Clopidogrel - The ACTIVE study

Oral anticoagulants still treatment of choice in atrial fibrillation

American Heart Association Scientific Sessions late-breaking news:

DALLAS, Nov. 14 – A trial testing treatment for irregular heartbeat ended early due to a 47 percent excess risk of stroke, heart attack and other vascular events in patients receiving the test therapy researchers reported at a late-breaking clinical trials session at the American Heart Association’s Scientific Sessions 2005.

Atrial fibrillation (AF) affects about one percent of the population and is associated with an increased risk of vascular events, particularly stroke, due to blood clots that form in the heart’s left atrial appendage (LAA).

To prevent stroke, doctors give AF patients anticoagulants, such as warfarin, said Stuart J. Connolly, M.D., F.R.C.P.C., director of the division of cardiology at McMaster University, Hamilton, Ont., Canada. He is lead author of the late-breaking clinical report on the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE).

According to Dr. Connolly, “ACTIVE-W was halted in September 2005 after the study’s Data & Safety Monitoring Board alerted the Steering Committee to the difference in efficacy clearly in favor of anticoagulation compared with clopidogrel plus aspirin,” he said.

Today’s late-breaking clinical trial report marked the first revelation of the data behind that decision.

He stressed that the other two arms of the same trial – ACTIVE-A and ACTIVE-I – are on-going. ACTIVE A is for patients unable to tolerate standard therapy with warfarin. ACTIVE I is examining the effect of blood pressure lowering in atrial fibrillation.

“Oral anticoagulation has been particularly successful for stroke prevention in AF,” Connolly said. “But warfarin is associated with many problems.”

Many patients are unable to tolerate warfarin because it can cause bleeding. Patients must be monitored monthly. The only alternative is aspirin, which provides only modest protection, Connolly added.

Clopidogrel plus aspirin is a standard treatment for other conditions, notably acute coronary syndrome and heart attack, which are characterized by arterial clots. It is also used during angioplasty procedures, in which a balloon-tipped catheter is threaded into the heart’s arteries and inflated to open narrowed vessels. AF would have been a new use for the treatment, Connolly explained, because the clots have a different pathophysiology.

ACTIVE-W included more than 6,500 patients with AF, and at least one additional stroke risk factor. Patients were randomly assigned either to anti-platelet therapy (clopidogrel plus aspirin) or to oral anticoagulation (usually with warfarin). For the primary endpoint of stroke, heart attack, embolism and vascular death, the test group had an annual risk of 5.6 percent compared to 3.9 percent for the warfarin group, an excess risk of 1.7 percent (47 percent relative increase), he said.

The researchers also reported no reduction in bleeding in the clopidogrel plus aspirin group compared to anticoagulation, Connolly added. “We expected less bleeding with clopidogrel plus aspirin, but the risk of major bleeds was not significantly different from warfarin. However, there was an important subgroup difference,” he said.

“During the study, we became concerned that we had enrolled a very high rate of patients who were already on warfarin,” he said. More than three-fourths of patients were already experienced with oral anticoagulation.

“We found that there were important differences in the treatment effects between the patients who had been on warfarin at baseline and those who were not, especially related to bleeding risk,” Connolly said.

Patients randomized to clopidogrel plus aspirin at the start of the study had a 36 percent excess risk of major bleeding if they had previously been on warfarin.

In contrast, for patients who had no prior warfarin use, the relative risk of having a major bleed was reduced by nearly the same amount (37 percent) when they received clopidogrel plus ASA.

“Anticoagulants such as warfarin are superior to clopidogrel plus aspirin for prevention of vascular events in patients with atrial fibrillation,” he said.

“Our study does not adequately address the question of whether this is true in patients without previous exposure to warfarin, but there is some evidence that the situation may be different in those patients,” he said, adding that ACTIVE A will shed light on that issue.

Co-authors are: the ACTIVE investigators.
Funding was provided by the Sanofi-Aventis and Bristol-Myers Squibb.
Statements and conclusions of study authors that are published in the American Heart Association scientific journals are solely those of the study authors and do not necessarily reflect association policy or position. The American Heart Association makes no representation or warranty as to their accuracy or reliability.