Clopidogrel and dabigatran are alternatives to warfarin


In patients unsuitable for warfarin, addition of clopidogrel to aspirin reduces the incidence of stroke by 28%, especially large disabling strokes, said Stuart Connolly, McMaster University, Hamilton, Canada, at the recent Boston AF Symposium. “Addition of clopidogrel to aspirin significantly reduces the risk of major haemorrhage, mostly gastro-intestinal,” he told delegates.

“About four years ago we published ACTIVE W, which showed that clopidogrel plus aspirin was less effective than warfarin and other anticoagulants in the primary outcome, which was a composite of vascular events. What was surprising was that there was an equal rate of haemorrhage in this group of patients with clopidogrel plus aspirin and warfarin,” Connolly said.

ACTIVE A, published in 2009, enrolled AF 7,554 patients unsuitable for warfarin. The main reasons were unwillingness to take warfarin (n=3,682, 48.7%), physician assessment that warfarin is inappropriate (n=3,105, 41.1%), and inability to comply with International Normalized Ratio (INR) monitoring (n=2,069, 27.4%).

“Patients in ACTIVE A and ACTIVE W had similar characteristics, same age, blood pressure, and almost the same CHADS2 score. What was different between the two groups is that the ACTIVE W patients were already mostly on warfarin by the time they were enrolled in the study as the ACTIVE A patients were mostly already on aspirin.”

The main result of ACTIVE A was a very substantial reduction in all-class stroke of 28% with the addition of clopidogrel to aspirin compared to placebo plus aspirin (p=0.00001). “Two thirds of all the strokes in this study are disabling or fatal strokes, so it shows that strokes in AF are big, the clots do not break when they get to brain, they block the artery and cause a large disabling stroke” he said. “On the other side of the coin, however, there was a price to pay for this benefit, an increase in the risk of bleeding. The risk of major bleeding went from a1.3 rate/year figure with aspirin to 2.0 with clopidogrel plus aspirin.”

Analysing stroke rates and risk reduction results in both studies, Connolly showed that rate per year with warfarin was 1.4 (ACTIVE W), clopidogrel plus aspirin was 2.4 (ACTIVE A and ACTIVE W), and aspirin alone was 3.3 (ACTIVE A). “There is a clear benefit with clopidogrel but it does not take us where we would like to be with warfarin.”

Dabigatran was evaluated in the RE-LY study, a randomised trial of long-term anticoagulation therapy, warfarin, compared with dabigatran. The results showed that the 110mg and 150mg of dabigatran were non-inferior to warfarin on the primary endpoint of reducing the incidence of stroke (ischaemic and haemorrhagic) and systemic embolism by 34%. There was no significant difference in the rate of major bleeding for dabigatran 150mg BID compared to warfarin. The rate of major bleeding with dabigatran 110mg BID (2.71%/year) was 20% lower compared to warfarin (p=0.003).

“On the other hand there was a slightly higher rate of acute myocardial infarction (MI). MI rates were low, above 0.25% per year, but there was about 30% myocardial infarction with dabigatran 150mg and 110mg,” said Connolly.

RE-LY was a global, phase III, randomised trial of 18,113 AF patients enrolled in more than 900 centres in 44 countries.