Findings from the RE-ALIGN study, presented at ESC 2013, indicate that dabigatran is associated with increased rates of thromboembolism and bleeding, compared with warfarin, in patients with mechanical heart valves. Judith Andersen offers her take on the research.
THE RE-ALIGN TRIAL
In a phase 2 dose-validation study of dabigatran, funded by the drug’s manufacturer, researchers enrolled patients who had undergone recent aortic- or mitral-valve replacement within the past 7 days, as well as patients who had undergone one of those procedures at least 3 months earlier. Participants were randomized, in a 2:1 ratio, to receive either dabigatran or warfarin. The dabigatran dose (150, 220, or 300 mg twice daily) was determined by a patient’s kidney function and adjusted to obtain a trough plasma level of ≥50 ng/mL. Warfarin dosing was adjusted to achieve a target INR of 2 to 3 or 2.5 to 3.5, depending on thromboembolic risk.
The trial was terminated prematurely after 252 patients were enrolled, because of excess thromboembolic and bleeding events in the dabigatran group. In an as-treated analysis, 32% of dabigatran recipients required dose adjustment or discontinuation of the drug. Ischemic or unspecified stroke occurred in 5% of dabigatran recipients and in no warfarin recipients; major bleeding (always pericardial bleeding) occurred in 4% and 2% of patients, respectively. Most thromboembolic and bleeding events occurred in patients who had undergone valve replacement within 7 days before randomization.
A CLINICIAN’S PERSPECTIVE
Judith Andersen: I have a prolonged love–hate relationship with dabigatran, which I don’t use for any other indication than atrial fibrillation, for reasons that make me suspect all direct thrombin inhibitors (DTIs) as universal anticoagulants: Bleeding and clotting complications are frequent attendees.
Atrial fibrillation is an invitation to thrombosis formation, but a weak one, such as stimulus rate. Stasis is permissive but not productive. Chance activation of the clotting system can create issues, but it does so in an episodic manner. Valve issues, in contrast, create constant mechanical and flow difficulties. Stasis, chamber dysfunction, mechanical heart-valve characteristics, and dysrhythmias are permissive and require constant, consistent prevention.
DTIs such as dabigatran reject short-term coagulation insults, but not consistently. These drugs abort many biologic antithrombotic mechanisms that may be necessary for long-term high-grade anticoagulation, such as that required by mechanical heart valves. Specifically, they inhibit protective mechanisms that depend on thrombin activation of downstream antithrombotic mechanisms, including the activation of protein C. Indeed, activation of protein C, a powerful inhibitor of hypercoagulability in turbulent coagulation areas, must be considered in circumstances related to mechanical heart valves. Given, too, that dabigatran must be taken twice daily, the issue of missed doses and inadequate coverage becomes important. Strong evidence from many studies suggests that moving from a once-daily medication strategy to twice — or thrice — daily creates a strong likelihood of missed doses and failed protection.
I was quite surprised that this trial was actually funded — and not surprised that it failed. It is both the best and the worst of anticoagulation strategies: It (1) inhibits local thrombin activity but (2) does not prevent thrombin generation and inhibits the physiologically inbuilt strategies to regulate thrombin activity — namely, protein C activation with subsequent inactivation of activated factor VIII and factor V — and other thrombin-mediated vascular control mechanisms. In this clinical situation, that is a combustive combination.
An inhibitor of thrombin generation — e.g., a powerful anti-Xa agent — would be a better alternative, as it would inhibit thrombin generation without also inhibiting protective mechanisms that would limit thrombin-mediated vascular hypercoagulability. A once-daily strategy would also make prevention more likely to be secure than reliance on twice-daily medication adherence.
JOIN THE DISCUSSION
How does the RE-ALIGN trial change your perception of dabigatran’s role in various clinical settings? Like Dr. Andersen, do you find the data unsurprising?