Optimal level of oral anticoagulant therapy for the prevention of arterial thrombosis in patients with mechanical heart valve prostheses, atrial fibrillation, or myocardial infarction: a prospective study of 4202 patients.

BACKGROUND: Oral anticoagulant therapy is effective for the prevention of arterial thromboembolism in various patient groups. The increased risk of hemorrhage remains the major drawback to this therapy and is associated with the intensity of anticoagulation. Finding the optimal intensity at which the overall incidence rate of both bleeding and thromboembolic events is minimized represents a way to improve the safety of oral anticoagulant treatment. METHODS: We evaluated all patients visiting the Leiden Anticoagulation Clinic with mechanical heart valve prostheses, atrial fibrillation, or myocardial infarction from 1994 to 1998. Untoward events were major thromboembolism and major hemorrhage. We calculated intensity-specific incidence rates of untoward events to assess the optimal intensity per indication of treatment. We enrolled 4202 patients for a total of 7788 patient-years. RESULTS: A total of 3226 hospital admissions were reported, 306 owing to an untoward event. Incidence rates of untoward events were around 4% per year for all indications: 4.3 (95% confidence interval [CI], 3.1-5.6) for patients with mechanical heart valve prostheses, 4.3 (95% CI, 3.7-5.1) for patients with atrial fibrillation, and 3.6 per year (95% CI, 3.0-4.4) for patients treated after a myocardial infarction. The optimal intensity of anticoagulation for patients with mechanical heart valve prostheses was an international normalized ratio (INR) of 2.5 to 2.9; for patients with atrial fibrillation, an INR of 3.0 to 3.4; and for patients after myocardial infarction, an INR of 3.5 to 3.9. CONCLUSION: Our study suggests target INRs of 3.0 for patients with mechanical heart valve prostheses and atrial fibrillation and 3.5 after myocardial infarction as a starting point in future clinical trials.

Risks of oral anticoagulant therapy with increasing age.

BACKGROUND: Oral anticoagulation in the elderly is a dilemma. Although many elderly patients have strict indications for treatment with coumarin derivatives, the tendency toward an increased bleeding risk with age is a matter of concern. We investigated the risk of hemorrhage and thromboembolism according to age in patients who were treated with oral anticoagulants in the routine setting of an anticoagulation clinic. METHODS: All patients of the Leiden Anticoagulation Clinic (Leiden, the Netherlands) who were treated because of mechanical heart valve prostheses (target, international normalized ratio [INR] of 3.5), atrial fibrillation (target, INR of 3.0), or after a myocardial infarction (target, INR of 3.0) between 1994 and 1998 were included in the study and grouped by age at the start of follow-up. We calculated incidence rates of major hemorrhage and thromboembolism per age group. RESULTS: We included 4202 patients: 842 patients younger than 60 years; 1200 patients aged between 60 and 70 years; 1464 patients aged between 71 and 80 years; and 696 patients older than 80 years. The incidence rate of major hemorrhage rose gradually with age from 1.5 per 100 patient-years for patients younger than 60 years to 4.2 per 100 patient-years for patients older than 80 years, yielding a hazard ratio of 2.7 (95% confidence interval, 1.7-4.4). The incidence rate of major thromboembolism rose from 1.0 per 100 patient-years for patients younger than 60 years to 2.4 per 100 patient-years for patients older than 80 years (hazard ratio, 2.2; 95% confidence interval, 1.2-4.2). CONCLUSIONS: The incidence of both bleeding and thromboembolic events increases sharply with advanced age. Because higher thromboembolic risk with age often makes it unfeasible to withhold oral anticoagulation from elderly patients, future studies should focus on ways to lower the bleeding risk.

Lowering the intensity of oral anticoagulant therapy: effects on the risk of hemorrhage and thromboembolism.

BACKGROUND: Oral anticoagulation is effective in the prevention of arterial thromboembolism. The major drawback of coumarin therapy is the increased risk of hemorrhage. Implementing the optimal intensity of oral anticoagulation, ie, the level at which thromboembolic events are prevented without introducing an excessive bleeding risk, is an important step to improve the safety of oral anticoagulant therapy. METHODS: We observed all patients of the Leiden Anticoagulation Clinic who were treated because of a mechanical heart valve or atrial fibrillation between January 1, 1995, and January 1, 1998, or because of cerebral ischemia between January 1, 1994, and January 1, 1998. In 1996, at the halfway point of follow-up, the target intensity for patients with a mechanical heart valve was lowered from 4.0 (range, 3.6-4.8) to 3.5 (range, 3.0-4.0) international normalized ratio, and for atrial fibrillation and cerebral ischemia, from 3.5 (range, 3.0-4.5) to 3.0 (range, 2.5-3.5) international normalized ratio. We compared incidence rates of hemorrhage and thromboembolism before and after the introduction of lower target intensities. RESULTS: Higher target treatments were given to 2341 patients (2863 patient-years) and lower target treatments to 2256 patients (2260 patient-years). After introduction of the lower target ranges, the overall incidence rate of major untoward events declined from 5.7 (95% confidence interval [CI], 4.9-6.7) to 3.6 (95% CI, 2.8-4.4) per 100 patient-years. The incidence of major bleeding fell from 3.6 (95% CI, 2.9-4.4) to 2.7 (95% CI, 2.1-3.5) and the incidence of major thromboembolism from 2.0 (95% CI, 1.5-2.5) to 0.8 (95% CI, 0.5-1.3) per 100 patient-years. CONCLUSION: Implementation of lower target intensities for coumarin therapy decreased the complication risk.

Oral anticoagulation in surgical procedures: risks and recommendations.

Surgery in anticoagulated patients is problematic. Coumarin therapy is often discontinued or reversed to reduce the perioperative bleeding risk. Meanwhile, the thromboembolic risk is enhanced. We sought to determine the frequency of bleeding and thromboembolism in anticoagulated patients undergoing routine surgery and to investigate the role of patient characteristics and the level of anticoagulation. We studied patients who attended the Leiden Anticoagulation Clinic for treatment relating to mechanical heart valve prostheses, atrial fibrillation or myocardial infarction and underwent surgery at the Leiden University Medical Centre between 1994 and 1998. Outcome events were bleeding and thromboembolism in the perioperative period. Seventy-two complications occurred in 603 interventions, yielding an overall frequency of 11.9% [95% confidence interval (CI): 9.3-14.9], 9.5% (n = 57) for haemorrhage and 2.5% (n = 15) for thromboembolism. Younger patients tended to have more complications [odds ratio (OR) for >65 years of age: 0.5, 95% CI 0.3-1.0] as did patients with atrial fibrillation (OR for atrial fibrillation versus mechanical heart valve prostheses: 1.8, 95% CI 0.8-4.2). High postoperative levels of anticoagulation were associated with a slightly increased risk of complications [OR international normalized ratio (INR) > 3 vs. INR < 2: 1.3, 95% CI 0.6-3.0]. We conclude that routine surgery in anticoagulated patients yields a high perioperative bleeding and thromboembolic risk. While neither patient characteristics nor the level of anticoagulation appeared to play a major role in the occurrence of complications, the risk was clearly associated to the type of surgery, with the highest risk in thoracic surgery.