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Clinical Journal of the American Society of Nephrology : CJASN logoLink to Clinical Journal of the American Society of Nephrology : CJASN
. 2020 Jul 16;15(8):1129–1138. doi: 10.2215/CJN.12201019

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, Meg J Jardine 1,8, Martin P Gallagher 1,9, Vlado Perkovic 1, Min Jun 1,
PMCID: PMC7409758  PMID: 32675281

Visual Abstract

graphic file with name CJN.12201019absf1.jpg

Keywords: hypertension, systolic blood pressure, chronic kidney disease, renal dialysis, Antihypertensive agents, Adverse events, Angiotensin-Converting Enzyme Inhibitors, Angiotensin Receptor Antagonists, Renin, Calcium Channel Blockers, blood pressure, Mineralocorticoid Receptor Antagonists, Peptidyl-Dipeptidase A, Cardiovascular Diseases, hypotension, risk factors

Abstract

Background and objectives

Elevated BP is an important risk factor for cardiovascular disease, with a prevalence of over 80% in patients undergoing maintenance dialysis. We assessed the comparative BP-lowering efficacy and the safety of BP-lowering drugs in patients undergoing maintenance dialysis.

Design, settings, participants, & measurements

We performed a frequentist random effects network meta-analysis of randomized, controlled trials evaluating BP-lowering agents in adult patients undergoing maintenance dialysis. Electronic databases (CENTRAL, MEDLINE, and Embase) were systematically searched (up to August 2018) for relevant trials. The main outcome was systolic BP reduction.

Results

Forty trials (4283 participants) met our inclusion criteria. Angiotensin-converting enzyme inhibitors, β-blockers, calcium-channel blockers, and aldosterone antagonists lowered systolic BP to a greater extent than placebo, with effect sizes ranging from −10.8 mm Hg (95% confidence interval, −14.8 to −6.7 mm Hg) for the aldosterone antagonists to −4.3 mm Hg (95% confidence interval, −7.2 to −1.5 mm Hg) for angiotensin-converting enzyme inhibitors. Aldosterone antagonists and β-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 β-blockers lowered systolic BP by 6.4 mm Hg (95% confidence interval, −11.4 to −1.4 mm Hg) and 4.4 mm Hg (95% confidence interval, −7.4 to −1.3 mm Hg), respectively. Systolic BP reduction was not different with angiotensin receptor blockers, α-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. β-Blockers and aldosterone antagonists may confer larger reductions, although treatment with aldosterone antagonists may be limited by adverse events.

Introduction

Cardiovascular diseases account for approximately half of all deaths in people with kidney failure receiving maintenance dialysis (1). Elevated BP is an important risk factor for cardiovascular disease, and its prevalence rises to 86% among patients undergoing maintenance dialysis (2). Although two earlier meta-analyses of randomized, controlled trials showed cardiovascular and survival benefit with BP-lowering pharmacotherapy (3,4), their comparative efficacy and safety are not well known because these patients have typically been excluded from large trials. Extrapolation of findings observed within patients not requiring maintenance dialysis is challenging as the benefits and tolerability of BP-lowering medications may be different, as has been observed for other cardiovascular medications (5).

A lack of head-to-head trials may limit the capacity of conventional pairwise meta-analyses to evaluate the comparative efficacy and safety of different classes of BP-lowering agents. Network meta-analysis uses direct and indirect evidence to simultaneously compare available treatments (6). In this review, we examine the comparative efficacy and safety of BP-lowering medications to reduce BP in patients with kidney failure requiring dialysis using network meta-analysis.

Materials and Methods

We conducted a systematic review according to the PRISMA guidelines (7). The study was preregistered with PROSPERO (CRD42016035487).

Data Sources and Searches

We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from database inception up to August 2018 using medical subject headings and text words relevant to BP-lowering agents, kidney failure, and clinical trials designs (Supplemental Table 1) without date or language restriction. We hand searched reference lists from retrieved records and clinical trials registries to identify any additional studies.

The titles and abstracts of retrieved records were screened independently by two investigators (C.A. and A.M.S.) according to the review eligibility criteria on the basis of a standardized approach. Any disagreement on the selection of studies was resolved in discussion with additional reviewers (M.J. and V.P.).

We included randomized, controlled trials that recruited adults (≥18 years old) requiring dialysis and assessed the efficacy of any class of BP-lowering therapy: angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), α-blockers, β-blockers, calcium-channel blockers, diuretics, centrally acting vasodilators, aldosterone antagonists, or direct renin inhibitors alone or in combination compared with control (placebo or standard of care) or another class of BP-lowering agents. Trials aiming to achieve specific BP targets using a range of therapies were excluded.

Data Extraction

Two authors (C.A. and A.M.S.) extracted and verified data after entry into a spreadsheet. Collected data included baseline characteristics (age, sex, comorbidities [diabetes, hypertension, baseline BP, and history of cardiovascular disease], type of dialysis, and drug use); trial data (trial design, sample size, follow-up duration, country, and year of publication); and outcomes data.

Quality Assessment

We assessed risk of bias in included trials using the Cochrane tool (8). Two authors (A.M.S. and B.S.) classified risk of bias for each study domain as low, unclear, or high. Any disagreement in risk of bias assessment was adjudicated by additional reviewers (M.J. and V.P.). Grading of Recommendations, Assessment, Development and Evaluation (GRADE) domains for network meta-analysis proposed by Salanti et al. (9) were used to assess confidence in each treatment comparison estimates.

Outcomes

We collected data on BP and the method of measurement, heart rate, and adverse events. The main outcome was mean difference in systolic BP measurements between assigned treatment groups. Other outcomes included diastolic BP, heart rate, discontinuation due to adverse events, hypotension, hyperkalemia, and serum potassium concentration.

Data Synthesis and Analyses

We used random effects pairwise (10) and network meta-analyses within a frequentist environment to obtain summary 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 both treatments. For example, on the basis of direct comparisons of interventions A versus B and B versus C, one can investigate the effects of intervention A versus C using indirect comparisons. The direct and indirect comparisons are then pooled to form a network effect (9). We assumed that eligible participants can be randomized to any of the network interventions. We checked the transitivity assumption by investigating the distribution of potential effect modifiers (age, baseline systolic BP, follow-up duration, sample size, population, and study methodological quality) (11). We assessed agreement between direct and indirect estimates in every closed loop of evidence using loop-specific and node-splitting approaches and for the entire network using design-by-treatment interaction model (global inconsistency test) (12,13).

For continuous outcomes, the mean differences and corresponding 95% confidence intervals (95% CIs) were calculated using end of trial mean values, their corresponding SD, and treatment arm size. For crossover trials, we calculated the SEMs from paired t statistics using a method described elsewhere (14). For dichotomous outcomes, relative risks (RRs) and corresponding 95% CIs were calculated using total number of patients randomized in each group as the denominator. Evidence of statistical heterogeneity in estimates between studies beyond the level of chance was estimated using the I2 statistic in the pairwise meta-analysis (15). We investigated possible sources of heterogeneity by comparing summary results obtained from subsets of studies, which compared the efficacy of BP-lowering drugs compared with control, grouped by class of BP-lowering drugs, age, proportion of men, baseline systolic BP, dialysis modality, type of BP measurements, median study size, and follow-up duration. We assumed the same heterogeneity variance (τ2) for all comparisons in the network meta-analysis (16) and compared its value with outcome- and treatment-specific empirical distribution of variances to assess the magnitude of heterogeneity in the entire network (17,18).

Publication bias was assessed using comparison-adjusted funnel plots for all active drugs against control (19). Statistical analyses were performed with Stata, version 15.1 (Stata, College Station, TX) using published methods (2022).

Results

Search Results and Characteristics of Included Studies

The electronic literature search retrieved 6406 records, of which 40 randomized trials met our inclusion criteria (Supplemental Figure 1). Supplemental Table 2 summarizes the characteristics of included studies, which were reported between 1986 and 2016. Among the 40 included trials, 32 included patients receiving hemodialysis, four enrolled patients receiving peritoneal dialysis, and four included both. Twenty-three trials were placebo controlled, six trials compared an intervention with standard of care, and 11 trials were head-to-head trials, of which two were three-arm trials. Thirty-seven trials had a parallel design, two were crossover trials, and one was a two-by-two factorial study.

The trials included a total of 4283 participants (sample size range, 8–469 participants), with a median proportion of men of 61%. Study follow-up duration ranged from 2 weeks to 3.5 years (median 6 months). The median age of trial participants was 57 years (range, 41–71 years). The mean baseline systolic BP was 148 mm Hg (range, 123–189 mm Hg). In 26 trials, mean baseline systolic BP was ≥140 mm Hg.

Included trials reported BP measurements in several ways: 19 (59%) studies reported predialysis BP measurement, five (16%) reported clinic BP, four (13%) reported home BP, three (9%) reported ambulatory BP measurement, and one (3%) trial measured postdialysis BP.

Risks of Bias and Confidence Rating

Overall, 14 trials (35%) were considered at low risk of bias; 10 (25%) were at unclear risk of bias, and 16 trials (40%) were at high risk of bias (Supplemental Figure 2, Supplemental Table 3). Of the included studies, 22 were double blinded, 15 were open label, and blinding was not specified in three trials.

For the systolic BP outcome, trials with some concerns regarding quality contributed 55% of direct evidence to the network of BP-lowering drugs. Trials with no concern regarding quality contributed 14% of direct evidence, whereas trials with major concerns contributed 31% of the direct evidence in the network (Supplemental Figure 3).

The GRADE confidence rating for effects of treatments on systolic BP is presented in Table 1. Confidence in network estimates varied; one comparison (β-blockers versus placebo) provided high confidence, six provided moderate confidence, 12 provided low confidence, and nine provided very low confidence.

Table 1.

Summary of confidence in effect estimates of BP-lowering agents in lowering systolic BP

Comparison Type of Evidence Confidence Rating Reasons for Downgrading
ACE inhibitors versus placebo Mixed Moderate Study limitationsa
ARBs versus placebo Mixed Very low Study limitationsa; imprecisionb; inconsistencyc
β-Blockers versus placebo Mixed High
Calcium-channel blockers versus placebo Mixed Moderate Study limitationsa
Aldosterone antagonists versus placebo Mixed Low Study limitationsa; heterogeneityd
α-Blockers versus placebo Indirect Very low Study limitationsa; imprecisionb; inconsistencye
Renin inhibitors versus placebo Indirect Very low Study limitationsa; imprecisionb; inconsistencye
ACE inhibitors versus ARBs Mixed Low Study limitationsa; imprecisionb
ACE inhibitors versus β-blockers Mixed Moderate Study limitationsa
ACE inhibitors versus calcium-channel blockers Mixed Moderate Study limitationsa
ACE inhibitors versus α-blockers Indirect Very low Study limitationsa; imprecisionb; inconsistencye
ACE inhibitors versus aldosterone antagonists Indirect Low Study limitationsa; inconsistencye
ACE inhibitors versus renin inhibitors Indirect Low Study limitationsa; inconsistencye
ARBs versus calcium-channel blockers Mixed Low Study limitationsa; imprecisionb
ARBs versus renin inhibitors Mixed Low Study limitationsa; inconsistencyc
ARBs versus α-blockers Indirect Very low Study limitationsa; imprecisionb; inconsistencye
ARBs versus β-blockers Indirect Very low Study limitationsa; imprecisionb; inconsistencye
ARBs versus aldosterone antagonists Indirect Low Study limitationsa; inconsistencye
α-Blockers versus β-blockers Mixed Low Study limitationsa; imprecisionb
α-Blockers versus calcium-channel blockers Indirect Very low Study limitationsa; imprecisionb; inconsistencye
α-Blockers versus aldosterone antagonists Indirect Very low Study limitationsa; imprecisionb; inconsistencye
α-Blockers versus renin inhibitors Indirect Low Study limitationsa; inconsistencye
β-Blockers versus calcium-channel blockers Mixed Moderate Study limitationsa
β-Blockers versus aldosterone antagonists Indirect Very low Study limitationsa; imprecisionb; inconsistencye
β-Blockers versus renin inhibitors Indirect Low Study limitationsa; inconsistencye
Calcium-channel blockers versus renin inhibitors Mixed Moderate Study limitationsa
Calcium-channel blockers versus aldosterone antagonists Indirect Low Study limitationsa; inconsistencye
Aldosterone antagonists versus renin inhibitors Indirect Low Study limitationsa; inconsistencye

ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.

a

The majority of evidence was at high or unclear risk of bias.

b

Confidence intervals for network estimates include values that would favor either treatment.

c

Confidence intervals for direct and indirect evidence provided different interpretation.

d

Substantial heterogeneity present between the included trials.

e

Only indirect evidence existed, and inconsistency could not be assessed.

There was no evidence of disagreement between direct and indirect evidence for all outcomes, except for heart rate outcome (ACE inhibitors versus placebo; P=0.05). The “design-by-treatment” interaction models found no evidence for global inconsistency for all outcomes except for serum potassium concentration outcome (P<0.001). Low heterogeneity existed in the network for all outcomes except for diastolic BP, heart rate (high), and hypotension (low to moderate) (Supplemental Tables 4 and 5).

Effects of BP-Lowering Pharmacotherapy

Systolic BP.

Twenty-five randomized trials involving 1681 participants formed the network for the systolic BP outcome (Figure 1). Four treatments (ACE inhibitors, β-blockers, calcium-channel blockers, and aldosterone antagonists) lowered systolic BP to a greater extent than placebo, with effect sizes ranging from −10.8 mm Hg (95% CI, −14.8 to −6.7 mm Hg) for aldosterone antagonists to −4.3 mm Hg (95% CI, −7.2 to −1.5 mm Hg) for ACE inhibitors (Figure 2). No separate effect was clearly identified for ARBs (−3.0 mm Hg; 95% CI, −8.7 to 2.6 mm Hg), α-blockers (−6.7 mm Hg; 95% CI, −14.1 to 0.7 mm Hg), or renin inhibitors (6.0 mm Hg; 95% CI, −0.5 to 12.4 mm Hg).

Figure 1.

Figure 1.

Diagram showing the networks of treatment comparison of BP-lowering agents for systolic BP and safety outcomes in the identified trials. The size of the node corresponds to the number of trials. The thickness of the line connecting two treatments corresponds to the number of patients. Numbers next to each line represent the number of trials that compared the connected treatments. Numbers in brackets correspond to the number of patients. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.

Figure 2.

Figure 2.

BP-lowering agents lowered systolic BP (millimeters of mercury) to a greater extent than placebo, and aldosterone antagonists and β-blockers may confer larger reductions. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; 95% CI, 95% confidence interval; MD, mean difference.

Aldosterone antagonists and β-blockers lowered systolic BP to a greater extent than ACE inhibitors, ARBs, calcium-channel blockers, and renin inhibitors (Figure 2). For example, compared with ACE inhibitors, aldosterone antagonists and β-blockers lowered systolic BP by 6.4 mm Hg (95% CI, −11.4 to −1.4 mm Hg) and 4.4 mm Hg (95% CI, −7.4 to −1.3 mm Hg), respectively. Systolic BP reduction was not detectably different with ARBs, α-blockers, and calcium-channel blockers compared with ACE inhibitors. Renin inhibitors were less effective at lowering BP compared with all other classes.

The comparison-adjusted funnel plot of placebo-controlled trials of BP-lowering drugs’ effect on systolic BP in patients receiving dialysis suggested no evidence of a small study effect in the network (Supplemental Figure 4), although few trials were available for each drug class.

We did not observe significant differences in pooled estimates for systolic BP across any of the subgroups assessed (P value for heterogeneity for all subgroups >0.05) (Figure 3).

Figure 3.

Figure 3.

Subgroup analyses for the effects of BP-lowering agents on systolic BP outcome compared with placebo showed no significant differences in pooled estimates across the assessed groups. ABPM, ambulatory BP monitoring; 95% CI, 95% confidence interval; MD, mean difference (millimeters of mercury).

Diastolic BP and Heart Rate.

A total of 22 trials (1553 patients) contributed to diastolic BP outcome (Supplemental Figure 11). β-Blockers showed an effect on diastolic BP compared with placebo (−4.4 mm Hg; −7.1 to −1.7 mm Hg). There was no detectable difference between other classes against placebo or each other (Supplemental Figure 5).

The network for the heart rate outcome is shown in Supplemental Figure 11. β-Blockers showed a reduction of heart rate by 21 beats per minute (95% CI, −26 to −16 beats per minute), a more marked effect than any other class (Supplemental Figure 6).

Discontinuation Due to Adverse Events.

Sixteen trials (1996 patients) contributed to the network for the risk of discontinuation due to adverse events (Figure 1). This risk was significantly increased with aldosterone antagonists (RR, 3.35; 95% CI, 1.32 to 8.49), ACE inhibitors (RR, 1.77; 95% CI, 1.09 to 2.87), and ARBs (RR, 1.57; 95% CI, 0.96 to 2.57) compared with control (Figure 4, Supplemental Figure 7), whereas there was no detectably increased risk with β-blockers (RR, 0.81; 95% CI, 0.27 to 2.39). Limited data were available for other classes.

Figure 4.

Figure 4.

A number of BP-lowering agents were associated with adverse events compared with control, including treatment discontinuation and hypotension. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; 95% CI, 95% confidence interval; RR, relative risk.

Hypotension.

Ten trials (1980 patients) contributed to the network for hypotension (Figure 1). Compared with control, ACE inhibitors (RR, 6.62; 95% CI, 1.48 to 29.54) and ARBs (RR, 1.53; 95% CI, 0.94 to 2.48) increased the risk of hypotension (Figure 4). Calcium-channel blockers (RR, 0.09; 95% CI, 0.02 to 0.50) and aldosterone antagonists (RR, 0.18; 95% CI, 0.03 to 0.90) were superior to ACE inhibitors in this regard (Supplemental Figure 8). Limited data were available for other classes.

Hyperkalemia and Serum Potassium Concentration.

Fourteen trials (2514 patients) contributed to the network for hyperkalemia (Figure 1). No clear differences between medication classes for hyperkalemia risk were observed (Figure 4, Supplemental Figure 9).

In a network of 15 trials (959 patients) (Supplemental Figure 11), aldosterone antagonists increased serum potassium concentrations by 0.32 meq/L (95% CI, 0.15 to 0.49 meq/L) compared with control, by 0.40 meq/L (95% CI, 0.08 to 0.71 meq/L) compared with ACE inhibitors, and by 0.54 meq/L (95% CI, 0.20 to 0.88 meq/L) compared with ARBs (Supplemental Figure 10).

Sensitivity Analyses

Because of heterogeneity in some loops of evidence involving calcium-channel blockers for systolic BP outcome (Supplemental Table 4), we removed the study by London et al. (23) (baseline mean systolic BP was 189 mm Hg). Although loop-specific heterogeneity (τ2) in all loops dropped to zero, the treatment estimates did not change. In addition, for the serum potassium concentration outcome, we split the control node to placebo and standard of care separately. The global inconsistency test showed a nonsignificant P value of 0.91 with no changes in treatment estimates. In further sensitivity analysis, we excluded trials with unclear or high risk of bias from the systolic BP network, and overall results remained largely unchanged, although some comparisons did not reach statistical significance (Supplemental Figure 12).

Discussion

This meta-analysis provides evidence that should guide the use of BP-lowering agents in patients undergoing maintenance dialysis. The pooled analysis showed an overall significant effect of BP-lowering agents in lowering systolic BP and suggests that aldosterone antagonists and β-blockers may produce greater reductions in systolic BP. The data also suggest that ACE inhibitors and calcium-channel blockers have important BP-lowering effects. The effects of α-blockers and ARBs were less precise. These data suggest that β-blockers and perhaps aldosterone antagonists may be considered as BP-lowering agents of choice where they are tolerated for people with kidney failure requiring maintenance dialysis.

There seem to be differences in the BP-lowering efficacy of different drug classes. Specifically, aldosterone antagonists and β-blockers appear superior to other classes of BP-lowering drugs at lowering systolic BP, whereas the effects of ACE inhibitors and ARBs appear less potent. There is a potential pathophysiologic rationale for reduced efficacy of agents targeting the renin-angiotensin system because renin is produced by the kidney, and levels may be lower in people with kidney failure (24,25). Conversely, both increased aldosterone levels (so called “relative hyperaldosteronism”), irrespective of volume status, and increased sympathetic drive may be important mechanisms underpinning the increased BP observed in people with kidney failure, providing a potential rationale for superior efficacy of aldosterone antagonists and β-blockers in people receiving dialysis (2628). It is noted, however, that our findings on the effects of aldosterone antagonists conflict with those reported in two recent trials (29,30), which showed no effect on systolic BP with spironolactone compared with placebo. It is possible that smaller size and suboptimal quality of earlier studies may have contributed to an overestimation of the treatment effect. Caution is thus warranted when interpreting these findings. The two ongoing clinical trials, ALCHEMIST (NCT01848639) and ACHIEVE (NCT03020303), should help better define the effectiveness and safety of spironolactone in patients undergoing maintenance dialysis.

Our study supports the use of β-blockers to lower BP in patients undergoing maintenance dialysis. However, β-blockers may be underused in clinical practice (31), and because included trials in our analysis are relatively small, future research is needed to evaluate the use of β-blockers as first-line BP-lowering agents in this patient population. In addition, water-soluble β-blockers are dialyzable, and they need to be supplemented after dialysis. This is important because observational evidence suggested possible harm with dialyzable compared with nondialyzable β-blockers (32).

Volume control is important for BP management. Achieving dry weight or increased dialysis frequency and/or time have been shown to lower BP in patients undergoing hemodialysis (3337). However, because few data were available, it is not clear how volume control in the included trials could potentially affect or modify BP-lowering effects of BP-lowering drugs.

It is important to consider the potential risks of BP-lowering agents in this population. We found the risk of drug discontinuation due to adverse events was increased, especially for ACE inhibitors, ARBs, and aldosterone antagonists. Hypotension risk was increased with ACE inhibitors and ARBs, whereas aldosterone antagonists increased serum potassium concentrations but not hyperkalemia. β-Blockers may also increase hyperkalemia and hypotension risk, but data were limited to evaluate these outcomes in our study (38,39). These insights into the nature of adverse outcomes may be particularly important in patients undergoing maintenance dialysis, in whom intradialytic hypotension, hyperkalemia, and the use of low dialysate potassium have all been associated with worse outcomes (40,41). On a related note, the use of potassium binders is a potentially practice-changing strategy, which may facilitate the use of BP-lowering agents that might increase the risk of hyperkalemia as observed with patiromer in the phase 2 AMBER trial (42).

The superiority of β-blockers and aldosterone antagonists in systolic BP lowering may translate to better cardiovascular morbidity and mortality risk reduction. HDPAL study (43) showed that lisinopril was associated with 2.29 times higher cardiovascular events compared with atenolol in 200 predominately black patients undergoing maintenance hemodialysis. However, both lisinopril and atenolol improved left ventricular mass index, and the BP-lowering effect was not significantly different. In our analysis, β-blockers were superior at lowering systolic BP (by 4.4 mm Hg) compared with ACE inhibitors (Figure 2), consistent with these findings. Other meta-analyses reported cardiovascular and mortality benefits with β-blockers (39) and aldosterone antagonists (44), but no clear effects on major cardiovascular events and mortality with ACE inhibitors and ARBs were observed in patients receiving maintenance dialysis (45).

This study has several strengths. It aggregates a comprehensive, methodologically rigorous overview of the available data, incorporating direct and indirect treatment effects of BP-lowering drugs against placebo or against each other. It includes a substantial number of studies and a much larger number of participants than any previous study of BP lowering in patients undergoing maintenance dialysis. It also has some important limitations. As with any systematic review, it is dependent on the quality of the included studies, which varied substantially as did the size and design of the included trials. Most of the data in the network for the outcome of systolic BP were derived from trials with unclear or high risk of bias, although overall findings remained largely unchanged after excluding studies with unclear or high risk of bias. There were relatively few head-to-head studies, leading to limited network connectivity and power to detect statistical inconsistencies and publication bias. Limited data may have also affected the stability of the point estimates, including those reported for aldosterone antagonists (46). The majority of trials were reporting predialysis BP measurements, and thus, subgroup analysis may be underpowered to detect important differences between different BP measurements methods. This also limited our ability to draw conclusions regarding BP variability, a predictor of adverse outcomes in patients with kidney failure (47,48). Adverse events were also inconsistently captured and reported, and thus, they should be interpreted with caution. Because included trials used different agents from different classes, we could not assess the effect of the doses on transitivity assumption. However, most of the included agents had doses that are within the therapeutic ranges for BP control (49). Lastly, this analysis focused on BP effects and did not evaluate the effects of BP-lowering agents on patient-reported outcomes.

In conclusion, our study provides important evidence regarding the comparative efficacy and safety of different classes of BP-lowering agents in managing BP in patients undergoing maintenance dialysis. It suggests, within the limitations of the available evidence, that β-blockers and aldosterone antagonists may have greatest systolic BP-lowering effect, although aldosterone antagonists have a higher risk of adverse effects. Therefore, β-blockers should be evaluated in further research as the first class of agents considered for the treatment of hypertension in this patient population.

Disclosures

Dr. Gallagher reports receiving honoraria from Shire and Amgen for speaking at scientific meetings. Dr. Jardine is responsible for research projects that have received unrestricted funding from Gambro, Baxter, CSL, Amgen, Eli Lilly, and Merck; has served on advisory boards sponsored by Akebia, Baxter, and Boehringer Ingelheim; and has spoken at scientific meetings sponsored by Janssen, Amgen, and Roche, with any consultancy, honoraria, or travel support paid to her institution. Dr. Jun reports receiving grant support from National Health and Medical Research Council of Australia project grant 1148060 and unrestricted grant support from VentureWise (a wholly owned commercial subsidiary of NPSMedicineWise) to conduct a commissioned project funded by AstraZeneca. Dr. Perkovic has participated in advisory boards for both Relypsa and AstraZeneca and has received honoraria and consultation fees from Tricida, Novartis, Amgen, Janssen, GlaxoSmithKline, Astellas, Boeringer Ingelheim, Baxter, Mitsubishi Tanabe, Retrophin, Merck, Abbvie, Novo Nordisk, AstraZeneca, Gilead, Durect, Servier, Eli Lilly, Relypsa, Pharmalink, Bayer, Bristol-Myers Squibb, and Tufts, with payments paid to his institution. All remaining authors have nothing to disclose.

Funding

None.

Supplementary Material

Supplemental Data

Acknowledgments

Dr. Perkovic and Dr. Shaman designed the study; Dr. Gallagher, Dr. Jardine, Dr. Jun, and Dr. Mihailidou revised the protocol; Dr. Shaman carried out the literature search; Dr. Arnott and Dr. Shaman independently screened trials for inclusion and extracted and verified data; Dr. Shaman and Dr. Smyth independently assessed the quality of included trials; Dr. Shaman analyzed the data and prepared figures and tables with support from Dr. Palmer; Dr. Shaman drafted the paper; Dr. Jun, Dr. Palmer, and Dr. Perkovic revised the paper; and Dr. Arnott, Dr. Gallagher, Dr. Jardine, Dr. Jun, Dr. Mihailidou, Dr. Palmer, Dr. Perkovic, Dr. Shaman, and Dr. Smyth approved the final version of the manuscript.

Footnotes

Published online ahead of print. Publication date available at www.cjasn.org.

See related editorial, “Drug Selection for Treating Hypertension in Dialysis Patients: More to Consider than BP-Lowering Potency,” on pages 1084–1086.

Supplemental Material

This article contains the following supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.12201019/-/DCSupplemental.

Supplemental Figure 1. Electronic searches in MEDLINE, Embase, and the Cochrane Central Register of Randomised Trials for trials on BP-lowering drugs in adults with kidney failure requiring dialysis.

Supplemental Figure 2. Domain-specific risk of bias assessment summary of included studies.

Supplemental Figure 3. Study limitations weighted by contribution of direct estimates to the network of BP-lowering drugs for systolic BP outcome.

Supplemental Figure 4. Comparison-adjusted funnel plot of placebo-controlled trials (n=17) of BP-lowering drugs effect on systolic BP in patients on dialysis.

Supplemental Figure 5. Network estimates of BP-lowering drugs effects on diastolic BP.

Supplemental Figure 6. Network estimates of BP-lowering drugs effects on heart rate.

Supplemental Figure 7. Network estimates of BP-lowering drugs effects on discontinuation due to adverse events.

Supplemental Figure 8. Network estimates of BP-lowering drugs effects on risk of hypotension.

Supplemental Figure 9. Network estimates of BP-lowering drugs effects on the risk of hyperkalemia.

Supplemental Figure 10. Network estimates of BP-lowering drugs effects on serum potassium.

Supplemental Figure 11. Network of treatment comparison of BP-lowering agents effects on diastolic BP, heart rate, and potassium concentration outcomes.

Supplemental Figure 12. Network estimates of BP-lowering drugs effects on systolic BP in trials with low risk of bias (n=9).

Supplemental Material. References.

Supplemental Table 1. Electronic search terms.

Supplemental Table 2. Characteristics of included studies.

Supplemental Table 3. Risk of bias assessments of all included trials.

Supplemental Table 4. Assessment of loop-specific (in closed loops of evidence) and overall inconsistency and heterogeneity.

Supplemental Table 5. Assessment of agreement between direct and indirect evidence using side-splitting approach for all outcomes.

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