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2017 SEP 30 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Data detailed on Heart Disorders and Diseases - Atrial Fibrillation have been [...]

Background: Warfarin is used for prophylaxis of venous thromboembolism in patients undergoing total knee arthroplasty. However, it is associated with rates of deep venous thrombosis (DVT) of approximately 38% to 55% and requires routine coagulation monitoring and frequent dose adjustment. Ximelagatran, an oral direct thrombin inhibitor, has shown promising efficacy and tolerability in patients undergoing total hip or knee arthroplasty. Objective: To compare the efficacy and safety of ximelagatran and warfarin for prophylaxis of venous thromboembolism after total knee arthroplasty. Design: Randomized, double-blind, parallel-group trial. Setting: 74 North American hospitals. Patients: 680 patients who had undergone total knee arthroplasty. Interventions: 7 to 12 days of treatment with oral ximelagatran, 24 mg twice daily, starting on the morning after surgery, or warfarin (target international normalized ratio, 2.5 [range, 1.8 to 3.0]), starting on the evening of the day of surgery. Measurements: Principal end points were asymptomatic DVT on mandatory venography; symptomatic DVT confirmed by ultrasonography or venography; symptomatic, objectively proven pulmonary embolism; and bleeding. All were assessed by blinded adjudication locally and at a central study laboratory. Results: On central adjudication, incidence of venous thromboembolism was 19.2% (53 of 276 patients) in the ximelagatran group and 25.7% (67 of 261 patients) in the warfarin group (difference, -6.5 percentage points [95% CI, -13.5 to 0.6 percentage points]; P=0.070). On local assessment, incidence was 25.4% in the ximelagatran group and 33.5% in the warfarin groups (P=0.043). In the ximelagatran and warfarin groups, respectively, major bleeding occurred in 1.7% and 0.9% of patients and minor bleeding occurred in 7.8% and 6.4% of patients. No variables related to bleeding differed significantly between the two groups. Conclusions: For prophylaxis of venous thromboembolism, fixed-dose ximelagatran started the morning after total knee arthroplasty is well tolerated and at least as effective as warfarin, but it does not require coagulation monitoring or dose adjustment.

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.

Anticoagulation with warfarin has been shown to be effective in preventing ischemic stroke in patients with atrial fibrillation. However, physicians have been reluctant to prescribe this therapy for patients age 60 and older because of the associated risk of bleeding during antithrombotic therapy. Four clinical features independently increase the risk of stroke in individuals with atrial fibrillation: previous stroke or transient ischemic attack, diabetes, history of hypertension, and advancing age. In individual patients, bleeding complications can be reduced by eliminating loading doses, monitoring therapy frequently during the initiation phase, targeting lower INRs, recognizing the potential for drug interactions, and identifying clinical risk factors. Fiore LD. Anticoagulation: Risks and benefits in atrial fibrillation. Geriatrics 1996; 51(June): 22-31., Oral anticoagulant therapy with warfarin is highly effective at reducing the incidence of recurrent thrombosis and pulmonary embolism in patients with established deep-vein thrombosis (DVT). Hemorrhage, the inescapable toxic effect [...]

Objective: To compare the effectiveness and safety of fixed-dose enoxaparin and adjusted-dose warfarin in preventing venous thromboembolism after knee arthroplasty. Design: A randomized, double-blind controlled trial. Setting: 8 university hospitals. Patients: 670 consecutive patients who had knee arthroplasty. Intervention: Patients were randomly assigned to receive enoxaparin (30 mg subcutaneously every 12 hours) or adjusted-dose warfarin (international normalized ratio, 2.0 to 3.0). Both regimens were started after surgery. Measurements: The primary end point was the incidence of deep venous thrombosis in patients with adequate bilateral venograms; the secondary end point was hemorrhage. Results: Among the 417 patients with adequate venograms, 109 of 211 warfarin recipients (51.7%) had deep venous thrombosis compared with 76 of 206 enoxaparin recipients (36.9%) (P = 0.003). The absolute risk difference was 14.8% in favor of enoxaparin (95% Cl, 5.3% to 24.1%). Twenty-two warfarin recipients (10.4%) and 24 enoxaparin recipients (11.7%) had proximal venous thrombosis (P > 0.2). The absolute risk difference was 1.2% in favor of warfarin (Cl, -7.2% to 4.8%). The incidence of major bleeding was 1.8% (6 of 334 patients) in the warfarin group and 2.1% (7 of 336 patients) in the enoxaparin group (P > 0.2). The absolute risk difference was 0.3% in favor of warfarin (Cl, -2.4% to 1.8%). Conclusions: A postoperative, fixed-dose enoxaparin regimen is more effective than adjusted-dose warfarin in preventing total deep venous thrombosis after knee arthroplasty. No differences were seen in the incidence of proximal venous thrombosis or clinically overt hemorrhage., The drug enoxaparin may be more effective than warfarin in preventing the formation of blood clots following surgery to reconstruct the knee. Researchers gave either a fixed dose of enoxaparin or a body weight-adjusted dose of warfarin to 670 patients who had undergone reconstructive knee surgery. Drugs were administered in the postoperative period. Use of enoxaparin was associated with a reduced risk of developing blood clots in the deep veins of the legs, as visualized by x-rays of the legs using radiographic contrast material. Enoxaparin reduced the relative risk of deep vein blood clots by 28.6%, and reduced the absolute risk by 14.8%. A 10% to 12% risk of developing blood clots near the surgical site was noted with use of both enoxaparin and of warfarin.

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.

Atrial fibrillation (AF) is a common arrhythmia that is an important independent risk factor for stroke. AF is present in over 2 million people in the United States.[1] The prevalence [...]

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.

The hypothesis that the combination of low-dose aspirin and warfarin therapy is more effective than aspirin alone in secondary prophylaxis after myocardial infarction is to be examined in w Coumadin Aspirin Reinfarction Study. This pilot study addressed the safety and anticoagulation effect of a fixed, low-dose combination in 114 patients (aged 64 [+ or -] 8 years, 85% men) with stable coronary artery disease receiving 3 mg of warfarin plus 80 mg of aspirin daily for 8 weeks. The international normalized ratio (INR) was measured within 72 hours of initial theraphy, and weekly. Of the 110 patients with evaluable INRs, 87 patients(79%) maintained the 3 + 90 mg combination, 19 (17%) had the dose reduced to 1 mg warfarin + 80 mg aspirin and 4 (4%) discontinued theraphy because of a confirmed INR of [greater than or equal to] 4.5. At steady state, patients had INRs of 1.48 [greater than or equal to] 0.41 (3 + 80 mg group) and 1.21 [+ or -] 0.23 (1 + 80) 80 mg group), and inter- and intra-patient variability (estimated by the mean of the between- and within-patient SDs at steady state) was 0.49 [+ or -] 0.08 and 0.13 [+ or -] 0.14, respectively. There was no apparent effect of age on INR distribution. Microscopic hematuria was the most frequent (20%) adverse clinical event, but was unrelated to the INR. Three patients required discontinuation of therapy because of bleeding events (persistent hematuria and epistaxis). A fixed low-dose combination of warfarin and aspirin results in a predictable and stable increase in the INR in a large proportion of patients with coronary artery disease. Provided that early INR testing is undertaken in order to identify patients with significant sensitivity to low-dose warfarin and to establish steady-state dosing,the Coumadin Aspirin Reinfarction Pilot Study suggests that this treatment modality may be safe for long-term administration as secondary prophylaxis. (Am J Cardiol 1994;74:657-661)

* Objective: To compare the relative risks and benefits of several clinical strategies for managing patients with chronic atrial fibrillation. * Design: Five recent randomized controlled trials of warfarin in atrial fibrillation, 6 randomized controlled trials of quinidine, and 13 longitudinal studies of low-dose amiodarone were used. A MEDLINE search was also done (1966 to present). * Measurements: A Markov decision analysis model was used to assess outcomes in large, hypothetical cohorts of patients with atrial fibrillation followed from 65 to 70 years of age within four clinical strategies: 1) no treatment; 2) warfarin; 3) electrical cardioversion followed by quinidine to maintain normal sinus rhythm; and 4) electrical cardioversion followed by low-dose amiodarone. * Results: In this hypothetical cohort, fewer patients had disabling events with amiodarone (1.4%) than with quinidine (1.8%), warfarin (2.6%), or no treatment (7.4%). Amiodarone appeared to be associated with the lowest 5-year mortality (13.6%) when compared with warfarin (14.4%), quinidine (15.2%), and no treatment (18.2%). In terms of quality-adjusted life-years, amiodarone had the highest expected value (4.75 years), followed by warfarin (4.72 years), quinidine (4.68 years), and no treatment (4.55 years). Amiodarone remained the preferred strategy using the most plausible scenarios of risks associated with atrial fibrillation. Choices among warfarin, quinidine, and no treatment depended on estimates of bleeding rates with warfarin, stroke rates after discontinuing warfarin, quinidine-related mortality, and the quality of life with warfarin. * Conclusion: Cardioversion followed by low-dose amiodarone to maintain normal sinus rhythm appears to be a relatively safe and effective treatment for patients with chronic atrial fibrillation., Cardioversion and low-dose amiodarone may be an effective treatment for chronic atrial fibrillation. Atrial fibrillation is the rapid, random contraction of individual fibers of the heart muscle causing an irregular, rapid heart beat. Cardioversion is used to restore the normal rhythm of the heart by electrical shock. Researchers applied a decision analysis model to a hypothetical set of patients based on the patients of 24 studies. They evaluated the efficacy of no treatment, warfarin, cardioversion followed by quinidine and cardioversion followed by low-dose amiodarone. Among the hypothetical patients, 1.4% had disabling cardiac events with amiodarone, compared to 1.8% with quinidine, 2.6% with warfarin and 7.4% with no treatment. Amiodarone was also associated with the lowest five-year mortality rate (13.6%) and the highest expected value for quality-adjusted life years (4.75 years) when compared to the other treatments.

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.)

A potential complication following surgery for a fractured hip is the development of deep vein thrombosis, clot formation in a deep vein. Elderly patients with hip fracture are especially at risk from the combination of injury to the leg, surgery, and immobilization. Methods of preventing thrombosis have been studied extensively in patients undergoing elective hip surgery. Newly developed heparinoids, low-molecular-weight heparin fractions, may be able to reduce the risk of thrombosis without increasing the risk of bleeding to the same extent as other anticoagulant medications. A clinical trial was undertaken of 263 patients undergoing surgical repair of hip fracture, to compare Lomoparan, a low-molecular-weight heparinoid, with warfarin (another anticoagulant) for usefulness and safety in preventing deep vein thrombosis. All patients were at least 45 years of age, and were operated on within four days of fracture. Both groups began anticoagulant treatment before surgery; one group of 132 patients received Lomoparan for seven days and then warfarin was added to the regimen, while the other group of 131 patients received only warfarin until the ninth postoperative day. Nine patients (7 percent) receiving Lomoparan developed deep vein thrombosis, compared with 28 patients (21 percent) of the warfarin-only group. The two groups did not differ significantly in loss of blood at the time of surgery, nor in need for blood transfusion. It is concluded that administration of Lomoparan is safe and effective in preventing deep vein thrombosis following surgical repair of hip fracture. (Consumer Summary produced by Reliance Medical Information, Inc.)

The most frequent fatal complication of total hip replacement surgery in patients not protected against it is venous thromboembolism, a condition in which a clot forms, travels within the circulatory system, and then obstructs blood flow. There are two methods of preventing thromboembolism: prevention of the condition itself, and secondary prevention or detecting the condition before it causes symptoms. There is little information on the cost-effectiveness of prevention of venous thromboembolism. Cost-effectiveness was analyzed in terms of lives saved and in terms of dollars spent for prevention and treatment. The patients studied had total hip replacement surgery and were over 39 years of age; their cases were either found in the published literature or drawn from a group of 195 patients seen at one institution. Two methods of primary prevention were studied, no prevention or use of low-dose warfarin; secondary prevention methods studied were clinical surveillance, routine duplex sonography (an imaging method that provides detailed views of the vessel wall structure), and routine venography (X-rays of the veins). There were a total of seven different combinations of prevention methods analyzed. Theoretical analysis suggests that low-dose warfarin combined with clinical surveillance reduces deaths from 20 to 4 per 1,000 patients and also reduces costs from $550,000 to $400,000 per 1,000 patients. This strategy is strongly recommended. Although use of either venography or duplex sonography routinely reduces deaths from 4 to 0.15 per 1,000 patients, the cost is increased by $200,000 per saved life when routine venography is used, and $50,000 per saved life when routine sonography is used. In summary, low-dose warfarin plus routine sonography reduces deaths from 20 to 0.3 per 1,000 patients, a dramatic improvement, but does not cost any more than not using prophylaxis. (Consumer Summary produced by Reliance Medical Information, Inc.)

In a prospective pilot trial of antithrombotic therapy in the acute coronary syndromes (ATACS) of resting and unstable angina pectoris or non-Q-wave myocardial infarction, 3 different antithrombotic regimens in the prevention of recurrent ischemic events were compared for efficacy. Ninety-three patients were randomized to receive aspirin (325 mg/day), or full-dose heparin followed by warfarin, or the combination of aspirin (80 mg/day) plus heparin and then warfarin. Trial antithrombotic therapy was added to standardized antianginal medication and continued for 3 months or until an end point was reached. Analysis, by intention-to-treat, of the 3-month end points, revealed the following: recurrent ischemia occurred in 7 patients (22%) after aspirin, in 6 patients (25%) after heparin and warfarin, and in 16 patients (43%) after aspirin combined with heparin and then warfarin; coronary revascularization occurred in 12 patients (38%) after aspirin, in 12 patients (50%) after heparin and warfarin, and in 22 patients (60%) after aspirin combined with heparin and then warfarin; myocardial infarction occurred in 1 patient (3%) after aspirin, in 3 patients (13%) after heparin and warfarin, and in no patient after aspirin combined with heparin and then warfarin; no deaths occurred after aspirin or after aspirin combined with heparin and then warfarin, but 1 patient (4%) died after warfarin alone; major bleeding occurred in 3 patients (9%) after aspirin, in 2 patients (8%) after heparin and warfarin, and in 3 patients (8%) after aspirin combined with heparin and then warfarin. Recurrent myocardial ischemia occurred at 3 [+ or -] 3 days after randomization. In those who had coronary angioplasty or bypass surgery, revascularization was performed at 6 [+ or -] 4 days. During trial therapy, no patient died, had a Q-wave myocardial infarction or a major bleed. Most bleeding complications consisted of blood transfusions during or immediately after bypass surgery. Only 25% of patients enrolled were discharged on trial therapy because of revascularization and withdrawals. Thus, irrespective of the antithrombotic regimen used, and even with aggressive combination therapy, a substantial fraction of patients with unstable angina or non-Q-wave myocardial infarction have recurrent myocardial ischemia and are referred for coronary revascularization. Antithrombotic therapy, coupled with early intervention after recurring ischemia, was associated with a low rate of death or myocardial infarction within the first 3 months. (Am J Cardiol 1990;66:1287-1292), In angina pectoris, diminished blood supply (ischemia) to the heart typically results in chest pain, but pain may also occur in the chest, arm, jaw, and back. Anginal pain may signal the onset of a heart attack and other life-threatening cardiovascular emergencies. A heart attack, or myocardial infarction, is usually caused by the blockage of a coronary artery by a blood clot, or thrombus. Antithrombotic treatment includes administering antiplatelet drugs (such as aspirin) or anticoagulant drugs (such as heparin); these agents inhibit blood clotting. When drug therapy is not effective in ameliorating symptoms of ischemia, more drastic (surgical) measures must be taken, such as coronary bypass or angioplasty. In order to ascertain the effectiveness of three different antithrombotic regimens, 93 patients suffering from angina or mild heart attack were assessed. The goal of the study was to determine if one of the treatments was more effective in preventing subsequent death or the need for surgical intervention. Patients were divided into three groups and received either aspirin alone, the anticoagulant drugs warfarin (coumadin) and heparin, or aspirin plus warfarin and heparin. They continued to receive standard antianginal treatments, including nitroglycerin and beta blockers or calcium antagonists. Follow-up continued for three months, or until an end point occurred (death, withdrawal from the study, surgery, heart attack, etc.). Only 25 percent of the original group of patients could be followed through the study period. The same percentage of patients in each group suffered recurrent ischemia, and required surgical treatment. One patient in the warfarin group died, and two or three patients in each group had a major bleeding episode. In spite of the fact that these three drug regimens are more rigorous than those previously used, a significant number of patients still require surgical intervention. However, antithrombotic therapy is still more favorable than the absence of preventative treatment. Within the study period, drug therapy and surgical treatment for recurrent ischemia were associated with a low rate of heart attack and death. (Consumer Summary produced by Reliance Medical Information, Inc.)

The thrombotic component in ischemic heart disease (IHD) is now universally recognized. It is therefore logical to consider modifying both fibrin formation and platelet function in primary (as well as secondary) prevention. The scientific case for evaluating lower-dose warfarin in primary prevention rests on the implications of the secondary prevention trials, increasing evidence of an association between the level of factor VII coagulant activity, [VII.sub.c], and the incidence of IHD, and the results of short-term lower-dose trials for the prevention of venous thrombosis and thromboembolism. The general case for considering aspirin in primary prevention is well known, but the potential value of low-dose aspirin in men at high risk needs to be established. Currently available evidence suggests that the combination of lower doses of both warfarin and aspirin in primary prevention may be effective and safe. The objective of the factorial Thrombosis Prevention Trial is to demonstrate a reduction in the incidence of IHD in men at high risk attributable to low-dose warfarin or low-dose aspirin, or both, with 1 group receiving both active treatments. The feasibility of this trial has been demonstrated. An international Normalized Ratio of about 1.5, achieved with an average daily dose of 4.6 mg warfarin, has resulted in no increase in the number of men ever reporting minor bleeding episodes, although rectal bleeding occurs more frequently in those men who do report this symptom. (Am J Cardiol 1990;66:7C-11C), It is not always appreciated that blood clots differ in composition according to location. Venous thrombi consist largely of fibrin and red blood cells, whereas arterial thrombi may consist of predominantly platelet bodies in the arterial wall or predominantly fibrin accumulations in the lumen of the artery. It is not always clear that treatments, which have been successful for venous thrombosis, such as warfarin (coumadin), will be useful in conditions associated with arterial thrombosis. Somewhat surprisingly, only recently has it come to be universally recognized that thrombosis plays a significant role in myocardial infarction, unstable angina pectoris, and sudden coronary death. Agents like aspirin are widely used to prevent the aggregation of platelets, but since fibrin deposition is also involved in coronary artery thrombosis, it is not unreasonable to employ prophylactic therapy directed at both clotting mechanisms. There is evidence that the use of oral anticoagulants like warfarin may reduce mortality after myocardial infarction by 20 percent. Taking into account that many of these deaths are due to electrical problems in the heart, the actual improvement in survival may be as high as 50 percent for those patients whose problems are clearly thrombotic. The Thrombosis Prevention Trial, now taking place in England, is designed to evaluate the effectiveness of low doses of aspirin, warfarin, or both in preventing ischemic heart disease among men in the top 20 percent of risk factors. By 1991, 6,000 men will have been enrolled, for a minimum of five years. Thus far, there has been little suggestion that there is any significant risk associated with the combination of low-dose warfarin and low-dose aspirin. There has been no increase in the number of men having reported some kind of bleeding episode. However, among men who have reported episodes of rectal bleeding, the frequency of rectal bleeding increased among those receiving treatment. (Consumer Summary produced by Reliance Medical Information, Inc.)

A NUMBER OF CLINICAL TRIALS HAVE BEEN REPORTED USING WARfarin alone or in combination with aspirin in patients with coronary artery disease. In the aggregate, they have been relatively inconclusive. [...]

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.