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Mineralocorticoid receptor antagonists for heart failure: systematic review and meta-analysis

BMC Cardiovascular DisordersBMC series – open, inclusive and trusted201616:246

https://doi.org/10.1186/s12872-016-0425-x

Received: 5 August 2016

Accepted: 25 November 2016

Published: 1 December 2016

Abstract

Background

Mineralocorticoid receptor antagonists (MRAs) have been associated with improved patient outcomes in patients with heart failure with reduced ejection fraction (HFrEF) but not preserved ejection fraction (HFpEF). We conducted a systematic review and meta-analysis of selective and nonselective MRAs in HFrEF and HFpEF.

Methods

We searched Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE. We included randomized controlled trials (RCT) of MRAs in adults with HFpEF or HFrEF if they reported data on major adverse cardiac events or drug safety.

Results

We identified 15 studies representing 16321 patients. MRAs were associated with a reduced risk of cardiovascular death (RR 0.81 [0.75–0.87], I2 0%), all-cause mortality (RR 0.83 [0.77–0.88], I2 0%), and cardiac hospitalizations (RR 0.80 [0.70–0.92], I2 58.4%). However, an a-priori specified subgroup analysis demonstrated that these benefits were limited to HFrEF (cardiovascular death RR 0.79 [0.73–0.86], I2 0%; all-cause mortality RR 0.81 [0.75–0.87], I2 0%; cardiac hospitalizations RR 0.76 [0.64–0.90], I2 68%), but not HFpEF (all-cause mortality RR 0.92 [0.79–1.08], I2 0%; cardiac hospitalizations RR 0.91 [0.67–1.24], I2 17%). MRAs increased the risk of hyperkalemia (RR 2.03 [1.78–2.31], I2 0%). Nonselective MRAs, but not selective MRAs increased the risk of gynecomastia (RR 7.37 [4.42–12.30], I2 0% vs. RR 0.74 [0.43–1.27], I2 0%). Evidence was of moderate quality for cardiovascular death, all-cause mortality and cardiovascular hospitalizations; and high-quality for hyperkalemia and gynecomastia.

Conclusions

MRAs reduce the risk of adverse cardiac events in HFrEF but not HFpEF. MRA use in HFpEF increases the risk of harm from hyperkalemia and gynecomastia. Selective MRAs are equally effective as nonselective MRAs, without a risk of gynecomastia.

Keywords

Heart failure Heart failure with reduced ejection fraction Heart failure with preserved ejection fraction Mineralocorticoid receptor antagonists Systematic review

Background

Heart failure (HF) has significant morbidity and is often a result of impaired left ventricular myocardial function [1]. HF with preserved ejection fraction (HFpEF) involves impaired myocardial function with normal left ventricle size and ejection fraction; in contrast, HF with reduced ejection fraction (HFrEF) involves an enlarged left ventricle size and reduced ejection fraction. Evidence-based HF treatment reduces morbidity and mortality in HFrEF [2]. HFpEF prevalence is rising due to an ageing population, however, there are no treatments which reduce morbidity and mortality [3]. Diagnosing HFpEF is often confounded by the occurrence of similar symptoms in patients with multiple medical comorbidities [3]. The most prevalent risk factor for HFpEF is hypertension [3]. Several RCTs have explored the benefits of β-blockers [4], ARBs [5], ACEi [6], and mineralocorticoid receptor antagonists (MRAs) [7] in HFpEF and identified trends towards reduced cardiovascular morbidity and mortality [8]. The lack of strong evidence in HFpEF treatment has led to considerable treatment variation [9].

MRAs can be selective (e.g., eplerenone) or nonselective (e.g., spironolactone). Eplerenone was synthesized through chemical modification of spironolactone in order to enhance binding of mineralocorticoid receptors while reducing off-target binding to progesterone or androgen receptors [10]. Eplerenone is associated with lower rates of impotence, gynecomastia or breast pain in comparison to spironolactone [11, 12].

MRAs found initial use in HF exacerbations as diuretics in patients’ refractory to combined ACEi and loop diuretic therapy [13]. However, spironolactone at doses with no significant diuretic effect was found to reduce cardiovascular mortality [14]. This effect was presumably due to a reduction in myocardial and vascular fibrosis [14]. This effect may arise from spironolactone blocking aldosterone’s ability to stimulate collagen synthesis at the myocardial level [15]. Spironolactone and eplerenone have demonstrated significant mortality benefit in HFrEF [11, 12]. In contrast, MRAs in HFpEF do not reduce all-cause mortality, however, they do reduce hospitalizations, improve quality of life, and improve echocardiographic measurements of diastolic function [16].

Chronically elevated aldosterone levels contribute towards structural changes in the heart which promote water retention, myocardial fibrosis, and increased arrhythmogenicity [17]. MRAs in HFpEF improved echocardiographic and biochemical measures of diastolic function [16, 18]. However, a large prospective RCT in HFpEF patients treated with spironolactone did not demonstrate a significant benefit in terms of cardiovascular outcomes [7].

Objectives

Our objectives were to evaluate the risks and benefits of MRA usage in adults with HF. We were particularly interested in differences between selective and nonselective MRAs in HFpEF and HFrEF in terms of cardiovascular outcomes and adverse effects.

Methods

Our systematic review and meta-analysis complies with the PRISMA statement [19].

Eligibility criteria

We included randomized controlled trials (RCTs) of MRAs vs. placebo or standard therapy in adults (≥18 years old) with HFpEF or HFrEF. Included trials evaluated nonselective MRAs (e.g., canrenone, spironolactone), and selective MRAs (e.g., eplerenone, finerenone). Included trials contained at least one outcome of interest: mortality (all-cause or cardiovascular), cardiovascular hospitalizations, hyperkalemia, or gynecomastia.

Literature search

We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2016), MEDLINE (January 1995 to January 29, 2016), and EMBASE (January 1995 to January 29, 2016) for articles meeting our inclusion criteria. Our search strategy for Ovid MEDLINE and EMBASE is in Appendix 1 and our search strategy for the Cochrane Register of Controlled Trials is in Appendix 2. Our search did not have any language restrictions. We excluded reviews, editorials, and conferences but not unpublished studies or abstracts.

Study selection

We entered the retrieved citations into Reference Manager (v12.0.3), and duplicate records were removed. One investigator (NB) screened citations for relevance based on their title and abstract. Both investigators reviewed the full text articles of relevant articles for study inclusion. Cohen’s kappa statistic was used to quantify chance-corrected agreement between the investigators. Disagreements on study inclusion were resolved through a consensus process of having a discussion between the two investigators.

Data collection and analysis

Both investigators extracted data independently from included articles. We resolved disagreements during data extraction by consensus. If data were incomplete or unclear we attempted to contact trial authors. We extracted the following items from each study: population (type of heart failure, study size), intervention (MRA type), control (placebo, none, other), and outcomes (all-cause mortality, cardiovascular mortality, hospitalizations, hyperkalemia, and gynecomastia/breast pain). We used each study’s definition of these outcomes.

Risk of bias

Our risk of bias assessment was completed using the Cochrane Risk of Bias Tool. It evaluates individual studies for several biases: selection, performance, detection, attrition and reporting. We evaluated the quality of evidence for each outcome using GRADE criteria [20], which evaluates an outcome across studies based on risk of bias, inconsistency, indirectness, imprecision and publication bias.

Statistical analysis

We obtained the relative risk for each outcome from the original study and used RevMan (version 5.3.5) and R [21, 22] to analyze data and generate figures. We used the Mantel-Haenszel method with a 95% confidence interval, and a random effects model to pool results. We quantified statistical heterogeneity using the I2 statistic. We interpreted an I2 value of 0–25% as low heterogeneity, 25–50% as moderate heterogeneity, and >50% as high heterogeneity. A priori we established two hypotheses to explain potential heterogeneity: HF type (HFpEF and HFrEF), and MRA type (selective, or nonselective). We assessed for publication bias using funnel plots for each outcome.

Results

Trial selection

We screened 2566 citations, and selected 36 for full text review. Of these, 15 articles [7, 11, 12, 18, 2333] met our inclusion criteria and were included in our systematic review (see Fig. 1). Overall, there was excellent agreement on trial eligibility (Cohen’s kappa 94%). We excluded articles from the systematic review because of treatment in a non-HF setting (N = 4), lack of relevant outcomes (N = 13), study duplication (N = 3), and not an RCT design (N = 1).
Fig. 1

Study selection flow diagram. Overview of process used to identify studies for inclusion in the systematic review. Three databases (MEDLINE, EMBASE, Cochrane) were searched for relevant articles. After identification, studies were screened against our inclusion criteria. Included studies were used in our meta-analysis

Trial characteristics

Table 1 reports the trial characteristics of the 15 RCTs containing 16321 patients. The patients had either HFpEF (N = 4027) or HFrEF (N = 12294) and the MRA treatment group was either nonselective, e.g., canrenone, spironolactone, N = 11 RCTs, 6678 patients; or selective, e.g., eplerenone, N = 4 RCTs, 9643 patients. Studies had an average length of follow-up of 15 months.
Table 1

Overview of trials meeting systematic review inclusion criteria

Author

Year

Population

Exp (N)

Cont (N)

Intervention

Drug dose

Follow-up (months)

Akbulut

2003

HFrEF, EF ≤ 35%, NYHA III

35

35

spironolactone

25 mg daily

3

Boccanelli

2009

HFrEF, EF ≤ 45%, NYHA II

215

223

canrenone

25 mg daily

12

Chan

2007

HFrEF, EF < 40%, NYHA I–III

23

25

spironolactone

25 mg daily

12

Cicoira

2002

HFrEF, EF ≤ 45%, NYHA III

54

52

spironolactone

25 mg daily

12

Deswal

2011

HFpEF, EF ≥ 50%, NYHA II–III

25

23

eplerenone

25 mg daily

6

Edelmann

2013

HFpEF, EF ≥ 50%, NYHA II–III

213

209

spironolactone

25 mg daily

12

Edwards

2009

HFpEF, CKD stage 2–3

56

56

spironolactone

25 mg daily

9

Zannad

2011

HFrEF, EF ≤ 35%, NYHA II

1364

1373

eplerenone

25–50 mg daily

21

Pitt

2003

MI + HFrEF, EF ≤ 40%

3319

3313

eplerenone

25–50 mg daily

16

Gao

2007

HFrEF, EF < 45%, NYHA II–IV

58

58

spironolactone

20 mg daily

6

Pitt

2013

HFrEF, EF ≤ 40%, CKD stage 2–3

63

65

spironolactone

25–50 mg daily

1

Pitt

1999

HFrEF, EF < 35%, NYHA III–IV

822

841

spironolactone

25–50 mg daily

24

Pitt

2014

HFpEF, EF ≥ 45%

1722

1723

spironolactone

15–45 mg daily

40

Udelson

2010

HFrEF, EF ≤ 35% NYHA II–III

117

109

eplerenone

50 mg daily

9

Vizzardi

2014

HFrEF, EF < 40%, NYHA I–II

65

65

spironolactone

25–100 mg daily

44

Risk of bias within included trials

Table 2 reports the quality of included studies. Five trials had unclear or absent allocation concealment [23, 25, 26, 28, 30]. Two studies had inadequate blinding and were of single-blind design [23, 32]. Two large studies were terminated early due to meeting pre-defined benefit criteria [11, 33]. Another two studies did not use intention-to-treat analysis. Overall, loss-to-follow-up was low with a range of 0 to 6.6%.
Table 2

Risk of bias summary for each study included in the meta-analysis

Author

Year

Allocation concealment

Blinding

Intention to treat analysis

Loss to follow-up (%)

Early trial termination

Akbulut

2003

Unclear

No

Yes

0.0

No

Boccanelli

2009

Yes

Yes

Yes

6.2

No

Chan

2007

Unclear

Yes

Yes

0.0

No

Cicoira

2002

Unclear

Yes

Yes

6.6

No

Deswal

2011

Yes

Yes

No

4.3

No

Edelmann

2013

Yes

Yes

Yes

1.2

No

Edwards

2009

Unclear

Yes

No

2.7

No

Zannad

2011

Yes

Yes

Yes

1.2

Yes

Pitt

2003

Yes

Yes

Yes

0.3

No

Gao

2007

Yes

Yes

Yes

0.0

No

Pitt

2013

No (open label Aldactone)

Yes

Yes

0.0

No

Pitt

1999

Yes

Yes

Yes

0.0

Yes

Pitt

2014

Yes

Yes

Yes

3.8

No

Udelson

2010

Yes

Yes

Yes

0.0

No

Vizzardi

2014

Yes

No

Yes

0.0

No

Results of meta-analysis

Table 3 reports a summary of findings. We included outcomes for cardiovascular death (7 RCTs), all-cause mortality (12 RCTs), cardiac hospitalization (10 RCTs), hyperkalemia (15 RCTs), and gynecomastia (N = 11 RCTs). Quality of evidence for cardiovascular death, all-cause mortality, and cardiac hospitalization were rated moderate; hyperkalemia and gynecomastia were rated high using GRADE guidelines [20]. For each outcome, HFrEF evidence was of high quality, but the quality of evidence for HFpEF was of moderate quality for all-cause mortality, cardiovascular death, and cardiac hospitalizations.
Table 3

Summary of findings for the effect of mineralocorticoid receptor antagonists in treating Heart Failure

Outcome

№ of participants (studies)

Quality of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with placebo

Risk difference with MRA

Cardiovascular death

15115

(7 RCTs)

MODERATEa

RR 0.81

(0.75 to 0.87)

155 per 1000

29 fewer per 1000

(39 fewer to 20 fewer)

Cardiovascular death - rEF

11670

(6 RCTs)

HIGH

RR 0.79

(0.73 to 0.86)

171 per 1000

36 fewer per 1000

(46 fewer to 24 fewer)

Cardiovascular death - pEF

3445

(1 RCT)

MODERATEb

RR 0.91

(0.74 to 1.11)

102 per 1000

9 fewer per 1000

(27 fewer to 11 more)

All cause mortality

15919

(12 RCTs)

MODERATEc

RR 0.83

(0.77 to 0.88)

182 per 1000

31 fewer per 1000

(42 fewer to 22 fewer)

All cause mortality - rEF

11892

(8 RCTs)

HIGH

RR 0.81

(0.75 to 0.87)

197 per 1000

38 fewer per 1000

(49 fewer to 26 fewer)

All cause mortality - pEF

4027

(4 RCTs)

MODERATEd

RR 0.92

(0.79 to 1.08)

136 per 1000

11 fewer per 1000

(29 fewer to 11 more)

Cardiac hospitalization

15669

(10 RCTs)

MODERATEd

RR 0.80

(0.70 to 0.92)

217 per 1000

43 fewer per 1000

(65 fewer to 17 fewer)

Cardiac hospitalization - rEF

11754

(7 RCTs)

MODERATEd

RR 0.76

(0.64 to 0.90)

245 per 1000

59 fewer per 1000

(88 fewer to 24 fewer)

Cardiac hospitalization - pEF

3915

(3 RCTs)

MODERATEd

RR 0.91

(0.67 to 1.24)

134 per 1000

12 fewer per 1000

(44 fewer to 32 more)

Hyperkalemia

16321

(15 RCTs)

HIGH

RR 2.03

(1.78 to 2.31)

37 per 1000

39 more per 1000

(29 more to 49 more)

Gynecomastia or breast pain - nonselective

6432

(8 RCTs)

HIGH

RR 7.37

(4.42 to 12.30)

5 per 1000

30 more per 1000

(16 more to 53 more)

Gynecomastia or breast pain - selective

9417

(3 RCTs)

HIGH

RR 0.74

(0.43 to 1.27)

7 per 1000

2 fewer per 1000

(4 fewer to 2 more)

CI Confidence interval, RR Risk ratio

aHigh quality of evidence for HFrEF, single study for HFpEF

bSingle trial with confidence interval which crossed unity

cHigh quality of evidence for HFrEF, moderate quality evidence for HFpEF

dConfidence interval of data crossed unity

Meta-analysis of cardiovascular death (see Fig. 2) revealed a significant risk reduction, RR 0.81 [0.75–0.87], I2 0% (low heterogeneity). Our analysis of cardiovascular death by HF type indicated only a single trial of HFpEF (TOPCAT) which had no significant reduction in cardiovascular death [7]. Using either selective or nonselective MRA had a similar reduction in cardiovascular death (Additional file 1: Figure S1).
Fig. 2

Forest plot of cardiovascular death with MRA use in HF. Seven trials reported cardiovascular death rates when using MRAs in HF compared to control. Our Forest plot has been subdivided according to HF type

Meta-analysis of all-cause mortality (see Fig. 3) revealed a significant risk reduction, RR 0.83 [0.77–0.88], I2 0% (low heterogeneity). HF type subgroups indicated the benefit was limited to HFrEF. Use of either a selective or nonselective MRA had a similar reduction in all-cause mortality (Additional file 2: Figure S2).
Fig. 3

Forest plot of all-cause mortality with MRA use in HF. Twelve trials reported all-cause mortality rates with MRA use in HF compared to control. Our Forest plot has been subdivided according to HF type

Meta-analysis of cardiac hospitalizations (see Fig. 4) revealed a significant risk reduction, RR 0.80 [0.70–0.92], I2 58.4% (high heterogeneity). Our a priori subgroup analysis partially explained the heterogeneity within this outcome, as a significant reduction in cardiac hospitalizations was found in the HFrEF and nonselective MRA subgroups (Additional file 3: Figure S3).
Fig. 4

Forest plot of cardiovascular hospitalizations with MRA use in HF. Ten trials reported cardiovascular hospitalization rates with MRA use in HF compared to control. Our Forest plot has been subdivided according to HF type

Hyperkalemia was significantly more common with MRA use, RR 2.03 [1.78–2.31], I2 0% (low heterogeneity), see Fig. 5. Subgroup analysis by MRA or HF type did not significantly influence the rate of hyperkalemia (Additional file 4: Figure S4).
Fig. 5

Forest plot of hyperkalemia with MRA use in HF. Fifteen trials reported hyperkalemia rates with MRA use in HF compared to control. Our Forest plot has been subdivided according to HF type

Gynecomastia was significantly more common with MRA use, RR 3.28 [1.18–9.10], I2 81.7% (high heterogeneity), see Fig. 6. MRA type explained this heterogeneity as selective MRAs did not produce significant amounts of gynecomastia (RR 0.74 [0.43–1.27], I2 0%) while nonselective MRAs did (RR 7.37 [4.42–12.30], I2 0%).
Fig. 6

Forest plot of gynecomastia with MRA use in HF. Eleven trials reported gynecomastia rates with MRA use in HF compared to control. Our Forest plot has been subdivided according to MRA type

Our analysis of funnel plots for each outcome except gynecomastia revealed no significant asymmetry (Additional file 5: Figure S5, Additional file 6: Figure S6, Additional file 7: Figure S7, Additional file 8: Figure S8 and Additional file 9: Figure S9) and suggested the absence of publication bias. Two MRA subgroups within the funnel plot for gynecomastia explained the asymmetry of the plot (Additional file 9: Figure S9).

Discussion

Summary of evidence

15 trials evaluated the use of MRAs compared to placebo or no treatment for HF. MRA use in patients with heart failure was associated with a significant reduction in adverse cardiovascular outcomes: cardiovascular death (RR 0.81 [0.75–0.87], I2 0%), all-cause mortality (RR 0.83 [0.77–0.88], I2 0%), and cardiac hospitalizations (RR 0.80 [0.70–0.92], I2 58.4%). Our a priori specified subgroup analysis demonstrated that the benefits of MRAs are limited to HFrEF. Both selective and nonselective MRAs increase the risk of hyperkalemia (RR 2.03 [1.78–2.31], I2 0%), but gynecomastia is limited to nonselective MRAs (nonselective MRAs RR 7.37 [4.42–12.30], I2 0% vs. selective MRAs RR 0.74 [0.43–1.27], I2 0%RR 7.37 [4.42–12.30).

Strengths and limitations

Our systematic review has strengths including adherence to PRISMA reporting guidelines. In addition, our conclusions are based on evidence of moderate and high quality (GRADE). HFpEF evidence was of moderate quality, and HFrEF evidence was of high quality for cardiovascular death and all-cause mortality. The quality of evidence for cardiovascular death and all-cause mortality was reduced due the evidence for MRA use in HFpEF being limited to a single trial with large effect size [7], and several smaller trials with confidence intervals crossing unity [18, 27, 28]. For cardiovascular hospitalizations, the quality of evidence was reduced by confidence intervals in HFpEF and HFrEF studies crossing unity [7, 33]. Evidence for hyperkalemia and gynecomastia with MRA usage was of high quality. Overall, the evidence supporting MRA use in HFrEF is based on a larger number of trials with significant effect sizes for reducing adverse cardiac events. In contrast, the evidence for MRA use in HFpEF is based on a smaller number of trials, only one of which had a significant reduction in cardiovascular hospitalizations but no other adverse cardiac events [7]. Finally, our conclusions supporting MRA usage in HFrEF align with current American Heart Association guidelines which recommend MRAs for patients with HFrEF and NYHA class II-IV symptoms or following acute MI complicated by HF and EF ≤ 40% [1].

Implications

Current guidelines suggest MRAs are useful in treating HFrEF and acute MI complicated by HF [1, 34]. We demonstrate that treatment of HFpEF with MRAs does not reduce adverse cardiac events. However, MRAs do cause harm from hyperkalemia (NNH 26 [20–34]) and gynecomastia (e.g., nonselective MRA, NNH 33 [19–63]). Selective MRAs offer a slight advantage in terms of no significant gynecomastia while having equivalent reductions in adverse cardiac outcomes. We suggest continued usage of MRAs in HFrEF, where there is a significant reduction in adverse cardiac outcomes, e.g., cardiovascular death (NNT 34 [26–50]), or all-cause mortality (NNT 32 [24–45]). We suggest that MRAs be avoided in HFpEF as they do not reduce adverse cardiovascular outcomes.

Conclusions

Our systematic review provides evidence that MRAs should not be used in HFpEF. MRA usage in HFpEF provides a risk of hyperkalemia and/or gynecomastia without reducing adverse cardiac events. In contrast, MRA usage in HFrEF significantly reduces adverse cardiac events.

Abbreviations

HF: 

Heart failure

HFpEF: 

Heart failure with preserved ejection fraction

HFrEF: 

Heart failure with reduced ejection fraction

MI: 

Myocardial infarction

MRA: 

Mineralocorticoid receptor antagonist

NNH: 

Number needed to harm

NNT: 

Number needed to treat

NYHA: 

New York Heart Association

RCT: 

Randomized controlled trial

RR: 

Relative risk

Declarations

Acknowledgements

None.

Funding

There was no funding for this study.

Availability of data and materials

The datasets generated and analyzed in this study are available from the corresponding author on request.

Authors’ contributions

NB: study conception and design, data acquisition, analysis, and interpretation, drafted manuscript. MM: study conception and design, data acquisition, analysis, interpretation, drafted manuscript. Both authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Medicine, Western University

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