Safety and cardiovascular effects of mineralocorticoid receptor antagonists for patients receiving hemodialysis: a systematic review and meta-analysis

Figures & data

Figure 1. Study flow diagram.

Table 1. Summarization of included studies.

Study	Study design	Subjects	ACEI/ARB	No. of subjects	Intervention	Control	Duration	Outcome measured
Saudan et al., 2003	Prospective, single-arm	HD patients	19/35	35	Spironolactone 12.5 mg thrice weekly for 2 weeks, 25 mg thrice weekly for 2 weeks	Baseline^d	8 weeks	Serum K^+
Hussain et al., 2003	Prospective, single-arm	HD > 4 months, serum K+ ≤5.5 mmol/L	6/15	15	Spironolactone 25 mg daily for 28 days	Baseline^d	4 weeks	Serum K^+, serum renin and aldosterone, incidence rate of hyperkalemia
Michea et al., 2004	Sequential, doubled-blind, placebo-controlled	HD > 18 months	0/9	9	Spironolactone 25 mg thrice weekly for 2 weeks, washout for 2 weeks, placebo for 2 weeks	Placebo	8 weeks	Serum K^+
Gross et al., 2005	RCT, double-blinded, crossover	HD > 3 months, predialysis serum K^+<6 mmol/L, not using ACEI/ARB	0/8	8	Spironolactone, 50 mg twice daily for 2 weeks	Placebo	2 weeks	BP, serum K^+, weight, PRA, 24-h urine volume, urine sodium, K^+, creatinine
Taheri et al., 2009	RCT, double-blinded	HD > 1 month, heart failure^b, LVEF ≤ 45%, treated with an ACEI or ARB and EPO, serum K^+≤5.5 mmol/L	16/16	16	Spironolactone 25 mg thrice weekly for 6 months	Placebo	6 months	LVEF, LVM, serum K^+
Matsumoto et al., 2009	Prospective, single-arm	HD > 2 years, predialysis serum K^+<6.5 mmol/L	29/50	50	Spironolactone 25 mg daily for 6 months	Baseline^d	6 months	Serum K^+
Vukusich et al., 2010	RCT, double-blinded	HD > 18 months, predialysis serum K^+<6 mmol/L, not using ACEI/ARB	0/53	53	Spironolactone 50 mg thrice weekly for 24 months	Placebo	24 months	BP, CIMT, serum K^+
Shavit et al., 2011	Prospective, single-arm	HD > 3 months, predialysis serum K^+<5.6 mmol/L	2/8	8	Eplerenone 25 mg twice daily for 4 weeks	Baseline^d	8 weeks	BP, serum K^+
Flevari et al., 2013	Sequential, placebo-controlled	HD > 12 months, predialysis serum K^+<6 mmol/L	11/14	14	Placebo for 4 weeks, spironolactone 50 mg thrice weekly	Placebo	4 months	BP, serum K^+, IVS, LVM. LVDD, LVSD, FS, RWT, E/A, RVD
Feniman-De-Stefano et al., 2015	RCT, double-blinded	HD, no previous hyperkalemia	14/17	17	Spironolactone 12.5 mg daily for 2 weeks, then adjusted according to K^+^a	Placebo	6 months	BP, serum K^+, LVM, LVDD, LVSD, EF, PWT, DA, ABPM, PWV, AI
Walsh et al., 2015	RCT, double blinded	HD > 90 days	65/154	154	Eplerenone 25 mg daily for 7 days then adjusted according to K^+^c	Placebo	13 weeks	Change of BP, serum K^+

Notes: Abbreviations: ABPM: ambulatory blood pressure monitoring; AI: augmentation index; ACEI: angiotensin-converting enzyme inhibitors; ARB: angiotensin II receptor blocker; BP: blood pressure; CIMT: carotid intima-media thickness; DA: diastolic dimension of the atrium; E/A: ratio of early-to-late diastolic filling; EF: ejection fraction; FS: fractional shortening; HD: hemodialysis; IVS: interventricular septum; K⁺: potassium; LVDD: left ventricular diastolic diameter; LVM: left ventricular mass; LVMI: left ventricular mass index; LVSD: left ventricular systolic diameter; PRA: plasma renin activity; PWT: posterior wall thickness; PWV: pulse wave velocity; RCT: randomized controlled trial; RVD: right ventricular diameter; RWT: relative wall thickness.

^aIf serum K⁺ <5.5 mmol/L, spironolactone 25 mg daily; if serum K⁺ between 5.5 and 5.9 mmol/L, spironolactone 12.5 mg daily; if serum K⁺≥6.0 mmol/L, drop.

^bNYHA class 3 and 4.

^cIf serum K⁺<6 mmol/L, eplerenone 50 mg daily; if serum K⁺>6 mmol/L, the dose was titrated down.

^d‘Baseline’ indicates that the baseline status of participants was used as control.

Figure 2. Risk of bias assessment. Potential risks of bias are assessed using the assessment tool developed by the Cochrane Collaboration¹⁷ and are presented.

Table 2. Effect of mineralocorticoid receptor antagonists on serum potassium level.

Study	Study design	No. of subjects	Intervention	Predialysis serum potassium level (mmol/L)
Saudan et al., 2003	Prospective, single-arm	35	Spironolactone 12.5 mg thrice weekly for 2 weeks, 25 mg thrice weekly for 2 weeks	After the 25 mg phase, spironolactone group: 4.9 ± 0.3, control group: 4.9 ± 0.7, p values not reported
Hussain et al., 2003	Prospective, single-arm	15	Spironolactone 25 mg daily for 28 days	4.6 ± 0.6 at baseline, 4.7 ± 0.6 at study completion, p = 0.19
Michea et al., 2004	Sequential, doubled-blind, placebo-controlled	9	Spironolactone 25 mg thrice weekly for 2 weeks, washout for 2 weeks, placebo for 2 weeks	Baseline: 4.53 ± 0.54, after spironolactone: 4.56 ± 3.39, after placebo: 4.67 ± 0.33, no significant differences
Gross et al., 2005	RCT, double-blinded, crossover	8	Spironolactone, 50 mg twice daily for 2 weeks	Spironolactone group: 5.0 ± 0.8, placebo group: 4.7 ± 0.5, p > 0.05
Taheri et al., 2009	RCT, double-blinded	16	Spironolactone 25 mg thrice weekly for 6 months	Differences of serum potassium concentration at the end of the study compared with the start: spironolactone: 1.02 ± 0.342, placebo: 0.083 ± 0.449, 95% CI (0.381–1.491), p = 0.004
Matsumoto et al., 2009	Prospective, single-arm	50	Spironolactone 25 mg daily for 6 months	Baseline: 4.96 ± 0.72, end of study: 5.18 ± 0.76, p < 0.05
Vukusich et al., 2010	RCT, double-blinded	53	Spironolactone 50 mg thrice weekly for 24 months	End of study, spironolactone: 4.9 ± 0.66, placebo: 4.6 ± 0.53, no significant differences; spironolactone increase serum potassium level by 0.012 per months (p < 0.001)
Shavit et al., 2011	Prospective, single-arm	8	Eplerenone 25 mg twice daily for 4 weeks	Baseline: 4.67 ± 0.2, week 4: 4.86 ± 0.38, p = 0.48
Flevari et al., 2013	Sequential, placebo-controlled	14	Spironolactone 50 mg thrice weekly	Baseline: 4.4 ± 0.72, after placebo: 4.7 ± 0.75, after spironolactone: 5.5 ± 0.75, p < 0.05
Feniman-De-Stefano et al., 2015	RCT, double-blinded	17	Spironolactone 12.5 mg daily for 2 weeks, then adjusted according to K^+^a	End of study, spironolactone: 5.0 ± 0.31, placebo: 4.9 ± 0.24, p = 0.244
Walsh et al., 2015	RCT, double blinded	154	Eplerenone 25 mg daily for 7 days then adjusted according to K^+^b	End of study, eplerenone: 4.9 ± 0.7, placebo: 4.9 ± 0.7, no significant difference; eplerenone increased serum potassium level by 0.16 (95% CI, 0.04–0.28)

^aIf serum K⁺<5.5 mmol/L, spironolactone 25 mg daily; if serum K⁺ between 5.5 and 5.9 mmol/L, spironolactone 12.5 mg daily; if serum K⁺≥6.0 mmol/L, drop.

^b If serum K⁺<6 mmol/L, eplerenone 50 mg daily; if serum K⁺>6 mmol/L, the dose was titrated down.

Figure 3. Effect of mineralocorticoid receptor antagonists on the predialysis serum level. Abbreviations: CI: confidence interval; IV: inverse variance; MRA: mineralocorticoid receptor antagonist.

Table 3. Effect of mineralocorticoid receptor antagonists on blood pressure.

Study	Study design	No. of subjects	Intervention	Predialysis serum potassium level (mmol/L)
Saudan et al., 2003	Prospective, single-arm	35	Spironolactone 12.5 mg thrice weekly for 2 weeks, 25 mg thrice weekly for 2 weeks	After the 25 mg phase, spironolactone group: 4.9 ± 0.3, control group: 4.9 ± 0.7, p values not reported
Hussain et al., 2003	Prospective, single-arm	15	Spironolactone 25 mg daily for 28 days	4.6 ± 0.6 at baseline, 4.7 ± 0.6 at study completion, p = 0.19
Michea et al., 2004	Sequential, doubled-blind, placebo-controlled	9	Spironolactone 25 mg thrice weekly for 2 weeks, washout for 2 weeks, placebo for 2 weeks	Baseline: 4.53 ± 0.54, after spironolactone: 4.56 ± 3.39, after placebo: 4.67 ± 0.33, no significant differences
Gross et al., 2005	RCT, double-blinded, crossover	8	Spironolactone, 50 mg twice daily for 2 weeks	Spironolactone group: 5.0 ± 0.8, placebo group: 4.7 ± 0.5, p > 0.05
Taheri et al., 2009	RCT, double-blinded	16	Spironolactone 25 mg thrice weekly for 6 months	Differences of serum potassium concentration at the end of the study compared with the start: spironolactone: 1.02 ± 0.342, placebo: 0.083 ± 0.449, 95% CI (0.381–1.491), p = 0.004
Matsumoto et al., 2009	Prospective, single-arm	50	Spironolactone 25 mg daily for 6 months	Baseline: 4.96 ± 0.72, end of study: 5.18 ± 0.76, p < 0.05
Vukusich et al., 2010	RCT, double-blinded	53	Spironolactone 50 mg thrice weekly for 24 months	End of study, spironolactone: 4.9 ± 0.66, placebo: 4.6 ± 0.53, no significant differences; spironolactone increase serum potassium level by 0.012 per months (p < 0.001)
Shavit et al., 2011	Prospective, single-arm	8	Eplerenone 25 mg twice daily for 4 weeks	Baseline: 4.67 ± 0.2, week 4: 4.86 ± 0.38, p = 0.48
Flevari et al., 2013	Sequential, placebo-controlled	14	Spironolactone 50 mg thrice weekly	Baseline: 4.4 ± 0.72, after placebo: 4.7 ± 0.75, after spironolactone: 5.5 ± 0.75, p < 0.05
Feniman-De-Stefano et al., 2015	RCT, double-blinded	17	Spironolactone 12.5 mg daily for 2 weeks, then adjusted according to K^+^a	End of study, spironolactone: 5.0 ± 0.31, placebo: 4.9 ± 0.24, p = 0.244
Walsh et al., 2015	RCT, double blinded	154	Eplerenone 25 mg daily for 7 days then adjusted according to K^+^b	End of study, eplerenone: 4.9 ± 0.7, placebo: 4.9 ± 0.7, no significant difference; eplerenone increased serum potassium level by 0.16 (95% CI, 0.04–0.28)

Notes: Abbreviations: DBP: diastolic blood pressure; SBP; systolic blood pressure.

^aIf serum K⁺<5.5 mmol/L, spironolactone 25 mg daily; if serum K⁺ between 5.5 and 5.9 mmol/L, spironolactone 12.5 mg daily; if serum K⁺≥6.0 mmol/L, drop.

^bIf serum K⁺<6 mmol/L, eplerenone 50 mg daily; if serum K⁺>6 mmol/L, the dose was titrated down.

Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ (Clinical Research Ed). 2011;343:d5928.

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