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Reduced Anticoagulation After Mechanical Aortic Valve Replacement: Interim Results From the Prospective Randomized On-X Valve Anticoagulation Clinical Trial Randomized Food and Drug Administration Investigational Device Exemption Trial
Study Questions:
What is the safety and efficacy of less aggressive anticoagulation with an international normalized ratio (INR) goal of 1.5-2.0 in high-risk patients following bileaflet mechanical aortic valve replacement, compared to standard anticoagulant therapy with an INR goal of 2.0-3.0?
Methods:
This was the first cohort of patients from the PROACT (Prospective Randomized On-X Anticoagulation Clinical Trial). In this multicenter trial, high-risk patients (defined as having chronic atrial fibrillation, left ventricular ejection fraction <30%, enlarged left atrium >50 mm in diameter, spontaneous echocardiographic contrast in the left atrium, vascular pathologic features, neurologic events, hypercoagulability, left or right ventricular aneurysm, lack of platelet response to aspirin or clopidogrel, and women receiving estrogen replacement therapy) were randomized to receive lower-dose warfarin (test INR, 1.5-2.0) or standard warfarin (control INR, 2.0-3.0), 3 months after mechanical aortic valve replacement with an approved bileaflet valve. All patients received 81 mg aspirin daily. Patients received point-of-care home INR testing. Primary endpoints included bleeding events, ischemic events, and death.
Results:
The mean INR was 2.50 ± 0.63 for the control and 1.89 ± 0.49 for the test groups (p < 0.0001). The test group experienced significantly lower major bleeding rates (1.48% vs. 3.26%/patient-year; p = 0.047). The incidence of stroke, transient ischemic attack, total neurologic events, and all-cause mortality was similar between the two groups.
Conclusions:
In the high-risk aortic valve replacement limb of the PROACT study, warfarin can be safely maintained at 1.5-2.0 following aortic valve replacement with the On-X Food and Drug Administration-approved bileaflet mechanical valve and is associated with less bleeding, compared to anticoagulation at standard intensity.
Perspective:
For a bileaflet mechanical valve, current guidelines recommend an INR range of 2.0-3.0 in the aortic position and 2.5-3.5 in the mitral position. Of course, the major limitations of this trial are small numbers and the noninferiority design. In a discussion accompanying the manuscript, there was concern about having combined efficacy (thrombotic events) endpoints with safety endpoints (bleeding). Nonetheless, the authors provide a starting point to establish the safety of the On-X bileaflet mechanical valve position in the aortic position in high-risk patients when the INR is maintained between 1.5-2.0 and aspirin is used concomitantly. Future PROACT cohorts will determine the safety and efficacy of aspirin and/or clopidogrel only compared with standard anticoagulant therapy in lower-risk patients, and standard anticoagulant therapy versus less intense anticoagulation in those with mitral valve prostheses.
Keywords: Heart Atria, Warfarin, Ticlopidine, Estrogen Replacement Therapy, Thrombophilia, United States Food and Drug Administration, Stroke Volume, Hemorrhage
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