Treating patients on new anticoagulant drugs

I agree with the authors of the new oral anticoagulants article that the drugs should be viewed ‘as useful arrows in the prescriber’s quiver of oral anticoagulants’ rather than to replace warfarin.1 However a previous Australian Prescriber comment2 did not adequately address the practical aspects of reversal of the newer anticoagulants.

Significant concerns have been raised about how the manufacturer of dabigatran may have withheld data in the RE-LY trial,3 with the possibility that issues about the bleeding risk were far greater than were acknowledged. This was particularly in light of the drug’s ‘fickle pharmacokinetics’ resulting in highly variable plasma concentrations4 and differences in how the different drug regulators managed this issue.5

Trials involving dabigatran versus warfarin may have underestimated major bleeding rates,6 and possibly the risk of gastrointestinal bleeding related to dabigatran and rivaroxaban compared to warfarin7 despite their touted safety profile.

There was also controversy with the ROCKET-AF trial of rivaroxaban,8 where serious allegations that a defective point-of-care device was used in the warfarin arm. This could have potentially affected the trial results and emphasises the importance of post-marketing trials to authenticate company-sponsored trials used to support the drug’s approval.

Even idarucizumab, the monoclonal antibody antidote to dabigatran (both from Boehringer Ingelheim), comes with a certain caveat not widely known – the median time to bleeding cessation was 11.4 hours for those with overt, uncontrollable, or life-threatening bleeding that was judged by the treating clinician to require a reversal agent.9 Hopefully, whatever a ‘life-threatening bleed’ is, 12 hours delay (before bleeding stops) is consistent with meaningful life.

Although the effect of reversal is up to 24 hours, ‘subsequent increases in dabigatran concentrations that occurred 12 hours after the administration of idarucizumab in six patients and 24 hours after the administration of idarucizumab in 16 patients were also evident by increases in the clotting times and may reflect the redistribution of extravascular dabigatran into the intravascular compartment’.9 Therefore the anticoagulation effect of dabigatran, taking 2–4 days post cessation to be safe from significant bleeding or major surgery, may still relapse 24 hours after the last dose of idarucizumab.

Conversely, warfarin can be reversed by vitamin K, prothrombin complex concentrate or fresh frozen plasma within 15 minutes to six hours.10

Clinicians and patients should be informed of these facts before embarking on therapy involving the newer anticoagulants.