Idarucizumab Reverses Dabigatran Regardless of Renal Function

Debra L Beck

October 01, 2019

Idarucizumab (Praxbind, Boehringer Ingelheim) reversed the anticoagulant effect of dabigatran (Pradaxa, Boehringer Ingelheim) in more than 98% of patients with life-threatening bleeding or who were facing urgent procedures, regardless of renal function, in a new study.

"Almost all patients treated with dabigatran who require reversal with idarucizumab can be expected to respond to therapy irrespective of baseline renal function," reported John W. Eikelboom, MBBS, McMaster University, Hamilton, Ontario, Canada, and colleagues.

Findings from the prespecified retrospective analysis of the RE-VERSE AD study were published in the October 8 issue of the Journal of the American College of Cardiology.

Although those with and without renal impairment had similar time to bleeding cessation, patients with renal impairment were more likely to have re-elevation of dabigatran levels (>20 ng/mL) 12 or 24 hours after receiving a fixed 5 mg dose of idarucizumab.

By 12 or 24 hours, 56% of patients with severe, 29.1% with moderate, and 9.2% with mild renal impairment had dabigatran levels above 20 ng/mL, compared with 8.3% of patients with normal renal function at baseline.

And although no patients with normal or mild renal impairment received a second dose of idarucizumab, three patients with moderate and five with severe renal impairment received a second dose a median of 51.4 hours after the first dose. Six of these cases were prompted by bleeding.

Eikelboom and colleagues note that the cutoff of 20 ng/mL was "arbitrary," but it corresponds with the lower limit of detection of dabigatran using the commercially available dTT assay.

"Furthermore, it is likely that most invasive procedures can be safely performed with even somewhat higher dabigatran levels," they add, emphasizing the conservative nature of their cutoff.

"I think this study is very reassuring and timely, especially for patients with chronic kidney disease, many of whom have been reluctant to use a NOAC," said Rola Khedraki, MD, in an interview with theheart.org | Medscape Cardiology.

Khedraki, a cardiologist at the Scripps Clinic, La Jolla, California, is the first author of an editorial published alongside the subanalysis results.

She added that the next step is to test these drugs in patients with end-stage renal disease, most of whom are still treated with warfarin.

The plasma half-life of dabigatran is 12 to 17 hours, but renal impairment can increase that substantially to 15 to 34 hours, said Khedraki.

"Just to give some perspective on current practices, in most cases of mild bleeding associated with DOACs like dabigatran, drug discontinuation and supportive measures can be employed, given their relatively short half-life," she added. "However, severe hemorrhage requires aggressive control with mechanical compression, depending on the site of bleeding, surgical or endoscopic homeostasis, and hemodynamic support with transfusion of blood products and fluids."

Because of the lack of specific reversal agents, nonspecific procoagulants like prothrombin complex concentrate and fresh-frozen plasma have been used off-label to at least partially reverse the anticoagulant effects of DOACs, with varying responses, Khedraki explained.

"Clearly, being armed with a specific reversal agent that can be used in patients at the highest risk of bleeding (i.e., those with CKD) is a huge step forward in being able to address bleeding complications in this population."

Idarucizumab was granted accelerated approval by the US Food and Drug Administration (FDA) in October 2015 on the basis of an interim analysis of the first 90 patients enrolled in RE-VERSE AD.

Full approval was granted in April 2018 and, as of the end of 2018, Boehringer-Ingelheim said that the drug was stocked in more than 3300 hospitals in all 50 states.

As reported in by theheart.org | Medscape Cardiology, results of the nearly 500-patient phase 3 trial were "overwhelmingly convincing," showing that two bolus doses of idarucizumab achieved full reversal of dabigatran within about 10 minutes. Full FDA approval was granted in April 2018 for patients in need of urgent surgery or with life-threatening or uncontrolled bleeding.

In this analysis, the 503 RE-VERSE AD participants were classified according to their baseline creatinine clearance: normal, at least 80 mL/min (n = 108); mild, 50 to less than 80 mL/min (n = 163); moderate, 30 to less than 50 mL/min (n = 127); and severe, less than 30 mL/min (n = 91). In 14 patients a baseline creatinine clearance measurement was missing.

Individuals with impaired renal function were more likely to be older, more often women, and had a lower body mass index, more comorbidities, higher CHADS2 scores, and higher dabigatran plasma levels despite lower dosing, compared with those with normal renal function.

Despite this, median reversal measured by diluted thrombin time was 100% within 4 hours of idarucizumab administration in all patients. The proportion of patients achieving complete reversal did not differ, according to baseline renal function: 98.4% of those with normal renal function achieved complete reversal, compared with 99.2%, 99.1%, and 97.6%, respectively, of those with mild, moderate, and severe renal impairment.

"Further studies should evaluate the safety and efficacy of idarucizumab as a specific reversal agent for dabigatran in patients with advanced kidney disease," the authors conclude.

Thirty-day mortality rates ranged from 9.0% to 11.0% among patients with normal, mild, or moderate renal impairment, rising to 24.0% for the 91 patients classified as having severe renal impairment at baseline.

"It is important to consider that renal function is not a static measure, and yet in this study, it was only assessed at baseline," write Khedraki and colleagues in their editorial.

Eikelboom agreed that the lack of postidarucizumab measures of renal function were a limitation of the trial, and the reseraachers had no information on whether the renal dysfunction was acute or chronic ("or acute on chronic").

The RE-VERSE AD trial was sponsored by Boehringer-Ingelheim. Eikelboom reported receiving funding and/or research support from Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, and Pfizer. Four of the eight authors (van Ryn, Reilly, Elsaesser, and Glund) on the paper are employees of Boehringer-Ingelheim. Khedraki reported no relationships relevant to the contents of this paper to disclose.

J Am Coll Cardiol. 2019;74:1760-1768, 1769-1771. Full text, Editorial

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