Elsevier

Cardiovascular Surgery

Volume 8, Issue 6, October 2000, Pages 491-498
Cardiovascular Surgery

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

https://doi.org/10.1016/S0967-2109(00)00069-7Get rights and content

Abstract

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.

Introduction

In patients with mechanical cardiac valves, our standard anticoagulation policy was to target an INR between 2.5 and 3.5. Studies of long-term oral anticoagulant therapy have shown that this regimen was as effective as, but safer than, a more intensive therapy 1, 2, 3, 4. However, reports have suggested that a lower INR between 2 and 2.5 combined to 300 mg dipyridamole offered a safe antithrombotic therapy to patients with bileaflet St Jude valve 5, 6, 7, 8, 9. Even though the use of combined therapy has been largely limited by the occurrence of intractable headache, dizziness, nausea, flushing and other dipyridamole-related side effects 4, 5. In order to overcome these side effects, we have used the generally tolerable 225 mg daily dose in combination with the suggested low-level anticoagulation regimen. This study was designed to compare the long-term safety and efficacy of such a combined therapy to our standard anticoagulation policy, which is applied in young rheumatic patients with St Jude mitral valve prosthesis.

Section snippets

Methods

Between January 1990 and December 1998, 486 rheumatic patients benefited from mitral valve replacement with St Jude Medical valve prosthesis. The patient criteria was: young patients ≤21 yr of age, of both sexes, have rheumatic mitral valve disease, with or without tricuspid valve incompetence and operated upon electively for first time mitral valve replacement. We excluded from this study, 51 patients who died during the hospital period (9.5%) from causes unrelated to a prosthetic valve or

Results

With the exception of a significantly larger left atrial diameter in patients on low-level combined therapy, both groups were comparable with respect to baseline characteristics (Table 1). Follow-up ranged from 1 to 8 yr, with a mean duration of 3.6±2.1 yr and a cumulative follow-up period of 1712.5 pt yr (1002.8 pt yr in standard monotherapy group and 709.7 pt yr in low-level combined therapy group). Sixteen patients (13 patients on standard monotherapy and three patients on low-level combined

Discussion

The pathophysiologic importance of platelet activation in thrombus formation and the increased platelet consumption in anticoagulated patients with prosthetic cardiac valves 11, 12have led to the clinical evaluation of a combined therapy with warfarin and dipyridamole. As early as 1969, a leading comparative prospective randomized trial has demonstrated that such a combination significantly decreased embolic events after cardiac valve replacement by 92% [13]. Similar trials were carried out on

Acknowledgements

This research was supported by a National Research Center grant (11/3/3/5/1/1998).

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