RE-ALIGN Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement Randomized, open-label Two groups undergoing implantation of a mechanical bileaflet valve in the aortic or mitral position or both (population A) if they had undergone implantation of a mechanical bileaflet mitral valve (with or without mechanical bileaf let aortic-valve replacement) more than 3 months before randomization (population B) Dosing regimens 150 mg twice daily in patients with a creatinine clearance of less than 70 ml per minute 220 mg twice daily in those with a creatinine clearance of 70 to 109 ml per minute, 300 mg twice daily in those with a clearance of 110 ml per minute or more measured trough plasma levels of dabigatran Study was discontinued early due to “excess thromboembolic and bleeding events among patients in the dabigatran group “

Results Thromboembolic events occurred in the dabigatran group at all trough levels “dabigatran is not appropriate as an alternative to warfarin for the prevention of thromboembolic complications in patients who require anticoagulation after the implantation of a prosthetic heart valve” Possibly the mechanism of action of dabigatran limits its effectiveness for this type of thrombus formation In vitro studies have demonstrated “high dose” rivaroxaban (300 ng/ml) is effective at preventing thrombus formation, while “low dose” rivaroxaban (30 ng/ml) was not

bleeding

The Concern Warfarin has several reversal agents (Vitamin K, FFP, etc.) Initially, there were no reversal agent for DOACs

Bleeding and Dabigatran: Data from RE-LY, RE-COVER, RE-COVER 2, RE-MEDY & RE-SONATE Only 31% of major bleeds on warfarin received vitamin K, so the numbers probably should look even worse. Significantly less Vitamin K and FFP used in the dabigatran group PRBCs transfused more often in dabigatran group (possibly explained by the increased amount of GI bleeding in that group)

Intracranial Hemorrhage and Dabigatran Data from RE-LY Rates of intracranial hemorrhage are significantly lower at all sites with either dabigatran dose than warfarin Data from the RE-LY trial

ICH Mortality and Dabigatran Despite the absence of a specific reversal agent (at the time), there was no significant mortality increase in patients taking dabigatran

Predictors of ICH on Dabigatran Age, prior CVA and ASA use were predictors of ICH with warfarin Only age was a predictor of ICH in patients taking dabigatran