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Comparative Efficacy and Safety of BP-Lowering Pharmacotherapy In Article Comparative Efficacy and Safety of BP-Lowering Pharmacotherapy in Patients Undergoing Maintenance Dialysis A Network Meta-Analysis of Randomized, Controlled Trials Ahmed M. Shaman,1,2 Brendan Smyth ,1,3 Clare Arnott,1,4 Suetonia C. Palmer,5 Anastasia S. Mihailidou,6,7 1,8 1,9 1 1 Due to the number of Meg J. Jardine, Martin P. Gallagher, Vlado Perkovic, and Min Jun contributing authors, the affiliations are Abstract listed at the end of Background and objectives Elevated BP is an important risk factor for cardiovascular disease, with a prevalence this article. of over 80% in patients undergoing maintenance dialysis. We assessed the comparative BP-lowering efficacy Correspondence: and the safety of BP-lowering drugs in patients undergoing maintenance dialysis. Dr. Min Jun, The George Institute for Design, settings, participants, & measurements We performed a frequentist random effects network meta-analysis Global Health, The of randomized, controlled trials evaluating BP-lowering agents in adult patients undergoing maintenance University of New dialysis. Electronic databases (CENTRAL, MEDLINE, and Embase) were systematically searched (up to August South Wales, Level 5, 1 King Street, 2018) for relevant trials. The main outcome was systolic BP reduction. Newtown, NSW 2042, Australia. Email: Results Forty trials (4283 participants) met our inclusion criteria. Angiotensin-converting enzyme inhibitors, mjun@georgeinstitute. b-blockers, calcium-channel blockers, and aldosterone antagonists lowered systolic BP to a greater extent than org.au placebo, with effect sizes ranging from 210.8 mm Hg (95% confidence interval, 214.8 to 26.7 mm Hg) for the aldosterone antagonists to 24.3 mm Hg (95% confidence interval, 27.2 to 21.5 mm Hg) for angiotensin- converting enzyme inhibitors. Aldosterone antagonists and b-blockers were superior to angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium-channel blockers, and renin inhibitors at lowering systolic BP. Compared with angiotensin-converting enzyme inhibitors, aldosterone antagonists and b-blockers lowered systolic BP by 6.4 mm Hg (95% confidence interval, 211.4 to 21.4 mm Hg) and 4.4 mm Hg (95% confidence interval, 27.4 to 21.3 mm Hg), respectively. Systolic BP reduction was not different with angiotensin receptor blockers, a-blockers, and calcium-channel blockers compared with angiotensin-converting enzyme inhibitors. Renin inhibitors were less effective. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists incurred risks of drug discontinuation due to adverse events and hypotension. Conclusions BP-lowering agents significantly reduced systolic BP in patients undergoing maintenance dialysis. b-Blockers and aldosterone antagonists may confer larger reductions, although treatment with aldosterone antagonists may be limited by adverse events. CJASN 15: 1129–1138, 2020. doi: https://doi.org/10.2215/CJN.12201019 Introduction dialysis is challenging as the benefits and tolera- Cardiovascular diseases account for approximately bility of BP-lowering medications may be different, half of all deaths in people with kidney failure as has been observed for other cardiovascular receiving maintenance dialysis (1). Elevated BP is medications (5). an important risk factor for cardiovascular disease, A lack of head-to-head trials may limit the capacity and its prevalence rises to 86% among patients of conventional pairwise meta-analyses to evaluate undergoing maintenance dialysis (2). Although two the comparative efficacy and safety of different classes earlier meta-analyses of randomized, controlled of BP-lowering agents. Network meta-analysis uses trials showed cardiovascular and survival benefit direct and indirect evidence to simultaneously com- with BP-lowering pharmacotherapy (3,4), their pare available treatments (6). In this review, we comparative efficacy and safety are not well known examine the comparative efficacy and safety of BP- because these patients have typically been excluded lowering medications to reduce BP in patients with from large trials. Extrapolation of findings ob- kidney failure requiring dialysis using network served within patients not requiring maintenance meta-analysis. www.cjasn.org Vol 15 August, 2020 Copyright © 2020 by the American Society of Nephrology 1129 1130 CJASN Materials and Methods Data Synthesis and Analyses We conducted a systematic review according to the We used random effects pairwise (10) and network meta- PRISMA guidelines (7). The study was preregistered with analyses within a frequentist environment to obtain summary PROSPERO (CRD42016035487). estimates of study outcomes. Network meta-analysis combines evidence about treatments from direct head-to-head trials and indirectly from studies that used a common comparator for Data Sources and Searches both treatments. For example, on the basis of direct compar- We searched MEDLINE, Embase, and the Cochrane isons of interventions A versus B and B versus C, one can Central Register of Controlled Trials from database in- investigate the effects of intervention A versus C using indirect ception up to August 2018 using medical subject headings comparisons. The direct and indirect comparisons are then and text words relevant to BP-lowering agents, kidney pooled to form a network effect (9). We assumed that eligible failure, and clinical trials designs (Supplemental Table 1) participants can be randomized to any of the network without date or language restriction. We hand searched interventions. We checked the transitivity assumption by reference lists from retrieved records and clinical trials investigating the distribution of potential effect modifiers registries to identify any additional studies. (age, baseline systolic BP, follow-up duration, sample size, The titles and abstracts of retrieved records were population, and study methodological quality) (11). We as- screened independently by two investigators (C.A. and sessed agreement between direct and indirect estimates in every A.M.S.) according to the review eligibility criteria on the closed loop of evidence using loop-specific and node-splitting basis of a standardized approach. Any disagreement on approaches and for the entire network using design-by-treat- the selection of studies was resolved in discussion with ment interaction model (global inconsistency test) (12,13). additional reviewers (M.J. and V.P.). For continuous outcomes, the mean differences and We included randomized, controlled trials that recruited corresponding 95% confidence intervals (95% CIs) were adults ($18 years old) requiring dialysis and assessed the calculated using end of trial mean values, their correspond- efficacy of any class of BP-lowering therapy: angiotensin- ing SD, and treatment arm size. For crossover trials, we converting enzyme (ACE) inhibitors, angiotensin receptor calculated the SEMs from paired t statistics using a method blockers (ARBs), a-blockers, b-blockers, calcium-channel described elsewhere (14). For dichotomous outcomes, blockers, diuretics, centrally acting vasodilators, aldoste- relative risks (RRs) and corresponding 95% CIs were calcu- rone antagonists, or direct renin inhibitors alone or in lated using total number of patients randomized in each combination compared with control (placebo or standard of group as the denominator. Evidence of statistical heteroge- care) or another class of BP-lowering agents. Trials aiming neity in estimates between studies beyond the level of chance to achieve specific BP targets using a range of therapies was estimated using the I2 statistic in the pairwise meta- were excluded. analysis (15). We investigated possible sources of heteroge- neity by comparing summary results obtained from subsets Data Extraction of studies, which compared the efficacy of BP-lowering drugs Two authors (C.A. and A.M.S.) extracted and verified compared with control, grouped by class of BP-lowering data after entry into a spreadsheet. Collected data included drugs, age, proportion of men, baseline systolic BP, dialysis baseline characteristics (age, sex, comorbidities [diabetes, modality, type of BP measurements, median study size, and hypertension, baseline BP, and history of cardiovascular follow-upduration.Weassumedthesameheterogeneity disease], type of dialysis, and drug use); trial data (trial variance (t2) for all comparisons in the network meta-analysis design, sample size, follow-up duration, country, and year (16) and compared its value with outcome- and treatment- of publication); and outcomes data. specific empirical distribution of variances to assess the magnitude of heterogeneity in the entire network (17,18). Publication bias was assessed using comparison-adjusted Quality Assessment funnel plots for all active drugs against control (19). Statistical We assessed risk of bias in included trials using the fi analyses were performed with Stata, version 15.1 (Stata, Cochrane tool (8). Two authors (A.M.S. and B.S.) classi ed College Station, TX) using published methods (20–22). risk of bias for each study domain as low, unclear, or high. Any disagreement in risk of bias assessment was adjudi- cated by additional reviewers (M.J. and V.P.). Grading of Recommendations, Assessment, Development and Evalu- Results ation (GRADE) domains for network meta-analysis pro- Search Results and Characteristics of Included Studies The electronic literature search retrieved 6406 records, of posed by Salanti et al. (9) were used to assess confidence in which 40 randomized trials met our inclusion
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