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Background: Postoperative venous thrombosis and pulmonary embolism present a major clinical threat to patients undergoing total hip or knee arthroplasty. We performed an economic evaluation of warfarin sodium and subcutaneous low-molecular-weight heparin sodium prophylaxis comparing cost and effectiveness. Methods: A consecutive series of 1436 patients who underwent hip or knee arthroplasty comparing these 2 regimens in a randomized trial with objective documentation of outcomes provided the opportunity to perform economic evaluations for Canada and the United States. Results: Deep vein thrombosis was documented in 231 (37.4%) of 617 patients given warfarin and in 185 (31.4%) of 590 patients given low-molecular-weight heparin (P=.03). In Canada, warfarin and low-molecular-weight heparin (tinzaparin sodium) incurred costs per 100 patients of $11 598 and $9197, respectively, providing a cost savings of $2401 for the low-molecular-weight heparin group. The drug cost of low-molecular-weight heparin (tinzaparin) was $6 per day and for warfarin was $0.32 per day. Sensitivity analysis showed that low-molecular-weight heparin is more costly if drug costs are increased by 1.5-fold (de, the cost of tinzaparin is increased from $6 per day to $8.82 per day or more). In the United States, the analysis was also not definitive; low-molecular-weight heparin was more costly than warfarin at drug costs of $15 and $2.01 per day, respectively. Conclusions: Our findings indicate that the decision to use low-molecular-weight heparin or warfarin prophylaxis in patients undergoing major joint replacement surgery is a finely tuned trade-off. Prophylaxis with low-molecular-weight heparin is equally or more effective than the more complex prophylaxis with warfarin. Major bleeding is uncommon but less frequent with warfarin use. The most significant parameters that influence the comparative cost-effectiveness are the cost of the drug, the cost of international normalized ratio monitoring, and the costs associated with major bleeding. The analysis also demonstrates that the results are health care system dependent (Canada vs US). In Canada, low-molecular-weight heparin (tinzaparin) is less costly because it avoids the need for international normalized ratio monitoring. In the United States, the drug cost for low-molecular-weight heparin will likely be the principal determinant of relative cost-effectiveness.

Background: The Stroke Prevention in Atrial Fibrillation II study compared warfarin vs aspirin for stroke prevention in atrial fibrillation. Bleeding complications importantly detracted from warfarin's net effectiveness, particularly among older patients. Objectives: To analyze bleeding complications according to assigned therapy. To identify risk factors for bleeding during anticoagulation. Methods: Eleven hundred patients (mean age, 70 years) were randomized to 325 mg of aspirin daily (enteric coated) vs warfarin (target prothrombin time ratio, 1.3 to 1.8; approximate international normalized ratio, 2.0 to 4.5). Major hemorrhages were defined prospectively. Results: The rate of major bleeding while receiving warfarin was 2.3% per year (95% confidence interval [CI], 1.7 to 3.2) vs 1.1% per year (95% CI, 0.7 to 1.8) while receiving aspirin (relative risk, 2.1; 95% CI, 1.1 to 3.1; P=.02). Intracranial hemorrhage occurred at 0.9% per year (95% CI, 0.5 to 1.5) with warfarin and 0.3% per year (95% CI, 0. 1 to 0.8) with aspirin (relative risk, 2.4; P=. 08). Age (P=.006), increasing number of prescribed medications (P=.007), and intensity of anticoagulation (P=.02) were independent risks for bleeding at any site during anticoagulation. The rate of major hemorrhage was 1.7% per year in patients aged 75 years or younger who received anticoagulation vs 4.2% per year in older patients (relative risk, 2.6, P=.009); rates by age for intracranial bleeding were 0.6% per year and 1.8% per year, respectively (P=.05). Conclusion: Advancing age and more intense anticoagulation increase the risk of major hemorrhage in patients given warfarin for stroke prevention.

Background: Patients with atrial fibrillation compared with those with sinus rhythm are at increased risk for thromboembolism, often mandating therapy directed at thromboembolism prevention. However, the safest, most efficacious strategy to prevent thromboembolism associated with atrial fibrillation is unknown. We developed a decision analysis to compare the risks and benefits of two common clinical strategies to prevent thromboembolism in the patient with atrial fibrillation: 1) sinus rhythm maintenance with quinidine sulfate or with amiodarone hydrochloride after cardioversion and (2) long-term anticoagulation with warfarin sodium. Methods: A search was conducted of the English-language MEDLINE databases of the National Library of Medicine dated 1966 through December 1992. The search was conducted by intersecting 'quinidine,' 'warfarin,' or 'amiodarone' with 'atrial fibrillation.' Six of 249 articles concerning quinidine and five of 20 articles concerning warfarin were judged by multiple reviewers to meet predetermined inclusion and exclusion criteria. To our knowledge, no randomized, placebo-controlled trials of amiodarone therapy for atrial fibrillation have been published. Five of 112 identified articles concerning amiodarone involved nonrandomized trials that met the remaining selection criteria and were included in this analysis. Results: Thromboembolic events and fatal nonthromboembolic adverse events during the course of therapy (defined as fatal proarrhythmia, fatal hemorrhage, and fatal noncardiac toxic effects) were considered to have equivalent weight. The total risk during therapy, defined as thromboembolic and fatal nonthromboembolic adverse events during the course of therapy, was evaluated over a range of baseline thromboembolism risks, from 1% to 20% per patient-year. Quinidine therapy compared with no therapy was associated with increased total risk, unless baseline thromboembolism risk exceeded 11% per patient-year. Total risk during warfarin therapy was less than total risk during quinidine therapy for the entire range of baseline thromboembolism risks, from 1% to 20% per patient-year. Total risk during warfarin or amiodarone therapy was similar and less than that with no therapy for the entire range of baseline risks. Conclusions: Based on data from randomized, controlled trials of quinidine and warfarin, warfarin therapy appears to be the safest strategy for thromboembolism prevention in the patient with atrial fibrillation. The role of low-dose amiodarone therapy appears promising and warrants further study in randomized, controlled trials.

Background: Enoxaparin sodium, a low-molecular-weight heparin, was recently approved for use in the United States to prevent deep-vein thrombosis after total hip replacement surgery. Its cost-effectiveness relative to prophylaxis with low-dose warfarin sodium is unknown. Methods: A decision-analytic model was developed to compare two strategies of prophylaxis for deep-vein thrombosis with a strategy of not using prophylaxis in a hypothetical cohort of 10 000 patients undergoing total hip replacement surgery. For each of these strategies, we estimated the expected number of cases of confirmed deep-vein thrombosis or pulmonary embolism, the expected number of thromboembolic deaths, and the expected costs of venous thromboembolic care, including prophylaxis, diagnosis, and treatment. Data were drawn primarily from the published literature. Results: Compared with no prophylaxis, the use of low-dose warfarin would be expected to reduce the number of cases of confirmed deep-vein thrombosis from about 1000 (per 10 000 patients) to 420 and the number of thromboembolic deaths from about 250 to 110. Expected costs of care related to deep-vein thrombosis also would be reduced from approximately $530 to $330 per patient. Prophylaxis with enoxaparin would be expected to reduce further the number of cases of confirmed deep-vein thrombosis and the number of thromboembolic deaths (to 250 and 70, respectively) but increase costs of care by approximately $50 per patient. The cost-effectiveness of enoxaparin (relative to low-dose warfarin) is estimated to be approximately $12 000 per death averted. Conclusion: Although enoxaparin is more costly than low-dose warfarin, its cost-effectiveness in total hip replacement compares favorably with that of other generally accepted medical interventions.

Atrial fibrillation is an abnormal, irregular heart beat that can cause the formation of blood clots in the heart. Fragments of these blood clots can break away and lodge elsewhere in the circulation, producing serious complications such as stroke. The use of the blood-thinning drug, or anticoagulant, warfarin in patients with atrial fibrillation can reduce the risk of stroke by 75 percent. In past years, the doses of warfarin were higher than those currently recommended, and posed a significant risk of bleeding. A survey was conducted to determine the attitudes of physicians toward the use of warfarin in atrial fibrillation. Of the 251 physicians who responded to the survey, 78 percent used warfarin for atrial fibrillation caused by disease of the heart valves, which is known to carry the highest risk of stroke, but only 18 percent used warfarin for atrial fibrillation of any cause. About 50 percent of these doctors avoided warfarin because of the risk of bleeding, 24 percent because they were not convinced that the drug prevented stroke, and 17 percent because they found it difficult to monitor patients on the drug. Although the evidence for the effectiveness of aspirin in preventing strokes is not as strong as that of warfarin, physicians prescribe aspirin for patients who have had transient ischemic attacks, stroke-like events that resolve in less than 24 hours. Dipyridamole, another drug with some anticlotting activity, was used by less than 25 percent of physicians. Recent studies may change the way that physicians prescribe warfarin. This new evidence suggests that the drug is more effective than previously realized in the prevention of stroke, and further, that lower doses appear to be equally effective and safer in terms of bleeding complications. The risk of stroke is sufficiently high in atrial fibrillation that physicians should reevaluate the use of warfarin. (Consumer Summary produced by Reliance Medical Information, Inc.)

Background: Antithrombotic prophylaxis using combined aspirin and low-dose warfarin is under evaluation in several clinical trials. However, combination therapy may result in increased gastrointestinal bloodloss and clinical bleeding vs conventional single-agent antithrombotic therapy. Methods: To assess differences in gastrointestinal blood loss, we measured quantitative fecal hemoglobin equivalents (HemoQuant, Mayo Medical Laboratory, Rochester, Minn) in 117 patients, mean age 71 years, 1 month after initiation of assigned therapy in the Stroke Prevention in Atrial Fibrillation III Study. Sixty-three of these patients who had characteristics for high risk of stroke were randomly assigned to conventional adjusted-dose warfarin therapy (international normalized ratio, 2.0 to 3.0) or low-dose combined therapy (warfarin [international normalized ratio, < 1.51 plus 325 mg/d of enteric-coated aspirin). The remaining 54 patients with low risk of stroke received 325 mg/d of enteric-coated aspirin. Results: Among the 63 patients at high risk of stroke, abnormal values (>2 mg of hemoglobin per gram of stool) were detected in 11% and values greater than 4 mg of hemoglobin per gram of stool were found in 8%. Mean ([+ or -] SD) values were more for those randomly assigned to receive combined therapy (1.7[+ or -]3.3 mg of hemoglobin per gram of stool vs adjusted-dose warfarin therapy, 1.0 [+ or -] 1.9 mg/g; P=.003). The 54 nonrandomized patients with low risk of stroke receiving aspirin alone had a mean ([+ or -]SD) HemoQuant value of 0.8[+ or -]0.7 mg of hemoglobin per gram of stool 1 month after entry in the study. Conclusions: Abnormal levels of fecal hemoglobin excretion were common in elderly patients with high risk of atrial fibrillation 1 month after randomization to prophylactic antithrombotic therapy. Combined warfarin and aspirin therapy was associated with greater fecal hemoglobin excretion than standard warfarin therapy, suggesting the potential for increased gastrointestinal hemorrhage.

Background: There is increased pressure on primary care physicians to monitor oral anticoagulation. Objective: To test the null hypothesis that oral anticoagulation care can be provided at least as well in primary care through a nurse-led clinic, involving near-patient testing and computerized decision support software, compared with routine hospital management based on a variety of clinical outcome measures. Methods: A randomized, controlled trial in 12 primary care practices in Birmingham, England (9 intervention and 3 control). Two control populations were used: patients individually randomly allocated as controls in the intervention practices (intrapractice controls) and all patients in control practices (interpractice controls). Intervention practices' patients were randomized to the intervention (practice-based anticoagulation clinic) or control (hospital clinic) group. The main outcome measure was therapeutic control of the international normalized ratio. Results: Three hundred sixty-seven patients were recruited (122 intervention patients, 102 intrapractice control patients, and 143 interpractice control patients). Standard measures of control of the international normalized ratio (point prevalence) showed no significant difference between the intervention and control groups. Data on proportion of time spent in the international normalized ratio range showed significant improvement for patients in the intervention group (paired t test, P = .008). Conclusions: Nurse-led anticoagulation clinics can be implemented in novice primary care settings by means of computerized decision support software and near-patient testing. Care given by this model is at least as good as routine hospital follow-up. The model is generalizable to primary health care centers operating in developed health care systems. Arch Intern Med. 2000;160:2343-2348