Prediction of hemorrhagic and thrombotic events in patients with mechanical heart valve prostheses treated with oral anticoagulants

Summary.  Background:  Variability in the intensity of anticoagulant therapy is considered a risk factor for complications, but it is unclear how best to quantify variability. Objective:  We evaluated the association of three methods to measure variability with complications of oral anticoagulant therapy. Methods:  We conducted a nested case–control study within a cohort of patients with prosthetic heart valves. 210 patients with a first hemorrhagic or thrombotic event during follow-up were selected with two controls per case, matched on age and sex. We calculated the time spent at an International Normalized Ratio below, above, and between 2.5 and 4.0, and the variance growth rate according to three different methods (A, B1, B2); method A combines variability and time in range, and methods B1 and B2 purely look at variability. Results:  Odds ratios of the variance growth rates for thrombotic events for patients in the second and third tertiles varied between 2 and 3, with the highest odds ratio for complications for the method that purely looked at variability. For hemorrhagic complications, the highest odds ratios were found for method A, which also incorporated time in range, with odds ratios of 2.6 (95% CI: 1.3–5.1) and 3.1 (95% CI: 1.6–6.0) for the second and third tertiles as compared to the first. The combination of time spent out of range with the highest tertile of variability increased the risk 2.6-fold (95% CI: 1.6–4.2) as compared to subjects with stable anticoagulation within the target range. Conclusion:  Unstable anticoagulation was associated with hemorrhagic and thrombotic complications. Method A was best associated with complications, but methods B1 and B2, in combination with time spent in range, were equally well associated. As we prefer to disentangle variability and intensity of anticoagulation, we propose to use methods B1 or B2 to reflect pure variability of oral anticoagulant therapy.