Clinical Scenario: In the middle of a busy night in the critical care area, an elderly woman comes in from an outside hospital with a known intracranial hemorrhage after a mechanical fall. While reviewing her medication list, you notice that she has A-fib and is taking Pradaxa for stroke prevention. You vaguely recall an email about a new reversal agent for this blood thinner. Can you do anything to prevent this woman’s bleed from worsening? Should she get Prothrombin Complex (PCC), or something else?
As you desperately try to find the Pradaxa email in your ever-more-crowded inbox, another patient rolls in. He’s a middle-aged man with multiple prior abdominal surgeries and a day of nausea and vomiting. His abdomen is distended and a CT of the abdomen and pelvis shows a closed-loop small bowel obstruction with signs of ischemia. You notice that this patient, too, is on Pradaxa. Given his need for emergent surgery, what should you do to minimize his risk of serious intraoperative and postoperative bleeding?
Literature Review: The development of the novel oral anticoagulants, or NOACs, was hailed by many physicians as a bold step forward in the fight against thrombo-embolic disease. Unlike their much-maligned predecessor, warfarin, these agents (which include direct thrombin inhibitors such as dabigatran (Pradaxa) and factor Xa inhibitors such as rivaroxaban (Xarelto) and apixaban (Eliquis)) do not require bridging with other agents upon initiation and do not suffer from warfarin’s innumerable interactions with medications and food products. Furthermore, labs are not routinely drawn for monitoring in patients on the NOACs, while patients on warfarin require frequent INR checks for titration. Preliminary research has indicated that they are just as efficacious as warfarin in preventing stroke and other thrombo-embolic complications, but with less risk of serious or life-threatening bleeding, especially intracranial hemorrhage . Finally - anticoagulants for busy patients who hate blood draws and love grapefruit!
The introduction of the NOACs did, however, cause some consternation in the emergency medicine community. Warfarin, although it was (and is) a messy drug with an unfortunate side effect profile, is easily reversed with vitamin K and FFP or PCC. Patients on warfarin who present to the ED with an acute hemorrhage (subarachnoid, gastrointestinal, traumatic, or otherwise) or who require emergent surgery can be reversed quickly, and the efficacy of their reversal can be tracked with a simple, widely available laboratory test, the prothrombin time / international normalized ratio (PT / INR). The NOACs had no such reversal agent, and no easily available lab test to track reversal in the case that it was required or attempted. Some suggested using PCC, with some support in the literature, but many emergency physicians were concerned that widespread use of the NOACs would lead to a plague of irreversible anticoagulation, to the detriment of some of their sickest patients.
Keenly aware of these concerns, the pharmaceutical giants behind the NOACs raced to develop specific reversal agents for their products. The first to gain FDA approval was idarucizumab (Praxbind), an anti-Pradaxa drug developed by Boehringer Ingelheim Pharmaceuticals (who are now proudly advertising that only Pradaxa has a specific FDA-approved reversal agent, although Portola is actively developing a reversal agent for the factor Xa inhibitors). Praxbind is now available at BJH and other BJC hospitals. But is this antidote the real deal? Has it been shown to improve patient-centered outcomes? How and when should we use it?
Idarucizumab is a humanized monoclonal antibody developed to bind dabigatran. It was initially developed, humanized, and tested in a rat model by Schiele and colleagues in 2013. They demonstrated that idarucizumab bound dabigatran with about 350 times greater affinity than dabigatran bound thrombin, and that infusion of idarucizumab into rats previously given dabigatran rapidly normalized laboratory tests of clotting function.1 A later study of idarucizumab in a porcine model again confirmed that addition of idarucizumab to blood taken from dabigatran-treated animals normalized coagulation parameters. This study also showed that idarucizumab, unlike PCC, did not cause over-correction of thrombin generation . Further animal testing, also in a porcine model, demonstrated that administration of idarucizumab to dabigatran-treated animals significantly reduced bleeding after blunt liver trauma .
Glund and colleagues performed the first study of idarucizumab in human volunteers in late 2014. They showed that idarucizumab had no effect on coagulation parameters in the absence of dabigatran, that peak exposure was achieved essentially instantaneously, and that the compound’s half life was very short, roughly 45 minutes . The same investigators also demonstrated that idarucizumab normalized coagulation parameters in healthy volunteers treated with dabigatran in a dose-dependent fashion. These effects were immediate, and were sustained over a 72 hour period in volunteers given at least 2 grams of idarucizumab .
On the strength of these results, a multicenter prospective cohort study called RE-VERSE AD was designed and approved to determine the real-world safety and efficacy of idarucizumab for the reversal of dabigatran in patients with serious bleeding, or who required emergent surgical or procedural intervention. In June 2015, the RE-VERSE AD investigators published their preliminary results, derived from the first 90 patients enrolled in the trial. The dose tested in this trial (5 g IV, administered as two infusions of 2.5 g no more than 15 minutes apart) was calculated to fully bind the 99th percentile of total body dabigatran load observed in the RE-LY trial that demonstrated the efficacy of dabigatran in stroke. Patients were eligible for inclusion if they were at least 18 years old and taking dabigatran. Patients were assigned to two groups: those with “over, uncontrollable, or life-threatening bleeding that was judged by the treating clinician to require a reversal agent” to group A, and those who required urgent surgery or other procedures that required normal hemostasis to group B. The primary outcome was the maximum percentage reversal of anticoagulation at 4 hours after administration of idarucizumab; this was determined by dilute thrombin time or ecarin clotting time (both tests correlate well with the presence of unbound dabigatran). Secondary outcomes included restoration of hemostasis.
51 patients were enrolled in group A, and 39 were enrolled in group B. Of the patients in group A, 18 had ICH, 20 had GI bleeding, 9 had bleeding “from trauma,” and 11 had “other” causes of bleeding. Of note, 22 patients (11 in group A, 11 in group B) were found to have normal dilute thrombin time at baseline, and 9 of these patients (4 in group A, 5 in group B) also had normal ecarin clotting time at baseline; these patients were excluded from the primary efficacy analysis. All patients analyzed had 100% reversal of anticoagulation at 4 hours.
Analysis of the secondary clinical outcomes was less helpful. Of the 51 patients in group A, 3 had no assessment of bleeding severity at baseline, and the time to cessation of bleeding could not be ascertained in 13 patients. In the remaining patients, the median investigator-reported time to cessation of bleeding was 114 hours, but there was no control group for comparison. In group B, one patient received idarucizumab to reverse a massive overdose of dabigatran, two patients were deemed too unstable for surgery, and 36 patients underwent surgery or procedure as planned. Of these, 33 (92%) had “normal intraoperative hemostasis” as reported by the surgeon or proceduralist. Obviously, these secondary outcomes were somewhat soft and subjective, and given the absence of a control group, it is not possible to draw firm conclusions about the effect of idarucizumab on patient-centered clinical outcomes.
RE-VERSE AD is ongoing, and publication of the final results should be enlightening. Its major limitation, of course, is the absence of a control group an overall small number of patients. The investigators commented that they felt that it would be unethical to randomize patients to a placebo agent or to another unproven reversal therapy, given the very strong laboratory data supporting the efficacy of idarucizumab and the absence of clear evidence demonstrating the efficacy of any alternative reversal agent. Animal and volunteer studies of dabigatran reversal with PCC, the most reasonable alternative agent, have produced mixed results .
While the ethical concerns raised by the authors are understandable, the absence of a control group does severely limit our ability to draw patient-centered conclusions from the RE-VERSE AD trial. However, given the absence of a plausible and proven alternative reversal agent, and the overwhelming laboratory evidence of anticoagulation reversal demonstrated in this and other trials, one could reasonably argue that idarucizumab is the best available treatment and should become standard of care. In fact, the Neurocritical Care Society and Society of Critical Care Medicine have formally recommended that idarucizumab be used as the first-line reversal agent in patients taking dabigatran who present with intracranial hemorrhage .
Take home Points: Idarucizumab rapidly and completely reverses the anticoagulant effects of dabigatran, as demonstrated by laboratory assessment of clotting parameters. While high-quality patient-centered outcome data are still lacking, it is reasonable to give idarucizumab to patients on dabigatran who are experiencing serious bleeding or who will require an emergent surgery or invasive procedure.
Submitted by Kevin Baumgartner, PGY-1
Faculty Reviewed: Evan Schwarz
Everyday EBM Editor: Maia Dorsett
Schiele et al. “A specific antidote for dabigatran: functional and structural characterization.” Blood 2013 May 2;121(18):3554-62
Honickel et al. “Reversal of dabigatran anticoagulation ex vivo: Porcine study comparing prothrombin complex concentrates and idarucizumab.” Thromb Haemostasis 2015; 113:728-740
Grottke et al. “Idarucizumab, a specific dabigatran reversal agent, reduces blood loss in a porcine model of trauma with dabigatran anticoagulation.” JACC 2015 Sept; 66(13):1516-23
Gund et al. “A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran.” Thromb Haemostasis 2015; 113:943-951
Glund et al. “Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial.” Lancet 2015; 386:680-90
Pollack et al. “Idarucizumab for dabigatran reversal.” N Engl J Med 2015; 373:511-20
Connolly et al. “Dabigatran versus warfarin in patients with atrial fibrillation.” N Engl J Med 2009; 361:1139-51.
Frontera et al. “Guidelines for reversal of antithrombotics in intracranial hemorrhage.” Neurocrit Care 2016; 24:6-46