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Dabigatran Reversal With Idarucizumab in Patients With Renal Impairment
John W Eikelboom1, Joanne van Ryn2, Paul Reilly3
1Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, Population Health Research Institute, Hamilton, Ontario, Canada; Department of Medicine, Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada.
Insights
Idarucizumab effectively reverses dabigatran in over 98% of patients, irrespective of kidney function. While dabigatran levels may re-elevate in impaired renal function, bleeding cessation and hemostasis remain consistent.
Area of Science:
- Pharmacology
- Nephrology
- Cardiology
Background:
- Dabigatran and its reversal agent, idarucizumab, are primarily cleared by the kidneys.
- Renal function significantly impacts the pharmacokinetics of many renally cleared medications.
Purpose of the Study:
- To assess the efficacy of idarucizumab in reversing dabigatran's effects across varying degrees of baseline renal function.
- To evaluate clinical outcomes in dabigatran-treated patients receiving idarucizumab based on their renal function status.
Main Methods:
- The RE-VERSE AD study analyzed 503 patients on dabigatran who received idarucizumab.
- Patients were stratified by baseline creatinine clearance (normal, mild, moderate, severe renal impairment).
- Dabigatran reversal extent and clinical outcomes were compared across these renal function groups.
Main Results:
- Idarucizumab achieved 100% median dabigatran reversal within 4 hours in all renal function groups.
- Over 98% of patients had undetectable unbound dabigatran levels post-administration.
- While dabigatran re-elevation by 12-24 hours was more frequent in severe renal impairment, bleeding cessation and procedural hemostasis were similar across groups.
- Severe renal impairment was associated with higher 30- and 90-day mortality rates.
Conclusions:
- Idarucizumab provides complete reversal of dabigatran in over 98% of patients, regardless of renal function.
- Despite potential for dabigatran re-elevation in renal impairment, clinical outcomes like bleeding cessation and hemostasis during procedures are comparable.
- Patients with severe renal impairment face increased mortality risks, highlighting the importance of monitoring.
Background:
Dabigatran and idarucizumab, its reversal agent, are renally cleared.
Objectives:
The purpose of this study was to determine the extent of reversal and outcomes according to baseline renal function in dabigatran-treated nondialysis patients receiving idarucizumab.
Methods:
In 503 patients in RE-VERSE AD (Reversal of Effects of Idarucizumab in Patients on Active Dabigatran), the extent of dabigatran reversal and clinical outcomes were compared according to baseline renal function (creatinine clearance: normal ≥80, mild 50 to <80, moderate 30 to <50, and severe <30 ml/min).
Results:
Compared with patients with normal renal function, those with impaired renal function were older, were more often women, and had lower body mass indexes, more comorbidities, higher CHADS2 scores, and higher dabigatran plasma levels despite more frequent use of lower-dose dabigatran regimens. Regardless of renal function, median reversal measured by dilute thrombin time was 100% within 4 h of idarucizumab administration, and over 98% of patients achieved this with corresponding undetectable levels of unbound dabigatran. By 12 or 24 h, 56% of patients with severe, 29.1% with moderate, and 9.2% with mild renal impairment had dabigatran levels >20 ng/ml compared with 8.3% of patients with normal renal function at baseline. Time to cessation of bleeding and the proportion with normal hemostasis with procedures were similar regardless of renal function, but patients with severe renal impairment had higher 30- and 90-day mortality rates.
Conclusions:
Idarucizumab completely reverses dabigatran in >98% of patients regardless of renal function. Although re-elevation of dabigatran levels within 12 to 24 h is more common with renal impairment, the time to bleeding cessation and the extent of hemostasis during procedures are similar. (Reversal of Dabigatran Anticoagulant Effect With Idarucizumab; NCT02104947).
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