Abstract & Commentary

Synopsis: The meta-analysis by Vink and colleagues demonstrates that patients with either aortic or mitral valve replacement will benefit from high-intensity VKA therapy.

Source: Vink R, et al. JACC. 2003;12:2042-2048.

Implanted mechanical heart valves have an increased risk of valve thrombosis often resulting in secondary systemic embolism both peripherally and into the cerebral circulation. Since life-long vitamin K antagonist (VKA) therapy (ie, usually Coumadin) significantly reduces the incidence rates of these serious complications, such therapy has been strongly recommended in the guidelines of the American College of Chest Physicians (ACP) since at least 1986.^1,2 However, since VKA therapy is, on occasion, associated with an increased incidence of severe and even fatal bleeding, the optimal intensity of VKA therapy has been defined as that intensity of therapy at which the incidence of both thromboembolic as well as bleeding complications is lowest. The 1986 ACP guidelines² recommended a prothrombin time with an international normalized ratio (INR) between 3.0 and 4.5 however, a significant study published in 1995 suggested that the optimal intensity of anticoagulation which resulted in the fewest adverse events was that intensity which resulted in an INR level between 2.5 and 4.9.³ Finally, the 2001 ACP guidelines recommended an INR target range between 2.0 and 3.5 for patients with implanted mechanical heart valves. Vink performed a meta-analysis of all eligible studies published between 1965-2002 reporting data on the incidences of thromboembolic and bleeding complications occurring in patients with mechanical heart valves prostheses receiving different intensities of VKA therapy.⁵ The 35 eligible studies reported findings in a total of 23,145 patients who were studied for 108,792 patient-years. The results revealed that patients with either aortic or mitral implanted mechanical valves would benefit when the target INR was higher than 3.0.

Comment by Harold L. Karpman, MD, FACC, FACP

The intensity of anticoagulant therapy for patients with mechanical heart valves has long been the subject of intense medical debate simply because adequate data has not been available. Because aortic valve prostheses have been considered less thrombogenic then prostheses in the mitral position,⁴ the target INR at the upper end of the range of 2.0-3.5 has been suggested for mitral valve replacements whereas the lower end of the range has been advised for aortic valves.⁵ The meta-analysis by Vink and his group demonstrates that patients with either aortic or mitral valve replacement will benefit from high-intensity VKA therapy since the number of thromboembolic events is lowest in both groups when the higher INR levels are targeted. Efficacy of treatment is clearly demonstrated because the total number of both thromboembolic and bleeding events in patients with aortic and mitral valve replacements were decreased in the high-intensity VKA therapy group..

The role of antiplatelet therapy in the long-term treatment of patients with mechanical heart valves remains controversial. One recent randomized trial⁶ demonstrated that adding 100 mg/d of aspirin to VKA therapy (INR, 3.0-4.5) was associated with fewer thromboembolic events than VKA therapy alone, although the rate of major bleeding was increased. Results of another trial⁷ revealed that aspirin (100 mg/d) in combination with VKA therapy was as effective as VKA therapy alone. These results do not provide sufficient evidence to recommend combination therapy however, until additional controlled studies are performed, the addition of antiplatelet therapy to VKA therapy should be considered for the prevention of thromboembolic events only in patients with exceptional thrombotic processes.

In conclusion, until a prospective study that addresses the intensity of VKA therapy in both aortic and mitral mechanical heart valve prostheses is performed, clinicians should consider increasing the target INR to between 3.0-4.5. and, since aortic prosthetic valves are considered less thrombogenic then prostheses in the mitral position, the target INR should be at the lower side of this range whereas the target INR should be in the upper side of this range for mitral prostheses. Obviously, a prospective controlled study is needed that will evaluate: 1) the benefits of varying intensities of VKA therapy in relationship to the position of the mechanical heart valve and, equally important, 2) whether or not antiplatelet therapy substantially diminishes the frequency of thromboembolism.

Dr. Karpman, Clinical Professor of Medicine, UCLA School of Medicine, is Associate Editor of Internal Medicine Alert.

References

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2. Stein PD, et al. Chest. 1986;89:46S-53S.

3. Cannegieter SC, at al. N Engl J Med. 1995;333:11-17.

4. Cannegieter SC, at al. Circulation. 1994;89:635-641.

5. Stein PD, at al. Chest. 2001;119:220S-227S.

6. Turpie AG, et al. N Engl J Med. 1993;329:524-529.

7. Meschengieser SS, et al. J Thorac Cardiovasc Surg. 1997;113:910-916.