October 23rd, 2012

Setback for Trial Studying Dabigatran After Mechanical Valve Surgery

Despite the recent advent of novel oral anticoagulants, the much-maligned warfarin remains the only current option available for patients who have received a mechanical valve. Now the first trial to explore this indication for a newer oral anticoagulant has suffered a setback.

Last year, Boehringer Ingelheim announced the launch of the RE-ALIGN trial, a phase 2, open-label, 12-week randomized comparison of warfarin and dabigatran (Pradaxa) in 400 patients who received a mechanical valve. There were two arms in the trial. The first arm randomized patients during their initial hospital stay. The second arm randomized patients more than 3 months after their surgery.

Now, following the advice of the trial’s Data Safety Monitoring Board, Boehringer Ingelheim has discontinued the first arm of the trial, the post-surgery arm, due to “lower than projected plasma levels of dabigatran in this population, and an imbalance in reports of thromboembolic events (primarily strokes).” The trial’s second arm is unaffected by this decision and will continue as planned.

Boehringer-Ingelheim says that the  news about RE-ALIGN does “not affect the positive benefit/risk profile of Pradaxa 150 mg for the current labeled indication” of stroke prevention in patients with nonvalvular atrial fibrillation. “RE-ALIGN is evaluating a different patient population and different doses than were studied in the RE-LY trial.”

Dabigatran has been approved in Europe, but not in the U.S., for venous thromboemoblism (VTE) prevention after knee and hip replacement surgery. Rivaroxaban (Xarelto) has been approved for both VTE prevention in the U.S. and Europe. To date, there have been no head-to-head comparisons of the newer anticoagulants.

According to a recent study in Circulation: Cardiovascular Quality and Outcomesdabigatran now has about 19% of the oral anticoagulant market, mostly for the approved treatment of AF “but increasingly for off-label indications” as well. A recent letter in the Journal of the American College of Cardiology provided information about the off-label use of dabigatran in two mechanical valve patients. Both patients developed thrombosis after switching to dabigatran from warfarin. The authors noted that “while there is a wealth of data and clinical experience on dosing and therapeutic response to warfarin in this context, these data are unavailable for dabigatran.” Although newer anticoagulants “hold tremendous promise for mechanical valve anticoagulation … there is a need for dose-finding studies and clinical trials to demonstrate safety and efficacy in this setting.”

One clinical cardiologist who did not wish to be identified offered the following perspective:

This is similar to the case reports (with all the usual caveats) where we have seen this signal with the novel anticoagulants…. it’s not intuitively clear why this is the case.  It may be that the dose is not optimized for mechanical valves.  It is worth noting that the drug levels in patients with mechanical valves were lower than anticipated based on pharmacokinetic calculations.  Maybe patients with mechanical valves have a different metabolism of the drug versus those that don’t have mechanical valves?  There may be an interaction with von Willebrand factor in the pharmacokinetics of dabigatran. Or maybe the dose is just too low and patients with mechanical valves need higher doses, just as we use a higher INR in patients with mechanical valves?  The science keeps evolving!

Sanjay Kaul made a similar point:

The anticoagulant dose requirement for mechanical valves is higher even for warfarin (INR targeted for 2.5 to 3.5) compared with atrial fibrillation or VTE indication (Target INR of 2 to 3). It is likely that the dabigatran dose tested in RE-ALIGN was not sufficiently effective early post surgery when the thrombotic risk is the highest.

Here is a letter sent by Boehringer Ingelheim to members of its speakers bureau:

Dear Valued Speaker:

Boehringer Ingelheim is committed to communicating ongoing, timely information regarding Pradaxa® (dabigatran etexilate esylate) to members of the speaker faculty.  The purpose of this letter is to provide an update on the RE-ALIGN clinical trial.

RE-ALIGN™ is a phase II trial designed to validate the dosing algorithm for dabigatran etexilate compared to warfarin in patients who have received a mechanical heart valve.  This multi-center, prospective, randomized, open-label, active comparator, two arm study is evaluating the safety and pharmacokinetics of 12 weeks treatment of oral dabigatran etexilate in patients who have undergone mechanical heart valve replacement.

In consultation with the Data Safety Monitoring Board, Boehringer Ingelheim has made the decision to discontinue the post-surgery arm of the trial.  Interim analysis indicates that the studied dosing algorithm delivers lower than projected plasma levels of dabigatran in this population, and an imbalance in reports of thromboembolic events (primarily strokes) has been identified.  The second arm, which includes patients who underwent surgery more than three months prior to enrollment in the trial, will continue.

RE-ALIGN is the first clinical study to evaluate an oral direct thrombin inhibitor (DTI) as an alternative to warfarin for use in patients with mechanical heart valves requiring anticoagulation therapy.  Patients have been enrolled in the RE-ALIGN trial at investigational sites in Europe and Canada.  No U.S. study sites have been initiated and randomization of patients has been suspended pending protocol amendment.

At Boehringer Ingelheim, patient safety is our top priority.  All regulatory authorities, clinical trial investigators, and patients involved in the RE-ALIGN trial are currently being informed and information will be updated on www.clinicaltrials.gov.  Pradaxa® (dabigatran etexilate mesylate) capsules are not approved for the prevention of thromboembolic complications in patients with mechanical heart valves.

The changes to the RE-ALIGN protocol do not affect the positive benefit/risk profile of Pradaxa 150 mg for the current labeled indication: reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.  RE-ALIGN is evaluating a different patient population and different doses than were studied in the RE-LY trial.

This letter is meant to provide background, should you receive an unsolicited question related to the RE-ALIGN trial.  Please do not share the content of this communication proactively during speaking engagements.  Should you have any questions or concerns regarding the RE-ALIGN trial, please do not hesitate to contact your Boehringer Ingelheim Medical Science Liaison or Medical and Technical Information at 1-800-542-6257.

Best Regards,

Dr. John Smith, MD, PhD

Senior Vice President, Medical Affairs

Boehringer Ingelheim Pharmaceuticals

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