London, UK - Results of the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-W) study, published in the June 10, 2006 issue of the Lancet, reaffirm the role of warfarin in stroke prevention in atrial-fibrillation (AF) patients and strongly suggest the way forward for new agents in this field will not take the form of antiplatelet drugs [1].

As previously reported by heartwire, principal investigator Dr Stuart Connolly (McMaster University, Hamilton, ON) presented the results from the warfarin arm of the ACTIVE-W at the American Heart Association 2005 meeting.

The trial, Connolly told heartwire when he first presented the results, underscores the difficulty of developing new drugs to replace an agent that, while tricky to use and unloved by patients and physicians alike, has been around for 50 years.

Now, commenting on the publication of the ACTIVE-W results, Connolly emphasized that the findings clearly favor oral anticoagulation for prevention of stroke in AF, but the devil is in the details.

"On the surface, this study strongly suggests carrying on with warfarin; what's lurking beneath the surface is that this study is primarily addressing the issue of patients already doing well on warfarin and what happens when they switch to clopidogrel plus aspirin," Connolly explained to heartwire. "And what it doesn't really address, unfortunately, is that there are a lot of people who aren't doing well on warfarin or who don't take warfarin at all. The subgroup analysis suggests, somewhat obliquely, that perhaps the story would be different in those types of patients."

While the best way to compare oral anticoagulation therapy with clopidogrel plus aspirin would be in patients not previously exposed to warfarin, the authors note, such a trial is unlikely to be done in the wake of ACTIVE-W. Whether dual antiplatelet therapy has any role at all to play in AF patients for stroke prevention may come from another arm of the ACTIVE trial (ACTIVE-A), which is examining patients who can't or won't take warfarin, randomizing patients to aspirin alone or a combination of aspirin plus clopidogrel.

That trial has only just finished enrollment of roughly 7500 patients and will be following them at least until the end of 2007, Connolly confirmed to heartwire. For now, he says, "there's no way of knowing if adding clopidogrel is beneficial if your patient is just on aspirin. If that turns out to be quite beneficial, that would be very important information, and there may well be a group of patients in whom it is appropriate to treat with clopidogrel plus aspirin."

That's a big "if," Connolly admits. "Except for ACTIVE-A, this is probably the end of antiplatelet agents in AF for the time being. If ACTIVE-A is surprisingly strong—which no one is really expecting right now, although stranger things have happened—it could revitalize it. But that would have to be a pretty powerful result—I'd say at least a 20% to 25% risk reduction. That's certainly not impossible, but we'll have to wait and see."

As such, ACTIVE-W should stand as an example for future trials, he says. "It certainly puts the challenge out to [people designing] future studies that you better be careful about this or you, too, may end up studying your new drug in patients who are very used to taking warfarin, and they'll likely do very well on warfarin in the trial, probably better than the average person who takes warfarin."

In an accompanying comment, Dr Freek WA Verheugt (University Medical Centre St Radboud, Nijmegen, the Netherlands) observes that the failure of dual antiplatelet therapy in AF patients at risk of stroke is a "disappointment" but adds to a growing list of trials in which bleeding risk over the long term negates any benefit of dual antiplatelet therapy [2].

"After ACTIVE-W, there is no indication whatsoever to change the current standard of care in high-risk patients with atrial fibrillation," Verheugt writes. "New developments are to be expected from innovative oral direct-thrombin blockers or oral factor-Xa inhibitors, rather than from available antiplatelet agents."