ARTICLE IN BRIEF
Reports of an excess of thromboembolic events in a dosing trial of dabigatran for mechanical heart value replacement led to an early halt to the study. Experts speculate why the therapy, found effective for stroke, might have a different effect for mechanical heart valve replacement.
A phase 2 dose-validation trial of the novel blood thinner dabigatran etexilate mesylate (Pradaxa) in patients with mechanical heart valves was cancelled early due to an excess number of bleeding and thrombolytic events.
Dabigatran, an oral direct thrombin inhibitor, has been tested as an alternative to warfarin in several clinical trials, but clotting and bleeding events have remained a concern. Post-marketing reports led the US Food and Drug Administration (FDA) to issue a warning last December that the drug should not be used to prevent strokes or blood clots in patients with mechanical valves.
The agency approved the drug in 2010 for preventing stroke and blood clots in atrial fibrillation (afib) patients after a 2009 clinical trial in more than 18,000 patients with atrial fibrillation and a risk of stroke showed clear benefits over warfarin. In April of this year, the agency added a warning to dabigatran labeling for afib patients that they are at increased risk of thrombotic events if they stop using the drug without switching to an adequate alternate anticoagulant.
The new study, the Randomized, phase II study to Evaluate the sAfety and pharmacokinetics of oraL dabIGatran etexilate in patients after heart valve replacemeNt, referred to as the RE-ALIGN trial, was a prospective dose-response study conducted at 39 centers in 10 countries investigating effective doses to reduce thrombolytic events in patients who had undergone aortic- or mitral-valve replacement with mechanical heart valves within seven days, or within three months.
Patients were randomly assigned to receive either dabigatran or warfarin, with selection of the initial dabigatran dose (150mg, 220mg, or 300mg twice daily) based on kidney function. Doses were adjusted to obtain a trough plasma level of at least 50 ng per milliliter, while the warfarin dose was adjusted to obtain an international normalized ratio of 2 to 3 or 2.5 to 3.5 on the basis of thromboembolic risk.
The trial was ended after 252 patients had been enrolled because of an excess of blood clots and bleeding events among subjects in the dabigatran group. Dose adjustment or discontinuation of dabigatran was required in 52 of 162 patients, or 32 percent. Ischemic or unspecified stroke occurred in nine patients in the dabigatran group, while there were none in the warfarin group. Nine patients in the dabigatran group experienced major pericardial bleeding. One person in that group died, as did two in the warfarin cohort.
The findings were reported in the Sept. 26 issue of the New England Journal of Medicine.
WHY MORE COMPLICATIONS?
“Possible explanations for the increase in thromboembolic complications with dabigatran include inadequate plasma levels of the drug and a mechanism of action that differs from that of warfarin,” said the study's principal investigator Frans Van de Werf, MD, PhD, professor and chair of the department of cardiovascular medicine at University Hospitals, in Leuven, Belgium. Dr. Van de Werf was part of the collaborative team effort that established the clinical utility of tissue plasminogen activator (tPA) in reducing permanent disabilities in ischemic stroke patients.
He told Neurology Today that using lower doses than were tested would have resulted in more embolic events, but that other blood thinners might become available that might be as good or better than warfarin, notably tecarfarin, a novel anticoagulant that is currently being studied in clinical trials.
There were more thromboembolic events among patients in the study who had undergone valve replacement surgery within a week of starting dabigatran than those treated three months earlier, he noted.
“Low drug levels soon after valve surgery may have allowed for early formation of blood clots that were not clinically manifested until later,” he said. “However, events also occurred among patients with higher trough plasma levels of dabigatran early after surgery, and among subjects in the earlier valve replacement group who had higher plasma levels than the former, suggesting that lower-than-expected drug levels cannot fully explain the increase in the rate of thromboembolic events.”
In addition, clots can be triggered by exposure of the blood to the artificial surface of artificial valve leaflets and the sewing ring used to attach the mechanical valves, which can activate the contact pathway of coagulation. In fact, most clots appear to have arisen from the sewing ring, he said.
IS WARFARIN DEAD?
“These newer, novel anticlotting drugs are better blood thinners, but we still see more patients on warfarin than anything else, probably because it only has to be taken once each day,” said Christopher Ellis, MD, assistant professor of medicine at Vanderbilt Heart and Vascular Institute at the Vanderbilt University Medical Center in Nashville, who has conducted clinical research on the use of dabigatran to reduce stroke and thromboembolism during left atrial catheter ablation for atrial fibrillation.
Yet something about using dabigatran as a blood thinner in mechanical heart valve procedures remains poorly understood, he told Neurology Today in a telephone interview.
“I find it confusing that dabigatran has shown to be superior to warfarin in preventing strokes when used for several other indications, but apparently not with mechanical valves, so this is a setback — a black eye for these novel anticoagulants. For now, I think this ends the testing of newer thinners for mechanical valve replacement. In this trial, there were more ischemic strokes in dabigatran patients, but that could have been a timing issue because many patients had recently undergone valve replacement surgery. Also, some of the patients may have missed a dose.”
He noted that mechanical valves may not be necessary for many patients due to increasing use of replacement valves from pigs and cows, which are quickly coated with endothelial cells and do not require anticoagulant therapy.
“Except for mechanical heart valves, where I believe there may be some as yet unknown reaction, dabigatran seems to work better than warfarin. I think the researchers thought that it would be a slam-dunk, so these findings come as a surprise.”
The biggest question, he noted, is what issues may arise with the use of other new and experimental anticoagulants.
LINK UP FOR MORE INFORMATION:
•. Eikelboom J, Connoly S, Van de Werf F, et al.., for the RE-ALIGN investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med
•. Ellis CR, Kaiser DW. The clinical efficacy of dabigatran etexilate for preventing stroke in atrial fibrillation patients. Vasc Health Risk Manag
•. Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial. Circulation
•. Diener HC, Connolly SJ, Ezekowitz MD, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. Lancet Neurol
•. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–1151.