30/09/2012
GEBRUIK GEEN DABIGATRAN BIJ MECHANOPROTHESEN
September 26, 2012 (Ottawa, Ontario) — Primary-care practitioners may be putting the lives of patients with prosthetic heart valves at risk by switching their anticoagulation from warfarin to newer agents such as dabigatran (Pradaxa, Boehringer Ingelheim), say Canadian researchers [1]. Dr Joel Price (University of Ottawa Heart Institute, ON) and colleagues report the cases of two women who had undergone valve replacement some years before and had been faring well on warfarin; they were switched to dabigatran and subsequently suffered valve thromboses.
"The message is that dabigatran has really been approved only for patients who have non-valvular AF, but people are starting off-label use because of the perceived convenience of the medication," senior author Dr Munir Boodhwani (University of Ottawa Heart Institute, ON ) told heartwire. "To go and use it off-label is potentially harmful. There is a need to educate a variety of people who are involved in the management of anticoagulation--for example, hematologists, family physicians, and internal-medicine specialists, as well as cardiologists.
"I do think these drugs carry a lot of promise to potentially be applicable in these contexts," he adds. "However, there is a need for dose-finding studies and clinical trials to demonstrate safety and efficacy in this setting. Until then, use of such agents off-label should be avoided. It's very premature and potentially dangerous. People might have thrombosis of their valve and may die from it without ever realizing that this was the problem," he stresses.
This is not the first time there has been concern about use of dabigatran and other new anticoagulants, many of which are also approved for use in venous thromboembolism. There have been warnings about bleeding events in patients being switched from warfarin to dabigatran in Australia, for example, and authorities there have urged doctors to carefully assess the suitability of patients for the new drug even when it is being used for an approved indication.
Patients Report Progressive Dyspnea After Switch to Dabigatran
In a letter to the editor, published online September 26, 2012 in the Journal of the American College of Cardiology, Price and colleagues outline the cases of the two patients they encountered. The first was a 51-year-old woman who had had a mechanical aortic valve fitted eight years previously and who had been compliant with warfarin therapy with no adverse events. Two months prior to presenting with a four-week history of progressive exertional dyspnea, her general practitioner had switched her from warfarin to dabigatran (150 mg twice daily) for mechanical-valve anticoagulation.
An echo revealed severe prosthetic aortic-valve stenosis and severe left ventricular dysfunction with a probable mass on the prosthesis. The patient was transferred to the Ottawa Heart Institute in cardiogenic shock and taken as an emergency to the operating room--with a partial thromboplastin time (aPTT) of 27 seconds--where she experienced a cardiac arrest. A transesophageal echo (TEE) followed by surgical exploration confirmed multiple masses on the prosthetic aortic valve, which was replaced without complication. Dialysis was performed while she was on bypass to reduce circulating levels of dabigatran; despite this, she experienced extensive coagulopathy. Fortunately, her postoperative course was uneventful, with complete end-organ recovery.
The second patient was a 59-year-old woman who had had a mechanical mitral-valve replacement in 2007 for rheumatic disease and who had presented for routine follow-up. She had been treated with warfarin for the past five years without complication. Three months earlier, her family physician had switched her to dabigatran (150 mg twice daily) and she reported progressive dyspnea over the past two months.
TEE showed a large thrombus on the atrial aspect of the valve, and the patient's aPTT was 54 seconds. Dabigatran was stopped, and three days later the patient was taken to the OR, where large amounts of thrombus were found on the mitral valve. A mitral-valve replacement and a tricuspid-valve repair were performed, and the patient had an uneventful recovery.
Wealth of Data on Warfarin for Prosthetic Valves; Wait for Dabigatran Trials
Price and colleagues note that both patients had been anticoagulated for years with warfarin and never experienced thrombotic or bleeding events. Within one month of being switched from warfarin to dabigatran, both became symptomatic and were subsequently diagnosed with thrombosis. "While a causal link is not certain, the temporal association is highly suggestive," they observe.
The failure of one patient to achieve adequate anticoagulation and the fact that a second experienced valve thrombosis despite therapeutic aPTT levels "highlights the importance of medication testing for a specific indication. AF may represent a lesser thrombotic risk than a mechanical prosthesis, particularly mitral," they state.
"While there are a wealth of data and clinical experience on dosing and therapeutic response to warfarin in this context, data are unavailable for dabigatran. Off-label use of novel drugs should be avoided until data from well-designed clinical studies are available."
To this end they note that RE-ALIGN--a phase 2 dose-finding trial with dabigatran in patients with mechanical valves--is now under way, employing doses ranging from 150 to 330 mg twice daily, adjusted based on renal function and the results of the Hemoclot (Aniara, West Chester, OH) assay.
