By Michael H. Crawford, MD

Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco

Dr. Crawford reports no financial relationships relevant to this field of study.

SYNOPSIS: A pragmatic clinical study of idarucizumab for counteracting the effects of the oral anticoagulant dabigatran showed rapid and complete reversal of its effects in patients with major bleeding or urgent surgery, without any adverse safety concerns.

SOURCE: Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal – full cohort analysis. N Engl J Med 2017;377:431-441.

One advantage of dabigatran therapy for stroke prevention in atrial fibrillation (AF) patients is the existence of an antidote, but how well does it work? Investigators performed a multicenter, international, prospective, open-label study of idarucizumab 5 mg IV in 503 patients on dabigatran needing anticoagulant reversal, the Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) study. The authors studied two groups of patients. Group A had life-threatening bleeding (n = 301). Group B required surgery and couldn’t wait eight hours for hemostasis to return after stopping dabigatran (n = 202). The primary endpoint was the maximum percent reversal of anticoagulation four hours after completion of the infusion of idarucizumab as measured by either the thrombin time or the ecarin clotting time. Serial blood samples for pharmacologic studies were performed over the first 24 hours after the infusion of idarucizumab. A second dose of idarucizumab was permitted for recurrent or continued bleeding or objective evidence of residual anticoagulant effect. Clinical outcomes were secondary endpoints. Adverse effects were attributed to idarucizumab if they occurred within five days. More than 95% of the patients were receiving dabigatran for stroke prevention in AF. The mean age was 78 years. The median percent reversed at four hours was 100%. Dabigatran concentrations fell from around 100 mg/mL to near zero within minutes of the infusion of idarucizumab and remained < 20 mg/mL for 24 hours. A second dose of idarucizumab was administered to only eight patients. In group A, 46% experienced gastrointestinal bleeding, and 33% experienced intracranial bleeding. The median time to cessation of bleeding was 2.5 hours after idarucizumab was administered. In group B, the planned surgery commenced at a median time of 1.6 hours. Perisurgical hemostasis was normal in 93%. At 90 days, about 7% of patients experienced a thrombotic event and 19% experienced mortality. There were no serious safety issues with idarucizumab administration. The authors concluded that idarucizumab was shown to rapidly reverse the anticoagulation caused by dabigatran without any serious safety issues.

COMMENTARY

Although idarucizumab worked well in animals and normal volunteers to reverse the effects of dabigatran, it is always useful to see how such agents work in real-world patients. Thus, this uncontrolled, pragmatically designed, open-label study is of interest. Clearly, idarucizumab rapidly drops dabigatran blood levels to near zero for at least 12 hours. Between 12 and 24 hours, some anticoagulant effect (dabigatran levels < 20 mg/mL) returned in about 20% of patients. The authors attributed this to the redistribution of dabigatran from extravascular spaces into the vasculature. This was associated with bleeding in only 10 patients. A second dose of dabigatran was administered to seven of these patients. Overall, only one dose of 5 mg of idarucizumab was given to 98% of patients. Anti-idarucizumab antibodies were detected in about 6% of patients, but at low titers. Three patients demonstrated possible hypersensitivity events: one with a rash who also started tramadol; one with vomiting and loss of consciousness who had intracerebral hemorrhage; and one with possible anaphylaxis who was started on amoxicillin. Other potential adverse events were observed in about one-quarter of patients, but all could be ascribed to worsening of the index event or the underlying condition of the patients.

In group B, the surgeons reported 95% of patients appeared to exhibit normal or mildly impaired hemostasis at a median start time of 1.6 hours after idarucizumab was administered. Considering these data and the safety of idarucizumab, surgery probably could start as soon as the idarucizumab is administered. In group A, the efficacy of idarucizumab is more difficult to determine. These were sick patients with a high mortality rate (7% at five days, 13% at 30 days). Also, there were many factors affecting hemostasis. Often, blood transfusions occurred and other products were administered. In addition, many received antiplatelet agents at a mean of four days, and most restarted anticoagulants at a mean of 13 days. Investigators started such agents within 72 hours in 23% of group A patients. Further, the authors noted that mortality reported in patients undergoing surgery or experiencing a major spontaneous bleeding event on warfarin is about 30%, which is higher than the 19% observed in this study. Finally, thrombotic events are to be expected if one rapidly reverses anticoagulation, but the 7% observed in this study is lower than that reported with warfarin. No procoagulant effect of idarucizumab has been observed in animals or normal human volunteers. Since there is no effective alternative to idarucizumab for reversing the effects of dabigatran, there was no comparison group, and the investigators believed that it was unethical to create a control group given the strength of the pre-clinical data. The FDA has approved idarucizumab at the doses used in this study. This makes dabigatran an attractive oral anticoagulant for patients who demonstrate indications for oral anticoagulation but are at high risk of bleeding.