BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com). If you have any questions on BMJ Open’s open peer review process please email [email protected] http://bmjopen.bmj.com/ on September 26, 2021 by guest. Protected copyright. 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 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 on September 26, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 18 BMJ Open 1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from 5 6 7 8 9 I, the Submitting Author has the right to grant and does grant on behalf of all authors of the Work (as defined 10 in the below author licence), an exclusive licence and/or a non-exclusive licence for contributions from authors 11 who are: i) UK Crown employees; ii) where BMJ has agreed a CC-BY licence shall apply, and/or iii) in accordance 12 with the terms applicable for US Federal Government officers or employees acting as part of their official 13 duties; on a worldwide, perpetual, irrevocable, royalty-free basis to BMJ Publishing Group Ltd (“BMJ”) its 14 licensees and where the relevant Journal is co-owned by BMJ to the co-owners of the Journal, to publish the 15 Work in this journal and any other BMJ products and to exploit all rights, as set out in our licence. 16 17 The Submitting Author accepts and understands that any supply made under these terms is made by BMJ to 18 the Submitting Author Forunless you peer are acting as review an employee on behalf only of your employer or a postgraduate 19 student of an affiliated institution which is paying any applicable article publishing charge (“APC”) for Open 20 Access articles. Where the Submitting Author wishes to make the Work available on an Open Access basis (and 21 intends to pay the relevant APC), the terms of reuse of such Open Access shall be governed by a Creative 22 Commons licence – details of these licences and which Creative Commons licence will apply to this Work are set 23 out in our licence referred to above. 24 25 Other than as permitted in any relevant BMJ Author’s Self Archiving Policies, I confirm this Work has not been 26 accepted for publication elsewhere, is not being considered for publication elsewhere and does not duplicate 27 material already published. I confirm all authors consent to publication of this Work and authorise the granting 28 of this licence. 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 26, 2021 by guest. Protected copyright. 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 Page 2 of 18 BMJ Open: first published as 10.1136/bmjopen-2019-036128 on 12 March 2020. Downloaded from 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.