September 1st, 2013

Is It Time to RE-ALIGN Our Thinking About Direct Thrombin Inhibitors?

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.


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.


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.


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?

Journal Watch Cardiology‘s coverage of this study

One Response to “Is It Time to RE-ALIGN Our Thinking About Direct Thrombin Inhibitors?”

  1. William DeMedio, MD says:

    The pendulum has swung for and against warfarin several times over the many years it has been used as an anticoagulant. We have a general ideal of how it works biochemically and a better idea of how it changes the outcomes of disease in actual people.I know both the harm and good it can do very well. It has multiple indications and many physicians are very well “tuned in” to how to manage warfarin therapy.

    Dabigatran, a relative newcomer, and a direct thrombin inhibitor, has many potential theoretical and practical advantages to the vitamin K antagonist class. The data in the REALIGN study has sort of kept my “alignment” to the fact it has one FDA indication, Stroke Prevention in Atrial Fibrillation (SPAF). The REALIGN study certainly suggests dabigatran use in clot inhibition in valve replacement is not better, and probably a worse, idea than the use of warfarin. I do not foresee it getting an FDA indication for this specific treatment area. However, in people who cannot tolerate warfarin, it may be a choice to consider. I disagree with Dr Andersen on one thing, this is a study that deserved funding. Theoretical concerns sometimes must take a backseat to the potential practical advantages in drug therapy. Now we have empirical evidence to support what to use first.

    I currently use dabigtran in SPAF, and only in people who make an informed decision to use it versus other options. The vast majority of patients with SPAF managed by me and my colleagues are still on warfarin, and there are even fewer on rivaroxiban and apixaban than there are on dabigatran. We manage a very large number of patients on warfarin, and in the 5 years I have been at my new practice I have not seen any serious adverse events associated with it. (I used warfarin for the duration of my career elsewhere and had only one serious complication,that of a woman who fell on her face and lost an eye due to an orbital hematoma. There were a few subdural hematomas. There were a few GI bleeds.There were no deaths proximally due to the warfarin.) We manage a broad range of anticoagulation patients, including the various types of venous thrombosis, venous embolism, valve replacement, and stroke prevention and arterial thrombosis and embolus prevention in conditions other than atrial fibrillation. Many of these patients are the frail very elderly. They have been on warfarin for many years.They probably would not have lived so well so long were it not for the anticoagulation.

    When dabigatran was first introduced into the United States pharmaceutical market, I had three main misgivings with it. The first was that it was a twice per day medicine with a relatively short half life and hence not very forgiving if doses were missed. The second was an issue with shelf life. If my frail elderly patient forgets to or can’t tightly close the bottle, the medicine will lose its efficacy in short order compared to warfarin. The third issue was with the lack of a reversal agent. I have a very good idea of what to do if my warfarin patient is in a serious accident or has a serious bleed. I do not know what to do for a person on one of the novel anticoagulants beyond general support, factor concentrates, maybe high doses of FFP and a few prayers and hopes.

    I am not knocking the novel anticoagulants, in fact I welcome new additions to our armamentarium. The novels will show their utility as clinical experience increases. However I do not see any of them becoming “replacements” for warfarin in the near future until we have the extensive clinical experience to support replacing warfarin.