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Aldosterone blockade and left ventricular dysfunction: a systematic review of randomized clinical trials

Justin A. Ezekowitz, Finlay A. McAlister
DOI: http://dx.doi.org/10.1093/eurheartj/ehn543 469-477 First published online: 9 December 2008

Abstract

Context Aldosterone blockade has been used to treat acute myocardial infarction (MI) and chronic heart failure.

Objective The aim of this study is to summarize the evidence on the efficacy of spironolactone (SP), eplerenone (EP), or canrenoate (CAN) in patients with left ventricular dysfunction.

Data sources A search of multiple electronic databases until June 2008 was supplemented by hand searches of reference lists of included studies and review articles, meeting abstracts, FDA reports, and contact with study authors and drug manufacturers.

Study selection and data extraction Studies were eligible for inclusion if they included patients with left ventricular systolic or diastolic dysfunction, treatment with SP, EP, or CAN vs. control, and reported clinical outcomes. Nineteen randomized controlled trials (four in acute MI and 15 in heart failure, n = 10 807 patients) were included—14 of SP, three of EP, and three of CAN. Analysis was performed using relative risks (RRs) with 95% confidence intervals (CIs) and a random effects model with statistical heterogeneity assessed by I2.

Data synthesis Aldosterone blockade reduced all-cause mortality by 20% (RR 0.80, 95% CI 0.74–0.87). All-cause mortality was reduced in both heart failure (RR = 0.75, 95% CI 0.67–0.84) and post-MI (RR 0.85, 95% CI 0.76–0.95) patients. Only nine trials reported hospitalizations, and the RR reduction was 23% (RR 0.77, 95% CI 0.68–0.87), although 98% of the outcomes came from two trials. Ejection fraction (EF) improved in the seven heart failure trials, which assessed this outcome (weighted mean difference 3.1%, 95% CI 1.6–4.5).

Conclusion We demonstrated a 20% reduction in all-cause mortality with the use of aldosterone blockade in a clinically heterogeneous group of clinical trial participants with heart failure and post-MI. In addition, we found a 3.1% improvement in EF. Further study in those with less severe symptoms or preserved systolic function is warranted.

Keywords
  • Heart failure
  • Spironolactone
  • Meta-analysis
  • Systematic review
See page 387 for the editorial comment on this article (doi:10.1093/eurheartj/ehp026)

Introduction

Heart failure and acute myocardial infarction (MI) each result in nearly 1 000 000 hospital admissions yearly in the USA, with in-hospital mortality rates up to 22% and 1-year mortality rates up to 30%.1,2 Profound neurohormonal alterations occur in both the diseases, and these alterations are associated with poorer outcomes.3 Renin–angiotensin–aldosterone modulators have been tested and proven to reduce the morbidity and mortality associated with MI and heart failure.4 Although aldosterone blockade in conjunction with other neurohormonal modulators has been tested in large randomized controlled trials,5,6 these agents are underused in clinical practice in part due to concerns raised about safety,7,8 despite class 1 recommendations for use from heart failure and MI guidelines.9,10 Furthermore, there has been no systematic review of the efficacy of aldosterone blockade in patients with diastolic heart failure.

We sought to clarify the efficacy of aldosterone blockers in patients with left ventricular dysfunction (including heart failure and post-MI), including their effects on ejection fraction (EF), quality of life, exercise capacity, hospitalizations, and mortality.

Methods

Types of studies, participants, comparators, and outcomes

Prospective, randomized controlled trials were included if they enrolled symptomatic or asymptomatic patients with left ventricular dysfunction, were ≥8 weeks in duration, and had at least one of the clinical outcomes of interest. The drugs of interest were spironolactone, eplerenone, or canrenoate; we included trials that evaluated the use of these drugs vs. placebo or active control. The primary outcome for the meta-analysis was all-cause mortality. Secondary outcomes include clinical outcomes all-cause (hospitalization), symptoms [New York Heart Association (NYHA) class and quality of life], functional capacity (exercise capacity, VO2max, and 6 min walk test), and EF. For safety outcomes, we used definitions of hyperkalaemia, renal failure, and gynecomastia as per the primary trial publication, where available.

Literature search

A medical librarian identified relevant databases and developed search strategies for the following terms including both MESH and keywords and their derivatives: aldosterone receptor antagonist, blocker, blockade, blocking agent, canrenoate, potassium canrenoate, canrenone, canrenoic acid, spironolactone, eplerenone, RN 52-01-7, RN 107724-20-9, Aldactone®, Inspra®, cardiovascular disease, and heart disease. Where appropriate, these search terms were combined with the highly sensitive Cochrane search strategy for identifying randomized controlled trials.11

The following electronic databases were searched from 1966 to June 2008 except where noted: MEDLINE®, Ovid Medline® In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials (1950–September 2007), EMBASE®, International Pharmaceutical Abstracts, Science Citation Index Expanded (via Web of Science®) (1900–September 2007), and PubMed. The trial registers Current Controlled Trials, ClinicalTrials.gov, Clinical Trials in Cardiology (www2.umdnj.edu/~shindler/trials/trials_a.html), National Heart Lung and Blood Institute, National Research Register, CenterWatch Drugs in Clinical Trials Database, and CardioSource were searched for additional unpublished trials. Additional websites including the FDA Center for Drug Evaluation and Research, Canadian Agency for Drugs and Technologies in Health, Trip Database, and Google Scholar were searched for unpublished randomized controlled trials and reports. The NLM (National Library of Medicine) Gateway, BioMed Central, and OCLC PapersFirst were searched for identification of meeting abstracts. References of included articles were hand-searched. The search was not limited by language or publication status and is considered up-to-date to June 2008. Manufacturers of aldosterone blockers were contacted for further information, and no additional information was provided in their response.

We used a two-step eligibility and selection process. First, a reviewer (J.A.E.) independently screened all titles and abstracts to determine whether an article met the general inclusion criteria (i.e. randomized trial, aldosterone blocker, human, and heart disease) and rated as ‘include’, ‘exclude’, or ‘unclear’. The full text of all articles marked as ‘include’ or ‘unclear’ was retrieved. Secondly, two reviewers (J.A.E. and F.A.M.) independently assessed the studies using specific inclusion and exclusion criteria. Disagreements were discussed between reviewers until consensus on inclusion was reached. If required, the investigators contacted the authors to clarify that individual publications reported on discrete patients. In cases of multiple publications involving the same or a portion of the same patients, the article with the most complete data was selected.

Data management

Extracted data included study characteristics, inclusion/exclusion criteria, baseline drug use, characteristics of participants, major adverse events, and outcomes. Quality assessment was performed using the methods of Jadad et al.12 and Schulz et al.13 Publication bias was assessed visually, with Begg's test and Egger's test.

Statistical analysis

Random-effects models were used for analyses in Review Manager 4.2.5 (The Cochrane Collaboration, Copenhagen, Denmark). Owing to the differences expected between studies (particularly in control group therapies), we decided a priori to combine results primarily using a random-effects model; fixed-effects models were considered in sensitivity analyses. Weighted mean differences (WMDs) with 95% confidence intervals (95% CI) were calculated for continuous variables using random-effects models. Statistical heterogeneity was assessed by the χ2 test and was quantified using the I2 statistic.14 Inclusion of studies with active control arms vs. placebo-controlled trials was assessed in sensitivity analyses. A priori, we decided to examine subgroups of asymptomatic vs. symptomatic left ventricular dysfunction, MI vs. other trials, and aetiology of heart failure. A two-sided P-value of <0.05 was considered significant for all analyses.

Role of the funding source

The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication.

Results

Two thousand six hundred and ten articles were found by the search strategy, of which 91 full-text articles met general inclusion criteria and were reviewed for strict inclusion or exclusion criteria (Figure 1). After applying strict inclusion and exclusion criteria, 19 randomized trials were included (Figure 1).5,6,1531

Figure 1

Flow diagram of study identification and selection.

The characteristics of included studies are shown in Table 1. Jadad scores varied widely (5 points,5,6,25 4 points,1820,22,31 3 points,15,17,23,24,2729 or ≥2 points16,21,26,30) and only five trials had clear allocation concealment.5,6,1820,25 Trials were conducted in multiple countries, and one non-English article was included.28 Seven studies reported industry funding,5,6,19,20,27,29,31 four were unclear,16,22,23,26 and the others reported non-industry funding. No publication bias was observed on the funnel plot, with Begg's test (P = 1.0) or Egger's test (P = 0.57).

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Table 1

Characteristics of included studies

StudyPatients; duration; locationInterventionNumber randomized (withdrawals or dropouts)Age (years)Gender, % maleIschaemic aetiology (%)Ejection fraction (%)
Agostoni et al.15HF; 6 months; ItalySpironolactone 25 mg15 (1)60.3 ± 9.4663640 ± 19
Placebo15 (0)57.7 ± 7.3806635 ± 11
Akbulut et al.16HF; 3 months; TurkeySpironolactone 25 mg35 (NR)58.9 (6.1)5410027.2 (2)
Metoprolol 12.5 mg35 (NR)59.7 (4.5)5410027.6 (3)
Usual care35 (NR)59.2 (5.3)5710027.9 (4)
Barr et al.17HF; 2 months; UKSpironolactone 50 mg (titrated to 100 mg)28 (2)68 (3)7910019 (7)
Placebo14 (0)70 (2)7110021 (5)
Berry et al.18HF; 3 months; UKSpironolactone 25 mg20 (0)65 (7.4)755028 (9)
Placebo20 (2)59 (9.5)809029 (8)
Boccanelli et al.19HF; 12 months; ItalyCanrenone 25 mg46763 (9)845240 (33–45)
Placebo
Chan et al.20HF; 12 months; ChinaSpironolactone+candesartan23 (0)61.4 (12.3)874826 (2)
Placebo+candesartan25 (0)65.0 (0.6)806428 (2)
Cicoira et al.21HF; 12 months; ItalySpironolactone 25 mg (titrated to 50 mg)54 (NR)62.5 (7.9)853533 (7)
Usual care52 (NR)61.7 (9.8)883334 (7)
Di Pasquale et al.22AMI; 6 months; ItalyCanrenoate IV 1 mg/h then oral 25 mg daily341 (33)62.6 (6)7110044.5 (6)
Placebo346 (30)62.8 (5)7110044.7 (9)
Gao et al.23HF; 6 months; ChinaSpironolactone 20 mg58 (NR)55 (13)646242 (11)
Placebo58 (NR)54 (12)666443 (10)
Modena et al.24AMI; 12 months; ItalyCanrenoate 50 mg24 (0)59 (10)7110047 (6)
Placebo22 (0)62 (13)7710046 (5)
Mottram et al.25HF; 6 months; AustraliaSpironolactone 25 mg15 (NR)61 (6)40NR68 (5)
Placebo15 (NR)62 (5)34NR67 (4)
Orea-Tejeda et al.26HF; 3 months; MexicoSpironolactone 25 mg14 (0)64 (22)294349 (5)
Usual care14 (0)65 (12)715752 (12)
Pitt31HF; 3 months; multipleSpironolactone 12.5, 25, 50, 75 mg174 (2)62 (12)80NRNR
Placebo40 (0)61 (12)83NRNR
Pitt and Roniker27HF; 3 months; multipleSpironolactone 25 mg, eplerenone 25 mg, 25 mg BID, 50 and 100 mg263 (33)61 (31–87)78NRNR
Placebo54 (3)
Pitt et al.5HF; 24 months* multipleSpironolactone 25 mg (titrated to 50 mg)822 (214)65 (12)755525.2 (6.8)
Placebo841 (200)65 (12)725425.6 (6.7)
Pitt et al.6AMI; 16 months; multipleEplerenone 25 mg (titrated to 50 mg)3319 (528)64 (11)7210033 (6)
Placebo3313 (493)64 (12)7010033 (6)
Rodriguez et al.28AMI; 6 months; ChileSpironolactone 25 mg TID23 (NR)58.8 (10.8)7810032.6 (2.9)
Ramipril 2.5 mg BID31 (NR)60.5 (10.2)7410034.5 (2.3)
Placebo24 (NR)58.6 (9)9210037.2 (2.6)
Study 40229HF; 3 months; JapanEplerenone 25, 50, 100 mg114 (16)64 (29–88)84NRNR
Placebo38 (3)
Tsutamoto et al.30HF; 4 months; JapanSpironolactone 25 mg20 (0)62.7 (2.8)75032.2 (2.2)
Placebo17 (0)65 (3.4)76036.6 (1.6)
  • All results are mean (standard deviation) or ±standard error of the mean, unless otherwise stated. AMI, acute myocardial infarction; HF, heart failure; IV, intravenous; NR, not reported; NYHA, New York Heart Association; RCT, randomized controlled trial; TID, three times per day.

  • *Mean duration of follow-up.

All trials were parallel arm trials and ranged in duration from 2 to 24 months. Of the trials included, 15 were conducted in patients with heart failure (3395 patients) and four trials (7412 patients) specifically testing aldosterone blockade after MI. Spironolactone was used in 14 trials, canrenoate in three trials, and eplerenone in three trials; placebo controls were used in all trials except three.16,21,26 Of these three trials, one used an active comparator (metoprolol) and usual care16 and two used usual care alone.21,26 One trial used an active comparator (ramipril) and placebo.28 Background medical therapy was inconsistently reported. Major inclusion criteria are shown in Table 2.

View this table:
Table 2

Major inclusion criteria for included studies

StudyNYHA classCreatinine (µmol/L)Serum potassium (mmol/L)Ejection fraction (%)
Agostoni et al.152–4<177<5.6NR
Akbulut et al.162–4<177<5.5<35
Barr et al.172–4<200NRNR
Berry et al.181–3<221≤5.0<40
Boccanelli et al.192<221≤5.0<45
Chan et al.20None<200≤5.0<40
Cicoira et al.21None<150≤5.0<45
Di Pasquale et al.22Killip 1–3<177≤5.0NR
Gao et al.232–4<221<5.5<45
Modena et al.24Killip 1–3<221<5.5NR
Mottram et al.252–4<221Hyperkalaemia ND>50
Orea-Tejeda et al.262–4NRNR>45
Pitt312–4<177<5.5≤35
Pitt and Roniker273–4NRNR<40
Pitt et al.53–4<221<5.0≤35
Pitt et al.62–4<221<5.0<40
Rodriguez et al.28None<177NRNR
Study 402292–4NRNR<40
Tsutamoto et al.302–4Renal failure NDHyperkalaemia ND<45
  • ND, not defined; NR, not reported.

Aldosterone blockade reduced all-cause mortality by 20% [relative risk (RR) 0.80, 95% CI 0.74–0.87, I2 = 0%] (Figure 2). Using data from the 14 trials in heart failure, all-cause mortality RR reduction was 25% (RR = 0.75, 95% CI 0.67–0.84, I2 = 0%), and in the four trials in MI, RR reduction was 15% (RR = 0.85, 95% CI 0.76–0.95, I2 = 0%). In the two MI trials that reported adjudicated death, sudden cardiac death was reduced (RR 0.80, 95% CI 0.66–0.96) and HF death trended towards significance (RR 0.80, 95% CI 0.63–1.02, P = 0.07).

Figure 2

Effect of aldosterone blockers on all-cause mortality in all randomized trials.

Only nine trials reported all-cause hospitalizations (1270 hospitalizations in 8699 patients), and the RR reduction was 23% (RR 0.77, 95% CI 0.68–0.87, P < 0.0001, I2 = 38%), although 98% of the weight came from two trials.5,6 Using data from two MI trials that reported hospitalization, no significant difference was seen (RR 0.49, 95% CI 0.08–3.22, P = 0.46, I2 = 54%), but for the seven HF trials, a 27% RRR was seen (RR 0.73, 95% CI 0.63–0.84, P < 0.0001, I2 = 0%).

Other outcomes were inconsistently reported. Three trials reported an improvement,5,23,30 and four trials reported no change16,20,26,31 in NYHA class, but due to inconsistency in methods of reporting, this cannot be further quantified. Quality of life was unchanged in two trials by Minnesota Living with Heart Failure15,20 and worsened in one trial by visual analogue scale.18 EF improved in seven heart failure trials by a WMD 3.1% (95% CI 1.6–4.5, P = 0.0001, I2 = 64%, Figure 3). In the three MI trials that reported EF before and after treatment, a non-significant EF improvement was seen (WMD 4.3%, 95% CI -1.0 to +9.6, P = 0.11); this was not statistically significant and had significant statistical heterogeneity (I2 = 96%). In two trials15,21 (n = 136 patients) that reported VO2peak results, a significant improvement was seen (WMD 1.46 mL/kg/min, 95% CI 0.06–2.76, P = 0.04, I2=0%).

Figure 3

Effect of aldosterone blockers on left ventricular ejection fraction in all randomized trials.

Sensitivity analysis

In the four HF trials with a follow-up period of ≥12 months, the mortality RR was 0.74 (95% CI 0.66–0.83, I2 = 0%, based on 728 deaths in 2258 patients), and for the 10 HF trials with <12 months follow-up, the mortality RR was 1.00 (95% CI 0.19–5.18, P = 1.0, based on 12 deaths in 1069 patients). Two trials25,26 exclusively recruited 58 patients with an EF >45%; no deaths or other events occurred in these trials and thus did not change the overall results. The year of publication or initial year of recruitment did not change the overall results. Exclusion of the two trials found in abstract19 or in FDA documents29 did not significantly alter the results.

Safety

Hyperkalaemia was reported in all but two trials (Table 3), with 3.0% of control and 5.9% of aldosterone-blockade patients reporting hyperkalaemia over a median follow-up of 1.25 years. The two longest trials had similar rates of serious hyperkalaemia (>6.0 mmol/L) over 24 months (RALES; absolute increase of 1.0% over placebo) and 16 months (EPHESUS; absolute increase of 1.6% over placebo), respectively. The three trials with the highest reported rates of hyperkalaemia were dose-finding trials using doses in excess of 50 mg of either EP or SP. Renal failure, using definitions from within each trial, happened to 8.9% of aldosterone-blockade patients and 1.6% of control patients. Gynecomastia was infrequently reported (1.6% of aldosterone-blockade patients and 0.5% of control patients). In trials using eplerenone, the rate was 0.5% in the eplerenone-treated patients and 0.5% in control patients, and in trials using spironolactone, the rate was 4.3% in the spironolactone-treated patients and 0.6% in the control patients.

View this table:
Table 3

Major adverse effects of included randomized controlled trials of aldosterone blockade

StudyHyperkalaemia, n (%)Worsening renal function, n (%)Gynecomastia, n (%)
ControlAldosterone blockadeControlAldosterone blockadeControlAldosterone blockade
Agostoni et al.15000001 (<1)
Akbulut et al.161 (<1)2 (<1)0000
Barr et al.1704 (1)04 (1)00
Berry et al.18000000
Boccanelli et al.19NRNRNRNRNRNR
Chan et al.2001 (<1)NRNRNRNR
Cicoira et al.2103 (1)NRNR02 (<1)
Di Pasquale et al.224 (<1)18 (5)4 (<1)18 (5)00
Gao et al.2301 (2)5 (9)6 (10)03 (5)
Modena et al.242 (1)3 (1)0000
Mottram et al.25000000
Orea-Tejeda et al.26000000
Pitt312 (1)27 (16)0000
Pitt et al.272 (4)58 (22)2 (4)58 (22)06 (2)
Pitt et al.510 (1)14 (2)NRNR9 (1)61 (10)
Pitt et al.6126 (4)180 (6)NRNR17 (<1)13 (<1)
Rodriguez et al.2800NRNR02 (1)
Study 402291 (6)4 (20)NRNR00
Tsutamoto et al.30NRNRNRNRNRNR
Total*148/4947 (3.0%)315/5314 (5.9%)11/654 (1.6%)86/959 (8.9%)26/4922 (0.5%)88/5291 (1.6%)
  • Definitions (where reported) of hyperkalaemia and renal failure varied between trials. NR, not reported.

  • *Total excludes trials that did not report outcome of interest.

Discussion

We demonstrated a 20% reduction in all-cause mortality with the use of aldosterone blockade in a clinically heterogeneous group of clinical trial patients with left ventricular dysfunction. We also found a 3.1% improvement in ejection fraction, although this result had significant statistical heterogeneity. Additionally, we found that in smaller trials with <12 months of therapy, there was no apparent benefit to aldosterone blockers and that the trials with the longest duration of follow-up were associated with the greatest reduction in all-cause mortality. However, early benefit was seen in the two largest trials powered to detect morbidity and mortality endpoints.

In patients post-MI, aldosterone blockade carries a class 1 indication for initiation post-MI,9 based primarily on the EPHESUS trial.6 We have identified three other smaller MI trials that support this recommendation, and although these trials use spironolactone or canrenoate, all were initiated within the index hospitalization. Indeed, a post hoc analysis of the EPHESUS identified that early initiation of eplerenone reduced the mortality rate as early as 30 days post-MI.32 Consistent with the guideline recommendations, aldosterone blockade should be initiated early and in those patients with heart failure signs or symptoms and at low risk for complications from aldosterone-blockade therapy.

Are the medications similar enough to be grouped together and does the data support a class effect?33 Spironolactone, the oldest of the compounds, differs from eplerenone by its lack of specificity for aldosterone receptors. Eplerenone is 100 times more specific for the aldosterone receptor and has limited affinity for androgen or progesterone receptors.34 Canrenoate is a competitive inhibitor of the aldosterone receptor and is metabolized to canrenone, the common active metabolite of spironolactone. All three medications have the same mechanisms of action, differing mainly by their side effect profile. One difference noted was the lower incidence of gynecomastia using eplerenone compared with canrenone or spironolactone, with <1% incidence in the largest and longest follow-up trial6 compared with a trial with similar duration and size but using spironolactone5 with a 10% incidence. The overall incidence of hyperkalaemia was 5.9% for patients on aldosterone blockers and 3.0% for the control group—similar to that of add-on therapy with candesartan.35 It is unlikely that a head-to-head comparison of all three aldosterone receptor-blocking drugs is ever likely to take place in heart failure or post-MI, and although caution should be exercised in extrapolating across different trials, there appears to be moderate evidence for a class effect for the aldosterone receptor blockers.

Heart failure and MI share many similarities in the underlying myocardial dysfunction that takes place initially and subsequently, however, significant differences exist in the timing of damage. Acute MI initiates a complex, profound, and rapid response in terms of cellular and extracellular remodelling. The changes in collagen synthesis and degradation exhibited by aldosterone blockade appear early and are sustained.24 In chronic heart failure patients, elevated procollagen type III amino-terminal peptide (PIIINP) levels predicted an increased spironolactone response in terms of collagen turnover and clinical outcomes.36 In the two largest trials, EPHESUS and RALES, a mortality benefit was seen as early as 30 days32 and 6 months,5 respectively.

We found a paucity of evidence on the effects of aldosterone blockers in patients with diastolic heart failure or in patients with systolic dysfunction but less severe symptoms. Ongoing large trials should resolve these residual areas of uncertainty. These trials include the Treatment of Preserved Cardiac function heart failure with an Aldosterone anTagonist trial (TOPCAT, funded by the National Heart Lung and Blood Institute, ClinicalTrials.gov Identifier NCT00094302), recruiting 4500 patients with diastolic heart failure and randomized to spironolactone or placebo; the Effect of Eplerenone in Chronic Systolic Heart Failure trial (EMPHASIS-HF, ClinicalTrials.gov Identifier NCT00232180), a trial in 2584 patients with NYHA class 2 symptoms; and the Reversal of Cardiac Remodeling with Eplerenone trial (REMODEL, ClinicalTrials.gov Identifier NCT00082589), recruiting 250 patients with NYHA 2 or 3 symptoms and an EF <35%.

Strengths and limitations

As with all systematic reviews, our analysis is limited by a paucity of data on certain outcomes. Despite an extensive search including contact with authors and industry, we were unable to find other studies on these agents. Study authors of six of the trials provided unpublished information, but important outcomes (e.g. quality of life, ejection fraction, and hospitalizations) were not systematically collected in all studies. Conversely, two studies provided detailed assessment of functional status with function VO2peak testing, showing a 1.46 ml/kg/min improvement, of similar or greater magnitude than seen with cardiac resynchronization.37 Limited duration of follow-up (only six trials extended 1 year or more) also limits our ability to make definite conclusions about the durability of the benefits seen with aldosterone blockers, although the limited data available did suggest that benefits were maintained beyond a year. In addition, the trials span a recruitment period of over a decade during which background medical therapy has changed. However, neither year of recruitment nor year of publication changed the overall results for mortality, indicating that although there may be differences in the overall rates of outcomes of patients with MI or heart failure, the relative benefits remain the same.

Implications of aldosterone blocker use in routine clinical practice

Health outcome studies have demonstrated that the risks of aldosterone blockers are higher in routine practice than in clinical trials, largely because of substantial ‘off-label’ use of spironolactone in HF patients who are at risk for hyperkalaemia or have significant renal dysfunction. For example, 31% of all spironolactone prescriptions to Medicare beneficiaries in 2001 (after publication of RALES) were for patients who would have been ineligible for RALES due to their potassium or creatinine levels at baseline.38 However, if aldosterone blockers are prescribed by experienced clinicians and patients are monitored as closely as in the trials, the benefit–safety profile of these agents can be similar to the trial data we present here.8 A number of case series of patients who developed hyperkalaemia on aldosterone blockers have identified the risk factors including abnormal renal function at baseline, diabetes mellitus, infrequent monitoring of serum electrolytes, use of higher doses of spironolactone (i.e. >50 mg/day), and concomitant use of non-steroidal anti-inflammatory drugs, or potassium supplements.39 A large heart failure trial of aldosterone blockade has shown significant all-cause mortality reduction on top of angiotensin-converting enzyme inhibition,5 whereas angiotensin receptor blocker (ARB) trials did not (and in the largest of the ARB trials, there was an absolute 2.7% increase in the incidence of hyperkalaemia and a 3.7% increase in creatinine over placebo);40 renin inhibitor trials are underway. Consideration of these and other factors (such as hypotension) should be taken into account when prescribing aldosterone blockers, and initiation of an aldosterone blocker should precede that of an ARB in most eligible patients already on an angiotensin-converting enzyme inhibitor.

Conclusions

Aldosterone blockade is associated with a significant reduction in mortality for selected patients with left ventricular dysfunction. The overall safety profile of this class of medication should be considered before prescribing, but used correctly should be considered a key medication. Ongoing studies will provide much needed data to address their role in patients with diastolic heart failure or in those with less severe symptom status.

Funding

J.A.E. is supported by the Canadian Institutes of Health Research Randomized Controlled Trials Program. F.A.M. is a Population Health Scholar supported by the Alberta Heritage Foundation for Medical Research and holds the Merck Frosst/Aventis Chair in Patient Health Management at the University of Alberta, Edmonton.

Conflict of interest: none declared.

Acknowledgements

We are indebted to the following authors who provided additional information regarding their studies: T. Tsutamoto, A. Struthers, P. Mottram, A. Orea-Tejeda, A. Boccanelli, A. Maggioni, and C. Berry. We also thank our medical research librarian, Tamara Durec, MLis, and statistical support from Ben Vandermeer, MSc.

References

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