Standard versus low-level anticoagulation combined to low-dose dipyridamole after mitral valve replacement

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Background: Although the addition of 300 mg dipyridamole to oral anticoagulants has been shown to decrease thromboembolic events after cardiac valve replacement, reports of combined therapy were few and some showed significant dipyridamole-related side effects and intolerance. The aim of this study was to compare the clinical effect of a standard monotherapy (targeting an international normalized ratio — INR — between 2.5 and 3.5) to a less intensive regimen (targeting an INR between 2 and 2.5) combined to a small dose of dipyridamole (225 mg/day). Methods: Between January 1990 and December 1998, 486 young rheumatic patients with a St Jude mitral valve prosthesis were assigned to follow either standard monotherapy (294 patients) or low-level combined therapy (192 patients). Phenindione has been the anticoagulant of choice. Up to a maximum daily dose of 100 mg, patients failing to achieve their target INR range were shifted to warfarin therapy. Prothrombin time was checked monthly and asymptomatic patients with a too low or a too high INR (<1.3 or >5) were briefly hospitalized for INR control. Complete blood picture, renal and hepatic profiles and full echocardiographic study were done biannually. Results: With the exception of a significantly larger left atrium in patients on low-level combined therapy ( P=0.001), both groups were comparable as regards to age and sex distribution, number of patients with atrial fibrillation, left atrial thrombus and history of stroke. Patients were monitored for 1712.6 pt yr and follow-up was 96.7% complete. No phenindione-related complications were observed (mean dose 62.3±21.4 mg), 20 patients (4.1%) had failed to achieve their target INR range and were switched to warfarin and only three patients (1.6%) had tolerable dipyridamole-related side effects. Compared to standard monotherapy, patients on low-level combined therapy showed significantly lower annualized rates: thromboembolism (1.6 vs 0.43%: risk reduction 71%; P=0.05), thromboembolism and hemorrhage (2.7 vs 0.7%: risk reduction 72%; P=0.005), death due to valve thrombosis or stroke (1.17 vs 0.14%: risk reduction 81%; P=0.04) as well as both non-fatal (3.3 vs 1.57%: risk reduction 51%; P=0.04) and total late postoperative complications (5.35 vs 3.14%: risk reduction 40%; P=0.04); respectively. However, total late mortality (32 patients; 1.8% per pt yr) was comparable among both groups. Conclusion: Low-level anticoagulation with phenindione combined to low dosage of dipyridamole was clinically more effective than the higher standard monotherapy. With respect to the prescribed doses, both drugs were well tolerated by almost all patients. Use of dipyridamole did not influence overall patients' survival.