(Circulation. 1997;96:2823-2829.)
© 1997 American Heart Association, Inc.
Articles |
Quantitative Overview of Randomized Trials of Amiodarone to Prevent Sudden Cardiac Death
From the Department of Health Research and Policy and the Department of Medicine, Stanford (Calif) University School of Medicine, and the VA Informatics Program and the VA Cooperative Studies Program, Palo Alto (Calif) VA Health Care System.
Correspondence to Mark A. Hlatky, MD, Stanford University School of Medicine, HRP Redwood Bldg, Room 150, Stanford, CA 94305-5092. E-mail mr.mah{at}forsythe.stanford.edu
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Abstract |
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Background Some randomized clinical trials of amiodarone therapy to prevent sudden cardiac death have had positive results and others have had negative results, but all were relatively small. This meta-analysis aimed to pool all trials to assess the effect of amiodarone on mortality and the impact of differences in patient population and study design on trial outcomes.
Methods and Results Fifteen randomized trials were identified, and outcome measures were combined by use of a random effects model. The effect of patient population and study design on total mortality was assessed by use of a hierarchical Bayes model. Amiodarone reduced total mortality by 19% (confidence limits, 6% to 31%; P<.01), with somewhat greater reductions in cardiac mortality (23%, P<.001) and sudden death (30%, P<.001). Mortality reductions were similar in trials enrolling patients after myocardial infarction (21%), with left ventricular dysfunction (22%), and after cardiac arrest (25%). There was a trend toward greater risk reduction in trials requiring evidence of ventricular ectopy (25%) than in the remaining trials (10%). The trials using placebo controls had considerably less risk reduction (10%) than trials with active controls (27%) or usual care controls (42%, posterior odds <0.02).
Conclusions Amiodarone reduced total mortality by 10% to 19% in patients at risk of sudden cardiac death. Amiodarone reduced risk similarly in patients after myocardial infarction, with heart failure, or with clinically evident arrhythmia. The apparent inconsistencies among results of randomized trials appear to be due to small sample sizes and the type of control group used, not the type of patient enrolled.
Key Words: meta-analysis • antiarrhythmia agents • death, sudden • prevention • amiodarone
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Introduction |
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Half of all deaths resulting from cardiac disease happen suddenly and unexpectedly, predominantly in patients with clinically evident heart disease. Because the outcomes of out-of-hospital cardiac arrest are so poor, preventive therapy targeted to patients with an established diagnosis of heart disease remains the most promising approach to reducing sudden cardiac death.
Amiodarone has shown considerable promise as a treatment to reduce sudden cardiac death. This drug has a complex pharmacological profile, multiple mechanisms of action, and the potential for serious side effects.1 2 It has been most widely used in patients with clinically evident arrhythmias such as resuscitated cardiac arrest or sustained ventricular tachycardia. Based on favorable experience in treating patients with symptomatic ventricular arrhythmia, a number of small clinical trials3 4 5 6 7 8 9 10 explored the potential efficacy of amiodarone as preventive therapy in patients without symptomatic arrhythmia. Initial experience in these trials was promising, and meta-analyses of these early studies suggested that amiodarone might have considerable efficacy in reducing mortality in patients at moderate to high risk of sudden death.11 12
Findings from several larger randomized trials of amiodarone have since been released. Among patients with heart failure, amiodarone significantly reduced mortality in the GESICA13 but not in the CHF-STAT14 trials. The divergent findings of these two trials have led to the suggestion that the underlying cause of heart failure may affect the efficacy of amiodarone.14 15 16 More recently, two large randomized trials of patients with recent myocardial infarction have been presented.17 18 CAMIAT showed a significant reduction in sudden death and resuscitated cardiac arrest,17 whereas EMIAT reported insignificant reductions in arrhythmic events and no change in total mortality.18 These two large, well-designed trials therefore also have seemingly contradictory results.
The findings of randomized trials of amiodarone are apparently inconsistent, but the largest study randomized <1500 patients; therefore, none of the studies was large enough to be definitive. While some of the apparent inconsistency among the trials may be due to the play of chance, these variations may also be due to differences in the enrolled populations or in the design of the studies. We therefore performed a quantitative overview of randomized trials to assess whether amiodarone reduced total mortality and, if so, whether sudden death was reduced selectively. We also sought to explore the effect on the summary outcomes of differences among trials in patient population and in study design.
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Methods |
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Data Retrieval
We retrieved from MEDLINE and BIOSIS all trials of amiodarone published between January 1985 and March 1997. Trials were included if (1) random allocation was used, (2) mortality outcomes were reported, and (3) treatment and follow-up lasted at least 3 months. Trials were excluded if (1) amiodarone was given intravenously, (2) treatment was for atrial arrhythmias or for nonarrhythmic indications, (3) the underlying cardiac disease was hypertrophic cardiomyopathy, or (4) patients could be randomized to an implantable cardiac defibrillator. We checked all cross-references and relevant conference proceedings and pursued professional contacts to identify all relevant trials. Studies were abstracted by two independent reviewers and were checked by a third with differences resolved by consensus.
Outcomes
The outcomes pooled across trials were (1) total mortality, (2)
cardiac death, and (3) sudden death, regardless of which outcome was
designated as the primary end point by the trial investigators. All
outcomes were analyzed at the longest follow-up time reported
for each trial.
We also performed three a priori subgroup analyses based on (1) the primary patient population (post–myocardial infarction, left ventricular dysfunction, or post–cardiac arrest), (2) whether the patient inclusion criteria required documentation of a minimum number of ventricular premature beats per hour on a 24-hour Holter recording, and (3) the type of control treatment (placebo, usual care, or active antiarrhythmic control).
Data Analysis
Odds ratios from the trials were combined by use of the
DerSimonian and Laird random-effects method to yield overall and
subgroup summary estimates. Analyses with this model were
performed with Meta-Analyst software. Nominal probability values were
reported without correction for multiple comparisons.
We used the hierarchical Bayes linear model as described by Du Mouchel and Harris19 to determine whether subgroups of trials had results that were systematically different from the others. The advantage of this method over the more commonly used Q statistic is that the latter detects only nonspecific heterogeneity, whereas the hierarchical Bayes approach can simultaneously account for three sources of variation in the estimate of treatment effects: specific hypothesized sources (such as differences in the patient population), unknown sources, and sampling error. As a result, Bayesian posterior probability estimates provide more statistical power for detecting differences between subgroups.19
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Results |
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Description of the Trials
We identified 31 randomized trials of amiodarone in patients at risk of sudden cardiac death. We excluded 16 trials: 11 trials had <3 months of follow-up, 3 trials had complex interventions that did not allow the effects of amiodarone to be separately assessed,20 21 22 and 2 trials included treatment with an implantable defibrillator.23 24
The remaining 15 trials3 4 5 6 7 8 9 10 13 14 17 18 25 26 27 randomized
5864 patients, 2936 to amiodarone and 2928 to control (Table 1
). The BASIS4 and
SSSD6 studies had three arms each, and we analyzed
only the usual care and amiodarone arms from these two studies.
Only those data reported using the intention-to-treat principle were
analyzed in the present overview, including the results
from the CAMIAT trial.17
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The trials varied widely in the proportion of patients with
coronary artery disease, clinical congestive heart failure,
prior myocardial infarction, and documented arrhythmia (Table 2). The average ejection fraction of the
trial populations ranged from 18% to 44%. Ten trials required
documentation of frequent ventricular ectopic activity as a
criterion for entry. The amiodarone maintenance dose
varied from 200 to 400 mg/d. The Q statistic did not reveal any
evidence of statistical heterogeneity in any of our
analyses (P>.10 for all analyses), although
this test has low statistical power.
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Overall Mortality
Total mortality was significantly reduced by amiodarone
after the results of all 15 reported trials were pooled (Fig 1). Total mortality in
amiodarone-treated patients was 16.5% versus 19.2% in the
control patients, with an amiodarone-to-control odds ratio of
0.81 (95% confidence interval [CI], 0.69 to 0.94;
P<.01). Cardiac mortality was 13.2% in
amiodarone-treated patients versus 16.4% in control patients,
for an odds ratio of 0.77 (95% CI, 0.66 to 0.89; P<.001).
Sudden death was 6.9% in amiodarone-treated patients versus
9.6% in control patients, for an amiodarone-to-control odds
ratio of 0.70 (95% CI, 0.58 to 0.85; P<.001). Noncardiac
mortality was insignificantly higher among amiodarone-treated
patients (3.2% versus 2.8%; odds ratio, 1.15; 95% CI, 0.85 to 1.56;
P=.37).
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Subgroup Analyses
Eight randomized trials were conducted with a principal inclusion
criterion of recent myocardial infarction, 5 trials with a principal
inclusion criterion of heart failure or left ventricular
dysfunction, and 2 trials with a principal inclusion criterion of prior
cardiac arrest. Total mortality, cardiac mortality, and sudden death
were reduced to a similar degree in each of these three categories
(Table 3). The hierarchical Bayes
analysis (Fig 2, top) suggested
that amiodarone had similar effects on total mortality
regardless of the patient population enrolled.
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Ten trials required some evidence of ventricular
arrhythmia prior to enrollment (frequent
ventricular ectopic activity in 8 trials and prior cardiac
arrest in 2 trials), while the remaining 5 trials did not. There was a
trend toward a greater reduction in total mortality by
amiodarone in the 10 trials that required some evidence of
arrhythmia (odds ratio 0.75; 95% CI, 0.62 to 0.91;
P=.004) than in the 5 trials that did not (odds ratio, 0.90;
95% CI, 0.71 to 1.15; P=.41). Hierarchical Bayes
analysis provided suggestive but not definitive evidence that
these two groups of trials had different results (Fig 2
, middle).
Eight of the trials used placebo controls, 4 trials used "usual
care" controls, and three trials used active controls. The medical
regimens used in "usual care" controls were not reported in
detail6 10 13 28 ; active control therapies included
propranolol,25 sotalol,26 and
individualized treatment with predominantly type I antiarrhythmic
agents27 (Table 1). The odds ratio for total mortality was
considerably lower in trials with "usual care" controls (odds
ratio, 0.58; 95% CI, 0.41 to 0.83; P=.003) and in trials
with active controls (odds ratio, 0.73; 95% CI, 0.43 to 1.25;
P=.25) than in trials with placebo controls (odds ratio,
0.90; 95% CI, 0.76 to 1.06; P=.20). The hierarchical Bayes
analysis strongly suggested (99% posterior probability) that
the placebo-controlled trials showed less amiodarone efficacy
than the "usual care"-controlled trials (Fig 2, bottom).
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Discussion |
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This quantitative overview suggests that amiodarone therapy reduces total mortality by between 10% (placebo-controlled trials only) and 19% (all trials) in patients at moderate to high risk of sudden cardiac death. Risk reductions were comparable across trials regardless of the patient population studied. Finally, the weight of available evidence suggests that the apparent inconsistencies among the results of randomized trials of amiodarone are more likely to be due to small sample sizes and differences in the type of control used (ie, placebo controls or not) than to differences in the clinical characteristics of the patients enrolled.
Amiodarone has a wide array of actions that may improve survival, including both type III and I antiarrhythmic properties, the ability to block both ß-adrenergic receptors and calcium channels, as well as antithyroid and vasodilator actions.1 2 We hypothesized at the outset of this study that if amiodarone were beneficial primarily because its antiarrhythmic effects, then sudden death should be more strikingly reduced than cardiac mortality or total mortality. Sudden death was indeed reduced to a greater extent than total mortality (30% versus 19%), but interpretation of cause-specific mortality as due to specific mechanisms is difficult and often controversial.29 First, it is possible that not all sudden deaths are truly due to an arrhythmic mechanism and that not all arrhythmic deaths are sudden.29 Second, true reductions in one cause of death may be offset by increases in deaths from alternative causes. Indeed, there was a trend in the present overview toward increased risk of noncardiac death among patients randomized to amiodarone (odds ratio, 1.15; P=.37). In trials of the implantable cardioverter-defibrillator, the primary end point has been total mortality in large part because of concerns that the device might convert sudden deaths to nonsudden cardiac deaths in some patients.30 Thus, although cause-specific rates of death are important to illuminate the mechanism of action of therapies, total mortality remains the most important end point. Nevertheless, the present overview strongly suggests that the reduction in sudden cardiac death afforded by amiodarone (30%) does indeed translate into a significant reduction in total mortality (19%).
Patients with recent myocardial infarction, congestive heart failure,
or prior symptomatic ventricular
arrhythmias have all been shown to have increased risk of
sudden death. These patient populations overlap to a considerable
extent, however, with many myocardial infarction patients having heart
failure and many cases of heart failure caused by prior myocardial
infarction. Thus, although randomized trials of amiodarone have
used different eligibility criteria, the patient populations actually
enrolled overlapped considerably in their clinical characteristics.
Indeed, even using the more powerful hierarchical Bayes model, we found
no evidence of significant heterogeneity in the trial
results that could be attributed to differences in the populations of
patients enrolled. This empirical evidence, coupled with the obvious
overlap of patient characteristics among the trials (Table 2), supports
the pooling of data from randomized trials of amiodarone,
whether they were conducted in patients with recent myocardial
infarction, heart failure, or prior cardiac arrest.
Ventricular ectopic activity on ambulatory
electrocardiography indicates a higher risk of
cardiac death31 32 33 34 and has been thought to indicate a
particular risk of sudden arrhythmic death.35 Some trials
of amiodarone required evidence of ventricular
ectopic activity before enrollment, whereas others did not. We found a
suggestive but not definitive trend toward greater risk reduction in
the trials that required evidence of ventricular ectopic
activity (Fig 2, middle). We were not able to analyze in
detail, however, the relationship between ventricular
ectopy and clinical outcomes because of the group level data
presented in published trial results. Pooling of individual
patient level data from randomized trials of amiodarone would
permit a more stringent test of the hypothesis that amiodarone
is more effective in patients with documented ventricular
ectopic activity. Fortunately, the investigators in the clinical trials
are planning to pool primary data from all amiodarone trials
(S. Connolly, personal communication, 1996); our results suggest that
examining the relationship between risk reduction and the degree of
preexisting ventricular ectopic activity would be of
particular value.
The primary benefit of randomization in clinical trials is that it helps to ensure equal distribution of potential confounding factors, both known and unknown, between treatment groups. In addition, blinding of patients and investigators to the assigned therapy ensures that all patients receive identical nonprotocol treatment. Trials that do not use placebo controls are inherently unblinded, which may lead to systemically different treatment of the patients with nonprotocol therapies after randomization. For example, if treating physicians knew that their usual care control patients were not receiving amiodarone, they may have disproportionately prescribed other therapies, such as type I antiarrhythmic agents. These other therapies may have increased the mortality in the usual care control group and thus artificially inflated the benefit of amiodarone.12 36 Alternatively, amiodarone patients may have received closer follow-up monitoring, thereby improving their outcome through detection and correction of other cardiac problems, such as congestive heart failure or myocardial ischemia. The specific medical therapies used in individual patients, particularly the use of type I antiarrhythmic drugs, were not reported in the trials that used usual care controls,6 10 13 28 so we were unable to test directly whether differences in use of other medications may have affected outcomes. Primary pooling of individual patient level data by trial investigators could address this issue directly by collecting and analyzing data on the use of other cardiac medications.
Using the hierarchical Bayes model, we found that the placebo-controlled studies showed considerably less amiodarone treatment effect (odds ratio, 0.90) than the usual care (odds ratio, 0.58) or active antiarrhythmic studies (odds ratio, 0.73). Because this observation is consistent with strong prior information about the value of using placebo controls in clinical trials, it is convincing despite the multiple hypotheses tested in this meta-analysis. The evidence suggests, in total, that the true risk reduction of amiodarone is likely to be closer to 10% than to 19%.
The findings reported here also suggest an alternative explanation for
the different results of the GESICA13 and
CHF-STAT14 trials. The GESICA trial found a significant
28% reduction in total mortality in patients randomized to
amiodarone, whereas the CHF-STAT study found an insignificant
13% reduction in mortality. In the GESICA study, >40% of the
patients had heart failure cause by either alcoholism or Chagas
disease, while only 39% of patients had a prior myocardial
infarction.13 In the CHF-STAT study, >70% of patients
had heart failure as a result of ischemic heart
disease.14 Commentaries on the findings of these two
trials15 16 have focused on the difference in proportion
of patients with ischemic heart disease to explain the
differences in results, based in part on an insignificant trend toward
improved outcome in CHF-STAT patients without ischemic heart
disease.14 Our results do not support this interpretation,
because patients with recent myocardial infarction, all of whom have
ischemic heart disease, appear to respond to amiodarone
similarly to other patients (Table 3). Furthermore, there was no
evidence of significant heterogeneity among trial
results according to the type of patient enrolled (Fig 2, top).
Finally, we found substantial evidence that trials with placebo
controls (like CHF-STAT) had systematically less striking risk
reductions than trials using usual care controls (like GESICA). Our
findings suggest that differences in trial design and methods, rather
than the patient populations enrolled, explain the difference in the
results of the GESICA and CHF-STAT studies.
Meta-analysis combines information about outcomes across "similar" trials, yet it is a subjective judgment whether trials are similar enough for pooling to be valid. A more objective approach would explore quantitatively how differences in trial design and clinical patient characteristics correlate with the observed trial results. The fixed effects approach to meta-analysis assumes that all trials estimate the same underlying treatment effect regardless of any study level or patient level differences. Clearly, this assumption is often unrealistic. The random effects approach assumes that the underlying treatment effect varies among trials, but in an unspecified way (hence the name "random effects"). The hierarchical Bayes model goes one step further and quantifies the contribution of known study level or patient level differences to the variability in the observed outcomes. Our hierarchical Bayes analysis suggested that differences in patient eligibility criteria were not systematically associated with differences in outcomes, so pooling trials with different inclusion requirements would be appropriate. However, the model also suggests that pooling of amiodarone trials with different types of control groups is problematic. Techniques that quantify the multiple sources of heterogeneity among trial results appear to be a promising methodological development for the field of meta-analysis.
This study has a number of limitations. Like all meta-analyses of published results,37 this analysis relied on information from trials that was reported in a variety of ways. Consequently, available data and definitions of clinical terms and outcomes varied among the studies. Second, the potential interaction between individual patient clinical characteristics and amiodarone treatment on outcomes could not be assessed with the published group level data. Thus, our analysis of the effect of individual patient factors such as left ventricular ejection fraction or frequency of ventricular ectopy on risk reduction was quite indirect. These two limitations may be overcome by the planned collaborative efforts by the clinical trial investigators to pool their primary patient level data. Third, to the extent that negative studies are published less often than positive studies,38 this meta-analysis may be biased toward a more optimistic assessment of the efficacy of amiodarone than is truly the case. Finally, meta-analysis of data from randomized clinical trials provides evidence regarding the efficacy of therapy in carefully selected and closely monitored patients. Rates of morbidity and mortality due to adverse effects of amiodarone, such as pulmonary fibrosis, are likely to be minimized in such circumstances. Clinical recommendations for the use of amiodarone should be based on judgments about its effectiveness in routine practice and on a careful balancing of potential risks and benefits in individual patients.
In conclusion, this quantitative review suggests that amiodarone reduces total mortality in patients at moderate to high risk of sudden death. The totality of evidence suggests the risk of death may be reduced by as much as 19%, but limiting evidence to that provided by placebo-controlled trials would suggest that the risk reduction may be closer to 10%. The risk reduction attributable to amiodarone appears to be similar in different patient populations.
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Acknowledgments |
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This work was supported by grant HS 08362 from the Agency for Health Care Policy and Research, Rockville, Md.
Received March 3, 1997; revision received June 3, 1997; accepted June 5, 1997.
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