Dabigatran etexilate is an oral direct thrombin inhibitor that has recently been approved for anticoagulation of nonvalvular atrial fibrillation (AF). While this medication possesses a number of characteristics that make it an attractive alternative to warfarin, its use for other indications currently remains untested. We report 2 cases of patients with mechanical heart valves who were switched from warfarin to dabigatran leading to thrombosis of their prosthetic valves.

A 51-year-old woman presented with a 4-week history of progressive exertional dyspnea. She underwent a mechanical aortic valve replacement 8 years prior. Two months earlier, her general practitioner switched her from warfarin to dabigatran (150 mg, twice daily) for mechanical valve anticoagulation. This patient did not have AF, had been compliant with warfarin therapy with no adverse events, and had normal renal function.

She had coarse crackles bilaterally and a 4/6 systolic murmur in the aortic area. An echocardiogram revealed severe prosthetic aortic valve stenosis and severe left ventricular dysfunction with a probable mass on the prosthesis. The patient was transferred to our institution in cardiogenic shock and taken emergently to the operating room. Immediately prior to the operation, the activated partial thromboplastin time (aPTT) was 27 s. The patient experienced a cardiac arrest in the operating room and was placed on cardiopulmonary bypass via the femoral vessels. A transesophageal echocardiogram confirmed multiple masses on the prosthetic aortic valve (Figure 39_gr1). Surgical exploration revealed extensive thrombi on the valve without pannus formation (Figure 39_gr2). The valve was replaced with a mechanical prosthesis without complication. Dialysis was performed while on cardiopulmonary bypass in an attempt to reduce circulating levels of dabigatran. Despite this the patient experienced extensive coagulopathy. Her subsequent post-operative course was uneventful with complete end-organ recovery.

A 59-year-old female with a prior mechanical mitral valve replacement presented for routine follow-up. Since her valve replacement for rheumatic mitral disease in 2007, the patient had been treated with warfarin without complication. The patient's family physician switched her to dabigatran (150 mg, twice daily) 3 months earlier. She was reportedly compliant with her medication. The patient was in sinus rhythm and had normal renal function. She reported progressive dyspnea over the past 2 months. Transesophageal echocardiogram revealed elevated transprosthetic gradients, an immobile anterior leaflet, and a large thrombus on the atrial aspect of the valve. The aPTT was 54 s. Dabigatran was stopped and 3 days later, the patient was taken to the operating room. Large amounts of thrombus were found on the mitral valve. A mitral valve replacement and tricuspid valve repair were performed. The patient had an uneventful recovery.

Thrombosis of a mechanical valve is a potentially fatal complication. With warfarin anticoagulation, the incidence of valve thrombosis is low (1). In both presented cases, patients were anticoagulated with warfarin and had never experienced thrombotic or bleeding events. One month after being switched from warfarin to dabigatran both patients became symptomatic and were subsequently diagnosed with thrombosis. While a causal link is not certain, the temporal association is highly suggestive.

Dabigatran is one of several novel oral anticoagulants evaluated as a substitute for warfarin. Regulatory approval was based on the pivotal RE-L-Y (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, which compared dabigatran to warfarin for the treatment of nonvalvular AF (2). This study demonstrated equivalent freedom from thrombotic events with fewer hemorrhagic events for low-dose dabigatran (110 mg, twice daily) and superior freedom from thrombotic events with equivalent bleeding with higher dose dabigatran (150 mg, twice daily). Additional advantages of dabigatran include stable dosing, no requirement for monitoring, and fewer interactions.

In vitro and animal studies suggest that Dabigatran for mechanical valve anticoagulation may be a potential therapeutic avenue ((3),4). Recently, enoxaparin was compared to dabigatran for anticoagulation of mechanical aortic valves. Dabigatran was found to reduce thrombus burden with a dose of 20 mg/kg twice daily, corresponding to an aPTT of 2 to 2.5 times normal in the porcine model. This question is now being addressed with a phase II clinical trial, RE-ALIGN (NCT01452347), which utilizes doses ranging from 150 to 330 mg twice daily, adjusted based on renal function and results of the Hemoclot assay.

The failure of 1 patient to achieve adequate anticoagulation despite a “highdose” and that a second experienced valve thrombosis despite therapeutic aPTT levels highlights the importance of medication testing for a specific indication. Furthermore, AF may represent a lesser thrombotic risk than a mechanical prosthesis, particularly mitral. 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.

Off-label use of novel drugs can jeopardize potential future applications in new disease contexts and should be avoided until data from well-designed clinical studies is available. Novel oral anticoagulants hold tremendous promise for mechanical valve anticoagulation. However, there is a need for dose-finding studies and clinical trials to demonstrate safety and efficacy in this setting.