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Hot Topic: The Optimal Range of Oral Anticoagulation in Patients with Mechanical Heart Valves Remains Controversial

Authors: Tera D. Moore, Henry I. Bussey, William D. Linn
Posted March 2004

University of Texas Health Science Center at San Antonio

Anticoagulant therapy with vitamin K antagonists (VKA) for patients with a mechanical heart valve has been the subject of intense debate for the past decade. Most of the published investigations lack data that would permit a firm conclusion about the optimal antithrombotic regimen for specific patients.¹

Vink and colleagues² performed a meta-analysis that compared two different intensities of vitamin K antagonists among patients with mechanical heart valves. A computerized search in the PubMed database from January 1965 to June 2002 was performed to retrieve studies with data on the incidences of thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. In addition, a manual search of reference lists from retrieved articles was done to identify additional articles. The inclusion criteria for selection of studies included: 1) the possibility to differentiate between aortic valve prosthesis and mitral valve prosthesis; 2) specification of the target INR or prothrombin time of VKA therapy; 3) no change in the target INR or prothrombin time ratio during follow-up; 4) thromboembolic and bleeding events classified according to Edmunds et al. or otherwise adequately classified; and 5) mean age of the patients older than 18 years. Studies were excluded if: 1) the number of patients lost to follow-up was larger than 5%; 2) the study included bioprostheses or caged-ball valves; 3) the patients received antiplatelet therapy in combination with VKA; and 4) the cohort was the same as reported in another included study.

Studies were analyzed separately with aortic and mitral valve prostheses. These studies were then subdivided into low- or high-intensity VKA therapy. Low-intensity VKA therapy was defined as a mean target INR of 3.0 or lower and high-intensity was defined as a mean target INR above 3.0. Thrombotest and prothrombin time ratios were converted to INR, using the international sensitivity index of the prothrombin time assays as reported by the authors or requested from them. The events were analyzed according to the guidelines for reporting morbidity and mortality after cardiac valvular operations of Edmunds et al.³ A total of 35 studies, with 23,145 patients, were included in the analysis. Twenty-six studies were eligible for analysis of both aortic and mitral prostheses, four studies only reported on aortic valve prostheses, and five other reports concerned mitral valve prostheses only.

With high-intensity VKA therapy, the incidence of aortic valve thrombosis was 0.87 per 1,000 patient-years and the incidence of embolism was 9.83 per 1,000 patient-years compared with 1.16 events per 1,000 patient-years and 13.09 per 1,000 patient-years for the low-intensity group, with risk ratios (RR) of 0.75, 95% CI 0.50 to 1.13 and 0.75, 95% CI 0.70 to 0.81, respectively. The total number of thromboembolic events (defined as the combination of valve thrombosis and embolism together) was 10.01 per 1,000 patient-years for the high-intensity group and 13.69 per 1,000 patient-years for the low-intensity group (RR = 1.23, 95% CI 0.68 to 0.78). There was an increase in the incidence of bleeding events in the high-intensity group compared with low-intensity VKA therapy (14.89 vs. 12.06 per 1,000 patient-years; RR = 1.23, 95% CI 1.16 to 1.31).

Patients who received high-intensity VKA therapy had a lower risk for mitral valve thrombosis and systemic embolization than those receiving low-dose VKA, with a RR of 0.60 (95% CI 0.47 to 0.76) and 0.79 (95% CI 0.74 to 0.84). The occurrence of bleeding complications did not differ with the use of high-dose VKA compared with low-dose VKA (12.94 vs. 11.96 events per 1,000 patient-years; RR = 1.08, 95% CI 1.00 to 1.16, p = 0.0524).

The number of valve thrombosis and thromboembolic events is significantly lower in the aortic valve group compared with the mitral valve group for both low-and high-intensity VKA therapy. High-intensity therapy significantly increased bleeding events in patients with prosthetic aortic valve compared with patients with a mitral valve (RR = 1.15, 95% CI 1.06 to 1.25). No difference in bleeding complications was observed between patients with aortic and mitral valves treated with low-intensity VKA (RR = 1.01, 95% CI 0.94 to 1.07). The total number of events (thromboembolism and bleeding) for both high- and low-intensity treatment was lower in the aortic valve group than for patients in the mitral valve group (RR 0.80, 95% CI 0.75 to 0.85, and RR 0.72, 95% CI 0.68 to 0.76).

The authors concluded that this analysis shows that both patients with aortic and mitral valve prostheses will benefit from high-intensity VKA therapy, with a target INR between 3.0 and 4.5. Because aortic valve prostheses are considered less thrombogenic than prostheses in the mitral valve position, a target INR at the lower side of this range is suggested for aortic valves, whereas a target INR at the upper side of this range is suggested for mitral valves.

The results of this study do not provide a definitive conclusion of what the goal INR should be for anticoagulation with mechanical heart valves due to many limitations. First, this is not a meta-analysis of similar randomized controlled trials, but a large number of case series that involved patients from a number of countries who received a variety of types of valves, some not used in the Unites States. The different series of patients may have been quite different from each other in terms of additional risk factors and/or concomitant conditions that may have increased their risk of thromboembolism or bleeding, and their degree of INR control may have been different. Next, studies were included that used prothrombin time ratio or thrombotest after they calculated the corresponding INR based on information they were provided regarding reagent sensitivity. This is questionable since the investigators are trying to determine what reagents were available at the time and this presumes that all patients were tested by the same lab. Another limitation was the inability to determine to what degree the targeted level of anticoagulation was actually achieved or what INR values were associated with thromboembolic and hemorrhagic events. Without this information, it is possible that all major events happened with INRs well outside the range that is being evaluated. The authors indicated that the mitral valve patients had lower thromboembolic event rates in the high INR group without a higher bleeding rate, but the p value for "no difference in bleeding" was 0.0524. Finally, the authors of this meta-analysis were from The Netherlands where they have had a national network of anticoagulation clinics for about 50 years and their patients, in case series and retrospective studies, have INRs in the target range approximately two-thirds of the time. In other settings, less than one-half of the INRs were in the target range. Consequently, targeting an INR >3.0 in The Netherlands may create significantly less bleeding risk than targeting the same INR in the United States. As previously noted, prospective studies that address both risk factors among patients with each type and location of prosthetic valve and the level of anticoagulation actually achieved are needed before controversy regarding prophylaxis can be resolved.¹

References

1. Stein PD, Alpert JS, Bussey HI, et al. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest 2001;119:220S-7S.

2. Vink R, Kraaijenhagen RA, Hutten VA, et al. The optimal intensity of vitamin K antagonists in patients with mechanical heart valves. J Am Coll Cardiol 2003;42:2042-2048.

3. Cannegieter SC, Rosendaal FR, Wintzen AR, et al. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Eng J Med 1995;333:11-7.

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