First NOAC Antidote, Idarucizumab, Approved; Likely Won’t Hold Up Interventions

Interventional cardiologists say the recent approval of the reversal agent idarucizumab is a welcome addition for clinicians who encounter situations in which the anticoagulant effect of dabigatran needs to be turned off quickly, but say they themselves are unlikely to use the drug regularly. Still, it marks a step forward in addressing concerns about the need for antidotes for the novel oral anticoagulants (NOACs).

The FDA gave idarucizumab (Praxbind), a humanized monoclonal antibody fragment that binds to dabigatran (Pradaxa; both Boehringer Ingelheim), accelerated approval on October 16, 2015, for use in patients who require emergency surgery or other urgent procedures or who have life-threatening or uncontrolled bleeding.

Since dabigatran’s approval 5 years ago, the lack of reversal agents for it and the other NOACs that have come on the market more recently, including rivaroxaban (Xarelto; Janssen), apixaban (Eliquis; Bristol-Myers Squibb), and edoxaban (Savaysa; Daiichi Sankyo), has been an issue. Idarucizumab is the first such agent to be approved, although others are in development.

“Patients who are being treated with NOACs are likely to undergo invasive procedures and even have trauma, so having a reversal agent provides some peace of mind for providers who see these patients in the operating room or in the emergency department,” Sunil V. Rao, MD, of Duke University Medical Center (Durham, NC), told TCTMD in an email.

The safety and efficacy of idarucizumab have been established in 3 trials with a total of 283 dabigatran-treated healthy volunteers. The reversal agent caused an immediate drop in plasma concentrations of dabigatran that was sustained for at least 24 hours. The most common adverse reaction reported was headache.

Idarucizumab also continues to be evaluated in REVERSE-AD, an ongoing single-cohort case series trial that includes dabigatran-treated patients who have uncontrolled or life-threatening bleeding or require emergency surgery or other invasive procedures that cannot be delayed at least 8 hours. An interim analysis published earlier this year showed that the median maximum reversal of anticoagulation was 100% in the first 4 hours, with 88% to 98% of patients achieving complete reversal. The effect was seen within minutes of drug administration. The most frequently reported adverse reactions were hypokalemia, delirium, constipation, pyrexia, and pneumonia.

Because idarucizumab was cleared under the FDA’s accelerated approval program, “continued approval for this indication may be contingent upon the results of [REVERSE-AD],” according to the drug’s label.

Little Use Foreseen in the Cath Lab

Daniel I. Simon, MD, of University Hospitals Case Medical Center (Cleveland, OH), told TCTMD in a telephone interview that the availability of a reversal agent like idarucizumab is essential for patients with trauma or life-threatening hemorrhage. The most common scenario in which it might be used is when dabigatran-treated A-fib patients fall and develop subdural hematomas and intracerebral bleeding, he said.

Patients taking warfarin can be given vitamin K or fresh frozen plasma to reverse anticoagulation, he noted, but the lack of effective antidotes for dabigatran and the other NOACs has been a major problem.

For interventional cardiologists specifically, however, idarucizumab will not have a large impact, Dr. Simon predicted, noting that 50% to 60% of patients are treated electively, which allows oral anticoagulation to be stopped 3 to 5 days before the procedure.

It is uncommon to have an ACS patient who is treated with one of the NOACs and most of those cases involve NSTEMI or unstable angina, he said, adding that even if those patients need to go in for catheterization the following day, much of the anticoagulant effect will have worn off without the need for reversal.

On the rare occasion when there is a dabigatran-treated STEMI patient, nothing would change from the usual approach, and the patient would be taken directly to the cath lab, he said, noting that idarucizumab is likely to cost several thousand dollars. “The same thing would happen when we have a patient who’s fully anticoagulated on warfarin,” he continued. “We just go the lab and do the procedure. We go radially if we can. If not, you go femoral and you [use a closure device]. You anticoagulate for the procedure with Angiomax or heparin. But we wouldn’t reverse for those patients.”

Dr. Rao agreed, highlighting both the role of radial and the cost issue. However, he added, “in the rare situation where a major complication occurs, like a coronary perforation, having this agent available is very important.”

Rare complications aside, there is not a great need for this type of reversal agent in interventional procedures, taking the risks, benefits, and costs of reversal into account, Dr. Simon said. “In the vast majority of cases it’s not going to factor in,” he said.

Clinical Impact Unclear

However comfortable interventional cardiologists may be with managing or avoiding bleeding complications, the fact remains that major, life-threatening bleeds do occur with dabigatran. As such, there is a significant need for a reversal agent like idarucizumab, Stephan Moll, MD, a hematologist at the University of North Carolina School of Medicine (Chapel Hill, NC), told TCTMD in a telephone interview.

Whether using idarucizumab actually improves clinical outcomes has not been established, he pointed out, noting that REVERSE-AD should have included a control group to provide more meaningful information on clinical outcomes.

Nevertheless, the antidote will have an important role in managing intracranial bleeds in particular, as well as bleeds into the retroperitoneal space or vital organs and intraabdominal or hemorrhages due to trauma, Dr. Moll said.

What will be important moving forward, he said, is to make sure that hospitals are prepared to reverse the effects of any anticoagulant without unnecessary delays. “Every emergency room in the United States needs to have a formal institutional anticoagulation reversal protocol in place,” he said.

Source: 
FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa: Praxbind approved for specific emergency situations [press release]. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm467300.htm. Published October 16, 2015. Accessed October 21, 2015.

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