The indications for oral anticoagulation therapy using coumarin derivatives have been expanded over the past few years, because the benefit of this treatment has been found to be greater than the risk. The most significant risk with coumadin therapy is hemorrhage, and this risk increases as the intensity of anticoagulation increases. However, the benefit of coumarin therapy also increases as the intensity of the therapy increases. Because of these factors, the optimal dosage that balances the risk and benefits has to be established. Prior studies have set the goals for the International Normalized Ratio (INR) for various indications. Although these INR goals have been established, they have not been validated. Torn and associates evaluated two oral anticoagulation regimens, comparing the incidence of hemorrhage and thromboembolic phenomena.
The study population included all patients at one anticoagulation clinic who were treated with coumadin for a mechanical heart valve, atrial fibrillation, or cerebral ischemia. During the study, the intensity of coumarin therapy was lowered in patients with mechanical heart valves from an INR range of 3.6 to 4.8 to a range of 3.0 to 4.0. The intensity also was lowered in patients with atrial fibrillation and cerebral ischemia from a range of 3.0 to 4.5 to a range of 2.5 to 3.5. Patients had follow-up at regular intervals during the study.
The main outcomes measured were major hemorrhagic and thromboembolic events. Hemorrhagic events included for analysis were extracranial and intracranial bleeds. Thromboembolic events included cerebral infarction, myocardial infarction, and peripheral arterial embolism. All adverse events were recorded, and it was noted whether they occurred on the higher or lower intensity coumarin therapy.
There were 2,341 patients enrolled in the higher intensity coumarin therapy group and 2,256 in the lower intensity group. The mean INR for all three treatment indications were lower when comparing higher with lower intensity therapy. When comparing major adverse events, the lower intensity group had significantly fewer events than the higher intensity group. The incidence of major bleeding declined when switching from higher to lower intensity therapy, going from 3.6 to 2.7 per 100 patient-years. The major reduction in the lowering of intensity of coumarin therapy was in the group with intracranial hemorrhage. The risk for thromboembolic events also decreased from 2.0 to 0.8 per 100 patient-years for the entire group.
The authors conclude that lower intensity oral anticoagulation therapy can be used. It results in a lower incidence of adverse events with no increase in the risk for thromboembolic events. They add that further studies are needed to continue the effort to define the best INR target for preventing thromboembolic events in patients with mechanical heart valves, atrial fibrillation, and cerebral ischemia.
In an accompanying editorial, O’Donnell and Hirsh point out that it is unlikely that one therapeutic range for coumarin therapy will be optimal, but that each indication will need further studies to determine exactly what INR levels will be best. They add that fixed-dose coumarin therapy is not acceptable. The most important aspect of managing coumarin therapy is to make sure that the therapeutic goal is reached and maintained.
editor’s note: Finding the optimal therapeutic range continues to be a difficult process. The higher the INR, the higher the risk for bleeding; the lower the INR, the higher the risk for thromboembolism. Torn and associates have demonstrated that lower intensity coumarin therapy does not result in a significant change in thromboembolic events.—k.e.m.