New-generation anticoagulants associated with bleeding after ACS in patients on antiplatelet therapy

New-generation anticoagulants are associated with increased bleeding risk when used after acute coronary syndrome (ACS) in patients taking antiplatelet agents, according to a new meta-analysis.

Researchers analyzed data from randomized, placebo-controlled trials that examined anti-Xa or direct thrombin inhibitors in post-ACS patients who were receiving antiplatelet therapy. Stent thrombosis, overall mortality rate and a composite end point including major ischemic events were evaluated as efficacy measures. Thrombolysis in myocardial infarction (MI) bleeding events were the safety end point. The researchers calculated the net clinical benefit of therapy by summing composite ischemic events and major bleeding events.

Results were published online Sept. 24 by Archives of Internal Medicine.

Seven trials published between Jan. 1, 2000 and Dec. 31, 2011 were included in the meta-analysis. The trials involved 31,286 patients who had been admitted to the hospital for unstable angina pectoris, ST-segment elevation MI, or non-ST-segment elevation MI. Patients with severe cardiac, renal or liver insufficiency and those with high bleeding risk were excluded. Follow-up ranged from three months to five years.

Overall, new-generation oral anticoagulants were associated with a significant increase in major bleeding in patients receiving antiplatelet therapy after ACS (odds ratio, 3.03; P<0.001). Risk for stent thrombosis or composite ischemic events was significantly but moderately reduced with the new agents, while no significant effect was seen on overall mortality. The new anticoagulants did not appear to provide an advantage over placebo in net clinical benefit (odds ratio, 0.98; P=0.57).

The authors noted that some of the included trials had high rates of drug discontinuation or had short follow-up periods. In addition, the trials evaluated different drugs in different dosages and used different definitions of composite outcomes. However, the authors concluded that anti-Xa and direct thrombin inhibitors are linked to increased major bleeding risk in ACS patients receiving antiplatelet therapy, to the point that the net clinical benefit of the drugs is neutral.

“Because the use of new-generation P2Y12 ADP-receptor antagonists may result in greater reductions of ischemic events, with substantially lower risk for bleeding complications, the role of oral anticoagulant agents after an ACS is debatable,” they wrote.

An invited commentary pointed out that while the relative risk for major bleeding seemed dramatic, the absolute risk increase was 0.9%, 1.3% for novel oral anticoagulants compared with 0.4% for control therapy. However, the absolute risk decreases for the composite ischemic outcome and for MI were −1.3% (6.5% vs. 7.8%) and −0.8% (3.7% vs. 4.5%), respectively, and the absolute risk differences for net clinical benefit and for overall death were each −0.5%.

“The benefit is largely canceled by the harm; therefore, the routine use of [novel anticoagulants] among patients with ACS is unwarranted,” the commentary author wrote. He called for additional research to examine the use of newer anticoagulants in specific populations of patients with ACS.