Last week’s FDA approval of a specific reversal agent for dabigatran and progress in specific antidotes to rivaroxaban and apixaban is reassuring for clinicians but it should not obscure the fact that these drugs are inherently safer than warfarin, says Professor Mark Crowther from McMaster University in Hamilton, Canada.
Idarucizumab, which reverses the direct thrombin inhibition of dabigatran, has also been approved recently by the European Medicines Agency.
Its efficacy was established in the RE-VERSE AD study (NEJM 2015; 373: 511-20), showing that a dose of 5 grams – a very large dose for a recombinant protein – completely reversed the anticoagulant effect of dabigatran within minutes in patients who had serious bleeding or required an urgent procedure.
“Development of reversal agents has been driven by perceptions of the epidemiology of NOAC-associated bleeding, but the reality is that warfarin is a more problematic drug,” Professor Crowther said.
In randomised clinical studies warfarin was associated with major or fatal bleeding in 12-14% of patients, despite the availability of antidotes, while the rate for the NOACs ranged from 7-10%.
“The evidence suggests that bleeding is not more common with the newer anticoagulants, there is a lower risk of intracranial haemorrhage, and emergency surgery is associated with less bleeding than patients treated with warfarin,” he said.
Clinical studies have also demonstrated that andexanet, a recombinant variant of factor Xa, can reverse the effects of factor Xa inhibitors including apixaban and rivaroxaban.
Reliance on reversal agents should not become routine and must not replace common-sense approaches to the treatment of bleeding complications or preparation for urgent surgery, Professor Crowther said.
“The first essential step is to apply the basic principles of bleeding management, starting with cessation of the drug,” he said.
In many cases the simple passage of time, for example before an operating theatre becomes available, will be sufficient for the anticoagulant’s effects to wane.
Most hospitals do not yet have reliable assays to check whether active drug is still present, so the likely contribution of the anticoagulant to the bleeding will remain a clinical judgment.