Hamilton, ON - One arm of the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) has been stopped prematurely because of a lower event rate in the warfarin group than in those taking a combination of clopidogrel and aspirin.

But the ACTIVE trial has two other parts, which are both continuing to enroll patients. These are evaluating clopidogrel plus aspirin vs aspirin alone in AF patients who can't or won't take warfarin and the role of blood-pressure lowering with irbesartan in AF.

The ACTIVE trial involves three separate studies known as ACTIVE W, ACTIVE A, and ACTIVE I. The ACTIVE W arm, the one that has been stopped, was fully enrolled with 6600 patients. They were randomized to standard therapy with oral anticoagulation (warfarin or a similar agent) or a combination of clopidogrel plus aspirin. The trial was stopped earlier this week on the recommendation of the data safety monitoring committee because warfarin was looking superior to the clopidogrel/aspirin combination in preventing vascular events. The first patients enrolled in this arm had started study medication in June 2003 and had therefore been followed for more than two years. The majority of patients had been followed for one year to 18 months.

The ACTIVE A arm, which is still continuing, is enrolling patients who can't or won't take warfarin. This part of the study is randomizing such patients to aspirin alone (the standard treatment for these patients) or a combination of aspirin plus clopidogrel. The A arm is aiming to include a total of 7500 patients and has so far enrolled 6000 patients.

The whole ACTIVE trial has a 2x2 factorial design, so that patients from both the W arm and the A arm are further randomized to irbesartan or placebo. This is to investigate whether lowering blood pressure with an angiotensin-receptor blocker (ARB) in AF patients will lead to a further reduction in vascular events.

The ACTIVE trial is being coordinated by Drs Stuart Connolly and Salim Yusuf (McMaster University, Hamilton, ON). In an interview with heartwire, Connolly emphasized that it was of utmost importance that both patients and investigators understand that only one arm of the trial was being stopped and that the other two arms are continuing to enroll patients. "Investigators have been sent letters instructing them that patients in the W arm should now be put on warfarin if they are not already on it. But another important message is that the A and I arms are continuing. The A arm is completely separate from the W arm, and the patients in the A arm should be totally unaffected by the stopping of the W arm. But because the irbesartan arm is a factorial design, many patients in the W arm will continue to be randomized to irbesartan or placebo. It is vitally important that the investigators and patients understand this, as we don't want patients in the A or I arms to drop out," he commented.

Connolly elaborated that while it was disappointing that the clopidogrel/aspirin combination did not appear to be as effective as warfarin, there was still the possibility that this combination may benefit those not willing or able to take the anticoagulant. "Yes, I'm disappointed about the W arm. It would have been great to have a drug regimen that was easier to use than warfarin, but we are still hopeful about the ACTIVE A and ACTIVE I arms. And we are reassured that the data safety monitoring committee has said these arms can continue," he told heartwire.

He explained that a recent US study has suggested that around 50% of AF patients at high risk of stroke are not receiving warfarin or a similar anticoagulant. "This is the target population of ACTIVE A. We may still be able to improve outcomes in this group," he said. On the irbesartan part of the trial, Connolly noted that previous studies have suggested that lowering blood pressure with an ACE inhibitor or ARB may give particular benefits to AF patients, and this is the hypothesis being tested in ACTIVE I. "It is therefore vitally important that everyone involved understands that just because the W arm has been stopped, this does not mean that there is any issue with the A or I parts of the trial, and these patients should continue to be enrolled and followed."

Full data from the ACTIVE W arm are now being collected, and it is hoped that these results will be presented at the upcoming American Heart Association meeting in November. Patients in the other two arms will continue to be followed until the end of 2007, with results planned to be reported in 2008.