Dabigatran, the first of the new oral anticoagulants to be approved (in October 2010), and the only direct thrombin inhibitor, has been the source of controversy over bleeding risk. A new retrospective cohort study seeks to compare the bleeding risk of dabigatran to warfarin. Using Medicare beneficiaries who were newly diagnosed with atrial fibrillation, 1302 were started on dabigatran and 8102 were started on warfarin and followed for up to 16 months. Dabigatran was associated with a higher risk of any bleeding event relative to warfarin (hazard ratio 1.30, 95% CI, 1.20-1.41) and a higher risk of major bleeding (intracranial hemorrhage, hemoperitoneum, hematuria, GI bleeding and other bleeding) (HR 1.58, 95% CI, 1.36-1.83) as well as a hazard ratio of 1.85 for gastrointestinal bleeding (CI 1.64-2.07). Dabigatran was associated with increased risk of major bleeding and GI bleeding for all subgroups analyzed, but the risk was especially high for African Americans and those with chronic kidney disease. Only intracranial bleeding was lower in the dabigatran group vs warfarin (HR 0.32, 95% CI, 0.20-0.50). The authors conclude that dabigatran should be prescribed with caution, especially in high risk patients (JAMA Intern Med. Published online Nov 03, 2014. doi:10.1001/jamainternmed.2014.5398). These findings are in contrast to the pivotal RE-LY trial which showed similar rates of major hemorrhage to warfarin, and was the basis for FDA approval for dabigatran (NEJM 2009;361:1139-1151).

There will likely soon be reversal agent for the target specific oral anticoagulants (TSOA)s. The reversal agent, called PER077 has been tested on the newest TSOA, edoxaban (which is nearing FDA approval to join rivaroxaban (Xarelto), apixaban (Eliquis) and dabigatran [Pradaxa]). TSOAs are easy to use but lack a proven reversal agent. In a recent study published in a letter to the NEJM, PER977 given as a single intravenous dose, was shown to bind to edoxaban and reverse the anticoagulant effect within minutes. Eighty healthy volunteers were given a 60 mg dose of edoxaban and predictably, the whole-blood clotting time increased by 37% over baseline. Three hours later patients were randomized to a single 100 to 300 mg dose of PER977 or placebo. In those receiving PER977, the whole –blood clotting time decreased within 10% of baseline in 10 minutes whereas the patients receiving placebo took 12-15 hours to normalize clotting time. The effect of PER977 lasted for 24 hours (NEJM November 5, 2014. DOI; 10.1056/NEJMc1411800). Neither edoxaban nor PER977 is available as yet but this is exciting news as it represents the first potential reversal agent for the new generation of anticoagulants. Previous studies have suggested that PER977 is also effective in reversing the effects of the all the TSOAs as well as unfractionated and low-molecular weight heparin.

The duration of antiplatelet therapy after coronary stenting is the subject of a new study. The standard has been one year of dual antiplatelet therapy with aspirin and a thienopyridine (clopidogrel [Plavix} or prasugrel [Effient]). But a new study suggests that longer dual therapy may improve outcomes. In a large multicenter trial, nearly 10.000 who had received a drug-eluting stent and 12 months of aspirin and a thienopyridine were randomized to an additional 18 months dual platelet therapy vs aspirin plus placebo. Aspirin plus a thienopyridine reduced the rate of stent thrombosis compared to placebo (0.4% vs 1.4% HR 0.29 [95% CI, 0.17-0.48]; P<0.001). Major adverse cardiovascular and cerebrovascular events were also significantly reduced (HR 0.71, P>0.001) as was the rate of myocardial infarction (HR 0.47, P<0.001). The all cause death rate was slightly higher in the dual therapy group (HR 1.32, P=0.05) and there was more major bleeding with dual therapy (2.5% vs 1.6%, P=0.001). The authors conclude that dual antiplatelet therapy beyond 1 year after a drug-eluting stent, compared to aspirin alone, is associated with lower rates of stent thrombosis and major adverse cardiovascular and cerebrovascular events but with a high rate of bleeding (NEJM published online November 16, 2014, DOI:10.1056/NEJMoa1409312). The increase in all-cause mortality is being further studied.

Nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk of bleeding in patients with atrial fibrillation (AF) according to a new study. In a study of over 150,000 patients with AF, nearly 54,000 were prescribed a NSAID during the 6.2 years of the study. The risk of serious bleeding within 3 months of taking a two week course of an NSAID was 3.5/1000 compared with 1.5/1000 for patients not on a NSAID. The risk was even higher if AF patients were on an oral anticoagulant. NSAIDs were associated with an increased risk of bleeding and thromboembolism regardless of antithrombotic regimens or NSAID type. Higher doses of NSAIDs increased the risk of bleeding and naproxen and diclofenac were associated with the highest risk. The authors recommend that “NSAIDs should be discouraged unless other possibilities… have been exhausted” in AF patients and physicians should “exercise caution with NSAIDs in patients with AF.” (Ann Int Med 2014;161:690-698). Although some NSAIDs conferred a higher risk, even the COX-2 inhibitors celecoxib and the now banned rofecoxib increased bleeding risk.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study. For questions and comments, please e-mail: leslie.hamlin @ahcmedia.com.