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Azimilide Post-Infarct Survival Evaluation - ALIVE
Description:
In this randomized, placebo-controlled, double-blind study, azimilide was investigated for its effects on mortality in patients with depressed left ventricular function after recent myocardial infarction (MI) and in a subpopulation of patients with low heart rate variability (HRV).
Hypothesis:
Azimilide will improve survival in recent post-myocardial infarction (post-MI) patients at risk of sudden death.
Study Design
Study Design:
Patients Enrolled: 3,717
Mean Follow Up: Up to one year
Female: 22
Patient Populations:
Men and women screened between days five and 21 post-MI with a LVEF of 15-35%. Patients at risk of sudden death (HRV <20 U) were further stratified with a 24-hour Holter ECG. (Thus, there is a general “at-risk” group as well as a “high-risk” group, the latter being distinguished by the additional risk of low heart rate variability).
Exclusions:
Factors that may predispose to nonarrhythmic death or a low risk of sudden cardiac death due to arrhythmia
Primary Endpoints:
All-cause mortality of patients with recent MI at risk of sudden death (recent MI, included between days 5-21 post-MI; low EF 15-35%), and comparison of azimilide and placebo in a subset of patients defined at high risk (above criteria plus low HRV <20 U)
Drug/Procedures Used:
Azimilide versus placebo to affect survival in recent post-MI patients at risk of sudden death
Concomitant Medications:
Angiotensin-converting enzyme (ACE) inhibitors, aspirin, and beta-blockers
Principal Findings:
Within the placebo group, the general at-risk population had one-year all-cause mortality of 9.5% versus 15% in the high-risk group (hazard ratio [HR], 1.65; p=0.0005). Thus, the trial assumption for determining sample size was well met: one-year all-cause mortality (the primary endpoint) among high-risk patients was estimated to be 15%. The one-year all-cause mortality rate was not influenced by New York Heart Association (NYHA) class, left ventricular ejection fraction (LVEF), gender, diabetes, beta-blocker therapy, or history of previous MI.
In the overall high-risk subgroup, no difference was found between the two treatment groups in all-cause mortality (88 deaths azimilide vs. 96 deaths placebo; HR 0.95; p=ns). (Sample size was further based on the assumption that azimilide would decrease all-cause mortality in this group by at least 45%.)
No significant difference was seen in the primary endpoint for the entire at-risk population (197 deaths azimilide vs. 196 placebo; HR 1.0).
For the trial as a whole, the HR was between 0.95 and 1.0, depending on which of the prespecified subgroups was being analyzed. Investigators found that age, gender, NYHA, LVEF, previous MI, diabetes, and the site of initiation (in or out of the hospital) made no material difference in the subgroup’s endpoint.
Although the effect of concomitant medication was not significant, it appeared that the HRs favored a treatment effect with azimilide independent of the coadministration of ACE inhibitors, aspirin, or beta-blockers. However, because nearly 75% of patients were taking at least one of the agents, only a small number of patients was available to analyze the impact of coadministered therapy.
Noncardiac mortality was reduced with azimilide treatment, while documented arrhythmia mortality was the same in both groups. However, undocumented arrhythmic mortality, wherein patients died suddenly of a presumed arrhythmic cause, was slightly higher, but not statistically so, in the azimilide cohort.
The azimilide arm had five (0.3%) cases of nonfatal torsade de pointes versus one (0.1%) in the placebo group; there was no substantial difference between the groups in regard to other ventricular arrhythmias.
There was an expected low incidence of neutropenia in this trial (15 azimilide patients vs. four placebo patients). None of the neutropenias was associated with life-threatening arrhythmias. All neutropenic patients recovered spontaneously and required no specific therapy for neutropenia.
Of the patients beginning the trial in sinus rhythm, significantly fewer azimilide patients developed atrial fibrillation, a prespecified trial endpoint (eight patients vs. 19 patients; HR 0.43; p=0.04). There was a nonsignificant trend favoring azimilide among patients who began the trial in atrial fibrillation and developed sinus rhythm.
The investigators concluded that low heart rate variability did identify a post-MI population at high mortality risk, that azimilide showed no benefit or adverse effect on all-cause mortality, that the initiation of azimilide in or out of hospital made no difference to the observed mortality, that there was only a low incidence of torsade de pointes and severe neutropenia associated with the use of azimilide, that fewer patients in normal sinus rhythm at baseline developed atrial fibrillation on azimilide than on placebo, and that given the safety of azimilide and its effect on atrial fibrillation seen in this trial and elsewhere, there should be continued development of azimilide to treat atrial fibrillation and atrial flutter.
Interpretation:
Azimilide is the first of a unique class of agents that prolongs the duration of the action potential by partially blocking both the slow and rapid component of the delayed rectifier potassium channel. The molecule is structurally unlike other class III antiarrhythmic agents; azimilide does not contain a methane sulfonamide. The kinetics of the drug are very favorable and allow once daily dosing for a period of 14 days to achieve a steady state.
Although there was no mortality benefit to azimilide, there was no arrhythmic harm conferred by the drug via an increase in mortality. During the trial presentation at the 2001 American Heart Association Annual Scientific Sessions, Dr. Douglas Zipes acknowledged that the study was well done, and speculated that a potential harmful effect might have been blunted by the high usage of concomitant medications or it might have been apparent with longer follow-up. Dr. Zipes also noted that although there were low rates of neutropenia and torsade de pointes, any increase in such occurrences generates concern and would likely create the need for azimilide to demonstrate even greater than normal effectiveness to achieve US Food and Drug Administration approval. A prospective, randomized, controlled trial would be necessary to substantiate differences in regard to atrial fibrillation or flutter.
References:
1) Camm AJ, Pratt CM, Schwartz PJ, et al. Mortality in patients after a recent myocardial infarction. A randomized, placebo-controlled trial of azimilide using heart rate variability for risk stratification. Circulation 2004;109:990-6.
2) ALIVE study design. Am J Cardiol 1998;81:35D-39D.
3) Tran HT. Azimilide dihydrochloride: a unique class III antiarrhythmic agent. Heart Dis 1999;1:114-6.
4) Azimilide. Drugs 2000;59:271-7.
5) Pritchett EL, Page RL, Connolly SJ, Marcello SR, Schnell DJ, Wilkinson WE. Antiarrhythmic effects of azimilide in atrial fibrillation: efficacy and dose-response. Azimilide Supraventricular Arrhythmia Program 3 (SVA-3) Investigators. J Am Coll Cardiol 2000;36:794-802.
6) Van Opstal JM, Leunissen JD, Wellens HJ, Vos MA.
Azimilide and dofetilide produce similar electrophysiological and proarrhythmic effects in a canine model of Torsade de Pointes arrhythmias. Eur J Pharmacol 2001;412:67-76.
7) Singh BN, Sarma JS. What niche will newer class III antiarrhythmic drugs occupy? Curr Cardiol Rep 2001;3:314-23.
8) Connolly SJ, Schnell DJ, Page RL, Wilkinson WE, Marcello SR, Pritchett EL. Dose-response relations of azimilide in the management of symptomatic, recurrent, atrial fibrillation. Am J Cardiol 2001;88:974-9.
Keywords: Neutropenia, Myocardial Infarction, Platelet Aggregation Inhibitors, Ventricular Function, Left, Imidazolidines, Death, Sudden, Piperazines, Electrocardiography, Heart Rate, Delayed Rectifier Potassium Channels, Torsades de Pointes, Stroke Volume, Atrial Fibrillation, Diabetes Mellitus, Sulfonamides, Atrial Flutter
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