ACTIVE-W Shows Warfarin Still "Tough to Beat" for Stroke Prevention in AF

Susan Jeffrey

June 09, 2006

June 8, 2006 — Results of a randomized trial comparing oral anticoagulation therapy with a combination of 2 antiplatelet agents, aspirin and clopidogrel, shows that warfarin remains the superior choice for preventing vascular events such as stroke and systemic embolus in patients with atrial fibrillation (AF).

However, the advantage afforded by randomization to oral anticoagulation therapy appeared to apply particularly to those who were already on oral anticoagulation at study entry, principal investigator Stuart Connolly, MD, from the Population Health Research Institute, Hamilton Health Sciences Corporation, Ontario, told Medscape.

"Warfarin works extremely well in patients who can take it and can stay in the therapeutic range, and those are the people who are in these trials. People who have trouble taking it tend to drop out of these studies and they're not available, so it's difficult," Dr. Connolly said. "It's a very tough drug to beat."

The findings, from the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events—W (ACTIVE-W) trial, are published in the June 10 issue of the Lancet. They were presented previously at the 2005 annual meeting of the American Heart Association.

ACTIVE Trials

Although warfarin has proven highly effective in preventing stroke in patients with AF, it is a difficult drug for patients to maintain in a therapeutic range, because it can be affected by a variety of factors such as other drugs or diet, Dr. Connolly pointed out. "It's estimated that the average patient on oral anticoagulation is not in the therapeutic range more than about half the time, so there's a need for better-tolerated, easier-to-use, effective antithrombotic agents, and we hypothesized that the combination of 2 antiplatelet drugs might provide that," he said.

The ACTIVE-W trial is one of 3 interrelated trials sponsored by Sanofi-Aventis and Bristol-Myers Squibb. Patients with AF and 1 or more additional risk factors for stroke included in this study were eligible for and willing to take oral anticoagulation therapy. A total of 6706 patients were randomized to receive anticoagulation therapy, generally with warfarin, to a target International Normalized Ratio (INR) of 2.0 – 3.0 or to a combination of 75 mg/day of clopidogrel with 75 – 100 mg/day of aspirin.

The primary outcome was first occurrence of stroke, non–central-nervous-system (CNS) systemic embolus, myocardial infarction, or vascular death.

"The study was stopped in August 2005 when the Data Safety and Monitoring Board indicated to us that there was overwhelming evidence of superiority of oral anticoagulant therapy to the antiplatelet therapy," Dr. Connolly said. There was a significant increase in the number of composite events seen with the antiplatelet regimen compared with oral anticoagulation, a result driven principally by a higher rate of stroke and non-CNS systemic embolus in the clopidogrel/aspirin group, the authors note.

ACTIVE W: Primary End Point by Treatment Group

End point
Oral Anticoagulation
Clopidogrel Plus Aspirin
Relative Risk (95% CI)
P
First occurrence of primary end-point event, n (annual risk %)
165 (3.93)
234 (5.60)
1.44 (1.18 – 1.76)
.0003

Major hemorrhage was similar between groups, but minor bleeds were more common in the clopidogrel/aspirin group, they note. Intracranial bleeds were also more common in this group, with 21 bleeds vs 11 with oral anticoagulation ( P = .08).

What makes their result "less clear-cut," Dr. Connolly added, is that subgroup analysis suggested the advantages seen with oral anticoagulation therapy relative to the clopidogrel/aspirin combination were most pronounced among the 77% of patients who had already been taking warfarin at enrollment in the trial.

Among those who were not already on warfarin, the risk of a primary-outcome event was "only moderately" higher on the combination therapy compared with oral anticoagulation, they report; however, for those who were already on an oral anticoagulant, the risk was much higher on clopidogrel and aspirin than if they were continued on oral anticoagulation.

Similarly, those who were not on oral anticoagulation at entry had less major bleeding with clopidogrel and aspirin than on oral anticoagulation, but if they were switched from oral anticoagulation to the clopidogrel/aspirin combination, they had more major bleeding on that treatment than if they remained on oral anticoagulation.

"For the outcome of net benefit (a composite of the primary outcome and major bleeding), the relative risk was 1.10 for those who were not on oral anticoagulation therapy at entry compared with 1.52 for those who were ( P interaction = .11)," the authors write.

Relative Risk With Clopidogrel Plus Aspirin vs Oral Anticoagulation for Outcomes in Patients With Clopidogrel Plus Aspirin vs Oral Anticoagulation Who Were and Were Not on Oral Anticoagulation at Study Entry
Outcome
Oral Anticoagulation at Entry
No Oral Anticoagulation at Entry
Primary outcome
1.50 (1.19 – 1.89)
1.27 (0.85 – 1.89)
Major bleeding
1.30 (0.94 – 1.79)
0.59 (0.32 – 1.08)
Net benefit
1.52 (1.25 – 1.85)
1.10 (0.78 – 1.55)

"They were preselected to be responders to oral anticoagulant therapy, that's why they were on it," Dr. Connolly said. "So we feel that our results apply primarily to patients who have already shown that they can tolerate oral anticoagulant therapy, and it doesn't answer the question, what about patients who are new to both therapies?" he told Medscape.

The other ACTIVE trials include ACTIVE-A, which enrolled those patients who were unwilling or unable to take anticoagulation for ACTIVE-W; they are randomized to clopidogrel vs placebo in addition to aspirin therapy. A third study, ACTIVE-I, is looking at the effect of adding the angiotensin receptor blocker irbesartan to eligible patients from both ACTIVE-W and ACTIVE-A in a 2 x 2 factorial design. Both of these latter studies are still ongoing.

"Good Old Warfarin"

In an editorial accompanying the paper, Freek W. A. Verheught, MD, from the Heartcenter at University Medical Center in Nijmegen, the Netherlands, points out that this trial showing the superiority of what he calls "good old warfarin" confirms there is "no indication whatsoever to change the current standard of care in high-risk patients with atrial fibrillation."


The results come on the heels of major disappointment in this field around development of ximelagatran, an oral direct-thrombin inhibitor that could be used in a fixed dose without monitoring, which was ultimately not approved due to an excess of liver toxicity, Dr. Verheught notes.

The lack of efficacy of the clopidogrel and aspirin combination, as well as the bleeding risk associated with it, are disappointing, Dr. Verheught writes. "But ACTIVE-W adds to the list of long-term studies with double-antiplatelet therapy when bleeding can be a problem. Whereas the benefit of aspirin plus clopidogrel outweighs the bleeding risk in trials of a year or less, in longer-term aspirin-plus-clopidogrel studies, this benefit is not seen."

Any further progress in this field is to be expected from developments with oral direct-thrombin inhibitors or oral factor Xa inhibitors, he concludes, "rather than from available antiplatelet agents."

Lancet. 2006;367:1903-1912, 1877-1878.


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