Gold-standard warfarin bests clopidogrel/aspirin combo in AF: ACTIVE-W

Shelley Wood

November 14, 2005

Dallas, TX - Dashing hopes yet again for an alternative to warfarin in atrial-fibrillation (AF) patients, the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events-W (ACTIVE-W) results, pitting a clopidogrel-plus-aspirin (ASA) combination against the gold standard, warfarin, clearly show clopidogrel/ASA to be a dismal disappointment.

Dr Stuart Connolly

As previously reported by heartwire , the data safety and monitoring board for the ACTIVE-W trial stopped it in September 2005 after a clear increase in efficacy was seen in the warfarin arm of the trial.

Providing full details on the data behind that decision during today's late-breaking clinical-trials session at the American Heart Association Scientific Sessions 2005, Dr Stuart Connolly (McMaster University, Hamilton, ON) emphasized that warfarin, despite its unpopularity among physicians and patients alike, still rules the field.

"Oral anticoagulation is the most effective treatment currently available for prevention of stroke and other vascular events in people with AF; however, to achieve this benefit it must be used in an optimal manner," Connolly stated.

The ACTIVE trial: Two other arms still ongoing

ACTIVE-W is just one of three arms in the ACTIVE trial; the two other arms—ACTIVE-A and ACTIVE-I—are still ongoing. At the time it was halted, ACTIVE-W had enrolled its target of 6600 patients, randomized to standard therapy with oral anticoagulation (warfarin) or clopidogrel plus aspirin, and followed them for approximately two years. The ACTIVE A arm, enrolling patients who can't or won't take warfarin, is randomizing patients to aspirin alone (standard treatment) or a combination of aspirin plus clopidogrel and aims to include a total of 7500 patients. ACTIVE-I reflects the 2x2 factorial design of the trial, such that patients from both the W arm and the A arm are further randomized to irbesartan or placebo to test whether lowering blood pressure with an angiotensin-receptor blocker (ARB) in AF patients will lead to a further reduction in vascular events.

-SW

As Connolly showed today, rates of vascular events, defined as stroke, embolism, MI, and vascular death—the primary end point of ACTIVE-W—were significantly higher in the clopidogrel/ASA group than in the warfarin group, a difference of 1.7% per year. Major bleeding events, however, were similar.

Vascular events and major bleeding: ACTIVE-W final results

 

End point Clopidogrel+ASA Warfarin Relative risk p
Vascular events (%/year) 5.64 3.63 1.45 0.0002
Major bleeding (%/year) 2.4 2.2 1.06 0.67
Important observations re: prior warfarin use

In subset analyses, however, clear differences emerged in trial outcomes among certain groups of ACTIVE-W trial participants. In all, Connolly noted, more than three quarters of the 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 clopidogrel/ASA or warfarin had similar rates of vascular events. 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 different between the clopidogrel/ASA and warfarin patients who had not been on prior warfarin.

"In the end, this trial is more about switching from oral anticoagulation to clopidogrel plus aspirin than it is about de novo initiation of clopidogrel plus aspirin," Connolly stated.

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

End point Relative risk p
Patients on warfarin prior to study 1.5 0.0006
Patients not on warfarin prior to study 1.32 0.17

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

End point Relative risk p
Patients on warfarin prior to study 1.27 0.14
Patients not on warfarin prior to study 0.58 0.09
Importance of maintaining target INR

Major bleeds, less surprisingly, were also more common among patients at centers where patients' INRs were not maintained within the target (2.0-3.0) most of the time. As Dr Jonathan Halperin (Mount Sinai Medical Center, New York, NY), who discussed the trial results following Connolly's presentation, observed, patients with INR values outside the therapeutic range more than 35% of the time did no better than patients taking clopidogrel/ASA, "the therapy that proved less effective in the trial as a whole."

Halperin also noted that Connolly et al's subset findings carry an important message for clinical practice and new clinical-trial design, in terms of whether patients are "starters" or "switchers" to new therapies.

"Starting therapy involves different considerations from the decision to switch a patient who has been stable on [oral anticoagulants] to the study regimen. The data from ACTIVE-W make it clear that starters face greater odds of adverse outcomes with anticoagulation and stand to gain more from alternative therapy than switchers or those continuing oral anticoagulation," Halperin commented. Adding that research is only now entering phase 2 and 3 trials for new anticoagulants, he said, "Investigators and federal regulators will have to look long and hard at the results Dr Connolly has shared with us today as they consider the challenges of trial design in this complex field."

To heartwire , Connolly acknowledged that despite its bad rap, warfarin has a lot of advantages, including 50 years of experience learning how to use it. "It's very hard to develop a new drug to replace warfarin. . . . Most patients going into any future trials are already going to be on it, and people who haven't responded well will have had a chance to identify themselves and drop out beforehand. So any new drug coming along is going to be comparing itself on a somewhat uneven playing field, which makes it very difficult for new drugs to be developed. There have been quite a lot of casualties already: not just clopidogrel plus aspirin, but also ximelagatran and more recently, idraparinux."

 
It's very hard to develop a new drug to replace warfarin.
 

Dr Gordon Tomaselli

Dr Gordon Tomaselli (Johns Hopkins School of Medicine, Baltimore, MD), who commented on the study for heartwire , called the trial results "disappointing" but still very instructive. He also acknowledged that while it could not have been predicted in advance, the failure of the clopidogrel/ASA arm makes some sense. "We know from many other AF studies that aspirin alone is not as good as warfarin. When those trials were done, we didn't have the other types of antiplatelet agents that we currently have. But mechanistically, we know that a clot in the heart is not a platelet clot, it's a blood cascade, a blood-clotting-factor clot, and antiplatelet agents just aren't particularly good against that cascade. On that basis, it's too bad that this didn't work out, but in a way, it's understandable, because there are different mechanisms of clot formation in AF."

Halperin echoed Tomaselli's sentiments in his discussion of ACTIVE-W. "While to those seeking treatment easier to manage than chronic anticoagulation the ACTIVE-W results may seem like another in a series of disappointments, these new data strengthen our understanding of the principles governing antithrombotic therapy for patients at risk of cardiogenic embolism."

Experts have not yet entirely abandoned hopes that clopidogrel/ASA might still prove better than aspirin in patients who cannot or will not take warfarin, the question being probed in ACTIVE-A. Asked to speculate on what might happen in that trial arm, given the performance of the clopidogrel-plus-aspirin combination in ACTIVE-W, Connolly said that only the final results from the trial would settle the question. Of note, the patients in ACTIVE-A will undoubtedly be older and sicker than those in ACTIVE-W, meaning that the trial populations will be impossible to compare, he added.

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