Idarucizumab, an investigational drug, rapidly and completely neutralizes the anticoagulant activity of dabigatran in most patients who have serious bleeding or require an urgent procedure, according to an interim analysis of the RE-VERSE AD trial published online June 22, 2015, ahead of print in the New England Journal of Medicine.

“There were no safety concerns among the 90 patients involved in this study—including patients who were given idarucizumab on clinical grounds but were later found to have had normal results on clotting tests at baseline,” say Charles V. Pollack Jr, MD, of Pennsylvania Hospital (Philadelphia, PA), and colleagues.

In the ongoing, multicenter RE-VERSE AD trial, up to 300 patients who are taking the oral thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim) will receive 5 g of IV idarucizumab (Boehringer Ingelheim) if they either:

• have overt, uncontrollable, or life-threatening bleeding judged to require a reversal agent (group A)
• or need surgery or other invasive procedures that cannot be delayed at least 8 hours for which normal hemostasis is required (group B). 

Idarucizumab is a humanized monoclonal antibody fragment with high affinity for dabigatran that selectively and immediately neutralizes its anticoagulant activity.

For the interim analysis, the investigators looked at 90 patients (median age 76.5 years; 56% men; median creatinine clearance 58 mL/min) who were enrolled from June 2014 through February 2015. There were51 patients in group A (16 of them hemodynamically unstable) and 39 in group B. More than 90% were receiving dabigatran for stroke prevention in the context of nonvalvular A-fib. The median patient-reported time from last dabigatran dose was 15.4 hours.

At study entry, 22 patients were determined by the dilute thrombin time test to have normal clotting and were excluded, leaving 68 patients—40 from group A and 28 from group B—for analysis of efficacy.

Quick Reversal Confirmed

The median maximum percentage reversal of anticoagulation (primary endpoint) was 100% (95% CI 100-100) in groups A and B, as assessed by both dilute thrombin time and ecarin clotting time. Reversal was evident soon after the first of 2 equal idarucizumab infusions. Among the patients who could be evaluated, dilute thrombin time was normalized in 98% of group A and 93% of group B, while ecarin clotting time was normalized in 89% and 88%, respectively. Similar results were seen with regard to activated partial-thromboplastin time and thrombin time.

At baseline, the median plasma concentration of unbound dabigatran was 84 ng/mL in group A and 76 ng/mL in group B. But after the initial administration of idarucizumab, the concentration had fallen in all but 1 patient to below 20 ng/mL—a level that the authors say produces little or no anticoagulant effect. At 4 hours, 83 of 86 patients had a concentration near the lower limit of quantification, with only 2 having high concentrations.

Among the 35 patients in group A for whom hemostasis could be ascertained, the metric was restored at a median of 11.4 hours. Among the 36 patients in group B who underwent urgent procedures, normal hemostasis was reported in 92%.

Overall, there were 18 deaths—9 in each group—with 10 due to vascular causes, including 5 fatal bleeding events. 

Thrombotic events occurred in 5 patients. Deep-vein thrombosis and pulmonary embolism were seen in 1 patient 2 days after treatment; the other events occurred more than 72 hours after idarucizumab administration. None of the patients were receiving antithrombotic therapy at the time. 

A total of 21 patients (13 in group A and 8 in group B) experienced serious adverse events. In addition to the deaths and thrombotic events, these included GI hemorrhage in 2 patients and post-op wound infection, delirium, right ventricular failure, and pulmonary edema in 1 patient each.

According to the authors, the 5-g dose of idarucizumab was selected on the basis of the highest range of plasma concentrations measured in the RE-LY trial. Though the concentration of unbound dabigatran was reduced to nearly undetectable levels in all but 1 patient immediately after treatment, the subsequent increases in the anticoagulant concentration seen in some patients after 12 and 24 hours may reflect the redistribution of extravascular dabigatran into the intravascular compartment, they suggest. “It is uncertain whether patients with such a response would benefit from additional idarucizumab,” the investigators add.

Lack of an Effective Antidote Unnerving 

In a telephone interview with TCTMD, Dr. Pollack said concern over the lack of a reversal agent for the novel oral anticoagulants is shared by many clinicians and emergency department (ED) doctors. Major bleeds in patients on these drugs are uncommon, he commented, but when they occur, they are “scary” to deal with.

In an accompanying editorial, Kenneth A. Bauer, MD, of Beth Israel Deaconess Medical Center (Boston, MA), writes: “With the growing use of direct oral anticoagulants, it would be advantageous to have reversal agents that can rapidly and completely neutralize the anticoagulant activity of the drug and restore normal hemostasis…. Given that there are no established reversal strategies for the direct oral anticoagulants, it is appropriate to undertake clinical trials of these agents without a control group.”

Assessment of Clinical Benefit Hampered by Trial Design?

However, Dr. Bauer notes the absence of a control group makes it difficult to assess the clinical benefit conferred by idarucizumab in patients with dabigatran-related bleeding.

“Given that the half-life of dabigatran is 12 to 14 hours if renal function is normal, how important is it to be able to neutralize the anticoagulant activity of dabigatran rapidly in addition to providing supportive care measures?” he asks. “[T]he location and size of the lesion along with the coexisting conditions of the patient may have a greater effect on prognosis than the ability to rapidly neutralize an anticoagulant that the patient is taking,” he says.

Dr. Pollack defended the trial’s use of a surrogate, pharmacodynamic primary endpoint. He explained that the study population of mostly of A-fib patients, who are typically older and have multiple comorbidities, is “just too heterogeneous a group to be able to power a study for clinical outcomes.” Even so, he added, “I think our clinical outcomes are quite impressive.” 

Moreover, Dr. Bauer notes, nearly one-quarter of the study population had “little or no circulating anticoagulant in their blood and would not be expected to benefit from the administration of idarucizumab. Thus, it will be useful to have activity measurements available for the various direct oral anticoagulants in real time to help guide the treatment of such patients and to prevent overutilization of what will surely be a costly medication.”

Dr. Pollack agreed in principle but added that “in the real world” the absence of real-time information on drug concentration is not usually problematic. In fact, he noted, ED doctors reverse warfarin in patients with an intracranial bleed before knowing their INR. Nonetheless, he added, “if when we finish the study it turns out that we can get some guidance from clotting assays, we will absolutely [take advantage of] that. But I think this drug’s use will be driven by clinical assessment.”

Asked to describe an ideal reversal agent, Dr. Pollack said it would need to provide safe, immediate, complete, and sustained reversal, with no prothrombotic effect or allergic concerns—much like idarucizumab—but also potentially neutralize multiple anticoagulants. “As an emergency physician, if I had 1 reversal agent I could go to no matter what the patient was taking, that might be an advantage.” However, he added, development of a universal antidote is considerably less far along than that of idarucizumab.

1. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;Epub ahead of print.
2. Bauer KA. Targeted anti-anticoagulants [editorial]. N Engl J Med. 2015;Epub ahead of print.

Related Stories:

• Dabigatran an Alternative to Warfarin for Stroke Prevention in A-Fib Patients
• Fallout from Bleeding Less Severe in Patients on Dabigatran Compared with Warfarin
• RE-LY: Dabigatran Safe, Effective Across Range of Renal Function