By Dana Leifer, MD
Source: Idarucizumab for Dabigatran Reversal. Charles V. Pollack, Jr., M.D., et. al. N Engl J Med. 2015; 373: 511-20
Several new oral anticoagulants are changing the approach to anticoagulation for patients with nonvalvular atrial fibrillation and deep venous thrombosis/pulmonary emboli. These drugs, which include dabigatran, a thrombin inhibitor, have been shown to be noninferior both in terms of safety and efficacy to warfarin, which was until recently, the only oral anticoagulant available. In some cases, these drugs have also been shown to be superior to warfarin. In addition, they do not require the intensive monitoring that is needed for warfarin, and they do not have the numerous interactions with other drugs and with diet. Use of these drugs has been limited, however, in part because of fears that they are not rapidly reversible in the event of a hemorrhage or a need for emergency surgery. Several different agents that may rapidly reverse one or more of the new oral anticoagulants are now under development.
In particular, Pollack and colleagues recently reported in the New England Journal of Medicine that idarucizumab, a humanized monoclonal antibody that binds specifically to dabigatran, reversed its anticoagulant effects within minutes. The study included 51 patients with serious acute bleeding (Group A), including 18 with intracranial hemorrhages, and 39 patients who needed emergency surgery (Group B). The ecarin clotting time (ECT), which is probably the best test for detecting the effects of dabigatran, was normalized in 89% of patients in group A and 88% of patients in group B when tests were done immediately after the first of the two doses of idarucizumab that patients received. The dilute thrombin time (TT), which is more widely available but less sensitive for detecting the effects of dabigatran was normalized in 98 and 93% of patients in groups A and B respectively. The ECT remained normal at 24 hours in 72% and 54% of patients respectively. For these analyses, the authors excluded the subsets of patients whose baseline ECT or TT was normal.
It is important to note that correction of laboratory abnormalities does not necessarily mean that there is clinical benefit. The paper presents limited data about clinical outcomes. There were 18 total deaths within the first month including 3 from intracranial hemorrhage within 96 hours. Deaths within 96 hours appeared to be related to the index event, while later deaths appeared related to coexisting conditions. These numbers do not seem surprising in view of the serious acute problems that all patients enrolled in the study had. Thrombotic complications (DVT, pulmonary emboli, left atrial clot, myocardial infarction, ischemic stroke) appeared in 5 patients from 2 to 26 days after treatment; anticoagulation had not been resumed in any of these patients, so again these results are not surprising.
COMMENTARY
Unfortunately, the authors report little about clinical outcomes. For patients in group B who underwent surgery, intraoperative hemostasis was described as normal in 92% of patients who underwent surgery emergently, so it is likely that there was at least subjective clinical benefit in Group B patients, though even for these patients, there was no control group.
For patients with intracranial hemorrhage, the authors state that modified Rankin scores were recorded at baseline and at 90 days, but they do not report data about the Rankin scores in this publication. We must hope that this information will be reported in a subsequent paper, but in the absence of a control population, this information will be difficult to interpret.
Despite the lack of data about clinical outcomes in this study, it is likely that the rapid reversal of anticoagulation achieved with idarucizumab will be beneficial. For intracranial hemorrhage patients in particular, there is a consensus in the field that rapid reversal of anticoagulation is critically important. Indeed, one of the performance metrics for comprehensive stroke centers is the percent of intracerebral hemorrhage patients with INR>1.4 who are treated with procoagulant agents. In this background, it is likely that a drug that immediately reverses the effects of dabigatran would have a clinical benefit for dabigatran-associated ICH.
In summary, idarucizumab rapidly reverses the effects of dabigatran and is likely to have important clinical benefits for patients with intracerebral hemorrhage and other disease processes in which reversal of anticoagulation is important. The recent paper by Pollack and colleagues, however, reported only limited results about clinical outcomes and lacked a control group that did not receive the study drug. Additional work will therefore be needed to determine if the drug actually improves clinical outcomes.
