Anaheim, CA - The antiarrhythmic drug azimilide has failed to reduce mortality, the primary endpoint in the Azimilide Post Infarct Survival Evaluation (ALIVE) trial of the drug's effect in post-MI patients. But the study still supports the continued development of azimilide for atrial fibrillation (AF), Dr John Camm (St George's Hospital, London, UK) told a late-breaking session today at the American Heart Association Scientific Sessions 2001.
Camm told heartwire that he was far from disappointed with the results: "We were rather satisfied...because for the very first time we were able to use a very sensitive trial design to see whether or not an antiarrhythmic drug...would stand a chance of reducing mortality in this population. We gave it a really good shot - with a very good trial design and lots of endpoints - and the drug simply didn't reduce the mortality, so I think we have settled an important issue." He added that, as a result of the ALIVE study, he did not think it was worth testing other antiarrhythmic drugs in this post-MI setting.
The key messages from ALIVE were that although azimilide had no benefit on mortality, it did not increase deaths either, Camm said. In addition, the trial showed that azimilide therapy can be started in or out of hospital (29% of patients took it as outpatients) and there was a low incidence of torsade de pointes and severe neutropenia with the drug. In addition, in a prespecified endpoint, fewer patients in sinus rhythm at baseline developed AF/flutter on azimilide than on placebo (8 versus 19: HR 0.43; p=0.04).
The best of results . . . and the worst
Dr Douglas Zipes (Indiana University, Indianapolis, IN), who was asked to discuss the late-breaking report on ALIVE, said it represented "the best of results and the worst of results...the best was that there was no increase in mortality [with azimilide], the worst was that there was no decrease in mortality. An antiarrhythmic that does not confer harm is certainly a blessing."
Zipes complimented Camm and colleagues on "a well-designed study with excellent care [of patients]." However, he noted that this "might have blunted a potentially harmful effect of azimilide," and that a longer follow-up time might have also have revealed a detrimental effect of the drug, "although that is pure speculation on my behalf." He also said that although the incidences of neutropenia and torsade de pointes were low with azimilide, "they are still both of concern and may impact upon its overall use...raising the bar of efficacy that the drug has to achieve to gain FDA approval." He concluded by stressing that the effects of azimilide on AF "must be demonstrated in a randomized, prospective controlled trial."
Azimilide, a new Iks/Ikr antiarrhythmic, has been in development for some time for AF by Procter & Gamble. In 1999 the FDA requested more data with the drug after a second pivotal trial failed to show a benefit. But at last year's Scientific Sessions, a meta-analysis of four AF trials with azimilide showed a significant overall effect of the drug at 100-mg and 125-mg doses.
ALIVE data
The primary objectives of ALIVE were to evaluate the effect of 100 mg of oral azimilide compared to placebo on all-cause mortality in 3381 recent (5-21 days) post-MI patients with low left ventricular ejection fraction (LVEF) who were at risk of sudden death and in a subgroup of 1264 patients with low heart rate variability (HRV less than or equal to 20 units) defined to be at high risk of sudden death.
Patient survival and safety were monitored for up to 1 year after randomization. The intent-to-treat analysis showed no effect of azimilide on mortality in all randomized patients and in the subgroup at high risk of mortality
Survival and safety of all patients
Treatment |
No of patients |
Deaths |
Hazard ratio of azimilide vs placebo |
p value |
| 1690 |
196 |
N/A |
N/A |
|
| 1691 |
197 |
1.0 |
0.979 |
Survival and safety of high-risk patients
Treatment |
No of patients |
Deaths |
Hazard ratio of azimilide vs placebo |
p value |
| 642 |
96 |
N/A |
N/A |
|
| 622 |
88 |
0.95 |
0.739 |
There were five cases of torsade de pointes in the azimilide group, compared with one among placebo patients, but none of these were fatal and they tended to occur among those with low potassium, Camm explained. And the neutropenia seen with azimilide recovered spontaneously and there were no serious infections or death as a result. He suggests that patients who take azimilide will only need to have their blood monitored for a relatively short period of time - around 2 to 3 months - because all incidences of this side effect were clustered around one time point.
When asked to respond to Zipes' comments, Camm told heartwire: "He was probably a bit harsh, but he had only just seen the data and I'm sure when he reflects on it he might change his mind. Most of the points that he made had something in their favor but you have to look at each of them. [With respect to the] torsade de pointes and neutropenia - it was all transient and nonfatal, it was easily managed, and we will have to do some monitoring but only early on."
Camm continued: "We have no intention of basing any claim [to AF] on this trial but it was strongly supportive evidence and it's not as though this wasn't a prespecified endpoint...we knew from the outset we'd be dealing with fairly small numbers - it's not like dealing with a heart failure population - but it certainly goes along with all the rest of the AF data on azimilide, so its very strongly supportive data."
Azimilide for AF
Development of azimilide for AF is continuing. Dr Alan Moore (Manager, Cardiac R&D, Procter & Gamble) told heartwirethat the company is committed to developing azimilide for AF because cardiologists have told them that there is a great, unmet need. In the US, an estimated 3 million people suffer from AF, and although there is a drug available to treat this condition there, dofetilide (Tikosyn® - Pfizer), there is very little use of this product because it requires hospitalization and monitoring because of the high incidence of torsades de pointes associated with it.
Moore said there are four trials of azimilide ongoing in patients with supraventricular arrhythmias - including one study of the drug in patients with implantable cardiac defibrillators - to support an application for approval in a broad indication.
The ASTAR trial is underway in North America and is looking at 125 mg of azimilide versus placebo in patients in sinus rhythm who have recurrent AF. The ACOMET 1 and 2 studies (being conducted in North America and Europe respectively) are three-arm trials examining a 125-mg dose of azimilide versus d-sotalol versus placebo. ASTAR and the two ACOMET studies have 6-month follow-up periods and have about a year and a half to go until completion. The trial in patients with ICDs - SHIELD - is actively recruiting and is looking at two doses of azimilide, 75 mg and 125 mg, versus placebo and will have a 1-year follow-up. Moore said the FDA has indicated to the company that one positive Phase 3 trial of azimilide in patients with ICDs will be sufficient to gain approval for this patient population.
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