Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Review: Amiodarone reduces mortality after MI and for congestive heart failure

ACP J Club. 1998 Jul-Aug;129:2. doi:10.7326/ACPJC-1998-129-1-002

Related Content in this Issue
• Companion Abstract and Commentary: Review: Amiodarone reduces all-cause mortality in patients at risk for sudden cardiac death

Related Content in the Archives
Review: Class II (β-blockers) and class III (amiodarone) antiarrhythmic agents reduce mortality in acute myocardial infarction


Source Citation

Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet. 1997 Nov 15;350:1417-24. [PubMed ID: 7371164]


Abstract

Question

Using individual patient data, what are the benefits and risks of amiodarone for patients who have congestive heart failure (CHF) or a history of myocardial infarction (MI)?

Data sources

Studies were identified through computerized databases and contact with authors and experts by the Amiodarone Trials Meta-Analysis Investigators (ATMAI).

Study selection

Randomized controlled trials comparing amiodarone with placebo or usual care in patients with CHF or a history of MI were selected.

Data extraction

Data were extracted on inclusion criteria, patient and disease characteristics, dose of amiodarone, type of control (placebo or usual care), duration of the study, and side effects. Main outcomes were all-cause mortality and arrhythmic or sudden death. Individual patient data were extracted or provided by trial investigators.

Main results

8 trials studied 5101 patients who had a history of MI, and 5 trials studied 1452 patients with CHF. All trials included a loading dose and a maintenance dose, both of which varied across studies. The combined mean follow-up was 1.4 years. The mean age of the patients was 61 years, 83% were men, 89% had a history of MI, 21% had nonischemic cardiomyopathy, 18% had diabetes, and 42% had ventricular tachycardia. The mean left ventricular ejection fraction was 31%. 29% of patients discontinued amiodarone early.

For all studies using intention-to-treat meta-analysis, the all-cause mortality rate was lower in the amiodarone group than in the control group (P = 0.03), as was the rate of arrhythmic or sudden death (P < 0.001) (Table). Heterogeneity was noted with differences in treatment effect among the individual trials. Subgroup analysis found no differences in benefit with amiodarone therapy among subgroups defined by sex, left ventricular ejection fraction, New York Heart Association class, age, ventricular premature depolarizations, or ventricular tachycardia.

Conclusion

Amiodarone leads to a modest reduction in all-cause mortality, death from arrhythmia, or sudden death in patients who have congestive heart failure or a history of myocardial infarction.

Source of funding: Sanofi, Paris, France.

For correspondence: Dr. S.J. Connolly, Hamilton Health Sciences Corporation, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada. FAX 905-521-8820.


Table. Amiodarone vs control for high-risk patients (congestive heart failure or history of myocardial infarction)*

Outcomes Weighted amiodarone Weighted control NNT
All-cause mortality 10.9%/y 12.3%/y 72
Arrhythmic or sudden death 4.0%/y 5.7%/y 77

*Abbreviation defined in Glossary.


Commentary

Several effective treatments, including β-antagonists, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists, are available to reduce mortality in patients with CHF or a history of MI (1, 2). However, many of these patients are still at increased risk for death caused by ventricular arrhythmia. Class I antiarrhythmic agents and D-sotalol (a class III potassium channel blocker) have been shown to be ineffective in these patients (3, 4). Amiodarone, a drug with a complex pharmacologic profile that includes anti-arrhythmic properties, has been studied in patients with CHF and recent MI; > 12 studies have reported inconclusive results.

The ATMAI trial used individual patient data from 8 studies of patients after MI and 5 studies of patients with CHF. Sim and colleagues used published summary data of the same 13 studies and 2 additional studies on patients who had cardiac arrest. These 2 approaches provide the similar overall conclusion that amiodarone modestly reduces all-cause mortality about 10% to 19%.

Major adverse drug effects from 6 double-blind, placebo-controlled studies were analyzed in the ATMAI study. Compared with patients receiving placebo, patients receiving amiodarone had an increased risk for hypothyroidism (odds ratio [OR] 7.3), hyperthyroidism (OR 2.5), pulmonary infiltrates (OR 3.1), bradycardia (OR 2.6), and liver dysfunction (OR 2.7). At the end of 2 years, more patients in the amiodarone group than in the control group had permanently discontinued the study medications (41% vs 27%), primarily because of adverse effects.

When sudden death was used as the outcome, both meta-analyses found an approximate 30% relative risk reduction, suggesting that amiodarone is effective in preventing arrhythmia-related deaths. Sim and colleagues also reported no difference in treatment among patients with CHF or a history of MI or cardiac arrest. A nonsignificant trend was shown toward larger treatment benefit in trials that required documentation of arrhythmia. The placebo-controlled trials showed fewer benefits with amiodarone than the usual-care controlled trials. This suggests that the larger benefits seen with usual care may simply be a reflection of the harmful arrhythmic effects of other drugs rather than of true amiodarone efficacy. Unfortunately, the drugs used in the usual-care controls were not reported in detail in the primary studies.

The ability to access the original individual patient data and the collaboration of study investigators allowed the ATMAI group to harmonize disparate data and do additional analyses. Of the 16 subgroup analyses, a significant result was found only for the total mortality outcome in the comparison among placebo-controlled trials and trials that used nonplacebo controls, supporting the finding of Sim and colleagues. The ATMAI group also found a higher risk for death in patients with symptomatic CHF. Because the relative treatment benefit is the same among different patient subgroups, the higher baseline risk translates to larger absolute benefits for patients treated with amiodarone.

Available evidence shows that amiodarone has a modest effect in reducing mortality in patients with CHF or who had MI and were at moderate to high risk. However, both meta- analyses had limitations, and several important questions remain. Both meta-analyses excluded trials of patients with implantable cardiac defibrillators; therefore, no conclusion is possible in this subgroup. A recent trial of patients resuscitated from near-fatal ventricular arrhythmias found implantable defibrillators to be superior to amiodarone for increasing survival (5). The large difference in treatment effect between the placebo-controlled trials and trials with usual-care control is unexplained. β-blockers and ACE inhibitors are now frequently used to treat high-risk patients. It is unclear if these drugs were consistently used and if interactions between these agents and amiodarone occurred. It is important to understand the potential interactions of amiodarone with either drug to appreciate the relative benefit. The benefits of amiodarone must also be weighed against the risks for adverse effects, especially potentially fatal pulmonary toxicity. Although a meta-analysis of individual patient data was done by the ATMAI group, multivariate meta-regression analysis using individual patient data was not done. Such an analysis may identify subgroups of patients who will benefit most from this treatment.

Joseph Lau, MD
New England Medical CenterBoston, Massachusetts, USA

Joseph Lau, MD
New England Medical Center
Boston, Massachusetts, USA


References

1. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials.JAMA. 1995;273:1450-6. [PubMed ID: 7654275]

2. Heidenreich PA, Lee TT, Massie BM. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. J Am Coll Cardiol. 1997;30:27-34. [PubMed ID: 9207617]

3. Waldo AL, Camm AJ, de Ruyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet. 1996;348:7-12. [PubMed ID: 8691967]

4. Hine LK, Laird NM, Hewitt P, Chalmers TC. Meta-analysis of empirical long-term antiarrhythmic therapy after myocardial infarction. JAMA. 1989;262:3037-40. [PubMed ID: 2509746]

5. The Antiarrhythmics versus Implantation Defibrillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. N Engl J Med. 1997;337:1576-83. [PubMed ID: 9411221]