ACTIVE-W: Warfarin still the best option for stroke prevention in AF

Shelley Wood

June 09, 2006

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 heart wire , 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 heart wire 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 heart wire . "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."

Fewer events, fewer bleeds with warfarin

ACTIVE-W was halted early due to clear superiority of warfarin. At the time it was stopped, the target enrollment had been reached: 6600 patients with AF plus at least one risk factor for stroke were randomized to standard therapy with oral anticoagulation (warfarin) or clopidogrel plus aspirin (ASA). Patients in the trial were followed for approximately two years.

At follow-up, rates of vascular events—the primary end point of the study, defined as stroke, embolism, MI, and vascular death—were significantly higher in the clopidogrel/ASA group than in the warfarin group, a difference of 1.7% per year. The biggest benefit of warfarin therapy was in stroke prevention; major bleeding events, however, were similar between the two therapies. When the primary outcome and bleeding events were combined to explore the net benefit of one treatment over the other, patients in the warfarin group were significantly less likely to experience the combined events.

Vascular events and major bleeding: ACTIVE-W final results

End point Clopidogrel+ASA (%/y) Warfarin (%/y) Relative risk 95% CI p
Vascular events 5.60 3.93 1.44 1.18-1.76 0.0003
Stroke 2.39 1.40 1.72 1.24-2.37 0.001
Major hemorrhage 2.42 2.21 1.10 0.83-1.45 0.53
Net benefit* 7.56 5.45 1.41 1.19-1.67 <0.0001
*Primary outcome and major bleed

Several important observations were made in specific subgroups. As Connolly presented previously, 77% of study participants had been taking warfarin at the time of study enrollment: in those patients who switched from warfarin to clopidogrel/ASA as a result of randomization to this arm of the study, the rate of vascular events was significantly higher than in patients who had been on warfarin before study enrollment and remained on warfarin during the study. By contrast, patients who had not been on warfarin before study initiation who were then randomized to warfarin showed a much more modest benefit of anticoagulation therapy over dual antiplatelet therapy. Rates of major bleeding, by contrast, were not significantly higher in patients who were on warfarin prior to the study, then switched to clopidogrel/ASA, than in nonswitchers, nor were they significantly different between the clopidogrel/ASA and warfarin patients who had not been on prior warfarin. Part of the differences seen between switchers and nonswitchers might be explained by the fact that people previously on warfarin were more likely to have better INR control during the study. During the study, patients randomized to anticoagulation had INR levels within the target range 64% of the time.

"If people tolerated warfarin better, they had lower rates of discontinuation and they had more INRs in the therapeutic range if they'd previously been on it, and that's probably the reason they do better, but that's not proven," Connolly told heartwire .

Risk of vascular events in patients randomized to clopidogrel/ASA vs randomization to warfarin

Risk (%/y) Clopidogrel+ASA Warfarin Relative risk (95% CI) p
Patients on warfarin prior to study 5.5 3.72 1.5 (1.19-1.89) 0.0005
Patients not on warfarin prior to study 5.89 4.71 1.27 (0.85-1.89) 0.24

Risk of major bleeding in patients randomized to clopidogrel/ASA vs randomization to warfarin

Risk (%/y) Clopidogrel+ASA Warfarin Relative risk p
Patients on warfarin prior to study 2.63 2.02 1.30 (0.94-1.79) 0.11
Patients not on warfarin prior to study 1.73 2.92 0.59 (0.32-1.08) 0.09
-SW

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."

Other classes of drug represent the way forward

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."

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