Pradaxa Bind

A 56-year-old man with multiple defibrillator therapies for recurrent post-infarct monomorphic ventricular tachycardia presents for an outpatient ablation procedure under general anesthesia. He takes warfarin for infrequent paroxysmal atrial fibrillation (AF). Unfortunately, his INR is 3.5. For a procedure that was anticipated to require placement of a large femoral arterial sheath, his preoperative instructions should have included interruption of his warfarin. This was not done, and as soon as there was mention of rescheduling his procedure, the patient was understandably not pleased. He was legitimately concerned about having recurrent VT in the interim, and had taken the week off from work. To avoid postponement of his ablation procedure, the team proposed reversal of his warfarin with fresh frozen plasma (FFP), but that would have required several units of product and result in a large volume load. The cardiac anesthesiologist stepped in. He proposed giving prothrombin complex concentrate (PCC). Apparently, it is routinely given to patients on warfarin who come in from home for urgent procedures such as cardiac transplantation. Data from a 2013 study showed that administration of 4-factor PCC to patients on vitamin K antagonists presenting with major bleeding is highly effective.1 After administration of PCC and vitamin K, the patient underwent a successful ablation procedure with adequate hemostasis. His INR was 1.8 at the end of the procedure. 

The example above highlights the issues that arise when patients prescribed anticoagulation need an urgent procedure. It has now been shown in several studies that patients who are at high risk for thromboembolism can safely undergo many cardiac procedures on uninterrupted warfarin instead of being bridged with heparin. However, there is less evidence that it is safe for patients taking one of the newer/novel oral anticoagulants (NOACs) to undergo an invasive procedure, and most surgeons will not operate on patients with a coagulopathy. What if this patient had been taking a NOAC instead of warfarin and had just taken a dose on the morning of his procedure? Can the anticoagulant effect of NOACs be reversed? There are limited data related to this question, and the answer depends on whether the NOAC is a direct thrombin inhibitor, such as dabigatran (Pradaxa, Boehringer Ingelheim), or a factor Xa inhibitor. There is data from a study in 2011 showing that PCC can immediately and completely reverse the anticoagulant effect of rivaroxaban in healthy volunteers, but has no influence on the anticoagulant action of dabigatran at the PCC dose used in the study.²

Fortunately, there is a new reversal agent for patients taking dabigatran: idarucizumab. Marketed as Praxbind, idarucizumab (Boehringer Ingelheim) is a monoclonal antibody fragment that binds free and thrombin-bound dabigatran, and neutralizes its activity. A study published in 2015 in the New England Journal of Medicine (RE-VERSE AD ClinicalTrials.gov number, NCT02104947; Funded by Boehringer Ingelheim) reported the outcomes of 90 patients taking dabigatran who had either serious bleeding (51 patients) or required an urgent procedure (39 patients) and were given 5g of intravenous idarucizumab.3 There was no control group. Within minutes, the reversal agent normalized the coagulation test results in 88-98% of the patients. Among the patients who underwent a procedure, mildly or moderately abnormal hemostasis was reported in only 3 patients. It appeared safe. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated.

Since the availability of NOACs for patients at risk for stroke due to AF, there has always been a concern relative to warfarin about the lack of a reversal agent in the event of major bleeding. When patients taking a NOAC are actively bleeding, it is usually a result of trauma, gastrointestinal bleeding, or intracranial bleeding. These patients are usually managed acutely by an emergency medicine physician or an intensivist. However, equally important is the option of reversing NOACs to allow for urgent procedures to be performed safely. Fortunately, there is now a highly effective, drug-specific reversal agent for dabigatran. It is important for invasive cardiac teams who care for patients often taking NOACs to be aware of this new option and have it readily available.

References

1. Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy and safety of a 4-factor pro- thrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013;128:1234-1243. 
2. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1573-1579.
3. Pollack CV Jr, Reilly RA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373:511-520.