NIHR DC Discover

NIHR Signal Aldosterone antagonists reduce deaths, including sudden deaths, in people with heart failure

Published on 17 May 2016

doi: 10.3310/signal-000239

In adults with longstanding heart failure or recent heart attack aldosterone antagonists reduced sudden cardiac deaths and deaths from any cause. There were important side effects, including an increase in kidney injury.

Most studies focussed specifically on left heart failure.

More research is needed to establish the place of these types of drugs in practice and clinical decision making should be mindful of the impact on effectiveness and side-effects.

The findings are in line with current NICE guidance, which include aldosterone antagonists as options in the management of people with this specific type of heart failure or with left ventricular dysfunction after a recent heart attack.

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Why was this study needed?

Conditions such as severe heart attacks or coronary artery disease damage heart muscle which becomes weaker. This reduces the amount of blood that the heart can pump leading eventually to heart failure, which affects about 900,000 people in the UK. Life expectancy is shortened and the risk of sudden cardiac death is increased.

Management, depending on the specific type of heart disease, uses a combination of lifestyle changes, medicines, devices or surgery to improve heart function and quality of life.

Aldosterone antagonists are a group of medicines often used to manage heart failure. They may reduce sudden deaths by preventing irregular heartbeats or other mechanisms. Smaller studies had shown some improved survival but adding together the findings of several studies was needed to confirm this effect.

What did this study do?

This systematic review and meta-analysis found 25 randomised controlled trials involving 19,333 adults with left heart failure or recent heart attack.

Trials compared aldosterone antagonists spironolactone (15 trials), eplerenone (seven trials) or canrenoate potassium (three trials) to a placebo in most cases. Five of the 25 trials were not placebo controlled. Other treatment for heart failure and coexisting disease was continued in most studies. Treatments lasted for an average of one year (range 3 to 44 months).

All trials were rated as high quality with a low risk of bias meaning the results should be reliable.

What did it find?

  • Compared to placebo or routine drug treatment, treatment with an aldosterone antagonist for people with heart failure significantly reduced the rate of sudden cardiac death from 6.09% in the placebo group to 4.89% in the treated group, an absolute difference of 1.2%. The relative risk was 0.81, 95% confidence interval 0.67 to 0.98.
  • For the other outcomes there was also an absolute reduction in
    • death from any cause (16.21% vs 19.96%), and
    • cardiovascular death (17.03% vs 22.54%).
  • The corresponding absolute reductions for people with recent heart attack were
    • sudden cardiac death (4.88% vs 6.08%),
    • death from any cause (11.64% vs 13.71%), and
    • cardiovascular death (10.35% vs 12.41%).
  • Hospitalisation for any reason was also significantly reduced with aldosterone antagonist treatment compared to placebo or routine drug treatment.
  • Overall, adverse event rates of common side effects were twice as high in people treated with aldosterone antagonists (5.19%) compared to placebo or routine drug treatment (2.67%). These adverse effects were hyperkalemia (8.6% vs 4.5%), worsening renal function (4.6% vs 3.1 %) or gynecomastia (1.8% vs 0.5%).

What does current guidance say on this issue?

NICE guidance on heart failure from 2010 recommends seeking specialist advice if a person still has symptoms, despite treatment with an ACE inhibitor and beta-blocker. The specialist could consider adding an aldosterone antagonist licensed for heart failure, particularly if the person has moderate to severe heart failure or has had a heart attack within the past month.

NICE guidance on myocardial infarction from 2013 recommends that people who have had an acute heart attack and who have symptoms and/or signs of heart failure and left ventricular systolic dysfunction, should be treated with an aldosterone antagonist licensed for post heart attack treatment. This treatment should start within three to 14 days of the heart attack, preferably after ACE inhibitor therapy.

What are the implications?

These findings suggest that aldosterone antagonists reduce sudden cardiac deaths, deaths from any cause, and hospitalisations for people with heart failure or a recent heart attack. Hyperkalaemia was the most common side effect.

The findings are in line with current NICE guidance. More information is needed on the cost-effectiveness of aldosterone antagonists for this population.

Citation and Funding

Le HH, El-Khatib C, Mombled M et al. Impact of aldosterone antagonists on sudden cardiac death prevention in heart failure and post-myocardial infarction patients: a systematic review and meta-analysis of randomised controlled trials. PLoS ONE. 2016;11(2):e0145958.

This study was funded by a scholarship from the French Ministry of Higher Education and Research.

Bibliography

NICE. Chronic heart failure in adults: management. CG108. London: National Institute of Health and Care Excellence; 2010.

NICE. Myocardial infarction: cardiac rehabilitation and prevention of further MI. CG172. London: National Institute of Health and Care Excellence; 2013.

Why was this study needed?

Conditions such as severe heart attacks or coronary artery disease damage heart muscle which becomes weaker. This reduces the amount of blood that the heart can pump leading eventually to heart failure, which affects about 900,000 people in the UK. Life expectancy is shortened and the risk of sudden cardiac death is increased.

Management, depending on the specific type of heart disease, uses a combination of lifestyle changes, medicines, devices or surgery to improve heart function and quality of life.

Aldosterone antagonists are a group of medicines often used to manage heart failure. They may reduce sudden deaths by preventing irregular heartbeats or other mechanisms. Smaller studies had shown some improved survival but adding together the findings of several studies was needed to confirm this effect.

What did this study do?

This systematic review and meta-analysis found 25 randomised controlled trials involving 19,333 adults with left heart failure or recent heart attack.

Trials compared aldosterone antagonists spironolactone (15 trials), eplerenone (seven trials) or canrenoate potassium (three trials) to a placebo in most cases. Five of the 25 trials were not placebo controlled. Other treatment for heart failure and coexisting disease was continued in most studies. Treatments lasted for an average of one year (range 3 to 44 months).

All trials were rated as high quality with a low risk of bias meaning the results should be reliable.

What did it find?

  • Compared to placebo or routine drug treatment, treatment with an aldosterone antagonist for people with heart failure significantly reduced the rate of sudden cardiac death from 6.09% in the placebo group to 4.89% in the treated group, an absolute difference of 1.2%. The relative risk was 0.81, 95% confidence interval 0.67 to 0.98.
  • For the other outcomes there was also an absolute reduction in
    • death from any cause (16.21% vs 19.96%), and
    • cardiovascular death (17.03% vs 22.54%).
  • The corresponding absolute reductions for people with recent heart attack were
    • sudden cardiac death (4.88% vs 6.08%),
    • death from any cause (11.64% vs 13.71%), and
    • cardiovascular death (10.35% vs 12.41%).
  • Hospitalisation for any reason was also significantly reduced with aldosterone antagonist treatment compared to placebo or routine drug treatment.
  • Overall, adverse event rates of common side effects were twice as high in people treated with aldosterone antagonists (5.19%) compared to placebo or routine drug treatment (2.67%). These adverse effects were hyperkalemia (8.6% vs 4.5%), worsening renal function (4.6% vs 3.1 %) or gynecomastia (1.8% vs 0.5%).

What does current guidance say on this issue?

NICE guidance on heart failure from 2010 recommends seeking specialist advice if a person still has symptoms, despite treatment with an ACE inhibitor and beta-blocker. The specialist could consider adding an aldosterone antagonist licensed for heart failure, particularly if the person has moderate to severe heart failure or has had a heart attack within the past month.

NICE guidance on myocardial infarction from 2013 recommends that people who have had an acute heart attack and who have symptoms and/or signs of heart failure and left ventricular systolic dysfunction, should be treated with an aldosterone antagonist licensed for post heart attack treatment. This treatment should start within three to 14 days of the heart attack, preferably after ACE inhibitor therapy.

What are the implications?

These findings suggest that aldosterone antagonists reduce sudden cardiac deaths, deaths from any cause, and hospitalisations for people with heart failure or a recent heart attack. Hyperkalaemia was the most common side effect.

The findings are in line with current NICE guidance. More information is needed on the cost-effectiveness of aldosterone antagonists for this population.

Citation and Funding

Le HH, El-Khatib C, Mombled M et al. Impact of aldosterone antagonists on sudden cardiac death prevention in heart failure and post-myocardial infarction patients: a systematic review and meta-analysis of randomised controlled trials. PLoS ONE. 2016;11(2):e0145958.

This study was funded by a scholarship from the French Ministry of Higher Education and Research.

Bibliography

NICE. Chronic heart failure in adults: management. CG108. London: National Institute of Health and Care Excellence; 2010.

NICE. Myocardial infarction: cardiac rehabilitation and prevention of further MI. CG172. London: National Institute of Health and Care Excellence; 2013.

Impact of Aldosterone Antagonists on Sudden Cardiac Death Prevention in Heart Failure and Post-Myocardial Infarction Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Published on 20 February 2016

Le, H. H.,El-Khatib, C.,Mombled, M.,Guitarian, F.,Al-Gobari, M.,Fall, M.,Janiaud, P.,Marchant, I.,Cucherat, M.,Bejan-Angoulvant, T.,Gueyffier, F.

PLoS One Volume 11 , 2016

BACKGROUND AND OBJECTIVES: Sudden cardiac death (SCD) is a severe burden of modern medicine. Aldosterone antagonist is publicized as effective in reducing mortality in patients with heart failure (HF) or post myocardial infarction (MI). Our study aimed to assess the efficacy of AAs on mortality including SCD, hospitalization admission and several common adverse effects. METHODS: We searched Embase, PubMed, Web of Science, Cochrane library and clinicaltrial.gov for randomized controlled trials (RCTs) assigning AAs in patients with HF or post MI through May 2015. The comparator included standard medication or placebo, or both. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Event rates were compared using a random effects model. Prospective RCTs of AAs with durations of at least 8 weeks were selected if they included at least one of the following outcomes: SCD, all-cause/cardiovascular mortality, all-cause/cardiovascular hospitalization and common side effects (hyperkalemia, renal function degradation and gynecomastia). RESULTS: Data from 19,333 patients enrolled in 25 trials were included. In patients with HF, this treatment significantly reduced the risk of SCD by 19% (RR 0.81; 95% CI, 0.67-0.98; p = 0.03); all-cause mortality by 19% (RR 0.81; 95% CI, 0.74-0.88, p<0.00001) and cardiovascular death by 21% (RR 0.79; 95% CI, 0.70-0.89, p<0.00001). In patients with post-MI, the matching reduced risks were 20% (RR 0.80; 95% CI, 0.66-0.98; p = 0.03), 15% (RR 0.85; 95% CI, 0.76-0.95, p = 0.003) and 17% (RR 0.83; 95% CI, 0.74-0.94, p = 0.003), respectively. Concerning both subgroups, the relative risks respectively decreased by 19% (RR 0.81; 95% CI, 0.71-0.92; p = 0.002) for SCD, 18% (RR 0.82; 95% CI, 0.77-0.88, p < 0.0001) for all-cause mortality and 20% (RR 0.80; 95% CI, 0.74-0.87, p < 0.0001) for cardiovascular mortality in patients treated with AAs. As well, hospitalizations were significantly reduced, while common adverse effects were significantly increased. CONCLUSION: Aldosterone antagonists appear to be effective in reducing SCD and other mortality events, compared with placebo or standard medication in patients with HF and/or after a MI.

Sudden cardiac death is defined as unexpected natural death from a cardiac cause within a short time period, generally within one hour from the onset of symptoms, in a person without any prior condition that would appear fatal.

Heart failure was considered by the authors in this review to be left ventricular failure which is the most common type, where there is weakening of the part of the heart that pumps blood around the body (the left ventricle).

Expert commentary

Consistent with insights from the some key trials, this meta-analysis clearly shows how aldosterone antagonists are effective in reducing the risk of sudden cardiac death and other mortality events, when compared with placebo or standard medications amongst patients with heart failure and/or after a myocardial infarction. Thus, aldosterone antagonists should be part of the holistic management of such patients.

Gregory Lip, Professor of Cardiovascular Medicine, University of Birmingham