Intracerebral hemorrhage: Pick your poison
THE NEWER ORAL ANTICOAGULANTS
As Goldstein and Greenberg mention, the ongoing development of new and potentially safer oral anticoagulants may affect how we approach these risk-benefit equations.
Three new oral anticoagulants—dabigatran (Pradaxa), apixaban, and rivaroxaban (Xarelto)—are being tested for various anticoagulant indications, and several phase III studies have recently closed or are nearing completion.
Dabigatran is an oral direct thrombin inhibitor currently available in Europe and Canada.
In the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial, the efficacy and safety of two different doses of dabigatran (110 mg twice daily or 150 mg twice daily) relative to warfarin were studied in more than 18,000 patients with atrial fibrillation. 9 The primary outcome measure was stroke or systemic embolism. Dabigatran 110 mg was not inferior to warfarin in terms of the primary outcome, while dabigatran 150 mg was superior. The rate of major bleeding was 3.36% per year in the warfarin group vs 2.71% in the 110-mg group (P = .003) and 3.11% in the 150-mg group (P not significant).
Additional safety data on this drug are available from the 2,500-patient RE-COVER trial.10 Dabigatran was not inferior to warfarin in the treatment of acute venous thromboembolism, with a similar rate of major bleeding and a lower rate of combined major plus nonmajor bleeding.
Apixaban, an oral direct factor Xa inhibitor, is in a phase III trial in patients with atrial fibrillation—Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE)11—comparing apixaban vs warfarin. Another phase III trial, AVERROES,12 was stopped early after a predefined interim analysis by the independent data-monitoring committee found clear evidence of benefit in the apixaban group.13 The AVERROES results were presented at the 2010 European Society of Cardiology Congress, August 28–September 1, Stockholm, Sweden.14
Rivaroxaban, another promising oral direct factor Xa inhibitor, is currently available in Europe and Canada for the prevention of thrombosis in orthopedic surgery patients. Rivaroxaban is also in large phase III trials for the treatment of acute venous thromboembolism15–17 and for the prevention of stroke in atrial fibrillation.18
Newer agents have drawbacks, too
These new agents need no laboratory monitoring, and they do not appear to be subject to the dose variability and the interactions with drugs and foods seen with vitamin K antagonists. As a result, they may pose less risk of anticoagulant-related ICH.
The decision to resume anticoagulation after anticoagulant-associated intracranial hemorrhage should be based on the risk of rebleeding vs the risk of thrombosis. Patients determined to be at high risk of thrombosis and low risk of rebleeding are the best candidates for resuming anticoagulation.
Still, for patients who suffer an anticoagulant- or warfarin-related ICH, these new anticoagulants are not likely to simplify the issue of restarting anticoagulant therapy. Unlike vitamin K antagonists, dabigatran and the direct factor Xa inhibitors have no known antidote for their anticoagulant effects. Animal data suggest that factor Xa concentrates may help,19 but for patients at risk of a second anticoagulant-related ICH, this does not provide much reassurance.
As with all clinical decisions in medicine, the potential benefits of any therapy should outweigh the risks. In the case of warfarin-related ICH, resuming anticoagulant therapy requires careful consideration of many factors, including patient preferences and tolerance of different levels of risk. As new and perhaps safer anticoagulants become available, clinicians may face such difficult questions less and less. But in the meantime, doctors and their patients are left to pick their poison.
