Disappointing Results with Dabigatran for Mechanical Valves

Despite being more durable than bioprosthetic valves, mechanical heart valves are often not chosen because of the requirement for lifelong anticoagulant therapy. It has been hoped that the newer generation of oral anticoagulants might eventually replace warfarin, making anticoagulation more tolerable and better accepted, since these agents don’t require continuous monitoring and have much fewer serious interactions with other drugs and food. So far, however, there has been no convincing demonstration that the the newer agents are as safe and effective as warfarin for this indication.

RE-ALIGN was a phase 2 dose-validation study of dabigatran in patients with mechanical heart valves. Results of the trial were presented at the European Society of Cardiology meeting in Amsterdam and published simultaneously in the New England Journal of Medicine.  Patients in the trial were randomized to dabigatran or warfarin.

After 252 patients had been randomized, the trial was stopped early due to an increase in thromboembolic and bleeding events in the dabigatran group:

Click here to read the full post on Forbes.

Comments

  1. There are potentially many other explanations why dabigatran did not
    work in patients with mechanical heart valves (MHV) and these are
    related to pharmacokinetics as well as pharmacology. In this case,
    large peak-trough plasma level ratio may have played a role in
    addition to hyper-activated factor XII as well as platelet derived
    mediators (following contact activation) such as polyphosphates that
    have been shown to completely reverse the anticoagulant effects of
    direct thrombin and direct factor Xa inhibitors as well as heparin
    but only partially reduce the anticoagulation effect of the VKA,
    warfarin. This reduction was shown to be overcome by having more
    warfarin in the circulation which may explain why MHV patients need
    to be kept at a higher INR of 2.5-3.5.

    We must thank Boehringer-Ingelheim and the investigators of RE-ALIGN study for being very courageous in releasing the full data set from the RE-ALIGN study. We hope other companies and experts also take a firm stance both in public and in professional arenas on the use of NOACs in MHV patients. Otherwise, in the absence of well-controlled
    clinical trials, the only way the world is going to know whether
    NOACs are safe or not in MHV patients is when multiple case-reports
    of death and disability from off-label use of NOACs in heart valve
    patients turn up in major cardiology journals and other news
    outlets.

    Pursuing a communication strategy that suggests until solid clinical
    data in MHV patients is available for NOACs they could be used in
    these patients (since animal models are not predictive) may also
    kill any new drug development in this space. Therefore, prosthetic
    heart valve patients may very well end up continuing to have only
    one OAC, warfarin (for the rest of their lives), a drug that has been shown to be sub-optimal in this patient group. This is not right.

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