Aldosterone antagonists for people with chronic kidney disease requiring dialysis

Takeshi Hasegawa, Hiroki Nishiwaki, Erika Ota, William Mm Levack, Hisashi Noma, Takeshi Hasegawa, Hiroki Nishiwaki, Erika Ota, William Mm Levack, Hisashi Noma

Abstract

Background: People with chronic kidney disease (CKD) requiring dialysis are at a particularly high risk of cardiovascular death and morbidity. Several clinical studies suggested that aldosterone antagonists would be a promising treatment option for people undergoing dialysis. However, the clinical efficacy and potential harm of aldosterone antagonists for people with CKD on dialysis has yet to be determined.

Objectives: This review aimed to evaluate the benefits and harms of aldosterone antagonists, both non-selective (spironolactone) and selective (eplerenone), in comparison to control (placebo or standard care) in people with CKD requiring haemodialysis (HD) or peritoneal dialysis (PD).

Search methods: We searched the Cochrane Kidney and Transplant Register of Studies up to 5 August 2020 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Selection criteria: We included parallel randomised controlled trials (RCTs), cross-over RCTs, and quasi-RCTs (where group allocation is by a method that is not truly random, such as alternation, assignment based on alternate medical records, date of birth, case record number, or other predictable methods) that compared aldosterone antagonists with placebo or standard care in people with CKD requiring dialysis.

Data collection and analysis: Two review authors independently extracted data and assessed risk of bias for included studies. We used a random-effects model meta-analysis to perform a quantitative synthesis of the data. We used the I² statistic to measure heterogeneity among the studies in each analysis. We indicated summary estimates as a risk ratio (RR) for dichotomous outcomes, mean difference (MD) for continuous outcomes, or standardised mean differences (SMD) if different scales were used, with their 95% confidence interval (CI). We assessed the certainty of the evidence for each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach.

Main results: We included 16 studies (14 parallel RCTs and two cross-over RCTs) involving a total of 1446 participants. Thirteen studies compared spironolactone to placebo or standard care and one study compared eplerenone to a placebo. Most included studies had an unclear or high risk of bias. Compared to control, aldosterone antagonists probably reduced the risk of death (any cause) for people with CKD requiring dialysis (9 studies, 1119 participants: RR 0.45, 95% CI 0.30 to 0.67; I² = 0%; moderate certainty of evidence). Aldosterone antagonist probably decreased the risk of death due to cardiovascular disease (6 studies, 908 participants: RR 0.37, 95% CI 0.22 to 0.64; I² = 0%; moderate certainty of evidence) and cardiovascular and cerebrovascular morbidity (3 studies, 328 participants: RR 0.38, 95% CI 0.18 to 0.76; I² = 0%; moderate certainty of evidence). While aldosterone antagonists probably increased risk of gynaecomastia compared with control (4 studies, 768 participants: RR 5.95, 95% CI 1.93 to 18.3; I² = 0%; moderate certainty of evidence), aldosterone antagonists may make little or no difference to the risk of hyperkalaemia (9 studies, 981 participants: RR 1.41, 95% CI 0.72 to 2.78; I² = 47%; low certainty of evidence). Aldosterone antagonists had a marginal effect on left ventricular mass among participants undergoing dialysis (8 studies, 633 participants: SMD -0.42, 95% CI -0.78 to 0.05; I² = 77%). In people with CKD requiring dialysis received aldosterone antagonists compared to control, there were 72 fewer deaths from all causes per 1000 participants (95% CI 47 to 98) with a number needed to treat for an additional beneficial outcome (NNTB) of 14 (95% CI 10 to 21) and for gynaecomastia were 26 events per 1000 participants (95% CI 15 to 39) with a number need to treat for an additional harmful outcome (NNTH) of 38 (95% CI 26 to 68).

Authors' conclusions: Based on moderate certainty of the evidence, aldosterone antagonists probably reduces the risk of all-cause and cardiovascular death and probably reduces morbidity due to cardiovascular and cerebrovascular disease in people with CKD requiring dialysis. For the adverse effect of gynaecomastia, the risk was increased compared to control. For this outcome, the absolute risk was lower than the absolute risk of death. It is hoped the three large ongoing studies will provide better certainty of evidence.

Trial registration: ClinicalTrials.gov NCT01128101 NCT01687699 NCT01691053 NCT01650012 NCT02285920 NCT00865449 NCT02490904 NCT01855334 NCT00328809 NCT03314493 NCT02190318 NCT03953950 NCT03020303 NCT01848639 NCT00277693.

Conflict of interest statement

TH: has a grant by JSPS KAKENHI Grant Number 19K03092 and consultancy agreement with Kyowa Kirin and has received speaker honoraria from Kyowa Kirin, Astellas, Baxter, Terumo, and Torii Pharmaceutical for activities unrelated to this review
H Nishiwaki: has declared that they have no conflict of interest
EO: has declared that they have no conflict of interest
WL: has declared that they have no conflict of interest
H Noma: has received consultant fees from Kyowa Kirinand lecture fees from Boehringer Ingelheim and Kyowa Kirin