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Sex differences in the efficacy of anti-hypertensive treatment in preventing cardiovascular outcomes and reducing blood pressure: protocol for a systematic review and meta-analysis
ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2019-036128
Article Type: Protocol
Date Submitted by the 01-Dec-2019 Author:
Complete List of Authors: Gasbarrino, Karina; Research Institute of the McGill University Health Centre, Medicine Labos, Christopher; Queen Elizabeth Health Complex, Cardiology Mastropietro, Victoria; McGill University Health Centre, Medical Library Hales, Lindsay; McGill University Health Centre, Medical Library Khan, Nadia; The University of British Columbia, Medicine Rabi, Doreen; University of Calgary Cumming School of Medicine, Medicine Daskalopoulou, Stella; Research Institute of the McGill University Health Centre, Medicine http://bmjopen.bmj.com/ Hypertension < CARDIOLOGY, CLINICAL PHARMACOLOGY, Protocols & guidelines < HEALTH SERVICES ADMINISTRATION & MANAGEMENT, Keywords: Cardiology < INTERNAL MEDICINE, Vascular medicine < INTERNAL MEDICINE
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1 2 3 1 Sex differences in the efficacy of anti-hypertensive treatment in preventing cardiovascular 4 2 outcomes and reducing blood pressure: protocol for a systematic review and meta-analysis 5 6 3 1 2 3 3 4 7 4 Karina Gasbarrino, Christopher Labos, Victoria Mastropietro, Lindsay Hales, Nadia A. 8 5 Khan, 5Doreen M. Rabi, 1Stella S. Daskalopoulou 9 6 10 7 Author Affiliations 11 8 1Vascular Health Unit, Research Institute of McGill University Health Centre, Department of 12 9 Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada 13 2 14 10 Department of Cardiology, Queen Elizabeth Health Complex, Montreal, Quebec, Canada 15 11 3Medical Library, McGill University Health Centre, Montreal, Quebec, Canada 16 12 4Department of Medicine,For Center peer for Health review Evaluation and Outcomesonly Science, University of 17 13 British Columbia, Vancouver, British Columbia, Canada 18 14 5Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, 19 15 Alberta, Canada; O'Brien Institute for Public Health, University of Calgary, Calgary, Alberta, 20 21 16 Canada 22 17 23 18 Emails 24 19 Karina Gasbarrino [email protected] 25 20 Christopher Labos [email protected] 26 21 Victoria Mastropietro [email protected] 27 22 Lindsay Hales [email protected] 28 29 23 Nadia A. Khan [email protected] 30 24 Doreen M. Rabi [email protected] 31 25 Stella S. Daskalopoulou [email protected] 32 26 http://bmjopen.bmj.com/ 33 27 Corresponding Author 34 28 Stella S. Daskalopoulou, MD, PhD. Department of Medicine, Research Institute of the McGill 35 29 University Health Centre, Glen Site, 1001 Decarie Boulevard, EM1.2230, Montreal, Quebec, 36 37 30 Canada, H4A 3J1. 38 31 39 32 Word Count 40
33 2,547 words on September 26, 2021 by guest. Protected copyright. 41 34 42 35 43 44 36 45 37 46 38 47 39 48 40 49 41 50 42 51 52 43 53 44 54 45 55 46 56 57 58 59 1 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 18 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 47 Abstract 4 48 5 6 49 Introduction: Hypertension is a leading cause of mortality worldwide and its prevalence is 7 50 expected to rise over the next decade. Sex differences exist in the epidemiology and the 8 51 pathophysiology of hypertension. It is well-established that anti-hypertensive treatment can 9 52 significantly reduce the risk for stroke and other CVD events. However, it remains unclear 10 53 whether this effect is dependent on sex. In this protocol we outlined a systematic review and 11 54 meta-analysis to summarize the current evidence evaluating and comparing the effectiveness of 12 55 anti-hypertensive therapy in 1) reducing blood pressure and 2) preventing cardiovascular 13 14 56 morbidity and mortality outcomes specifically in men versus women. 15 57 16 58 Methods and analysis:For The followingpeer electronic review databases willonly be searched: MEDLINE, 17 59 Embase, The Cochrane Library, PubMed, CINAHL Plus, Web of Science, grey literature 18 60 (Google Scholar), and several trial registries. Search strategies will be designed to identify 19 61 human (18+) randomized (and non-randomized) controlled trials, prospective and retrospective 20 21 62 cohort studies, and case-control studies concerning ‘sex-specific differences associated with the 22 63 efficacy of anti-hypertensive treatment’. Two investigators will independently review each 23 64 article included in the final analysis. Primary outcomes investigated are cardiovascular morbidity 24 65 and mortality and systolic and diastolic blood pressure. Pooled analyses will be conducted using 25 66 fixed-effects (Mantel–Haenszel) or random-effects (DerSimonian–Laird) models. Publication 26 67 bias will be assessed by visual inspection of funnel plots and by Begg’s and Egger’s statistical 27 68 tests. Between-studies heterogeneity will be measured using the I2 test. Sources of heterogeneity 28 29 69 will be explored by sensitivity, subgroup, and meta-regression analyses. 30 70 31 71 Dissemination: This is the first meta-analysis that will directly compare the efficacy of an anti- 32 72 hypertensive treatment regimen between men and women. Findings will be shared through http://bmjopen.bmj.com/ 33 73 scientific conferences and societies, social media, and consumer advocacy groups. Results will 34 74 be used to inform the current guidelines for management of hypertension in men and women by 35 75 demonstrating the importance of implementing sex-specific recommendations. 36 76 37 77 Keywords: sex, hypertension, blood pressure, anti-hypertensive therapy, cardiovascular 38 39 78 morbidity, cardiovascular mortality 40 79 on September 26, 2021 by guest. Protected copyright. 41 80 42 81 43 82 44 83 45 84 46 47 85 48 86 49 87 50 88 51 89 52 90 53 54 91 55 92 56 93 57 58 59 2 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 18 BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 94 Article Summary – Strengths and limitations of this study 4 95 5 6 96 The first meta-analysis that will directly and comprehensively compare the efficacy of 7 97 anti-hypertensive treatment regimens between men and women 8 98 Limited to controlled clinical trials, cohort, and case-control studies performed in humans 9 99 There will be no restrictions on the class or dosage of anti-hypertensive medications used 10 100 No studies will be excluded based on the risk of bias assessment 11 12 101 Sources of heterogeneity will be explored by sensitivity and subgroup analyses 13 102 14 103 Abbreviations 15 104 CVD – cardiovascular disease 16 105 RR – risk ratio For peer review only 17 106 CI – confidence interval 18 19 107 RCT – randomized controlled trial 20 108 21 109 Introduction 22 110 Hypertension is a leading cause of mortality worldwide and its prevalence is expected to rise 23 1,2 111 over the next decade in both men and women . While it is estimated that 1.13 billion people 24 1 25 112 worldwide have hypertension, fewer than 1 in 5 people with hypertension are under control . A 26 113 strong relationship exists between hypertension and cardiovascular disease (CVD), whereby an 27 114 increase in blood pressure is associated with an increase in the risk of myocardial infarction, 28 stroke, and CVD-related mortality3,4. Specifically, a meta-analysis of individual data from 61 29 115 30 116 prospective studies reported that at the ages of 40-69 years, a 20 mmHg increase in systolic 31 117 blood pressure (or equivalently 10 mmHg increase in diastolic blood pressure) was associated 32 3 118 with a 2-fold increase in stroke and ischemic heart disease death rates . Therefore, improving http://bmjopen.bmj.com/ 33 hypertension control rates can considerably reduce the burden of CVD. A meta-analysis 34 119 35 120 combining data from 42 clinical trials demonstrated that anti-hypertensive therapy is highly 36 121 effective in preventing the occurrence of CVD morbidity and mortality; treatment of 37 hypertension was associated with a reduction in the risk of stroke (risk ratio [RR]: 0.68; 95% 38 122 39 123 confidence interval [CI]: 0.61-0.76), coronary heart disease (RR: 0.86; 95% CI: 0.80-0.93), 40 congestive heart failure (RR: 0.54; 95% CI: 0.45-0.66), and CVD mortality (RR: 0.84; 95% CI:
124 on September 26, 2021 by guest. Protected copyright. 5 41 125 0.78-0.90) compared with no drug treatment . 42 126 Studies indicate that sex differences exist in the relative contribution of cardiovascular 43 6 44 127 risk factors in women and men . Furthermore, the prevalence of hypertension differs between 7 45 128 men and women across the life-span . It is well-established that men are more likely to develop 8 46 129 hypertension at a younger age compared with premenopausal women . However, after 47 menopause women display a more rapid increase in the prevalence of hypertension relative to 48 130 49 131 men, such that after 60-65 years of age hypertension rates in women exceed those observed in 8,9 8 50 132 men . As a result, these older women have greater CVD burden than men of similar age . 51 10 133 Despite these sex disparities, hypertension is often poorly controlled in older women . 52 Although the bioavailability of cardiovascular drugs may differ by sex11, there exists no 53 134 54 135 sex-specific guidelines for hypertension management, as it remains unclear whether the effect of 8 55 136 anti-hypertensive treatment in reducing cardiovascular risk is dependent on sex . Many of the 56 57 58 59 3 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 18 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 early clinical trials that examined the efficacy of anti-hypertensive medication in blood pressure 4 137 5 138 control and cardiovascular outcomes, collected data in either men alone or combined results for 12 6 139 men and women . Since women were heavily under-represented in these trials, any sex-specific 7 140 analyses that were performed were severely underpowered. As a result, a systematic review that 8 summarized the results from these early trials concluded that the evidence on the efficacy of anti- 9 141 13 10 142 hypertensive treatment specifically in women is weak . Therefore, gaining better understanding 11 143 of how women respond to anti-hypertensive medication is a clinical priority. 12 144 Recognizing the importance of implementing sex-specific evidence into clinical practice 13 145 guidelines, in this protocol we outlined a systematic review and meta-analysis to summarize the 14 146 current evidence evaluating the effectiveness of anti-hypertensive therapy in 1) reducing blood 15 16 147 pressure and 2) preventingFor cardiovascular peer morbidityreview and mortality only outcomes for each sex 17 148 separately. Moreover, we aim to determine whether the treatment effect differs significantly 18 149 between women and men. 19 150 20 151 Methods and design 21 152 22 23 153 Registration: 24 154 This protocol was written in accordance with the “Preferred Reporting Items for Systematic 25 155 Review and Meta-Analysis Protocols (PRISMA-P)” guidelines14 (see check-list in Appendix 1). 26 156 Our systematic review and meta-analysis protocol will be registered with the International 27 157 Prospective Register of Systematic Reviews (PROSPERO) after feed-back and peer review. 28 158 29 159 Eligibility criteria: 30 31 160 Studies will be selected according to the criteria outlined below. 32 161 http://bmjopen.bmj.com/ 33 162 Study designs 34 163 We will include randomized controlled trials (RCTs), controlled (non-randomized) clinical trials, 35 164 prospective and retrospective comparative cohort studies, and case-control or nested case-control 36 165 studies performed in humans. Cross-sectional studies, case series, case reports, reviews, 37 166 commentaries, letters, editorials, conference abstracts, and unpublished data will be excluded. 38 39 167 All animal and in vitro studies will not be considered. 40 168 on September 26, 2021 by guest. Protected copyright. 41 169 Participants 42 170 We will include studies involving adult men and women (18 years or older) regardless of race or 43 171 ethnicity, with clinical indication for anti-hypertensive therapy. Other comorbid conditions, in 44 172 addition to hypertension (as diagnosed using established diagnostic criteria)15, will be allowed. 45 46 173 However, studies restricted to populations with unrelated conditions/diseases (e.g., cancer) will 47 174 not be considered. Studies that do not report and authors fail to provide data separately for men 48 175 and women will be excluded. 49 176 50 177 Interventions 51 178 The intervention will consist of anti-hypertensive medications, which are used for the 52 179 pharmacologic management of hypertension, as well as the prevention of its complications, such 53 54 180 as stroke and myocardial infarction. Several classes of anti-hypertensive regimens exist 55 181 including, diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, 56 182 calcium channel blockers, β-blockers, as first line medications, as well as α-blockers, α-2 57 58 59 4 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 18 BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 183 receptor agonists, combined α- and β-blockers, central agonists, peripheral adrenergic inhibitors, 4 184 and vasodilators16. There will be no restrictions on the class or dosage of anti-hypertensive 5 6 185 medications used. 7 186 8 187 Comparators 9 188 Several comparisons will be included: 10 189 1) Comparison of the efficacy of anti-hypertensive therapy in men versus women 11 190 2) Comparison of subjects treated with anti-hypertensive medication versus placebo (or an 12 13 191 active control) 14 192 3) Comparisons among different dosages and classes of anti-hypertensive medications. 15 193 4) Subgroup analyses will also be performed as stated below in section ‘data synthesis’. 16 194 For peer review only 17 195 Outcomes 18 196 Primary: cardiovascular (including cerebrovascular) morbidity and mortality, change in systolic 19 197 and diastolic blood pressure. 20 21 198 Secondary: all-cause mortality, drug adherence, adverse events. 22 199 Studies will be excluded if they do not report any of the primary outcomes. 23 200 24 201 Timing 25 202 There will be no restrictions by date of publication. 26 203 27 204 Setting 28 29 205 There will be no restrictions by type of setting. 30 206 31 207 Language 32 208 There will be no language restrictions. http://bmjopen.bmj.com/ 33 209 34 210 Information sources: 35 36 211 The following electronic bibliographic databases will be searched for relevant studies: 37 212 MEDLINE (via Ovid), EMBASE Classic + Embase (via Ovid), The Cochrane Central Register 38 213 of Controlled Trials (via The Cochrane Library), PubMed, CINAHL Plus (via EBSCO), Web of 39 214 Science (via Clarivate), and grey literature (Google Scholar). Additionally, the International 40
215 Clinical Trials Registry Platform Search Portal, the International Standard Randomized on September 26, 2021 by guest. Protected copyright. 41 216 Controlled Trial Number Registry, and ClinicalTrials.gov will be searched for ongoing or 42 217 recently completed trials. To ensure literature saturation, reference lists of eligible studies or of 43 44 218 relevant meta-analyses and reviews identified through the search will be hand-searched. 45 219 46 220 Search strategy: 47 221 Literature search strategies will be developed using medical subject headings and text words 48 222 related to ‘sex differences’, ‘anti-hypertensive medication’, and ‘blood pressure’. A search 49 223 strategy will be developed for MEDLINE, and the search terms will be adapted for use with the 50 224 other bibliographic databases. No date or language limits will be applied on the search. The 51 225 literature search will be limited to human subjects and adults ≥18 years of age. Conference 52 53 226 abstracts, commentaries, and letters will be excluded from the search. Search strategies will be 54 227 peer-reviewed by two librarians. A draft MEDLINE search strategy is included in Appendix 2. 55 228 56 229 57 58 59 5 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 18 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 230 Study records: 4 231 Data management 5 6 232 Literature search results will be uploaded to Rayyan, an Internet-based software program that 7 233 facilitates collaboration among reviewers during the screening process. Prior to uploading to the 8 234 software, duplicates will be removed. 9 235 10 236 Selection process 11 237 Firstly, two authors, KG and CL, will independently screen the titles and abstracts of studies 12 238 yielded by the search in order to identify potentially eligible records. They will be unaware of the 13 14 239 study’s authors’ names and journal title to avoid the introduction of a bias in the selection 15 240 process. Full text reports for all studies that appear to meet the inclusion criteria or where there is 16 241 any uncertainty willFor then be screenedpeer independently review by the same only authors (KG and CL) to select 17 242 studies for final inclusion. Disagreements at all stages of the selection process will be resolved 18 243 through consensus with the corresponding author (SSD). We will contact study authors via email 19 244 for additional information where necessary to resolve questions concerning the eligibility of the 20 21 245 proposed study. If authors do not respond within four weeks of initial contact, a follow-up email 22 246 will be sent. If authors do not respond after four weeks of the second contact, the study will not 23 247 be considered in the analysis. 24 248 25 249 Data collection process 26 250 Data extraction will be performed independently by KG and CL. Data will be preferentially 27 251 extracted from result tables in the selected articles. If the data are not listed in the tables, the text 28 29 252 in the results section will be carefully read for any important information. If the data are only 30 253 available from graphs, the data will be extracted manually using the Image J® software version 31 254 1.47t (ImageJ, US National Institutes of Health, Bethesda, MD, http://imagej.nih.gov/ij/, 1997– 32 255 2015). Extracted data will include study and population characteristics, details on blood pressure, http://bmjopen.bmj.com/ 33 256 intervention details, and patient outcomes of interest. Authors will be contacted in case further 34 257 information and clarifications are needed using the same strategy as mentioned previously. 35 258 36 37 259 Data items 38 260 Data items that will be extracted from each included article are presented in Table 1. 39 261 40
Table 1. Data items to be extracted from each included article on September 26, 2021 by guest. Protected copyright. 41 Data Item Details to be extracted 42 Study characteristics complete author list, publication year, journal, funding source, 43 44 geographical location of study, study design, randomization 45 method if applicable, total number of subjects per group 46 Patient characteristics average age, sex distribution, average body mass index, type of 47 hypertension, duration of hypertension, average systolic and 48 diastolic blood pressure at baseline, list of other comorbidities 49 Intervention generic name of anti-hypertensive medication, type of control 50 51 used, dosage, frequency and duration of treatment, delivery 52 method 53 Results duration of follow-up, achieved systolic and diastolic blood 54 pressure, cardiovascular (and cerebrovascular) morbidity and 55 mortality, all-cause mortality, drug compliance, adverse effects 56 57 58 59 6 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 18 BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 262 Outcomes and prioritization 4 263 To be included, study outcomes have to be available according to sex. For primary outcomes, 5 6 264 data involving the change in systolic and diastolic blood pressure (in mmHg) between baseline 7 265 and follow-up will be extracted, as well as effect estimates for cardiovascular (and 8 266 cerebrovascular) morbidity and mortality, including fatal and/or non-fatal myocardial infarction, 9 267 fatal and/or non-fatal stroke, fatal and/or non-fatal heart failure (including hospitalizations), 10 268 major adverse cardiac events and cardiovascular death. Effect estimates for all-cause mortality 11 269 will be extracted as a secondary outcome, along with drug compliance (in %) and the number of 12 270 subjects experiencing at least one side-effect (including but not limited to, allergic reaction/ 13 14 271 angioedema/ skin rash, electrolyte disturbances, cough, peripheral edema, diarrhea or 15 272 constipation, nausea or vomiting, skin rash, agitation or anxiety, insomnia, palpitations). 16 273 For peer review only 17 274 Risk of bias in individual studies 18 275 Risk of bias assessment for randomized controlled trials will be performed using the modified 19 276 Cochrane Risk of Bias tool. Judgements, expressed as high, low, or unclear risk, will be made 20 21 277 independently by two authors, KG and CL, based on the criteria for judging the risk of bias. 22 278 Disagreements will be resolved first by discussion and then by consulting a third author (SSD) 23 279 for arbitration. For cohort and case-control studies risk of bias assessment will be performed 24 280 using the 9-item Newcastle-Ottawa Quality Assessment Scale. Three parameters will be 25 281 evaluated: (1) population selection, (2) comparability of results, and (3) ascertainment of 26 282 exposure or outcome. Similarly, two independent reviewers, KG and CL, will perform each 27 283 quality assessment, consulting a third reviewer (SSD) when necessary. Studies will be 28 29 284 considered of high quality if the total score is ≥7/9. No studies will be excluded based on the risk 30 285 of bias assessment. 31 286 32 287 Data analysis: http://bmjopen.bmj.com/ 33 288 34 289 Synthesis 35 290 Meta-analyses will be conducted separately for men and women to evaluate the effect of anti- 36 37 291 hypertensive therapy on 1) blood pressure and 2) cardiovascular morbidity and mortality 38 292 outcomes. Pooled analyses will be conducted using fixed-effects (Mantel–Haenszel) or random- 39 293 effects (DerSimonian–Laird) models and considered significant at P< 0.05. Data concerning 40
294 systolic and diastolic blood pressure will be expressed as mean differences (with 95% CIs). Data on September 26, 2021 by guest. Protected copyright. 41 295 concerning each cardiovascular morbidity and mortality outcome will be expressed as summary 42 296 RR with 95% CIs. Numbers needed to treat (NNT) estimates, which is the number of patients 43 44 297 who must be treated to prevent one adverse outcome, will be calculated. Between-studies 2 45 298 heterogeneity will be measured using the I test. The Mantel-Haenszel method will be used for 46 299 the fixed effect model if tests of heterogeneity are not significant. In case of statistically 47 300 significant between-studies heterogeneity, the DerSimonian-Laird random-effects model will be 48 301 applied. 49 302 50 303 Sources of heterogeneity will be explored by sensitivity and subgroup analyses, stratifying 51 52 304 studies by various factors, including study design, risk of bias, follow-up duration, age (e.g., 53 305 younger vs older women, younger vs older men, younger women vs younger men, older women 54 306 vs older men), ethnicity/race, type of hypertension, class of anti-hypertensive therapy, and 55 307 treatment dosage. Meta-regression analyses will also be performed to assess the effect of 56 57 58 59 7 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 18 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 308 confounding variables (i.e., body mass index, smoking status, cholesterol levels, history of prior 4 309 CVD, type 2 diabetes mellitus, chronic kidney disease). 5 6 310 7 311 All statistical analyses for meta-analysis will be performed using STATA Software, version 13.0 8 312 (STATA Corporation, College Station, TX, USA). 9 313 10 314 Meta-bias(es) 11 315 Publication bias will be assessed by visual inspection of funnel plots and by Begg’s and Egger’s 12 316 statistical tests, if at least 9 studies are available. P< 0.05 will be considered evidence of small 13 14 317 study effects. In order to determine whether outcome reporting bias is present, we will evaluate 15 318 whether the protocol of the RCT was published before recruitment of patients of the study was 16 319 started. Moreover, weFor will compare peer outcomes review reported in the onlyprotocol and the published report. 17 320 18 321 Confidence in cumulative estimate 19 322 The quality of evidence for all outcomes will be judged using the Grading of Recommendations 20 17 21 323 Assessment, Development and Evaluation (GRADE) Working Group criteria . 22 324 23 325 Discussion 24 326 Hypertension is a major risk factor for CVD, placing it as the most common cause of death 1,2 25 327 world-wide . Overwhelming evidence indicates that sex differences exist in the epidemiology 26 18 27 328 and the pathophysiology of hypertension . Specifically, premenopausal women have lower 28 329 incidence and severity of hypertension, and thus a lower incidence of CVD, than age-matched 8,9 29 330 men . However, this cardio-protection is compromised post-menopause, where the risk of 30 8,9 31 331 hypertension increases sharply in women . 32 332 We expect that this sexual dimorphism may also extend to the treatment efficacy of anti- http://bmjopen.bmj.com/ 33 333 hypertensive medication. It is well-established that anti-hypertensive treatment can significantly 34 5 35 334 reduce the risk for stroke and other CVD events . However, it remains unclear whether this 36 335 effect is dependent on sex. Moreover, it is not established whether different classes of anti- 37 336 hypertensive drugs routinely used in clinical practice work similarly in men and women. 38 337 Currently, hypertension guidelines do not report sex-specific recommendations. Evaluation of 39 338 these differences is required to ensure the best possible care for both men and women living with 40 339 hypertension. Thus, herein, we provide a protocol of a systematic review and meta-analysis that on September 26, 2021 by guest. Protected copyright. 41 340 summarizes the current evidence evaluating sex differences in the efficacy of anti-hypertensive 42 43 341 treatment in reducing CVD outcomes and blood pressure. To our knowledge, this is the first 44 342 meta-analysis that will directly and comprehensively compare the efficacy of anti-hypertensive 45 343 treatment regimens between men and women. 46 344 We will share the findings of these meta-analyses through scientific conferences and 47 345 societies, social media, and consumer advocacy groups. Importantly, the results will be used to 48 346 inform the current guidelines for management of hypertension in men and women by 49 347 demonstrating the importance of implementing sex-specific recommendations. It may determine 50 51 348 which classes of anti-hypertensive medications may be more effective in men and in women. 52 349 Treatment strategies for hypertension and CVD that are tailored according to sex could lead to 53 350 improved outcomes for the affected individuals. 54 351 55 352 56 57 58 59 8 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 18 BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 353 Acknowledgements 4 354 Not applicable 5 6 355 7 356 Funding 8 357 This protocol is supported by Hypertension Canada. SS Daskalopoulou is a Senior Chercheur- 9 358 Boursier Clinicien supported by the Fonds de recherche du Québec – Santé. NK is funded by a 10 359 Michael Smith Foundation in Health Research Career Scientist Award. 11 360 12 361 Availability of Data and Materials 13 14 362 The datasets used and/or analyzed during the current study are available from the corresponding 15 363 author on reasonable request. 16 364 For peer review only 17 365 Author Contributions 18 366 SSD is the guarantor. KG and SSD designed the research. KG drafted the manuscript. KG, CL, 19 367 and SSD contributed to the development of the inclusion/exclusion search criteria, data 20 21 368 extraction criteria, and statistical analysis methods. VM and LH led the development of the 22 369 search strategy. NAK and DMR critically revised the protocol. All authors read, provided 23 370 feedback and approved the final protocol. 24 371 25 372 Ethics Approval and Consent to Participate 26 373 Not applicable 27 374 28 29 375 Patient and Public Involvement 30 376 Patients or the public were not involved in the design, or conduct, or reporting, or dissemination 31 377 plans of our research 32 378 http://bmjopen.bmj.com/ 33 379 Competing Interests 34 380 The authors declare that they have no competing interests. 35 381 36 37 382 38 383 39 384 40
385 on September 26, 2021 by guest. Protected copyright. 41 386 42 43 387 44 388 45 389 46 390 47 391 48 392 49 393 50 51 394 52 395 53 396 54 397 55 398 56 57 58 59 9 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 18 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 399 4 400 References: 5 6 401 7 402 1. World Health Organization. Hypertension. 2019; https://www.who.int/news-room/fact- 8 403 sheets/detail/hypertension 9 404 2. Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S, Murray CJ. Selected major risk 10 405 factors and global and regional burden of disease. Lancet (London, England). 11 406 2002;360:1347-1360 12 407 3. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual 13 14 408 blood pressure to vascular mortality: A meta-analysis of individual data for one million 15 409 adults in 61 prospective studies. Lancet (London, England). 2002;360:1903-1913 16 410 4. MacMahon S,For Peto R, peer Cutler J, Collins review R, Sorlie P, Neaton only J, et al. Blood pressure, 17 411 stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: 18 412 Prospective observational studies corrected for the regression dilution bias. Lancet 19 413 (London, England). 1990;335:765-774 20 21 414 5. Psaty BM, Lumley T, Furberg CD, Schellenbaum G, Pahor M, Alderman MH, et al. 22 415 Health outcomes associated with various antihypertensive therapies used as first-line 23 416 agents: A network meta-analysis. Jama. 2003;289:2534-2544 24 417 6. Vitale C, Mendelsohn ME, Rosano GM. Gender differences in the cardiovascular effect 25 418 of sex hormones. Nature reviews. Cardiology. 2009;6:532-542 26 419 7. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart 27 420 disease and stroke statistics-2016 update: A report from the american heart association. 28 29 421 Circulation. 2016;133:e38-360 30 422 8. Beth L. Abramson KS, Leslie L. Davis, Biljana Parapid. Women and hypertension: 31 423 Beyond the 2017 guideline for prevention, detection, evaluation, and management of high 32 424 blood pressure in adults. 2018 http://bmjopen.bmj.com/ 33 425 9. Wenger NK, Arnold A, Bairey Merz CN, Cooper-DeHoff RM, Ferdinand KC, Fleg JL, et 34 426 al. Hypertension across a woman's life cycle. Journal of the American College of 35 427 Cardiology. 2018;71:1797-1813 36 37 428 10. Lloyd-Jones DM, Evans JC, Levy D. Hypertension in adults across the age spectrum: 38 429 Current outcomes and control in the community. Jama. 2005;294:466-472 39 430 11. Luzier AB, Killian A, Wilton JH, Wilson MF, Forrest A, Kazierad DJ. Gender-related 40
431 effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. on September 26, 2021 by guest. Protected copyright. 41 432 Clinical pharmacology and therapeutics. 1999;66:594-601 42 433 12. Garcia M, Mulvagh SL, Merz CN, Buring JE, Manson JE. Cardiovascular disease in 43 44 434 women: Clinical perspectives. Circulation research. 2016;118:1273-1293 45 435 13. Ljungman C, Mortensen L, Kahan T, Manhem K. Treatment of mild to moderate 46 436 hypertension by gender perspective: A systematic review. Journal of women's health. 47 437 2009;18:1049-1062 48 438 14. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred 49 439 reporting items for systematic review and meta-analysis protocols (prisma-p) 2015: 50 440 Elaboration and explanation. BMJ (Clinical research ed.). 2015;350:g7647 51 52 441 15. Nerenberg KA, Zarnke KB, Leung AA, Dasgupta K, Butalia S, McBrien K, et al. 53 442 Hypertension canada's 2018 guidelines for diagnosis, risk assessment, prevention, and 54 443 treatment of hypertension in adults and children. The Canadian journal of cardiology. 55 444 2018;34:506-525 56 57 58 59 10 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 18 BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 445 16. American Heart Association. Types of blood pressure medications. 2017; 4 446 https://www.heart.org/en/health-topics/high-blood-pressure/changes-you-can-make-to- 5 6 447 manage-high-blood-pressure/types-of-blood-pressure-medications 7 448 17. Grade home. http://www.gradeworkinggroup.org 8 449 18. Regitz-Zagrosek V, Kararigas G. Mechanistic pathways of sex differences in 9 450 cardiovascular disease. Physiological reviews. 2017;97:1-37 10 451 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39 40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 11 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
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1 1 2 3 PRISMA-P 2015 Checklist 4 5 6 This checklist has been adapted for use with systematic review protocol submissions to BioMed Central journals from Table 3 in Moher D et al: 7 8 Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Systematic Reviews 2015 4:1 9 10 An Editorial from the Editors-in-Chief of Systematic Reviews details why this checklist was adapted - Moher D, Stewart L & Shekelle P: 11 12 Implementing PRISMA-P: recommendationsFor for prospective peer authors. review Systematic Reviews 2016only 5:15 13 14 Information reported Line Section/topic # Checklist item 15 Yes No number(s)
16 http://bmjopen.bmj.com/ ADMINISTRATIVE INFORMATION 17 18 Title 19 Identification 1a Identify the report as a protocol of a systematic review 2 20 Update 1b If the protocol is for an update of a previous systematic review, identify as such N/A 21 If registered, provide the name of the registry (e.g., PROSPERO) and registration number in the 22 Registration 2 Abstract 23 Authors 24 on September 26, 2021 by guest. Protected copyright. Provide name, institutional affiliation, and e-mail address of all protocol authors; provide physical 4-30 25 Contact 3a 26 mailing address of corresponding author 27 Contributions 3b Describe contributions of protocol authors and identify the guarantor of the review 365-370 28 If the protocol represents an amendment of a previously completed or published protocol, identify Amendments 4 29 as such and list changes; otherwise, state plan for documenting important protocol amendments 30 Support 31 32 Sources 5a Indicate sources of financial or other support for the review 356-359 33 Sponsor 5b Provide name for the review funder and/or sponsor N/A 34 Role of N/A 5c Describe roles of funder(s), sponsor(s), and/or institution(s), if any, in developing the protocol 35 sponsor/funder 36 INTRODUCTION 37 38 Rationale 6 Describe the rationale for the review in the context of what is already known 109-143 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
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2 1 2 Information reported Line 3 Section/topic # Checklist item 4 Yes No number(s) 5 Provide an explicit statement of the question(s) the review will address with reference to 144-149 6 participants, interventions, comparators, and outcomes (PICO) Objectives 7 7 8 9 METHODS 10 Specify the study characteristics (e.g., PICO, study design, setting, time frame) and report 159-208 11 Eligibility criteria 8 characteristics (e.g., years considered, language, publication status) to be used as criteria for 12 eligibility for theFor review peer review only 13 Describe all intended information sources (e.g., electronic databases, contact with study authors, 210-218 Information sources 9 14 trial registers, or other grey literature sources) with planned dates of coverage 15 Present draft of search strategy to be used for at least one electronic database, including planned 220-227 16 Search strategy 10 http://bmjopen.bmj.com/ limits, such that it could be repeated 17 18 STUDY RECORDS 19 Data management 11a Describe the mechanism(s) that will be used to manage records and data throughout the review 231-234 20 State the process that will be used for selecting studies (e.g., two independent reviewers) through 236-247 Selection process 11b 21 each phase of the review (i.e., screening, eligibility, and inclusion in meta-analysis) 22 Describe planned method of extracting data from reports (e.g., piloting forms, done independently, 249-257 Data collection process 11c 23 in duplicate), any processes for obtaining and confirming data from investigators 24 List and define all variables for which data will be sought (e.g., PICO items, funding sources), on September 26, 2021 by guest. Protected copyright. any 259-261 Data items 12 25 pre-planned data assumptions and simplifications 26 Outcomes and List and define all outcomes for which data will be sought, including prioritization of main and 262-272 27 13 prioritization additional outcomes, with rationale 28 Describe anticipated methods for assessing risk of bias of individual studies, including whether this 274-285 29 Risk of bias in 14 will be done at the outcome or study level, or both; state how this information will be used in data 30 individual studies synthesis 31 32 DATA 33 15a Describe criteria under which study data will be quantitatively synthesized 289-292 34 If data are appropriate for quantitative synthesis, describe planned summary measures, methods 292-301 35 15b of handling data, and methods of combining data from studies, including any planned exploration 36 Synthesis of consistency (e.g., I 2, Kendall’s tau) 37 Describe any proposed additional analyses (e.g., sensitivity or subgroup analyses, meta- 303-309 15c 38 regression) 39 15d If quantitative synthesis is not appropriate, describe the type of summary planned N/A 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
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3 1 2 Information reported Line 3 Section/topic # Checklist item 4 Yes No number(s) 5 Specify any planned assessment of meta-bias(es) (e.g., publication bias across studies, selective 314-319 Meta-bias(es) 16 6 reporting within studies) 7 Confidence in 321-323 17 Describe how the strength of the body of evidence will be assessed (e.g., GRADE) 8 cumulative evidence 9 10 11 12 For peer review only 13 14 15
16 http://bmjopen.bmj.com/ 17 18 19 20 21 22 23
24 on September 26, 2021 by guest. Protected copyright. 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 16 of 18 BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations 4 and Daily <1946 to September 16, 2019> 5 6 # Searches Results 7 1 exp Hypertension/ 247434 8 9 2 hypertens*.tw,kf. 420857 10 3 ((high* or elevat* or greater* or control*) adj4 (blood or systolic or diastolic) adj4 68657 11 pressure*).tw,kf. 12 13 4 1 or 2 or 3 501365 14 5 Sex Characteristics/ 52287 15 16 6 Sex/ For peer review only 7632 17 7 Sex ratio/ 9049 18 19 8 Sex Factors/ 254781 20 9 ((sex* or gender* or man or men or male* or woman or women or female*) adj3 (difference* 336361 21 or different or characteristic* or ratio* or factor* or imbalanc* or issue* or specific* or 22 disparit* or dependen* or dimorphism* or gap or gaps or influenc* or discrepan* or distribut* 23 or composition*)).tw,kf. 24 25 10 or/5-9 559186 26 11 4 and 10 24653 27 28 12 exp Antihypertensive Agents/ 254343 29 13 (antihypertensiv* or anti-hypertensiv* or ((anti?hyperten* or anti-hyperten*) adj5 (therap* or 52111 30 treat* or effective*))).tw,kf. 31 32 14 Calcium Channel Blockers/ 36287 http://bmjopen.bmj.com/ 33 15 (calcium adj2 (channel* or exogenous*) adj2 (block* or inhibitor* or antagonist*)).tw,kf. 20534 34 35 16 (agatoxin or amlodipine or anipamil or aranidipine or atagabalin or azelnidipine or 86627 36 azidodiltiazem or azidopamil or azidopine or belfosdil or benidipine or bepridil or 37 brinazarone or calciseptine or caroverine or cilnidipine or clentiazem or clevidipine or 38 columbianadin or conotoxin or cronidipine or darodipine or deacetyl n nordiltiazem or 39 deacetyl n o dinordiltiazem or deacetyl o nordiltiazem or deacetyldiltiazem or 40 dealkylnorverapamil or dealkylverapamil or deutolperisone or devapamil or dexniguldipine or on September 26, 2021 by guest. Protected copyright. 41 dexverapamil or diclofurime or diltiazem or diperdipine or diproteverine or dopropidil or 42 dotarizine or efonidipine or elgodipine or elnadipine or emopamil or enecadin or eperisone or 43 etripamil or falipamil or fantofarone or fasudil or felodipine or fendiline or flordipine or 44 flosatidil or fluspirilene or fostedil or furnidipine or gabapentin or gallopamil or iganidipine 45 or isoperisone or isradipine or lacidipine or lemildipine or lercanidipine or lifarizine or 46 lomerizine or manidipine or mepamil or mepirodipine or mesudipine or meta nisoldipine or 47 mibefradil or mirogabalin or modipafant or monatepil or n methylbepridil or n nordiltiazem or 48 naltiazem or nexopamil or nicardipine or nifedipine or niguldipine or niludipine or 49 nilvadipine or nimodipine or nisoldipine or nitrendipine or norgallopamil or norverapamil or 50 olradipine or omega agatoxin or omega conotoxin or oxodipine or palonidipine or perhexiline 51 or pimozide or pinokalant or pontuc or pranidipine or pregabalin or riodipine or ronipamil or 52 sagandipine or semotiadil or silperisone or siratiazem or tamolarizine or teludipine or 53 54 temiverine or terodiline or tolperisone or trelnarizine or verapamil or watanidipine or 55 xestospongin C or zonisamide).nm,tw,kf. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 18 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 17 Calcium/ 263148 4 5 18 limit 17 to yr="1966-1967" 2861 6 19 Calcium/ai 1873 7 8 20 limit 19 to yr="1968-1981" 707 9 21 Ion Channels/ 34899 10 11 22 limit 21 to yr="1979-1981" 1461 12 23 exp Angiotensin-Converting Enzyme Inhibitors/ 42827 13 14 24 (("Angiotensin-Converting Enzyme" or ACE) adj5 (inhibit* or antagoni*)).tw,kf. 37120 15 25 ("kininase ii" adj2 (antagoni* or inhibit*)).tw,kf,nm. 150 16 For peer review only 17 26 (alacepril or altiopril or ancovenin or benazepril or benazeprilat or captopril or ceranapril or 30970 18 cilazapril or cilazaprilat or deacetylalacepril or delapril or enalapril or enalaprilat or 19 epicaptopril or fasidotril or fasidotrilat or foroxymithine or fosinopril or fosinoprilat or 20 gemopatrilat or idrapril or ilepatril or imidapril or imidaprilat or indolapril or libenzapril or 21 lisinopril or moexipril or moexiprilat or omapatrilat or pentopril or pentoprilat or perindopril 22 or perindoprilat or pivopril or quinapril or quinaprilat or ramipril or ramiprilat or rentiapril or 23 s nitrosocaptopril or sampatrilat or spirapril or spiraprilat or temocapril or temocaprilat or 24 teprotide or trandolapril or trandolaprilat or utibapril or utibaprilat or vasopeptidase inhibitor 25 or zabicipril or zabiciprilat or zofenopril or zofenoprilat).nm,tw,kf. 26 27 27 Enzyme Inhibitors/ 129341 28 28 limit 27 to yr="1975-1987" 1738 29 30 29 exp Angiotensin Receptor Antagonists/ 22877 31 30 (angiotensin adj2 receptor adj2 (blocker* or antagonist*)).tw,kf,nm. 17015 32 31 (abitesartan or azilsartan or candesartan or elisartan or embusartan or eprosartan or fimasartan 20235 http://bmjopen.bmj.com/ 33 34 or fonsartan or forasartan or irbesartan or losartan or milfasartan or olmesartan or olodanrigan 35 or pomisartan or pratosartan or ripisartan or saprisartan or sartan derivative or sparsentan or 36 tasosartan or telmisartan or valsartan or zolasartan or irbesarten).nm,tw,kf. 37 32 Angiotensin II Type 1 Receptor Blockers/ 8428 38 39 33 limit 32 to yr="2004-2010" 5146 40 34 beta-blocker*.tw,kf,nm. 29516 on September 26, 2021 by guest. Protected copyright. 41 35 (adaprolol or afurolol or alprenolol or alprenolol derivative or befunolol or beta 1 adrenergic 72506 42 43 receptor blocking agent or beta 2 adrenergic receptor blocking agent or beta 3 adrenergic 44 receptor blocking agent or bfe 55 or bopindolol or bornaprolol or 45 bromoacetylalprenololmenthane or bucindolol or bucumolol or bufetolol or bufuralol or 46 bunitrolol or bunolol or bupranolol or butofilolol or carazolol or carpindolol or carteolol or 47 carvedilol or cloranolol or deacetylmetipranolol or dexpropranolol or diacetolol or 48 dichlorisoprenaline or dihydroalprenolol or dilevalol or diprafenone or ersentilide or 49 exaprolol or falintolol or falintolol oxalate or flestolol or hydroxybenzylpindolol or indenolol 50 or iodopindolol or iprocrolol or isamoltane or isoxaprolol or labetalol or levobunolol or 51 levomoprolol or mepindolol or mercuderamide or metipranolol or moprolol or nadolol or 52 nifenalol or oberadilol or oxprenolol or pafenolol or pamatolol or penbutolol or pindolol* or 53 primidolol or prizidilol or procinolol or pronetalol or propranolol or proxodolol or ridazolol or 54 soquinolol or soquinolol mucate or sotalol or spirendolol or tazolol or tertatolol or tienoxolol 55 or tilisolol or timolol or tolamolol or toliprolol or trasitensin or trepress or tribendilol or 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 18 BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 viskaldix or xibenolol or zoleprodolol or acebutolol or atenolol or betaxolol or bisoprolol 4 fumarate or carteolol hydrochloride or metoprolol tartrate or metoprolol succinate or 5 6 penbutolol sulfate or solotol hydrochloride).nm,tw,kf. 7 36 exp Diuretics/ 78470 8 37 diuretic*.tw,kf. 38785 9 10 38 Furosemide/ 11727 11 39 (furosemide or frusemide or fursemide or frusemid or fusid or lasix or errolon or furanthril or 16850 12 furantral).nm,tw,kf. 13 14 40 (acetazolamide or alilusem or amisometradine or ammonium acetate or bemitradine or 61739 15 besulpamide or brocrinat or chlormerodrin or diclofenamide or epinine or ethoxzolamide or 16 fenquizone or ibopamineFor or indapamidepeer or meralluridereview or mercaptomerin only or mercumatilin or 17 merethoxylline or mersalyl or methazolamide or meticrane or niravoline or osmotic diuretic 18 agent or pamabrom or perhexiline or perhexiline maleate or sitalidone or skf 105494 or 19 theobromine or theophylline or tiamizide or tienilic acid or tienoxolol or traxanox or triniton 20 or tripamide or viskaldix or chlorthalidone or chlorothiazide or hydrochlorothiazide or 21 metolazone or amiloride hydrochloride or triamterene or bumetanide or bisoprolol or 22 bendrofluazide).nm,tw,kf. 23 24 41 exp Mineralocorticoid Receptor Antagonists/ 9160 25 42 (antialdosteron* or anti aldosterone* or spironolacton* or eplerenon* or canreno* or 12684 26 ((aldosterone* or mineralocorticoid*) adj3 antagonist*)).tw,kf,nm. 27 28 43 (trilostane or apararenone or canrenoate potassium or canrenoic acid or canrenone or 9903 29 canrenone derivative or eplerenone or esaxerenone or finerenone or mespirenone or 30 mexrenoate potassium or mexrenoic acid or mexrenone or oxprenoate potassium or 31 spironolactone or spiroxasone).nm,tw,kf. 32 44 Aldosterone/ 23836 http://bmjopen.bmj.com/ 33 34 45 limit 44 to yr="1966-1977" 4553 35 46 alpha?blocker*.tw,kf,nm. 32 36 37 47 (doxazosin mesylate or prazosin hydrochloride or terazosin hydrochloride).tw,kf. 208 38 48 Methyldopa.tw,kf,nm. 4633 39 40 49 Central agonist*.tw,kf,nm. 14 on September 26, 2021 by guest. Protected copyright. 41 50 (alpha methyldopa or clonidine hydrochloride or guanabenz acetate or guanfacine 1228 42 hydrochloride).tw,kf. 43 44 51 (Peripheral adj2 adrenergic adj2 inhibitor*).tw,kf. 1 45 52 (guanadrel or guanethidine monosulfate or reserpine).nm,tw,kf. 18266 46 47 53 (blood vessel dilator* or vasodilator*).tw,kf,nm. 68457 48 54 (hydralazine hydrochloride or minoxidil).tw,kf,nm. 2200 49 50 55 12 or 13 or 14 or 15 or 16 or 18 or 20 or 22 or 23 or 24 or 25 or 26 or 28 or 29 or 30 or 31 or 567100 51 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 45 or 46 or 47 or 48 or 49 or 52 50 or 51 or 52 or 53 or 54 53 56 11 and 55 3304 54 55 57 (Animals/ or Models, animal/ or Disease models, animal/) not Humans/ 4582726 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 18 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 58 ((animal or animals or canine* or cat or cats or dog or dogs or feline or hamster* or lamb or 2320147 4 lambs or mice or monkey or monkeys or mouse or murine or pig or pigs or piglet* or porcine 5 6 or primate* or rabbit* or rats or rat or rodent* or sheep* or veterinar*) not (human* or 7 patient*)).ti,kf,jw. 8 59 57 or 58 4970127 9 10 60 56 not 59 3117 11 61 (exp child/ or exp infant/ or adolescent/) not exp adult/ 1820849 12 62 (newborn* or new-born* or neonat* or neo-nat* or infan* or child* or adolesc* or paediatr* 1433304 13 14 or pediatr* or baby* or babies* or toddler* or kid or kids or boy* or girl* or juvenile* or 15 teen* or youth* or pubescen* or preadolesc* or prepubesc* or preteen or tween).ti. 16 63 (pediatr* or paediatr*).jw.For peer review only 551915 17 18 64 61 or 62 or 63 2368164 19 65 60 not 62 3045 20 66 limit 65 to (comment or editorial or letter) 35 21 22 67 65 not 66 3010 23 68 remove duplicates from 67 3006 24 25 26 27 28 29 30 31 32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39 40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
Sex differences in the efficacy of anti-hypertensive treatment in preventing cardiovascular outcomes and reducing blood pressure: protocol for a systematic review and meta-analysis
ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2019-036128.R1
Article Type: Protocol
Date Submitted by the 23-Jan-2020 Author:
Complete List of Authors: Gasbarrino, Karina; Research Institute of the McGill University Health Centre, Medicine Labos, Christopher; Queen Elizabeth Health Complex, Cardiology Mastropietro, Victoria; McGill University Health Centre, Medical Library Hales, Lindsay; McGill University Health Centre, Medical Library Khan, Nadia; The University of British Columbia, Medicine Rabi, Doreen; University of Calgary Cumming School of Medicine, Medicine Daskalopoulou, Stella; Research Institute of the McGill University Health Centre, Medicine http://bmjopen.bmj.com/ Primary Subject Cardiovascular medicine Heading:
Secondary Subject Heading: Pharmacology and therapeutics
Hypertension < CARDIOLOGY, CLINICAL PHARMACOLOGY, Protocols & guidelines < HEALTH SERVICES ADMINISTRATION & MANAGEMENT, Keywords: Cardiology < INTERNAL MEDICINE, Vascular medicine < INTERNAL MEDICINE on September 26, 2021 by guest. Protected copyright.
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1 2 3 1 Sex differences in the efficacy of anti-hypertensive treatment in preventing cardiovascular 4 2 outcomes and reducing blood pressure: protocol for a systematic review and meta-analysis 5 6 3 1 2 3 3 4 7 4 Karina Gasbarrino, Christopher Labos, Victoria Mastropietro, Lindsay Hales, Nadia A. 8 5 Khan, 5Doreen M. Rabi, 1Stella S. Daskalopoulou 9 6 10 7 Author Affiliations 11 8 1Vascular Health Unit, Research Institute of McGill University Health Centre, Department of 12 9 Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada 13 2 14 10 Department of Cardiology, Queen Elizabeth Health Complex, Montreal, Quebec, Canada 15 11 3Medical Library, McGill University Health Centre, Montreal, Quebec, Canada 16 12 4Department of Medicine,For Center peer for Health review Evaluation and Outcomesonly Science, University of 17 13 British Columbia, Vancouver, British Columbia, Canada 18 14 5Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, 19 15 Alberta, Canada; O'Brien Institute for Public Health, University of Calgary, Calgary, Alberta, 20 21 16 Canada 22 17 23 18 Emails 24 19 Karina Gasbarrino [email protected] 25 20 Christopher Labos [email protected] 26 21 Victoria Mastropietro [email protected] 27 22 Lindsay Hales [email protected] 28 29 23 Nadia A. Khan [email protected] 30 24 Doreen M. Rabi [email protected] 31 25 Stella S. Daskalopoulou [email protected] 32 26 http://bmjopen.bmj.com/ 33 27 Corresponding Author 34 28 Stella S. Daskalopoulou, MD, PhD. Department of Medicine, Research Institute of the McGill 35 29 University Health Centre, Glen Site, 1001 Decarie Boulevard, EM1.2230, Montreal, Quebec, 36 37 30 Canada, H4A 3J1. 38 31 39 32 Word Count 40
33 2,764 words on September 26, 2021 by guest. Protected copyright. 41 34 42 35 43 44 36 45 37 46 38 47 39 48 40 49 41 50 42 51 52 43 53 44 54 45 55 46 56 57 58 59 1 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 18 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 47 Abstract 4 48 5 6 49 Introduction: Hypertension is a leading cause of mortality worldwide and its prevalence is 7 50 expected to rise over the next decade. Sex differences exist in the epidemiology and 8 51 pathophysiology of hypertension. It is well-established that anti-hypertensive treatment can 9 52 significantly reduce the risk for stroke and other CVD events. However, it remains unclear 10 53 whether this effect is dependent on sex. In this protocol we outlined a systematic review and 11 54 meta-analysis to evaluate the effects of anti-hypertensive therapy in 1) reducing blood pressure 12 55 and 2) preventing cardiovascular morbidity and mortality outcomes for each sex separately. 13 14 56 15 57 Methods and analysis: The following electronic databases will be searched: MEDLINE, 16 58 Embase, The CochraneFor Library, peer PubMed, CINAHLreview Plus, Web only of Science, grey literature 17 59 (Google Scholar), and several trial registries. Search strategies will be designed to identify 18 60 human adult (≥18) randomized (and non-randomized) controlled trials, prospective and 19 61 retrospective cohort studies, and case-control studies concerning ‘sex-specific differences 20 21 62 associated with the efficacy of anti-hypertensive treatment’. A preliminary search strategy was 22 63 developed for MEDLINE (1946 – September 16, 2019). Two investigators will independently 23 64 review each article included in the final analysis. Primary outcomes investigated are 24 65 cardiovascular morbidity and mortality and systolic and diastolic blood pressure. Pooled analyses 25 66 will be conducted using the random-effects model. Publication bias will be assessed by visual 26 67 inspection of funnel plots and by Begg’s and Egger’s statistical tests. Between-studies 27 68 heterogeneity will be measured using the I2 test (P<0.10). Sources of heterogeneity will be 28 29 69 explored by sensitivity, subgroup, and meta-regression analyses. 30 70 31 71 Ethics and dissemination: This is the first meta-analysis that will comprehensively compare the 32 72 efficacy of anti-hypertensive treatment regimens between men and women. Findings will be http://bmjopen.bmj.com/ 33 73 shared through scientific conferences and societies, social media, and consumer advocacy 34 74 groups. Results will be used to inform the current guidelines for management of hypertension in 35 75 men and women by demonstrating the importance of implementing sex-specific 36 76 recommendations. Ethical considerations are not applicable for this protocol. 37 77 38 39 78 Keywords: sex, hypertension, blood pressure, anti-hypertensive therapy, cardiovascular 40 79 morbidity, cardiovascular mortality on September 26, 2021 by guest. Protected copyright. 41 80 42 81 43 82 44 83 45 84 46 47 85 48 86 49 87 50 88 51 89 52 90 53 54 91 55 92 56 93 57 58 59 2 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 18 BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 94 Article Summary – Strengths and limitations of this study 4 95 5 6 96 The first meta-analysis that will comprehensively compare the efficacy of anti- 7 97 hypertensive treatment regimens between men and women 8 98 There will be no restrictions on the class or dosage of anti-hypertensive medications used 9 99 No studies will be excluded based on the risk of bias assessment and studies will be 10 100 analyzed separately based on study design 11 12 101 Sources of heterogeneity will be explored by sensitivity and subgroup analyses 13 102 An individual patient data meta-analysis will not be undertaken and is a limitation of our 14 103 study 15 104 16 105 Abbreviations For peer review only 17 106 CVD – cardiovascular disease 18 19 107 RR – risk ratio 20 108 CI – confidence interval 21 109 RCT – randomized controlled trial 22 110 23 111 Introduction 24 112 Hypertension is a leading cause of mortality worldwide and its prevalence is expected to rise 25 1,2 26 113 over the next decade in both men and women . While it is estimated that 1.13 billion people 1 27 114 worldwide have hypertension, fewer than 1 in 5 people with hypertension are under control . A 28 115 strong relationship exists between hypertension and cardiovascular disease (CVD), whereby an 29 increase in blood pressure is associated with an increase in the risk of myocardial infarction, 30 116 3,4 31 117 stroke, and CVD-related mortality . Specifically, a meta-analysis of individual data from 61 32 prospective studies reported that at the ages of 40-69 years, a 20 mmHg increase in systolic 118 http://bmjopen.bmj.com/ 33 119 blood pressure (or equivalently 10 mmHg increase in diastolic blood pressure) was associated 34 with a 2-fold increase in stroke and ischemic heart disease death rates3. Therefore, improving 35 120 36 121 hypertension control rates can considerably reduce the burden of CVD. A meta-analysis 37 122 combining data from 123 large-scale blood pressure lowering trials demonstrated that anti- 38 hypertensive therapy is highly effective in preventing the occurrence of CVD morbidity and 39 123 40 124 mortality; treatment of hypertension was associated with a reduction in the risk of stroke (risk on September 26, 2021 by guest. Protected copyright. 41 125 ratio [RR]: 0.73; 95% confidence interval [CI]: 0.68-0.77), coronary heart disease (RR: 0.83; 42 126 95% CI: 0.78-0.88), heart failure (RR: 0.72; 95% CI: 0.67-0.78), and all-cause mortality (RR: 43 0.87; 95% CI: 0.84-0.91) compared with no drug treatment5. 44 127 45 128 Studies indicate that sex differences exist in the relative contribution of cardiovascular 6 46 129 risk factors in women and men . Furthermore, the prevalence of hypertension differs between 7 47 130 men and women across the life-span . It is well-established that men are more likely to develop 48 hypertension at a younger age compared with premenopausal women8. However, after 49 131 50 132 menopause women display a more rapid increase in the prevalence of hypertension relative to 51 133 men, such that after 60-65 years of age hypertension rates in women exceed those observed in 52 8,9 8 134 men . As a result, these older women have greater CVD burden than men of similar age . 53 Despite these sex disparities, hypertension is often poorly controlled in older women10. 54 135 11 55 136 Although the bioavailability of cardiovascular drugs may differ by sex , there exists no 56 137 sex-specific guidelines for hypertension management, as it remains unclear whether the effect of 57 58 59 3 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 18 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 anti-hypertensive treatment in reducing cardiovascular risk is dependent on sex8. Many of the 4 138 5 139 early clinical trials that examined the efficacy of anti-hypertensive medication in blood pressure 6 140 control and cardiovascular outcomes, collected data in either men alone or combined results for 12 7 141 men and women . Since women were heavily under-represented in these trials, any sex-specific 8 analyses that were performed were severely underpowered. As a result, a systematic review that 9 142 10 143 summarized the results from these early trials concluded that the evidence on the efficacy of anti- 13 11 144 hypertensive treatment specifically in women is weak . Therefore, gaining better understanding 12 145 of how women respond to anti-hypertensive medication is a clinical priority. 13 146 Recognizing the importance of implementing sex-specific evidence into clinical practice 14 15 147 guidelines, in this protocol we outlined a systematic review and meta-analysis to summarize the 16 148 current evidence evaluatingFor thepeer effects of anti-hypertensivereview therapy only in 1) reducing blood pressure 17 149 and 2) preventing cardiovascular morbidity and mortality outcomes for each sex separately. 18 150 Moreover, we aim to determine whether the treatment effect differs significantly between 19 151 women and men. 20 152 21 153 Methods and design 22 23 154 24 155 Registration: 25 156 This protocol was written in accordance with the “Preferred Reporting Items for Systematic 26 157 Review and Meta-Analysis Protocols (PRISMA-P)” guidelines14 (see check-list in Appendix 1). 27 158 Our systematic review and meta-analysis protocol will be registered with the International 28 159 Prospective Register of Systematic Reviews (PROSPERO) after feed-back and peer review. 29 30 160 31 161 Eligibility criteria: 32 162 Studies will be selected according to the criteria outlined below. http://bmjopen.bmj.com/ 33 163 34 164 Study designs 35 165 We will include randomized controlled trials (RCTs), controlled (non-randomized) clinical trials, 36 166 prospective and retrospective comparative cohort studies, and case-control or nested case-control 37 38 167 studies performed in humans. Cross-sectional studies, case series, case reports, reviews, 39 168 commentaries, letters, editorials, conference abstracts, and unpublished data will be excluded. 40 169 All animal and in vitro studies will not be considered. on September 26, 2021 by guest. Protected copyright. 41 170 42 171 Participants 43 172 We will include studies involving adult men and women (18 years or older) regardless of race or 44 173 ethnicity, with clinical indication for anti-hypertensive therapy15. The studies included will be 45 46 174 restricted to a hypertensive cohort who received anti-hypertensive treatment strictly for 47 175 hypertension and not for other cardiovascular conditions (other than hypertension) or non- 48 176 cardiovascular indications (e.g. migraine). If the hypertensive cohorts present with other comorbid 49 177 conditions, this will be allowed in order to represent clinical reality. However, studies restricted to 50 178 a specific cohort who is studied after suffering from an acute event (e.g. post-MI, post-stroke, 51 179 congestive heart failure) or who is on dialysis, will not be considered. Studies that only report sex 52 53 180 aggregated data will be excluded. 54 181 55 182 56 183 57 58 59 4 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 18 BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 184 Interventions 4 185 The intervention will consist of anti-hypertensive medications, which are used for the 5 6 186 pharmacologic management of hypertension, as well as the prevention of its complications, such 7 187 as stroke and myocardial infarction. Several classes of anti-hypertensive regimens exist 8 188 including, diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, 9 189 calcium channel blockers, β-blockers, as first line medications, as well as α-blockers, α-2 10 190 receptor agonists, combined α- and β-blockers, central agonists, peripheral adrenergic inhibitors, 11 191 and vasodilators16. There will be no restrictions on the class or dosage of anti-hypertensive 12 192 medications used. 13 14 193 15 194 Comparators 16 195 Several comparisonsFor will be included:peer review only 17 196 1) Comparison of the efficacy of anti-hypertensive therapy in men versus women 18 197 2) Comparison of subjects treated with anti-hypertensive medication versus placebo (or an 19 198 active control) 20 21 199 3) Comparisons among different dosages and classes of anti-hypertensive medications. 22 200 4) Subgroup analyses will also be performed as stated below in section ‘data synthesis’. 23 201 24 202 Outcomes 25 203 Primary: cardiovascular (including cerebrovascular) morbidity and mortality, change in systolic 26 204 and diastolic blood pressure. 27 205 Secondary: all-cause mortality, drug adherence, adverse events. 28 29 206 Studies will be excluded if they do not report any of the primary outcomes. 30 207 31 208 Timing 32 209 There will be no restrictions by date of publication. http://bmjopen.bmj.com/ 33 210 34 211 Setting 35 36 212 There will be no restrictions by type of setting. 37 213 38 214 Language 39 215 There will be no language restrictions. 40
216 on September 26, 2021 by guest. Protected copyright. 41 217 Information sources: 42 218 The following electronic bibliographic databases will be searched for relevant studies: 43 44 219 MEDLINE (via Ovid), EMBASE Classic + Embase (via Ovid), The Cochrane Central Register 45 220 of Controlled Trials (via The Cochrane Library), PubMed, CINAHL Plus (via EBSCO), Web of 46 221 Science (via Clarivate), and grey literature (Google Scholar). Additionally, the International 47 222 Clinical Trials Registry Platform Search Portal, the International Standard Randomized 48 223 Controlled Trial Number Registry, and ClinicalTrials.gov will be searched for ongoing or 49 224 recently completed trials. To ensure literature saturation, reference lists of eligible studies or of 50 225 relevant meta-analyses and reviews identified through the search will be hand-searched. 51 226 52 53 227 Search strategy: 54 228 Literature search strategies will be developed using medical subject headings and text words 55 229 related to ‘sex differences’, ‘anti-hypertensive medication’, and ‘blood pressure’. A search 56 230 strategy will be developed for MEDLINE, and the search terms will be adapted for use with the 57 58 59 5 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 18 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 231 other bibliographic databases. No date or language limits will be applied on the search. The 4 232 literature search will be limited to human subjects and adults ≥18 years of age. Conference 5 6 233 abstracts, commentaries, and letters will be excluded from the search. Search strategies will be 7 234 peer-reviewed by two librarians. A draft MEDLINE search strategy is included in Appendix 2. 8 235 9 236 Study records: 10 237 Data management 11 238 Literature search results will be uploaded to Rayyan, an Internet-based software program that 12 239 facilitates collaboration among reviewers during the screening process. Prior to uploading to the 13 14 240 software, duplicates will be removed. 15 241 16 242 Selection process For peer review only 17 243 Firstly, two authors, KG and CL, will independently screen the titles and abstracts of studies 18 244 yielded by the search in order to identify potentially eligible records. They will be unaware of the 19 245 study’s authors’ names and journal title to avoid the introduction of a bias in the selection 20 21 246 process. Full text reports for all studies that appear to meet the inclusion criteria or where there is 22 247 any uncertainty will then be screened independently by the same authors (KG and CL) to select 23 248 studies for final inclusion. Disagreements at all stages of the selection process will be resolved 24 249 through consensus with the corresponding author (SSD). We will contact study authors via email 25 250 for additional information where necessary to resolve questions concerning the eligibility of the 26 251 proposed study. If authors do not respond within four weeks of initial contact, a follow-up email 27 252 will be sent. If authors do not respond after four weeks of the second contact, the study will not 28 29 253 be considered in the analysis. 30 254 31 255 Data collection process 32 256 Data extraction will be performed independently by KG and CL. Data will be preferentially http://bmjopen.bmj.com/ 33 257 extracted from result tables in the selected articles. If the data are not listed in the tables, the text 34 258 in the results section will be carefully read for any important information. If the data are only 35 259 available from graphs, the data will be extracted manually using the Image J® software version 36 37 260 1.47t (ImageJ, US National Institutes of Health, Bethesda, MD, http://imagej.nih.gov/ij/, 1997– 38 261 2015). Extracted data will include study and population characteristics, details on blood pressure, 39 262 intervention details, and patient outcomes of interest. Authors will be contacted in case further 40
263 information and clarifications are needed using the same strategy as mentioned previously. on September 26, 2021 by guest. Protected copyright. 41 264 42 265 Data items 43 44 266 Data items that will be extracted from each included article are presented in Table 1. 45 267 46 Table 1. Data items to be extracted from each included article 47 Data Item Details to be extracted 48 Study characteristics complete author list, publication year, journal, funding source, 49 geographical location of study, study design, randomization 50 51 method if applicable, total number of subjects per group 52 Patient characteristics average age, sex distribution, average body mass index, type of 53 hypertension (e.g. sustained hypertension, masked hypertension, 54 white-coat hypertension, nocturnal hypertension), duration of 55 56 57 58 59 6 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 18 BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 hypertension, average systolic and diastolic blood pressure at 4 baseline, list of other comorbidities 5 6 Intervention generic name of anti-hypertensive medication, type of control 7 used, dosage, frequency and duration of treatment, delivery 8 method 9 Results duration of follow-up, achieved systolic and diastolic blood 10 pressure, cardiovascular (and cerebrovascular) morbidity and 11 mortality, all-cause mortality, drug compliance, adverse events, 12 13 permanent treatment discontinuations 14 268 15 269 Outcomes and prioritization 16 270 To be included, studyFor outcomes peer have to be review available according only to sex. For primary outcomes, 17 271 data involving the change in systolic and diastolic blood pressure (in mmHg) between baseline 18 272 and follow-up will be extracted, as well as effect estimates for cardiovascular (and 19 20 273 cerebrovascular) morbidity and mortality, including fatal and/or non-fatal myocardial infarction, 21 274 fatal and/or non-fatal stroke, fatal and/or non-fatal heart failure (including hospitalizations), 22 275 major adverse cardiac events and cardiovascular death. Effect estimates for all-cause mortality 23 276 will be extracted as a secondary outcome, along with drug compliance (in %), and safety 24 277 outcomes, i.e., the incidence of adverse events (including but not limited to, allergic reaction/ 25 278 angioedema/ skin rash, electrolyte disturbances, cough, peripheral edema, diarrhea or 26 279 constipation, nausea or vomiting, skin rash, agitation or anxiety, insomnia, palpitations), and 27 28 280 permanent treatment discontinuations because of adverse events (in %). 29 281 30 282 Risk of bias in individual studies 31 283 Risk of bias assessment for randomized controlled trials will be performed using the modified 32
284 Cochrane Risk of Bias tool. Judgements, expressed as high, low, or unclear risk, will be made http://bmjopen.bmj.com/ 33 285 independently by two authors, KG and CL, based on the criteria for judging the risk of bias. 34 35 286 Disagreements will be resolved first by discussion and then by consulting a third author (SSD) 36 287 for arbitration. For cohort and case-control studies, risk of bias assessment will be performed 37 288 using the 9-item Newcastle-Ottawa Quality Assessment Scale. Three parameters will be 38 289 evaluated: (1) population selection, (2) comparability of results, and (3) ascertainment of 39 290 exposure or outcome. Similarly, two independent reviewers, KG and CL, will perform each 40 291 quality assessment, consulting a third reviewer (SSD) when necessary. Studies will be on September 26, 2021 by guest. Protected copyright. 41 292 considered of high quality if the total score is ≥7/9. No studies will be excluded based on the risk 42 43 293 of bias assessment. 44 294 45 295 Data analysis: 46 296 47 297 Synthesis 48 298 Meta-analyses will be conducted separately for men and women to evaluate the effect of anti- 49 299 hypertensive therapy on 1) blood pressure and 2) cardiovascular morbidity and mortality 50 51 300 outcomes. Data concerning systolic and diastolic blood pressure will be expressed as mean 52 301 differences (with 95% CIs). Data concerning each cardiovascular morbidity and mortality 53 302 outcome will be expressed as summary RR with 95% CIs. Numbers needed to treat (NNT) 54 303 estimates, which is the number of patients who must be treated to prevent one adverse outcome, 55 304 will be calculated. Between-studies heterogeneity will be measured using the I2 test; significance 56 57 58 59 7 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 18 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 305 threshold will be set at P< 0.10. Pooled analyses will be conducted using the random-effects 4 306 (DerSimonian–Laird) model irrespective of the underlying heterogeneity across studies. 5 6 307 Standardization of treatment effect according to blood pressure lowering will not be 17,18 7 308 performed . 8 309 9 310 Evidence obtained from randomized interventional studies will not be evaluated together with 10 311 non-randomized and/or epidemiological evidence as this will introduce several types of bias in 11 312 our analyses. Thus, analyses will be stratified based on study design and risk of bias with 12 313 randomized controlled trials being included in the primary synthesis. Other sources of 13 14 314 heterogeneity will also be explored by sensitivity and subgroup analyses, stratifying studies by 15 315 various factors, including follow-up duration, age (e.g., younger vs older women, younger vs 16 316 older men, younger Forwomen vs peer younger men, review older women vs only older men), ethnicity/race, type of 17 317 hypertension (e.g. sustained hypertension, masked hypertension, white-coat hypertension, 18 318 nocturnal hypertension), class of anti-hypertensive therapy, and treatment dosage. Meta- 19 319 regression analyses will also be performed to assess the effect of confounding variables (i.e., 20 21 320 body mass index, smoking status, cholesterol levels, history of prior CVD, type 2 diabetes 22 321 mellitus, chronic kidney disease). 23 322 24 323 All statistical analyses for meta-analysis will be performed using STATA Software, version 13.0 25 324 (STATA Corporation, College Station, TX, USA). 26 325 27 326 Meta-bias(es) 28 29 327 Publication bias will be assessed by visual inspection of funnel plots and by Begg’s and Egger’s 30 328 statistical tests, if at least 9 studies are available. P< 0.05 will be considered evidence of small 31 329 study effects. In order to determine whether outcome reporting bias is present, we will evaluate 32 330 whether the protocol of the RCT was published before recruitment of patients of the study was http://bmjopen.bmj.com/ 33 331 started. Moreover, we will compare outcomes reported in the protocol and the published report. 34 332 35 333 Confidence in cumulative estimate 36 37 334 The quality of evidence for all outcomes will be judged using the Grading of Recommendations 38 335 Assessment, Development and Evaluation (GRADE) Working Group criteria19. 39 336 40
337 Patient and Public Involvement: on September 26, 2021 by guest. Protected copyright. 41 338 Patients or the public were not involved in the design, or conduct, or reporting, or dissemination 42 339 plans of our research 43 44 340 45 341 Discussion 46 342 Hypertension is a major risk factor for CVD, placing it as the most common cause of death 1,2 47 343 world-wide . Overwhelming evidence indicates that sex differences exist in the epidemiology 48 344 and the pathophysiology of hypertension20. Specifically, premenopausal women have lower 49 50 345 incidence and severity of hypertension, and thus a lower incidence of CVD, than age-matched 8,9 51 346 men . However, this cardio-protection is compromised post-menopause, where the risk of 52 8,9 53 347 hypertension increases sharply in women . We expect that this sexual dimorphism may also 54 348 extend to the treatment efficacy of anti-hypertensive medication. It is well-established that anti- 55 349 hypertensive treatment can significantly reduce the risk for stroke and other CVD events5. 56 350 However, it remains unclear whether this effect is dependent on sex. Moreover, it is not 57 58 59 8 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 18 BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 351 established whether different classes of anti-hypertensive drugs routinely used in clinical practice 4 352 work similarly in men and women. Currently, hypertension guidelines do not report sex-specific 5 6 353 recommendations. Evaluation of these differences is required to ensure the best possible care for 7 354 both men and women living with hypertension. Thus, herein, we provide a protocol of a 8 355 systematic review and meta-analysis that summarizes the current evidence evaluating sex 9 356 differences in the efficacy of anti-hypertensive treatment in reducing CVD outcomes and blood 10 357 pressure. To our knowledge, this is the first meta-analysis that will comprehensively compare the 11 358 efficacy of anti-hypertensive treatment regimens between men and women. In addition to 12 359 analyzing more recent trial data on this topic, than a previously performed meta-analysis of 13 21 14 360 randomized trials (prior to 2006) , we will also include non-randomized and epidemiological 15 361 evidence, and we will perform several sub-analyses, as appropriate. 16 362 For peer review only 17 363 Ethics and dissemination 18 364 We will share the findings of these meta-analyses through scientific conferences and societies, 19 365 social media, and consumer advocacy groups. Importantly, the results will be used to inform the 20 21 366 current guidelines for management of hypertension in men and women by demonstrating the 22 367 importance of implementing sex-specific recommendations. It may determine which classes of 23 368 anti-hypertensive medications may be more effective in men and in women. Treatment strategies 24 369 for hypertension and CVD that are tailored according to sex could lead to improved outcomes for 25 370 the affected individuals. Ethical considerations are not applicable for this protocol. 26 371 27 372 Acknowledgements 28 29 373 Not applicable 30 374 31 375 Funding 32 376 This protocol is supported by Hypertension Canada. SS Daskalopoulou is a Senior Chercheur- http://bmjopen.bmj.com/ 33 377 Boursier Clinicien supported by the Fonds de recherche du Québec – Santé. NK is funded by a 34 378 Michael Smith Foundation in Health Research Career Scientist Award. 35 379 36 37 380 Availability of Data and Materials 38 381 The datasets used and/or analyzed during the current study are available from the corresponding 39 382 author on reasonable request. 40
383 on September 26, 2021 by guest. Protected copyright. 41 384 Author Contributions 42 385 SSD is the guarantor. KG and SSD designed the research. KG drafted the manuscript. KG, CL, 43 44 386 and SSD contributed to the development of the inclusion/exclusion search criteria, data 45 387 extraction criteria, and statistical analysis methods. VM and LH led the development of the 46 388 search strategy. NAK and DMR critically revised the protocol. All authors read, provided 47 389 feedback and approved the final protocol. 48 390 49 391 Ethics Approval and Consent to Participate 50 392 Not applicable 51 52 393 53 394 Competing Interests 54 395 The authors declare that they have no competing interests. 55 396 56 57 58 59 9 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 18 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 397 References: 4 398 5 6 399 1. World Health Organization. Hypertension. 2019; https://www.who.int/news-room/fact- 7 400 sheets/detail/hypertension 8 401 2. Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S, Murray CJ. Selected major risk 9 402 factors and global and regional burden of disease. Lancet (London, England). 10 403 2002;360:1347-1360 11 404 3. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual 12 405 blood pressure to vascular mortality: A meta-analysis of individual data for one million 13 14 406 adults in 61 prospective studies. Lancet (London, England). 2002;360:1903-1913 15 407 4. MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, et al. Blood pressure, 16 408 stroke, and coronaryFor heartpeer disease. reviewPart 1, prolonged differencesonly in blood pressure: 17 409 Prospective observational studies corrected for the regression dilution bias. Lancet 18 410 (London, England). 1990;335:765-774 19 411 5. Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, et al. Blood 20 21 412 pressure lowering for prevention of cardiovascular disease and death: A systematic 22 413 review and meta-analysis. Lancet. 2016;387:957-967 23 414 6. Vitale C, Mendelsohn ME, Rosano GM. Gender differences in the cardiovascular effect 24 415 of sex hormones. Nature reviews. Cardiology. 2009;6:532-542 25 416 7. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart 26 417 disease and stroke statistics-2016 update: A report from the american heart association. 27 418 Circulation. 2016;133:e38-360 28 29 419 8. Beth L. Abramson KS, Leslie L. Davis, Biljana Parapid. Women and hypertension: 30 420 Beyond the 2017 guideline for prevention, detection, evaluation, and management of high 31 421 blood pressure in adults. 2018 32 422 9. Wenger NK, Arnold A, Bairey Merz CN, Cooper-DeHoff RM, Ferdinand KC, Fleg JL, et http://bmjopen.bmj.com/ 33 423 al. Hypertension across a woman's life cycle. Journal of the American College of 34 424 Cardiology. 2018;71:1797-1813 35 425 10. Lloyd-Jones DM, Evans JC, Levy D. Hypertension in adults across the age spectrum: 36 37 426 Current outcomes and control in the community. Jama. 2005;294:466-472 38 427 11. Luzier AB, Killian A, Wilton JH, Wilson MF, Forrest A, Kazierad DJ. Gender-related 39 428 effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. 40
429 Clinical pharmacology and therapeutics. 1999;66:594-601 on September 26, 2021 by guest. Protected copyright. 41 430 12. Garcia M, Mulvagh SL, Merz CN, Buring JE, Manson JE. Cardiovascular disease in 42 431 women: Clinical perspectives. Circulation research. 2016;118:1273-1293 43 44 432 13. Ljungman C, Mortensen L, Kahan T, Manhem K. Treatment of mild to moderate 45 433 hypertension by gender perspective: A systematic review. Journal of women's health 46 434 (2002). 2009;18:1049-1062 47 435 14. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred 48 436 reporting items for systematic review and meta-analysis protocols (prisma-p) 2015: 49 437 Elaboration and explanation. BMJ (Clinical research ed.). 2015;350:g7647 50 438 15. Nerenberg KA, Zarnke KB, Leung AA, Dasgupta K, Butalia S, McBrien K, et al. 51 52 439 Hypertension canada's 2018 guidelines for diagnosis, risk assessment, prevention, and 53 440 treatment of hypertension in adults and children. The Canadian journal of cardiology. 54 441 2018;34:506-525 55 56 57 58 59 10 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 18 BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 442 16. American Heart Association. Types of blood pressure medications. 2017; 4 443 https://www.heart.org/en/health-topics/high-blood-pressure/changes-you-can-make-to- 5 6 444 manage-high-blood-pressure/types-of-blood-pressure-medications 7 445 17. Brunstrom M, Carlberg B. Standardization according to blood pressure lowering in meta- 8 446 analyses of antihypertensive trials: Comparison of three methodological approaches. J 9 447 Hypertens. 2018;36:4-15 10 448 18. Thomopoulos C, Michalopoulou H. Outcome standardization to blood pressure reduction 11 449 in meta-analyses: Sailing in uncharted waters. J Hypertens. 2018;36:31-33 12 450 19. Grade home. http://www.gradeworkinggroup.org 13 14 451 20. Regitz-Zagrosek V, Kararigas G. Mechanistic pathways of sex differences in 15 452 cardiovascular disease. Physiological reviews. 2017;97:1-37 16 453 21. Turnbull F, WoodwardFor peer M, Neal B, reviewBarzi F, Ninomiya only T, Chalmers J, et al. Do men and 17 454 women respond differently to blood pressure-lowering treatment? Results of 18 455 prospectively designed overviews of randomized trials. Eur Heart J. 2008;29:2669-2680 19 456 20 21 22 23 24 25 26 27 28 29 30 31 32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39 40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 11 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
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1 1 2 3 PRISMA-P 2015 Checklist 4 5 This checklist has been adapted for use with systematic review protocol submissions to BioMed Central journals from Table 3 in Moher D et al: 6 Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Systematic Reviews 2015 4:1 7 8 9 An Editorial from the Editors-in-Chief of Systematic Reviews details why this checklist was adapted - Moher D, Stewart L & Shekelle P: 10 Implementing PRISMA-P: recommendations for prospective authors. Systematic Reviews 2016 5:15 11 12 For peer review only Information reported Line 13 Section/topic # Checklist item 14 Yes No number(s) 15 ADMINISTRATIVE INFORMATION
16 http://bmjopen.bmj.com/ Title 17 18 Identification 1a Identify the report as a protocol of a systematic review 2 19 Update 1b If the protocol is for an update of a previous systematic review, identify as such N/A 20 21 If registered, provide the name of the registry (e.g., PROSPERO) and registration number in the Registration 2 22 Abstract 23 Authors
24 on September 26, 2021 by guest. Protected copyright. Provide name, institutional affiliation, and e-mail address of all protocol authors; provide physical 4-30 25 Contact 3a 26 mailing address of corresponding author 27 Contributions 3b Describe contributions of protocol authors and identify the guarantor of the review 384-389 28 If the protocol represents an amendment of a previously completed or published protocol, identify 29 Amendments 4 as such and list changes; otherwise, state plan for documenting important protocol amendments 30 31 Support 32 Sources 5a Indicate sources of financial or other support for the review 375-378 33 34 Sponsor 5b Provide name for the review funder and/or sponsor N/A 35 Role of N/A 5c Describe roles of funder(s), sponsor(s), and/or institution(s), if any, in developing the protocol 36 sponsor/funder 37 38 INTRODUCTION 39 Rationale 6 Describe the rationale for the review in the context of what is already known 111-145 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
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2 1 2 Information reported Line 3 Section/topic # Checklist item 4 Yes No number(s) 5 Provide an explicit statement of the question(s) the review will address with reference to 146-151 6 participants, interventions, comparators, and outcomes (PICO) 7 Objectives 7 8 9 METHODS 10 Specify the study characteristics (e.g., PICO, study design, setting, time frame) and report 161-215 11 Eligibility criteria 8 characteristics (e.g., years considered, language, publication status) to be used as criteria for 12 eligibility for theFor review peer review only 13 Describe all intended information sources (e.g., electronic databases, contact with study authors, 217-225 14 Information sources 9 trial registers, or other grey literature sources) with planned dates of coverage 15
Present draft of search strategy to be used for at least one electronic database, including plannedhttp://bmjopen.bmj.com/ 227-234 16 Search strategy 10 17 limits, such that it could be repeated 18 STUDY RECORDS 19 237-240 20 Data management 11a Describe the mechanism(s) that will be used to manage records and data throughout the review 21 State the process that will be used for selecting studies (e.g., two independent reviewers) through 242-253 Selection process 11b 22 each phase of the review (i.e., screening, eligibility, and inclusion in meta-analysis) 23 Describe planned method of extracting data from reports (e.g., piloting forms, done independently, 255-263
Data collection process 11c on September 26, 2021 by guest. Protected copyright. 24 in duplicate), any processes for obtaining and confirming data from investigators 25 List and define all variables for which data will be sought (e.g., PICO items, funding sources), any 265-268 26 Data items 12 27 pre-planned data assumptions and simplifications 28 Outcomes and List and define all outcomes for which data will be sought, including prioritization of main and 269-280 13 29 prioritization additional outcomes, with rationale 30 Describe anticipated methods for assessing risk of bias of individual studies, including whether 282-293 Risk of bias in 31 14 this will be done at the outcome or study level, or both; state how this information will be used in individual studies 32 data synthesis 33 DATA 34 35 15a Describe criteria under which study data will be quantitatively synthesized 298-300 36 Synthesis If data are appropriate for quantitative synthesis, describe planned summary measures, methods 300-308 37 15b of handling data, and methods of combining data from studies, including any planned exploration 38 of consistency (e.g., I 2, Kendall’s tau) 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
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3 1 2 Information reported Line 3 Section/topic # Checklist item 4 Yes No number(s) 5 Describe any proposed additional analyses (e.g., sensitivity or subgroup analyses, meta- 310-321 6 15c regression) 7 8 15d If quantitative synthesis is not appropriate, describe the type of summary planned N/A 9 Specify any planned assessment of meta-bias(es) (e.g., publication bias across studies, selective 326-331 Meta-bias(es) 16 10 reporting within studies) 11 Confidence in 333-335 12 17 Describe how the strength of the body of evidence will be assessed (e.g., GRADE) cumulative evidence For peer review only 13 14 15
16 http://bmjopen.bmj.com/ 17 18 19 20 21 22 23
24 on September 26, 2021 by guest. Protected copyright. 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 16 of 18 BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations 4 and Daily <1946 to September 16, 2019> 5 6 # Searches Results 7 1 exp Hypertension/ 247434 8 9 2 hypertens*.tw,kf. 420857 10 3 ((high* or elevat* or greater* or control*) adj4 (blood or systolic or diastolic) adj4 68657 11 pressure*).tw,kf. 12 13 4 1 or 2 or 3 501365 14 5 Sex Characteristics/ 52287 15 16 6 Sex/ For peer review only 7632 17 7 Sex ratio/ 9049 18 19 8 Sex Factors/ 254781 20 21 9 ((sex* or gender* or man or men or male* or woman or women or female*) adj3 336361 22 (difference* or different or characteristic* or ratio* or factor* or imbalanc* or issue* or 23 specific* or disparit* or dependen* or dimorphism* or gap or gaps or influenc* or 24 discrepan* or distribut* or composition*)).tw,kf. 25 10 or/5-9 559186 26 27 11 4 and 10 24653 28 12 exp Antihypertensive Agents/ 254343 29 30 13 (antihypertensiv* or anti-hypertensiv* or ((anti?hyperten* or anti-hyperten*) adj5 52111 31 (therap* or treat* or effective*))).tw,kf. 32 http://bmjopen.bmj.com/ 33 14 Calcium Channel Blockers/ 36287 34 15 (calcium adj2 (channel* or exogenous*) adj2 (block* or inhibitor* or 20534 35 antagonist*)).tw,kf. 36 37 16 (agatoxin or amlodipine or anipamil or aranidipine or atagabalin or azelnidipine or 86627 38 azidodiltiazem or azidopamil or azidopine or belfosdil or benidipine or bepridil or 39 brinazarone or calciseptine or caroverine or cilnidipine or clentiazem or clevidipine 40 or columbianadin or conotoxin or cronidipine or darodipine or deacetyl n on September 26, 2021 by guest. Protected copyright. 41 nordiltiazem or deacetyl n o dinordiltiazem or deacetyl o nordiltiazem or 42 deacetyldiltiazem or dealkylnorverapamil or dealkylverapamil or deutolperisone or 43 devapamil or dexniguldipine or dexverapamil or diclofurime or diltiazem or 44 diperdipine or diproteverine or dopropidil or dotarizine or efonidipine or elgodipine or 45 elnadipine or emopamil or enecadin or eperisone or etripamil or falipamil or 46 47 fantofarone or fasudil or felodipine or fendiline or flordipine or flosatidil or fluspirilene 48 or fostedil or furnidipine or gabapentin or gallopamil or iganidipine or isoperisone or 49 isradipine or lacidipine or lemildipine or lercanidipine or lifarizine or lomerizine or 50 manidipine or mepamil or mepirodipine or mesudipine or meta nisoldipine or 51 mibefradil or mirogabalin or modipafant or monatepil or n methylbepridil or n 52 nordiltiazem or naltiazem or nexopamil or nicardipine or nifedipine or niguldipine or 53 niludipine or nilvadipine or nimodipine or nisoldipine or nitrendipine or norgallopamil 54 or norverapamil or olradipine or omega agatoxin or omega conotoxin or oxodipine or 55 palonidipine or perhexiline or pimozide or pinokalant or pontuc or pranidipine or 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 18 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 pregabalin or riodipine or ronipamil or sagandipine or semotiadil or silperisone or 4 5 siratiazem or tamolarizine or teludipine or temiverine or terodiline or tolperisone or 6 trelnarizine or verapamil or watanidipine or xestospongin C or zonisamide).nm,tw,kf. 7 17 Calcium/ 263148 8 9 18 limit 17 to yr="1966-1967" 2861 10 19 Calcium/ai 1873 11 12 20 limit 19 to yr="1968-1981" 707 13 21 Ion Channels/ 34899 14 15 22 limit 21 to yr="1979-1981" 1461 16 23 exp Angiotensin-ForConverting peer Enzyme Inhibitors/ review only 42827 17 18 24 (("Angiotensin-Converting Enzyme" or ACE) adj5 (inhibit* or antagoni*)).tw,kf. 37120 19 25 ("kininase ii" adj2 (antagoni* or inhibit*)).tw,kf,nm. 150 20 21 26 (alacepril or altiopril or ancovenin or benazepril or benazeprilat or captopril or 30970 22 ceranapril or cilazapril or cilazaprilat or deacetylalacepril or delapril or enalapril or 23 enalaprilat or epicaptopril or fasidotril or fasidotrilat or foroxymithine or fosinopril or 24 fosinoprilat or gemopatrilat or idrapril or ilepatril or imidapril or imidaprilat or 25 indolapril or libenzapril or lisinopril or moexipril or moexiprilat or omapatrilat or 26 pentopril or pentoprilat or perindopril or perindoprilat or pivopril or quinapril or 27 quinaprilat or ramipril or ramiprilat or rentiapril or s nitrosocaptopril or sampatrilat or 28 29 spirapril or spiraprilat or temocapril or temocaprilat or teprotide or trandolapril or 30 trandolaprilat or utibapril or utibaprilat or vasopeptidase inhibitor or zabicipril or 31 zabiciprilat or zofenopril or zofenoprilat).nm,tw,kf. 32 27 Enzyme Inhibitors/ 129341 http://bmjopen.bmj.com/ 33 34 28 limit 27 to yr="1975-1987" 1738 35 29 exp Angiotensin Receptor Antagonists/ 22877 36 37 30 (angiotensin adj2 receptor adj2 (blocker* or antagonist*)).tw,kf,nm. 17015 38 31 (abitesartan or azilsartan or candesartan or elisartan or embusartan or eprosartan or 20235 39 fimasartan or fonsartan or forasartan or irbesartan or losartan or milfasartan or 40 on September 26, 2021 by guest. Protected copyright. 41 olmesartan or olodanrigan or pomisartan or pratosartan or ripisartan or saprisartan 42 or sartan derivative or sparsentan or tasosartan or telmisartan or valsartan or 43 zolasartan or irbesarten).nm,tw,kf. 44 32 Angiotensin II Type 1 Receptor Blockers/ 8428 45 46 33 limit 32 to yr="2004-2010" 5146 47 34 beta-blocker*.tw,kf,nm. 29516 48 49 35 (adaprolol or afurolol or alprenolol or alprenolol derivative or befunolol or beta 1 72506 50 adrenergic receptor blocking agent or beta 2 adrenergic receptor blocking agent or 51 beta 3 adrenergic receptor blocking agent or bfe 55 or bopindolol or bornaprolol or 52 bromoacetylalprenololmenthane or bucindolol or bucumolol or bufetolol or bufuralol 53 or bunitrolol or bunolol or bupranolol or butofilolol or carazolol or carpindolol or 54 carteolol or carvedilol or cloranolol or deacetylmetipranolol or dexpropranolol or 55 diacetolol or dichlorisoprenaline or dihydroalprenolol or dilevalol or diprafenone or 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 18 BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 ersentilide or exaprolol or falintolol or falintolol oxalate or flestolol or 4 5 hydroxybenzylpindolol or indenolol or iodopindolol or iprocrolol or isamoltane or 6 isoxaprolol or labetalol or levobunolol or levomoprolol or mepindolol or 7 mercuderamide or metipranolol or moprolol or nadolol or nifenalol or oberadilol or 8 oxprenolol or pafenolol or pamatolol or penbutolol or pindolol* or primidolol or 9 prizidilol or procinolol or pronetalol or propranolol or proxodolol or ridazolol or 10 soquinolol or soquinolol mucate or sotalol or spirendolol or tazolol or tertatolol or 11 tienoxolol or tilisolol or timolol or tolamolol or toliprolol or trasitensin or trepress or 12 tribendilol or viskaldix or xibenolol or zoleprodolol or acebutolol or atenolol or 13 betaxolol or bisoprolol fumarate or carteolol hydrochloride or metoprolol tartrate or 14 metoprolol succinate or penbutolol sulfate or solotol hydrochloride).nm,tw,kf. 15 16 36 exp Diuretics/ For peer review only 78470 17 18 37 diuretic*.tw,kf. 38785 19 38 Furosemide/ 11727 20 21 39 (furosemide or frusemide or fursemide or frusemid or fusid or lasix or errolon or 16850 22 furanthril or furantral).nm,tw,kf. 23 40 (acetazolamide or alilusem or amisometradine or ammonium acetate or bemitradine 61739 24 or besulpamide or brocrinat or chlormerodrin or diclofenamide or epinine or 25 ethoxzolamide or fenquizone or ibopamine or indapamide or meralluride or 26 mercaptomerin or mercumatilin or merethoxylline or mersalyl or methazolamide or 27 28 meticrane or niravoline or osmotic diuretic agent or pamabrom or perhexiline or 29 perhexiline maleate or sitalidone or skf 105494 or theobromine or theophylline or 30 tiamizide or tienilic acid or tienoxolol or traxanox or triniton or tripamide or viskaldix 31 or chlorthalidone or chlorothiazide or hydrochlorothiazide or metolazone or amiloride 32 hydrochloride or triamterene or bumetanide or bisoprolol or http://bmjopen.bmj.com/ 33 bendrofluazide).nm,tw,kf. 34 35 41 exp Mineralocorticoid Receptor Antagonists/ 9160 36 42 (antialdosteron* or anti aldosterone* or spironolacton* or eplerenon* or canreno* or 12684 37 ((aldosterone* or mineralocorticoid*) adj3 antagonist*)).tw,kf,nm. 38 39 43 (trilostane or apararenone or canrenoate potassium or canrenoic acid or canrenone 9903 40 or canrenone derivative or eplerenone or esaxerenone or finerenone or on September 26, 2021 by guest. Protected copyright. 41 mespirenone or mexrenoate potassium or mexrenoic acid or mexrenone or 42 oxprenoate potassium or spironolactone or spiroxasone).nm,tw,kf. 43 44 44 Aldosterone/ 23836 45 45 limit 44 to yr="1966-1977" 4553 46 47 46 alpha?blocker*.tw,kf,nm. 32 48 47 (doxazosin mesylate or prazosin hydrochloride or terazosin hydrochloride).tw,kf. 208 49 50 48 Methyldopa.tw,kf,nm. 4633 51 49 Central agonist*.tw,kf,nm. 14 52 53 50 (alpha methyldopa or clonidine hydrochloride or guanabenz acetate or guanfacine 1228 54 hydrochloride).tw,kf. 55 51 (Peripheral adj2 adrenergic adj2 inhibitor*).tw,kf. 1 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 18 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from
1 2 3 52 (guanadrel or guanethidine monosulfate or reserpine).nm,tw,kf. 18266 4 5 53 (blood vessel dilator* or vasodilator*).tw,kf,nm. 68457 6 54 (hydralazine hydrochloride or minoxidil).tw,kf,nm. 2200 7 8 55 12 or 13 or 14 or 15 or 16 or 18 or 20 or 22 or 23 or 24 or 25 or 26 or 28 or 29 or 30 567100 9 or 31 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 45 or 46 or 10 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 11 12 56 11 and 55 3304 13 57 (Animals/ or Models, animal/ or Disease models, animal/) not Humans/ 4582726 14 15 58 ((animal or animals or canine* or cat or cats or dog or dogs or feline or hamster* or 2320147 16 lamb or lambs orFor mice or monkeypeer or monkeys review or mouse or only murine or pig or pigs or 17 piglet* or porcine or primate* or rabbit* or rats or rat or rodent* or sheep* or 18 veterinar*) not (human* or patient*)).ti,kf,jw. 19 20 59 57 or 58 4970127 21 60 56 not 59 3117 22 23 61 (exp child/ or exp infant/ or adolescent/) not exp adult/ 1820849 24 62 (newborn* or new-born* or neonat* or neo-nat* or infan* or child* or adolesc* or 1433304 25 paediatr* or pediatr* or baby* or babies* or toddler* or kid or kids or boy* or girl* or 26 juvenile* or teen* or youth* or pubescen* or preadolesc* or prepubesc* or preteen or 27 tween).ti. 28 29 63 (pediatr* or paediatr*).jw. 551915 30 64 61 or 62 or 63 2368164 31 32 65 60 not 62 3045 http://bmjopen.bmj.com/ 33 34 66 limit 65 to (comment or editorial or letter) 35 35 67 65 not 66 3010 36 37 68 remove duplicates from 67 3006 38 39 40 on September 26, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml