foppa 2002 13 55 (43-65) Not reported Brazil Hypertensive and centrally obese 23 g 15 mins 130 83 101.8 (9.45) 72 (8.72) Hering 2011 24 44 Not reported Not reported 13 hypertensives and 11 normotensives 1 g/kg 20 mins Hypertensive: 150 (21) Normotensive: 136 (13.2) Hypertensive: 91 (14.4) Normotensive: 76 (10) Not reported Hypertensive: 72 (7.2) Normotensive: 70 (10) Karatzi 2005 15 52.4 Not reported Greece Coronary artery disease 30 g Not reported 109.8 (9.2) 80.7 (10.8) 92.7 (9) 67.1 (13.1) Karatzi 2013 16 28.5 77.5 Greece Healthy and non-smokers 20 g 15 mins 115.4 (6.2) 68.5 (5.4) 83.2 (6.5) 60 (8.1) 101 Study ID Randomized Participants, N Mean age (range), years Mean body weight, kg Ethnicity/ Country Health condition Reported dose of alcohol Duration of intervention Baseline SBP (SD) Baseline DBP (SD) Baseline MAP (SD) Baseline HR (SD) Kawano 1992 13 55.2 (22-70) 65.2 Japanese Mild to moderate essential hypertension 51g Not reported 159(18.8) 91.3(12) Not reported 61.5 Kawano 2000 10 54 (32-67) 70 (60-78) Japanese Mild essential hypertension 55.3 g (1 mL/kg BW) 60 mins 147 91 Not reported 65 Koenig 1997 15 20-35 76 German Healthy 10 ml/kg BW 30 mins 127 (11) 80 (9.5) Not reported Not reported Kojima 1993 21 56.5 (33-73) Not reported Japanese Essential hypertension 1 mL/kg BW 30 mins 146 (18.33) 89 (9.2) 108 (9.2) 59 (9.2) 102 Study ID Randomized Participants, N Mean age (range), years Mean body weight, kg Ethnicity/ Country Health condition Reported dose of alcohol Duration of intervention Baseline SBP (SD) Baseline DBP (SD) Baseline MAP (SD) Baseline HR (SD) Mahmud 2002 8 21-40 70 Not reported Healthy, normotensive and non-smokers 56 g (0.8 g/kg of BW) 10 mins 93.3 (10) 67 (8) Not reported Not reported Maufrais 2017 24 23.3 62.9 Europe Healthy 0.4 g/kg 5 mins Not reported Not reported 81 (9.8) 69 (9.8) Maule 1993 10 31 (22-51) 68.1 (50-81) England Healthy 34 g (0.5 g/kg BW) 10 mins 122 70 87 (10.8) 62 (6.3) Narkiewicz 2000 19 26 Not reported Not reported Healthy 1 g/kg BW 30 mins 111 (11.2) 61 (7.5) 79 (7.5) 57 (7.5) 103 Study ID Randomized Participants, N Mean age (range), years Mean body weight, kg Ethnicity/ Country Health condition Reported dose of alcohol Duration of intervention Baseline SBP (SD) Baseline DBP (SD) Baseline MAP (SD) Baseline HR (SD) Nishiwaki 2017 11 21.1 (20-22) 62.6 Japanese Healthy non smoking 11g and 19.25 g 5 mins 123 (6.63) 71(6.63) 89 (6.63) 59(9.94) Potter 1986 16 22 (20-30) 77 England Healthy normotensive 0.75 g/kg 15 mins 122.5 (11) 72.5 (9) Not reported 63.2 (8) Rosito 1999 40 22.2 (19-30) Not reported Brazil Healthy 60 g 1 hour 124.2 (10.7) 76.2 (9.4) Not reported 70.5 (12.6) 104 Study ID Randomized Participants, N Mean age (range), years Mean body weight, kg Ethnicity/ Country Health condition Reported dose of alcohol Duration of intervention Baseline SBP (SD) Baseline DBP (SD) Baseline MAP (SD) Baseline HR (SD) Rossinen 1997 20 39-68 Not reported Not reported Coronary artery disease and myocardial ischemia. Patients were taking usual medicine. 1.25 g/kg 1 hours 30 mins 132 (16) Not reported Not reported 69.5 Stott 1987 10 18-31 56-101 England Healthy 1.3 g/kg 1 hour 115.5 67 Not reported 70.5 Stott 1991 8 81 (70-96) 68.4 Scotland Normotensive 0.5 g/kg 15 mins 130 (18.3) 77.5 (15.5) not reported 57 (7.5) Van de borne 1997 16 26 Not reported Not reported Healthy 1 g/kg 30 mins Not reported Not reported 79 (8) 59(8) 105 Study ID Randomized Participants, N Mean age (range), years Mean body weight, kg Ethnicity/ Country Health condition Reported dose of alcohol Duration of intervention Baseline SBP (SD) Baseline DBP (SD) Baseline MAP (SD) Baseline HR (SD) Williams 2004 13 59 (48-70) 86 New Zealand Coronary artery disease 0.52 g/kg 20 mins 135 (11) 82 (7) Not reported 55 (11) Zeichner 1985 48 20.9 (19-23) Not reported America Healthy 1 g/kg 20 mins 115.5 (10.2) 70.4 (9.1) Not reported 69.4 (12.10) 106 Appendix E : Funnel plots Figure E-1: Funnel plot: Medium dose Alcohol versus Placebo, outcome: 2.4 Heart rate. 107 Figure E-2: Funnel plot: High dose alcohol versus Placebo, outcome SBP. 108 Figure E-3: Funnel plot: High dose alcohol versus Placebo, outcome DBP. 109 Figure E-4: Funnel plot: High dose alcohol versus Placebo, outcome MAP. 110 Figure E-5: Funnel plot: High dose alcohol versus Placebo, outcome HR. 111 Figure E-6: Funnel plot: Medium dose Alcohol versus Placebo, outcome SBP. 112 Figure E-7:Funnel plot: Medium dose Alcohol versus Placebo, outcome DBP. 113 Figure E-8: Funnel plot: Medium dose Alcohol versus Placebo, outcome MAP. 114 Appendix F : Results from sensitivity analysis Table F-1: Comparison between the effect estimates by fixed-effect model and random-effects model. Outcomes or subgroup Mean difference, IV, Fixed effect model, 95% CI Mean difference, IV, Random effects model, 95% CI 2.1 SBP (≤6 hours) -5.63 [-8.25, -3.02] Heterogeneity: Chi² = 24.51; df = 9 (P = 0.004); I² = 63% Test for overall effect: Z = 4.22 (P < 0.0001) -6.15 [-10.55, -1.75] Heterogeneity: Chi² = 24.51; df = 9 (P = 0.004); I² = 63% Test for overall effect: Z = 2.74 (P = 0.006) 2.2 DBP (≤6 hours) -4.01 [-6.02, -2.00] Heterogeneity: Chi² = 21.81; df = 9 (P = 0.009); I² = 59% Test for overall effect: Z = 3.91 (P < 0.0001) -3.76 [-7.02, -0.50] Heterogeneity: Chi² = 21.81; df = 9 (P = 0.009); I² = 59% Test for overall effect: Z = 2.26 (P = 0.02) 2.3 MAP (≤6 hours) -2.17 [-3.68, -0.65] Heterogeneity: Chi² = 38.36; df = 12 (P = 0.0001); I² = 69% Test for overall effect: Z = 2.80 (P = 0.005) -2.92 [-5.76, -0.07] Heterogeneity: Chi² = 38.36; df = 12 (P = 0.0001); I² = 69% Test for overall effect: Z = 2.01 (P = 0.04) 115 Table F-2: Effect estimates given by blinded studies compared to unblinded studies. Outcomes Blinded studies, Mean difference, IV, Fixed effect model, 95% CI Unblinded studies, Mean difference, IV, Fixed effect model, 95% CI 2.1 SBP (<6 hours) -4.56 [-8.39, -0.73] Heterogeneity: Chi² = 2.14, df = 3 (P = 0.54); I² = 0% Test for overall effect: Z = 2.33 (P = 0.02) -6.57 [-10.15, -3.00] Heterogeneity: Chi² = 21.80, df = 5 (P = 0.0006); I² = 77% Test for overall effect: Z = 3.60 (P = 0.0003) 2.2 DBP (<6 hours) -1.50 [-4.89, 1.89] Heterogeneity: Chi² = 1.99, df = 3 (P = 0.57); I² = 0% Test for overall effect: Z = 0.86 (P = 0.39) -5.37 [-7.86, -2.87] Heterogeneity: Chi² = 16.57, df = 5 (P = 0.005); I² = 70% Test for overall effect: Z = 4.22 (P < 0.0001) 2.3 MAP (<6 hours) -0.11 [-3.39, 3.18] Heterogeneity: Chi² = 8.24, df = 4 (P = 0.08); I² = 51% Test for overall effect: Z = 0.06 (P = 0.95) -4.93 [-8.83, -1.02] Heterogeneity: Chi² = 21.61, df = 7 (P = 0.003); I² = 68% Test for overall effect: Z = 2.47 (P = 0.01) 2.4 HR (<6 hours) 4.35 [2.31, 6.40] Heterogeneity: Chi² = 2.33, df = 3 (P = 0.51); I² = 0% Test for overall effect: Z = 4.17 (P < 0.0001) 4.92 [2.77, 7.08] Heterogeneity: Chi² = 7.37, df = 7 (P = 0.39); I² = 5% Test for overall effect: Z = 4.48 (P < 0.00001) 116 Appendix G : Forest plots Figure G-1: Low dose of alcohol versus placebo, outcome: SBP 117 Figure G-2: Low dose of alcohol versus placebo, outcome: DBP Figure G-3: Low dose of alcohol versus placebo, outcome: MAP 118 Figure G-4: Low dose of alcohol versus placebo, outcome: HR 119 Figure G-5: Medium dose of alcohol versus placebo, outcome: SBP 120 Figure G-6: Medium dose of alcohol versus placebo, outcome DBP 121 Figure G-7: Medium dose of alcohol versus placebo, outcome MAP 122 Figure G-8: Medium dose of alcohol versus placebo, outcomes HR 123 Figure G-9: High dose of alcohol versus placebo, outcomes SBP 124 Figure G-10: High dose of alcohol versus placebo, outcome DBP 125 Figure G-11: High dose of alcohol versus placebo, outcome MAP 126 Figure G-12: High dose of alcohol versus placebo, outcome HR 127 Appendix H : Additional table Table H-1: Comparison between older participants and younger participants Analysis Older participants (mean age >50), Mean difference, IV, Fixed effect model, 95% CI Younger participants (mean age <50), Mean difference, IV, Fixed effect model, 95% CI 2.1 SBP (<6 hours) -11.25 [-15.63, -6.87] Test for overall effect: Z = 5.04 (P < 0.00001); df = 3 (P = 0.03); I² = 66% -2.52 [-5.78, 0.74] Test for overall effect: Z = 1.52 (P = 0.13), df = 5 (P = 0.31); I² = 16% 2.2 DBP (<6 hours) -7.82 [-11.08, -4.57] Test for overall effect: Z = 4.71 (P < 0.00001); df = 3 (P = 0.008); I² = 74% -1.66 [-4.22, 0.89] Test for overall effect: Z = 1.28 (P = 0.20); df = 5 (P = 0.91); I² = 0% 3.1 SBP (<6 hours) -6.71 [-11.23, -2.18] Test for overall effect: Z = 2.91 (P = 0.004); df = 3 (P = 0.92); I² = 0% -3.04 [-4.87, -1.20]; Test for overall effect: Z = 3.24 (P = 0.001); df = 11 (P = 0.010); I² = 56% 3.2 DBP (<6 hours) -4.30 [-7.32, -1.27] Test for overall effect: Z = 2.78 (P = 0.005); df = 2 (P = 0.25); I² = 27% -1.67 [-3.33, -0.01] Test for overall effect: Z = 1.97 (P = 0.05); df = 10 (P = 0.13); I² = 34% 128 Table H-2: Comparison between very high dose of alcohol compared to lower high dose alcohol Outcomes Very high dose (≥60 g) Mean difference, IV, Fixed effect model, 95% CI Lower high dose (31-59) Mean difference, IV, Fixed effect model, 95% CI 3.1. SBP -5.12 [-7.32, -2.92] Test for overall effect: Z = 4.57 (P < 0.00001); df = 7 (P = 0.02); I² = 56% -1.20 [-3.90, 1.49] Test for overall effect: Z = 0.88 (P = 0.38); df = 7 (P = 0.47); I² = 0% 3.2. DBP -3.21 [-5.49, -0.92] Test for overall effect: Z = 2.75 (P = 0.006); df = 5 (P = 0.22); I² = 29% -1.65 [-3.53, 0.23] Test for overall effect: Z = 1.72 (P = 0.09); df = 7 (P = 0.10); I² = 41% 3.3. MAP 2.17 [-4.09, -0.25] Test for overall effect: Z = 2.21 (P = 0.03); df = 7 (P = 0.04); I²= 52% -0.47 [-2.83, 1.90] Test for overall effect: Z = 0.39 (P = 0.70); df = 8 (P = 0.63); I² = 0% 3.4. HR 5.43 [3.76, 7.11] Test for overall effect: Z = 6.35 (P < 0.00001); df = 9 (P = 0.76); I² = 0% 6.09 [3.67, 8.51] Test for overall effect: Z = 4.93 (P < 0.00001); df = 6 (P = 0.005); I² = 67%
Thesis/Dissertation
eng
Pharmacology and Therapeutics
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
Effect of alcohol on blood pressure : a systematic review and meta-analysis
Text