Ronelle E. Stevens, PharmD, RPh, CACP
Choosing the right anticoagulation agent and duration of therapy remains controversial.
The world’s first successful heart valve surgery was performed 90 years ago by Elliot Cutler, MD.1
Forty years later, Albert Starr, MD, and Lowell Edwards, an engineer, collaborated to pioneer the development of the first successful, FDA-approved, mechanical caged-ball heart valve. Since then, more than 80 mechanical heart valve models have been developed.
Contributing to the long-standing success of these interventions, anticoagulation remains a key step in the prevention of valve thrombosis and thromboembolic stroke. The best approach in anticoagulant optimization is debatable.
Challenges in Optimal Anticoagulation
The foundation of therapy has been oral vitamin K antagonists, such as warfarin managed to a target international normalized ratio (INR) of 2.0 to 3.5, depending on the choice of valve and other risk factors. Warfarin has the most evidence supporting its use, but it is a less than ideal agent given its difficulty to optimize and maintain.2,3
There’s a delicate balance that necessitates frequent monitoring when managing clotting versus bleeding risks. Postoperatively, there may be an exaggerated risk of anticoagulant-related hemorrhage secondary to suboptimal nutritional status and hepatic impairment, making warfarin management a hindrance.2
To minimize the delay in achieving their therapeutic goal, patients are often “bridged” with unfractionated or low-molecular-weight heparin.
Adding to the controversy, in 2002, the FDA issued a boxed warning that stated that enoxaparin was “not recommended for thromboprophylaxis in patients with prosthetic heart valves” secondary to a small study in which enoxaparin monotherapy was administered to pregnant women post-mechanical valve implantation. Insufficient data existed to support extrapolation to all populations, however, and the statement was softened to conclude that there was insufficient evidence to support the long-term use of enoxaparin in patients with mechanical prosthetic heart valves.4
The search for alternative prophylaxis often pushes clinicians to off-label options. Dabigatran has been approved in the United States for patients with nonvalvular atrial fibrillation. Due to its perceived convenience, some physicians have begun to prescribe it off label for mechanical valves. Two notable reports were published in the Journal of the American College of Cardiology
in September 2012 that revealed the development of thrombosis in patients within 1 month of being switched from warfarin to dabigatran.5
Subsequent to these reports, the phase 2 dose-finding RE-ALIGN trial of dabigatran in prosthetic heart valves was halted post-interim review. It revealed that patients taking dabigatran were more likely to experience strokes, myocardial infarction, and valve thromboses versus patients taking warfarin. Additionally, there was more bleeding in the dabigatran population. The FDA has now taken the stance that dabigatran is contraindicated in patients with mechanical heart valves, further noting that its use in bioprosthetic recipients “has not been evaluated and cannot be recommended.”6,7
Duration of Therapy
Patients undergoing mechanical mitral valve replacement require lifelong anticoagulation. There is some debate surrounding the duration of therapy for patients receiving bioprosthetic aortic valves. The American College of Chest Physicians recommends aspirin alone pending other thromboembolic risk factors, whereas the American College of Cardiology/ American Heart Association guidelines recommend a 3-month course of warfarin plus aspirin. More recently, Merie and colleagues of Denmark published their epidemiologic findings that suggest that patients with bioprosthetic implants should remain on warfarin for 6 months postoperatively. Their data provided evidence that the early discontinuation of warfarin post aortic valve implantation was associated with increased cardiovascular death. Patients maintained on warfarin experienced 3.2 fewer thromboembolic events per 100 person-years (P = .03) and 4.4 fewer cardiovascular deaths per 100 person years (P = .003) versus those not taking warfarin.8,9
One should not forfeit the wealth of data and clinical experience that we have with warfarin for the sake of off-label novel alternatives, as it is prudent to wait for the outcomes of well-conducted trials. Warfarin with or without aspirin remains the proven mainstay of therapy in patients with mechanical and bioprosthetic heart valve replacement.
Dr. Stevens is an advanced practice anticoagulation pharmacist for the Partners Heathcare System and an adjunct clinical assistant professor of pharmacy at Northeastern University’s Bouvé College of Health Sciences in Boston, Massachusetts. This column’s information is based on current studies and references, but it may be changed without notice with newer studies or with different populations.
Elliott Carr Cutler papers, 1911-1948. HMS c170. Harvard Medical Library, Francis A. Countway Library of Medicine, Boston, MA.
Ageno W, Turpie AG. Exaggerated initial response to warfarin following heart valve replacement. Am J Cardiol. 1999;84:905-908.
Pibarot P, Dumesnil JG. Prosthetic heart valves: selection of the optimal prosthesis and long-term management. Circulation. 2009;119(7):1034-1048.
Goldhaber SZ. “Bridging” and mechanical heart valves: perils, promises, and predictions. Circulation. 2006;113:470-472.
Price J, Hynes M, Labinaz M, Ruel M, Boodhwani M. Mechanical valve thrombosis with dabigatran. J Am Coll Cardiol. 2012;60(17):1710-1711. doi:10.1016/j.jacc.2012.06.039. http://content.onlinejacc.org.
Boehringer Ingelheim. Boehringer Ingelheim discontinues phase II trial in patients with artificial heart valves [press release]. December 11, 2012.
Food and Drug Administration. Drug safety communication: Pradaxa (dabigatran etexilate mesylate) should not be used in patients with mechanical prosthetic heart valves. December 19, 2012.
Mérie C, Køber L, Skov Olsen P, et al. Association of warfarin therapy duration after bioprosthetic aortic valve replacements with risk of mortality, thromboembolic complications and bleeding. JAMA. 2012; 308:2118-2125.
Mehta SR, Weitz JI. Warfarin after bioprosthetic aortic valve implantation. JAMA. 2012;308:2147-2148.