Target-Specific Oral Anticoagulants Are Associated with Reduced Risk of Bleeding

Analysis of a dozen phase III trials indicates that patients with atrial fibrillation face significantly less risk of major, fatal, and intracranial bleeding if they take target-specific oral anticoagulants rather than vitamin K antagonists.

Analysis of a dozen phase III trials indicates that patients with atrial fibrillation (AF) face significantly less risk of major, fatal and intracranial bleeding if they take target-specific oral anticoagulants rather than vitamin K antagonists.

Researchers from McMaster’s University gathered trial data for 57,850 patients who received oral anticoagulants to 44,757 patients who received vitamin K antagonists.

Patients in different trials used different oral anticoagulants. Dabigatran (Pradaxa) and rivaroxaban (Xarelto) were each used in 4 of the studies while apixaban (Eliquis) and edoxaban (Lixiana) were used in 2 studies apiece.

Median treatment durations ranged from 1.6 to 2 years in the 5 trials on patients with AF, and from 3 to 12 months in 7 additional trials on patients with venous thromboembolism (VTE).

Patients who received oral anticoagulants were more than 25% less likely than those who received vitamin K antagonists to experience overall major bleeding (relative risk [RR] = 0.72; 95% CI, 0.62-0.85, P<.01).

Their comparative risk of fatal bleeding was even lower (RR=0.53; 95% CI, 0.43-0.64, P<.01) as was the risk of intracranial bleeding (RR=0.43; 95% CI, 0.37-0.5, P<.01).

The research team believes their meta-study has effectively settled a significant question about the safety of oral anticoagulants.

“Vitamin K antagonists (VKAs) have been the standard of care for treatment of thromboembolic diseases,” wrote the authors of the paper, which just appeared in the journal Blood. “Novel oral anticoagulants (TSOACs) have been developed and found to be at least non-inferior to VKAs with regards to efficacy but the risk of bleeding with TSOACs remains controversial.”

But the authors acknowledged no remaining controversy by the time they reached their conclusion.

“When compared to VKAs, TSOACs are associated with less major bleeding, fatal bleeding, intracranial bleeding, clinically relevant non-major bleeding and total bleeding,” they wrote. “Additionally, TSOACs do not increase the risk of GI bleeding.”

The team’s conclusion echoes some prior research, but some earlier trials suggested that oral anticoagulants might put patients at greater risk for serious bleeding than vitamin K antagonists.

The Randomized Evaluation of Long‐term anticoagulant therapY (RE‐LY) trial compared outcomes for patients who took warfarin with those who took 110 mg of dabigatran and those of a third group that took 150 mg of dabigatran. It found that only the lower dose of the oral anticoagulant was associated with significantly less serious bleeding than warfarin.

Another trial, which compared dabigatran to warfarin in patients with mechanical heart valves, was stopped early because of an increase in thrombotic events and an increase in postsurgery bleeding with dabigatran.

A trial that compared rivaroxaban to warfarin, on the other hand, found that the newer drug was associated with about the same overall risk of major bleeding as warfarin but a significantly lower risk of intracranial bleeding (0.5% versus 0.7%; P=.02) and fatal bleeding (0.2% versus 0.5%; P=.003) than the older drug.

A trial of apixaban, moreover, found a reduction in bleeding risk for patients with AF, one that ranged from 11% to 31% depending on which definition of major bleeding the researchers used.

Such results may suggest that different targeted oral anticoagulants create different risks, but the authors of the new study did not attempt to differentiate individual medications and issued their conclusions for the entire class of medications.