“What are direct oral anticoagulants (DOACs) and how are they managed differently from Warfarin? I’m concerned that they may not have a specific reversal agent. What do doctors do to manage heavy bleeding or surgery in patients on DOACs?”

For over half a century, vitamin K antagonists, such as warfarin, were the only available oral anticoagulant. Although very effective in reducing stroke in patients with atrial fibrillation and treating and preventing venous thromboembolism, warfarin is one of the most difficult and dangerous drugs we use in clinical practice. The biggest concern is serious bleeding, particularly intracranial hemorrhage which is frequently fatal or results in permanent neurologic disability.

Over the past few years, we now have four approved alternatives to warfarin called DOACs – originally called novel oral anticoagulants but now more commonly referred to as non-vitamin K antagonist oral anticoagulants or direct oral anticoagulants (DOACs). In general, the DOACs are more effective than warfarin and safer, particularly with respect to serious bleeding. DOACs cause half as much fatal and life-threatening bleeding [particularly ICH] than warfarin. Also they are more convenient than warfarin in that they do not require frequent blood monitoring and can be given safely in fixed doses.

Despite the attractiveness of these new agents, adoption has been as rapid as one would have expected. There are many reasons for this but one important aspect is the issue of reversal. Although warfarin causes much more serious bleeding than DOACs, physicians and patients are comforted by the notion that they can reverse warfarin with vitamin K and administration of clotting factors. Although the “reversal” of warfarin is a bit of myth, the lack of an ability to reverse the DOACs is a perceived limitation of these agents. There is now an approved reversal agent for factor IIa inhibitor dabigatran called idarucizumab. It is an antibody to dabigatran and reverses the anticoagulant effect of dabigatran within minutes and has no apparent side effects. For the factor Xa inhibitors [apixaban, edoxaban, rivaroxaban] there is a reversal agent in late stage clinical development called andexanent alpha that appears to work really well and is safe. It acts as a decoy, binding to the factor Xa inhibitors and preventing them from exerting their anticoagulant effects. Andexanent alpha is not approved yet so if serious bleeding occurs while taking a factor Xa inhibitor administration of clotting factors [PCC: prothrombin complex concentrates], as we do in warfarin bleeds, is advised.

Although certainly these antidotes or reversal agents are a welcomed advance and have given tremendous comfort to physicians and patients, we must remember that serious bleeding with the DOACs is very uncommon, so these agents will need to be used infrequently.  For most mild bleeding with DOACs, simply holding 1-2 doses of the drug [they all have very short half-lives] and general supportive measures are all that is needed.

Christian T. Ruff, MD, MPH
TIMI Study Group
Cardiovascular Division
Brigham and Women’s Hospital
Harvard Medical School
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