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.

Shyan Goh
Orthopaedic surgeon
Meadowbrook, Qld

Paul Chin and Matthew Doogue, the authors of the article, comment:

Dr Goh raises important concerns about the reversal of anticoagulation with the new oral anticoagulants in the setting of bleeding, particularly in relation to dabigatran.

Dabigatran therapy was found to be non-inferior to warfarin in terms of major bleeding risk and mortality in the randomised controlled trials that preceded the availability of the reversal agent, idarucizumab^11-13 It is possible that idarucizumab will improve the safety of dabigatran to the extent that it is superior to the safety of warfarin, for example by rapid reversal before acute surgery or in the event of a major gastrointestinal haemorrhage.

The durability of anticoagulation reversal is a concern with both the new anticoagulants and warfarin. For warfarin, laboratory coagulation monitoring is important following the use of reversal agents, as its long half-life (around 40 hours) may outlast the half-lives of the reversal agents.¹ The use of INR and associated threshold values requiring action are routinely used in monitoring of patients on warfarin.¹⁰ However, it remains to be established which laboratory tests and what thresholds should be used to monitor patients treated with the new anticoagulants in the setting of bleeding requiring anticoagulation reversal. For dabigatran, the thrombin clotting time and the measurement of plasma dabigatran concentrations are expected to be particularly informative for clinical decision making.^14,15