Substantial bleeding hazard with combination antithrombotic treatment in AF patients

In patients with atrial fibrillation (AF), combinations of warfarin, aspirin, and clopidogrel are associated with increased risks of serious nonfatal and fatal bleeding, with dual warfarin and clopidogrel therapy and triple therapy carrying a more than three-fold higher risk than warfarin alone, a new Danish study shows. But such treatment does not appear to be associated with a significant reduction in ischemic stroke.

The study, published in the September 13, 2010, issue of the Archives of Internal Medicine, was conducted by a team led by Dr Morten Hansen (University Hospital Gentofte, Copenhagen, Denmark).

Hansen noted that this research is similar to a previous study conducted in MI patients, which showed almost identical results.

Hansen told that "this bleeding risk is extremely hazardous and is leading to many deaths. Physicians need to think more carefully about the bleeding risk before prescribing another anticoagulant on top of warfarin, and consider carefully the need to place a stent—which will require clopidogrel treatment—in patients with AF taking warfarin."

He explained that many AF patients who take warfarin to prevent stroke also have ischemic heart disease, so take aspirin, and then many go on to have ACS and/or to receive a stent and are put on clopidogrel. "This is a big problem. We don't know if these three drugs together are useful or if the risk of bleeding outweighs the benefit. It is likely that you don't need all these drugs on board together, but this hasn't been formally tested so we don't really know what to do."

He added that "the most commonly used combination is aspirin and warfarin in patients with AF and ischemic heart disease, but this more than doubles the risk of serious bleeding versus warfarin alone, and we don't know that there is any added benefit over warfarin monotherapy. My recommendation would be to just take the warfarin. And for such patients who have ACS [or a] stent and are put on clopidogrel, the best advice, I think, is to use triple therapy for the shortest time possible, which means drug-eluting stents should be avoided, and even bare-metal stents should only be given to patients with real clear-cut indication."

The current study involved all Danish patients surviving a first-time hospitalization for AF between 1997 and 2006 whose posthospital therapy was warfarin, aspirin, and clopidogrel, alone or in combination. Hansen et al used national registries to track such patients, their prescribed medications, and subsequent hospitalizations for bleeding or deaths due to bleeding. Cox proportional hazards models were used to estimate risks of nonfatal and fatal bleeding. The models were adjusted for age, sex, year of index AF admission, comorbidities, and concomitant medical treatment.

A total of 118 606 patients surviving AF hospitalization were identified, of whom 82 854 (69.9%) had at least one prescription filled for warfarin, aspirin, or clopidogrel after discharge. During a mean follow-up of 3.3 years, 13 573 patients (11.4%) experienced a hospitalization or death due to bleeding, with 12 191 (10.3%) experiencing nonfatal bleeding and 1 381 (1.2%) experiencing fatal bleeding. Most bleeding events were gastrointestinal. Results showed that bleeding increased with each antithrombotic added; the highest rates were seen in patients taking clopidogrel and warfarin together and in those taking all three antithrombotics. But there did not appear to be any significant benefit of combination therapy on the incidence of ischemic stroke.

Effect of multiple antithrombotics on serious bleeding and ischemic stroke rates 

Antithrombotic	Hospitalization or death due to bleeding (% per year)	HR (95% CI) for bleed (warfarin as reference)	HR (95% CI) for ischemic stroke (warfarin as reference)
Warfarin	3.9	1.0	1.00
Aspirin	3.7	0.93 (0.88-0.98)	1.83 (1.73-1.94)
Clopidogrel	5.6	1.06 (0.87-1.29)	1.86 (1.52-2.27)
Aspirin + clopidogrel	7.4	1.66 (1.34-2.04)	1.56 (1.17-2.10)
Warfarin + aspirin	6.8	1.83 (1.72-1.96)	1.27 (1.14-1.40)
Warfarin + clopidogrel	13.9	3.08 (2.32-3.91)	0.70 (0.35-1.40)
Warfarin + aspirin + clopidogrel	15.7	3.70 (2.89-4.76)	1.45 (0.84-2.52)