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Therapeutics

Review: Amiodarone reduces all-cause mortality in patients at risk for sudden cardiac death

ACP J Club. 1998 Jul-Aug;129:3. doi:10.7326/ACPJC-1998-129-1-003

Related Content in this Issue
• Companion Abstract and Commentary: Review: Amiodarone reduces mortality after MI and for congestive heart failure

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


Source Citation

Sim I, McDonald KM, Lavori PW, Norbutas CM, Hlatky MA. Quantitative overview of randomized trials of amiodarone to prevent sudden cardiac death. Circulation. 1997 Nov 4;96:2823-9. [PubMed ID: 9386144]


Abstract

Question

Can amiodarone reduce the risk for all-cause mortality and cardiac and sudden cardiac death?

Data sources

Studies were identified by searching the MEDLINE and BIOSIS databases, contacting colleagues, and scanning bibliographies of relevant studies and conference proceedings.

Study selection

Randomized controlled trials were selected if they were published from 1985 to March 1997, mortality was reported as an outcome (all-cause, cardiac, and sudden), and treatment and follow-up were > 3 months. Exclusion criteria were use of intravenous amiodarone, treatment of atrial arrhythmias or nonarrhythmic indications, hypertrophic cardiomyopathy as the underlying cardiac disease, or patient allocation to an implantable defibrillator.

Data extraction

Data were extracted on patients, type of control (placebo, active control, or usual care), arrhythmia status, dose of amiodarone, and length of follow-up. Patients had left ventricular dysfunction or had had myocardial infarction (MI) or cardiac arrest.

Main results

15 trials of 5864 patients were included. Meta-analysis showed that patients who received amiodarone had a decreased risk for all-cause mortality (P < 0.01), cardiac death (P < 0.01), and sudden death (P < 0.001) (Table) but not noncardiac death (3.2% vs 2.8%, P = 0.37). The odds ratios (ORs) showed similar reductions in subgroup analyses: Among patients who received amiodarone compared with controls, the all-cause mortality rates were, respectively, 10.2% and 11.8% (OR 0.79, 95% CI 0.60 to 1.04) for patients with a history of MI, 33.2% and 38.5% (OR 0.78, CI 0.59 to 1.05) for patients who had left ventricular dysfunction, and 21.7% and 27.1% (OR 0.75, CI 0.43 to 1.29) for patients with a history of cardiac arrest. Similar ORs were found for cardiac and sudden death. For patients who had evidence of arrhythmias (10 trials), all-cause mortality was decreased (P = 0.004).

Conclusion

Amiodarone therapy leads to modest reductions in the risk for all-cause mortality, cardiac death, and sudden death in all patients who have had myocardial infarction or cardiac arrest or who have left ventricular failure.

Source of funding: Agency for Health Care Policy and Research.

For correspondence: Dr. M.A. Hlatky, Stanford University School of Medicine, HRP Redwood Building, Room 150, Stanford, CA 94305-5092, USA. FAX 650-725-6951.


Table. Amiodarone vs control for patients at risk for sudden cardiac death*

Outcomes Weighted amiodarone Weighted control NNT (95% CI)
All-cause mortality 17% 19% 30 (17 to 95)
Cardiac death 13% 16% 31 (21 to 152)
Sudden death 6.9% 9.6% 38 (26 to 76)

*Abbreviations defined in Glossary; NNT and CI calculated from data in article.


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]