The use of glycoprotein IIb/IIIa receptor inhibitors in unstable angina.
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Angina, Unstable↗
Biomedical subjects
A G Turpie
Publications and source records attributed to A G Turpie.
Use of a clinical model for safe management of patients with suspected pulmonary embolism.
BACKGROUND: The low specificity of ventilation-perfusion lung scanning complicates the management of patients with suspected pulmonary embolism. OBJECTIVE: To determine the safety of a clinical model for patients with suspected pulmonary embolism. DESIGN: Prospective cohort study. SETTING: Five tertiary care hospitals. PATIENTS: 1239 inpatients and outpatients with suspected pulmonary embolism. INTERVENTIONS: A clinical model categorized pretest probability of pulmonary embolism as low, moderate, or high, and ventilation-perfusion scanning and bilateral deep venous ultrasonography were done. Testing by serial ultrasonography, venography, or angiography depended on pretest probability and lung scans. MEASUREMENTS: Patients were considered positive for pulmonary embolism if they had an abnormal pulmonary angiogram, abnormal ultrasonogram or venogram, high-probability ventilation-perfusion scan plus moderate or high pretest probability, or venous thromboembolic event during the 3-month follow-up. All other patients were considered negative for pulmonary embolism. Rates of pulmonary embolism during follow-up in patients who had a normal lung scan and those with a non-high-probability scan and normal serial ultrasonogram were compared. RESULTS: Pretest probability was low in 734 patients (3.4% with pulmonary embolism), moderate in 403 (27.8% with pulmonary embolism), and high in 102 (78.4% with pulmonary embolism). Three of the 665 patients (0.5% [95% CI, 0.1% to 1.3%]) with low or moderate pretest probability and a non-high-probability scan who were considered negative for pulmonary embolism had pulmonary embolism or deep venous thrombosis during 90-day follow-up; this rate did not differ from that in patients with a normal scan (0.6% [CI, 0.1% to 1.8%]; P > 0.2). CONCLUSION: Management of patients with suspected pulmonary embolism on the basis of pretest probability and results of ventilation-perfusion scanning is safe.
Algorithms↗
Sensitivity and specificity of a rapid whole-blood assay for D-dimer in the diagnosis of pulmonary embolism.
BACKGROUND: Patients with suspected pulmonary embolism often have nondiagnostic lung scans and may present in circumstances where lung scanning is unavailable. Levels of D-dimer, a fibrin-specific product, are increased in patients with acute thrombosis; this may simplify the diagnosis of pulmonary embolism. OBJECTIVE: To determine the sensitivity and specificity of a whole-blood D-dimer assay in patients with suspected pulmonary embolism and in subgroups of patients with low pretest probability of pulmonary embolism or nondiagnostic lung scans. DESIGN: Prospective cohort. SETTING: Four tertiary care hospitals. PATIENTS: 1177 consecutive patients with suspected pulmonary embolism. MEASUREMENTS: All patients underwent an assessment of pretest probability by use of a standardized clinical model, a D-dimer assay, ventilation-perfusion lung scanning, and bilateral compression ultrasonography. Patients in whom pulmonary embolism was not initially diagnosed were followed for 3 months. Accordingly, patients were categorized as positive or negative for pulmonary embolism. RESULTS: Of the 1177 patients, 197 (17%) were classified as positive for pulmonary embolism. Overall, the D-dimer assay showed a sensitivity of 84.8% and a specificity of 68.4%. In 703 patients (3.4%) with a low pretest probability of pulmonary embolism, the likelihood ratio associated with a negative D-dimer test result was 0.27, resulting in a posterior probability of 1.0% (95% CI, 0.3% to 2.2%). In 698 patients with nondiagnostic lung scans (previous probability, 7.4%), the likelihood ratio associated with a negative D-dimer test result was 0.36, resulting in a posterior probability of 2.8% (CI, 1.4% to 4.8%). CONCLUSIONS: A normal D-dimer test result is useful in excluding pulmonary embolism in patients with a low pretest probability of pulmonary embolism or a nondiagnostic lung scan.
Algorithms↗
Clinical potential of antithrombotic drugs in coronary syndromes.
Thrombosis is responsible for most of the acute manifestations of coronary artery disease, including unstable angina and non-Q-wave myocardial infarction. Antithrombotic therapy with antiplatelet agents and anticoagulants plays a major role in decreasing the risk of ischemic events in such patients. As thrombin generation plays a key role in the pathogenesis of thrombosis, recent studies have focused on thrombin inhibition in the management of acute ischemia. Heparin is the most widely used anticoagulant in the acute phase. Heparin given in therapeutic doses intravenously has been shown to be more effective than aspirin in decreasing the risk of death or myocardial infarction in patients with unstable angina. Low-molecular-weight heparin (LMWH) has improved pharmacologic and pharmacokinetic properties over standard heparin and this may provide greater efficacy and safety. LMWH may be given at fixed subcutaneous dose without monitoring and, therefore, is of greater clinical utility and is more cost-effective than standard heparin. Several LMWHs have been evaluated in the management of acute coronary syndromes and have shown equivalent or improved efficacy compared with standard heparin. As heparin in combination with aspirin is now the treatment of choice in acute unstable coronary syndromes, LMWH could potentially improve the outcome in such patients.
Angina, Unstable↗
Low-molecular-weight heparins in non-ST-segment elevation ischemia: the ESSENCE trial. Efficacy and Safety of Subcutaneous Enoxaparin versus intravenous unfractionated heparin, in non-Q-wave Coronary Events.
Combination antithrombotic therapy with heparin plus aspirin decreases the risk of recurrent ischemic events in patients with acute coronary syndromes without persistent ST-segment elevation. Compared with standard unfractionated heparin, low-molecular-weight heparin (LMWH) has a more predictable antithrombotic effect, is easier to administer, and does not require coagulation monitoring. At 176 hospitals in 3 continents, 3,171 patients with rest unstable angina or non-wave myocardial infarction were randomly assigned to either enoxaparin (a LMWH), 1 mg/kg twice daily subcutaneously, or to continuous intravenous unfractionated heparin, for a minimum of 48 hours to a maximum of 8 days. Trial medication was administered in a double-blind, placebo-controlled fashion. At 14 days, the primary endpoint, the composite risk of death, myocardial infarction, or recurrent angina with electrocardiographic changes or prompting intervention, was significantly lower in patients assigned to enoxaparin compared with heparin (16.6% vs 19.8%; odds ratio [OR] 1.24; 95% confidence interval [CI] 1.04-1.49; p = 0.019). At 30 days, the composite risk of death, myocardial infarction, or recurrent angina remained significantly lower in the enoxaparin group compared with the unfractionated heparin group (19.8% vs 23.3%, OR 1.23; 95% CI 1.0-1.46, p = 0.016). The rate of revascularization procedures at 30 days was also significantly lower in patients assigned to enoxaparin (27.1% vs 32.2%, p = 0.001). The 30-day incidence of major bleeding complication was 6.5% versus 7.0% (p = not significant), but the incidence of minor bleeding was significantly higher in the enoxaparin group (13.8% vs 8.8%, p <0.001) due primarily to injection-site ecchymosis. Thus, combination antithrombotic therapy with enoxaparin plus aspirin is more effective than unfractionated heparin plus aspirin in decreasing ischemic outcomes in patients with unstable angina or non-Q-wave myocardial infarction in the early (30 days) phase. The lower recurrent ischemic event rate seen with the LMWH, enoxaparin, is achieved without an increase in major bleeding, but with an increase in minor bleeding complications due mainly to injection-site ecchymosis.
Adolescent↗
A randomized comparison of a computer-based dosing program with a manual system to monitor oral anticoagulant therapy.
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Administration, Oral↗
Economic assessment of low-molecular-weight heparin (enoxaparin) versus unfractionated heparin in acute coronary syndrome patients: results from the ESSENCE randomized trial. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events [unstable angina or non-Q-wave myocardial infarction].
BACKGROUND: In the ESSENCE trial, subcutaneous low-molecular-weight heparin (enoxaparin) reduced the 30-day incidence of death, myocardial infarction, and recurrent angina relative to intravenous unfractionated heparin in 3171 patients with acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction). No increase in major bleeding was seen. METHODS AND RESULTS: Of the 936 ESSENCE patients randomized in the United States, 655 had hospital billing data collected. For the remainder, hospital costs were imputed with a multivariable linear regression model (R2=.86). Physician fees were estimated from the Medicare Fee Schedule. During the initial hospitalization, major resource use was reduced for enoxaparin patients, with the largest effect seen with coronary angioplasty (15% versus 20% for heparin, P=.04). At 30 days, these effects persisted, with the largest reductions seen in diagnostic catheterization (57% versus 63% for heparin, P=.04) and coronary angioplasty (18% versus 22%, P=.08). All resource use trends seen in the US cohort were also evident in the overall ESSENCE study population. In the United States, the mean cost of a course of enoxaparin therapy was $155, whereas that for heparin was $80. The total medical costs (hospital, physician, drug) for the initial hospitalization were $11 857 for enoxaparin and $12620 for heparin, a cost advantage for the enoxaparin arm of $763 (P=.18). At the end of 30 days, the cumulative cost savings associated with enoxaparin was $1172 (P=.04). In 200 bootstrap samples of the 30-day data, 94% of the samples showed a cost advantage for enoxaparin. CONCLUSIONS: In patients with acute coronary syndrome, low-molecular-weight heparin (enoxaparin) both improves important clinical outcomes and saves money relative to therapy with standard unfractionated heparin.
Acute Disease↗
Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study.
OBJECTIVE: To evaluate the safety of withholding anticoagulant treatment from patients with clinically suspected deep vein thrombosis but normal findings on compression ultrasonography. DESIGN: Compression ultrasonography was done with a simplified diagnostic procedure limited to the common femoral vein in the groin and the popliteal vein extending down to the trifurcation of the calf veins. Patients with normal ultrasonography findings at presentation were retested 1 week later. MAIN OUTCOME MEASURE: The incidence of venous thromboembolic complications during follow up for 6 months in patients in whom anticoagulant treatment was withheld on the basis of normal results on two ultrasonography tests 1 week apart. SETTING: University research centres in four hospitals. RESULTS: A total of 1702 patients were included in the study. Abnormal results on compression ultrasonography at presentation or at 1 week were found in 400 and 12 patients, respectively, for a prevalence of deep vein thrombosis of 24%. None of the patients were lost to follow up. Venous thromboembolic complications during the week of serial testing occurred in a single patient and in eight patients during 6 months' follow up, resulting in a cumulative rate of venous thromboembolic complications of 0.7% (95% confidence interval 0.3% to 1.2%). The mean number of extra hospital visits and additional tests required per initially referred patient was 0.8. CONCLUSION: It is safe to withhold anticoagulant treatment from patients with clinically suspected deep vein thrombosis who have a normal result on compression ultrasonography at the time of presentation and at 1 week.
Adolescent↗
Management strategies for a better outcome in unstable coronary artery disease.
Unstable coronary artery disease is a term encompassing both unstable angina and non-Q-wave (non-ST-segment elevation) myocardial infarction. Patients with these conditions are at risk of early progression to acute myocardial infarction and death. Thus, management of these conditions must aim to reduce long-term mortality and morbidity. Risk stratification is crucial for the identification of patients whose risk of early progression is high; they may require coronary angiography and (if suitable) either percutaneous transluminal coronary angioplasty or coronary artery bypass surgery. No single variable can accurately predict risk, but considerable data are emerging to show that biochemical markers of myocardial injury, such as troponin-T and troponin-I, are valuable in combination with electrocardiographic findings and clinical features. Routine early invasive procedures (coronary angiography with or without revascularization) have not yet been shown to have any significant advantage over conservative regimens for the majority of patients. Antiplatelet, anticoagulant, and anti-ischemic agents remain the mainstay of treatment in the acute phase. New agents, such as glycoprotein IIb/IIIa receptor inhibitors and low-molecular-weight heparins, as well as antithrombins and Factor Xa inhibitors add to the treatments currently available. Thrombolytic agents are contraindicated in the absence of ST-segment elevation. After clinical stabilization, ongoing assessment should include exercise testing for all patients who are able; other imaging techniques should be used for patients unable to exercise. A profile indicating a high risk of future events is an indication for elective angiography and consideration for revascularization.
Algorithms↗
Pharmacology of the low-molecular-weight heparins.
Unfractionated heparin (UFH) is widely used to both treat and prevent venous thromboembolism. More recently, UFH has been used to prevent death and myocardial infarction in patients with unstable angina or acute myocardial infarction and acute occlusion in those undergoing percutaneous coronary revascularization. However, its poor bioavailability (when administered in low doses subcutaneously), its mechanism of clearance, and its short half-life make its anticoagulant activity difficult to predict and maintain. To overcome these limitations, low-molecular-weight heparins (LMWHs) have been developed that have greater bioavailability and a longer half-life in plasma. Because LMWHs provide more predictable anticoagulant activity compared with subcutaneous UFH, it is not necessary to monitor the activated partial thromboplastin time during treatment. These newer agents are as effective as UFH in the prophylaxis and treatment of thromboembolic and cardiac disorders and, by allowing shorter hospital stays, are more cost effective. Thus LMWHs offer clear pharmacokinetic advantages over UFH. More studies are needed to determine the extent to which clinically available LMWHs can be used in place of UFH.
Anticoagulants↗
Antithrombotic therapy in coronary ischaemia: the expanding role of low-molecular-weight heparin.
Low-molecular-weight heparins (LMWHs) have been rigorously evaluated in the management of acute coronary ischaemia. The results of clinical trials suggest that LMWHs are effective in reducing major ischaemic outcomes in patients with unstable angina and non-Q-wave myocardial infarction. In one study, LMWH was shown to be more effective than heparin. The clinical utility of LMWHs given subcutaneously in a fixed-dose without the need for monitoring results in major cost savings. The accumulating evidence suggests that LMWHs are safe, effective alternatives to standard heparin in unstable coronary disease and offer practical and therapeutic advantages, representing an important advance in the management of acute coronary ischaemia.
Anticoagulants↗
Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves.
Permanent therapy with oral anticoagulants offers the most consistent protection in patients with mechanical heart valves. Antiplatelet agents alone do not consistently protect patients with mechanical prosthetic heart valves, including patients in sinus rhythm with St. Jude valves in the aortic position. Levels of oral anticoagulants that prolong the INR to 2.0 to 3.0 appear satisfactory for patients with bileaflet mechanical valves in the aortic position, provided they are in sinus rhythm and the left atrium is not enlarged. Oral anticoagulant levels that prolong the INR to 2.5 to 3.2 are satisfactory for patients with bileaflet mechanical aortic valves and atrial fibrillation. Oral anticoagulant levels that prolong the INR to 2.5 to 3.5 are satisfactory for tilting disk valves and bileaflet prosthetic valves in the mitral position. Experience is sparse in patients with caged ball valves who had prothrombin time ratios reported in terms of INR. It has been suggested that the most advantageous INR level in patients with caged ball or caged disk valves should be as high as 4.0 to 4.9. However, others have shown a high rate of major hemorrhage with an INR that is even somewhat lower (3.0 to 4.5). The problem is self-limited, however, because few such valves are being inserted. Aspirin, in addition to oral anticoagulants, in patients with mechanical heart valves has been shown to diminish the frequency of thromboemboli. The risk of bleeding may not be increased if the INR is low. A low rate of both thromboemboli and bleeding has been shown with an INR of 2.5 to 3.5 in combination with aspirin at a dose of 100 mg/d. There are no investigations in which an aspirin dose of 81 mg/d in combination with oral anticoagulants was evaluated. Dipyripdamole may be effective in reducing the rate of thromboemboli without increasing the rate of bleeding, but data are insufficient to recommend dipyridamole over low doses of aspirin. Patients with bioprosthetic valves in the mitral position, as well as patients with bioprosthetic valves in the aortic position, may be at risk for thromboemboli during the first 3 months after surgery. Among patients during the first 3 months after surgery with bioprosthetic valves in the mitral position, oral anticoagulants administered at an INR of 2.0 to 2.3 were as effective as at an INR of 2.5 to 4.5: additionally, fewer bleeding complications were seen.
Administration, Oral↗
Prevention of venous thrombosis after elective hip surgery.
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Anticoagulants↗
Management of acute coronary syndromes with low molecular weight heparin: TIMI 11A and 11B.
The role of antithrombotic therapy has been studied in patients with acute coronary ischemia without ST segment elevation. Unfractionated heparin (UFH) has been found to decrease the rate of myocardial infarction (MI), and to reduce overall mortality and recurrent MI in a series of trials in patients with unstable angina and non-Q wave MI. UFH is limited due to its unpredictable antithrombotic effect, poor bioavailability when given subcutaneously, requirement for hospitalization and need for frequent laboratory monitoring. Conversely, low molecular weight heparins (LMWHS) offer a number of advantages over UFH. LMWHs have a predictable antithrombotic response, good bioavailability following subcutaneous administration and longer half-life than UFH, require less frequent monitoring than UFH and can be administered in fixed or weight-adjusted subcutaneous dosages once or twice daily. The safety and efficacy of the LMWH enoxaparin are evaluated in the Thrombolysis in Myocardial Infarction (TIMI) 11 program. TIMI 11 A was designed to compare the safety and tolerability of two dosage regimens of enoxaparin in patients with unstable angina or non-Q wave MI, whereas TIMI 11B was designed as a phase III trial, comparing the efficacy and safety of enoxaparin with those of UFH in the acute phase, and the efficacy and safety of extended administration of LMWH with those of placebo for 45 days. TIMI 11A found that the rate of major hemorrhage was significantly lower for the lower enoxaparin dose (1.0 mg/kg). The results of the published studies indicate that LMWHs are effective in reducing major ischemic outcomes in patients with unstable angina and non-Q wave MI. The results of the TIMI 11B trial will be available in late 1998.
Acute Disease↗
Guidelines for management of left-sided prosthetic valve thrombosis: a role for thrombolytic therapy. Consensus Conference on Prosthetic Valve Thrombosis.
OBJECTIVES: We sought to form a consensus recommendation for management of prosthetic valve thrombosis (PVT) from previous case and uncontrolled reports from a consensus of international specialists. BACKGROUND: PVT and thromboembolism relate to inadequate anticoagulation and valve type and location. PVT is suspected by history (dyspnea) and auscultation (muffled valve sounds or new murmurs) and confirmed by Doppler echocardiography showing a marked valve gradient. METHODS: A consensus conference was held to recommend management of left-sided PVT. RESULTS: Transesophageal Doppler echocardiography is used to visualize abnormal leaflet motion and the size, location and mobility of thrombus. Thrombolysis is used for high risk surgical candidates with left-sided PVT (New York Heart Association functional class III or IV) because cerebral thromboembolism may occur in 12% of patients. Duration of thrombolysis depends on resolution of pressure gradients and valve areas to near normal by Doppler echocardiography performed every few hours. Lysis is stopped after 72 or 24 h if there is no hemodynamic improvement (operation indicated). Heparin infusion with frequent measurement of activated partial thromboplastin time (aPTT) begins when aPTT is more than twice control levels and can be converted to warfarin (international normalized ratio [INR] 2.5 to 3.5) plus aspirin (81 to 100 mg/day). Patients in functional class I or II have lower surgical mortality, and those with large immobile thrombi on the prosthetic valve or left atrium have responded to endogenous lysis with combined subcutaneous heparin every 12 h (aPTT 55 to 80 s) plus warfarin (INR 2.5 to 3.5) for 1 to 6 months. Operation is advised for nonresponders or patients with mobile thrombi. CONCLUSIONS: Thrombolysis, followed by heparin, warfarin and aspirin, is advised for high risk surgical candidates with left-sided PVT.
Aortic Valve↗
New frontiers in the management of unstable coronary artery disease.
Thrombotic occlusion is responsible for most acute manifestations of coronary artery disease, including unstable angina and non-Q-wave myocardial infarction. Antiplatelet therapy plays a major role in reducing the risk of ischemic events in such patients. Since thrombin generation is vital to the pathogenesis of thrombosis, recent studies have focused on thrombin inhibition in the management of acute ischemia. Heparin is the most widely used anticoagulant for acute management of thrombosis and is the treatment of choice in preventing and treating venous thromboembolism. Given in therapeutic doses intravenously, it is more effective than aspirin in reducing the risk of death or myocardial infarction in patients with unstable angina. Low-molecular-weight (LMW) heparins have improved pharmacologic and pharmacokinetic properties over standard heparin that may result in greater efficacy and safety. LMW heparins may be given in a fixed dose subcutaneously without monitoring, resulting in greater clinical utility and cost-effectiveness compared with standard heparin. Given subcutaneously in fixed, weight-adjusted doses they are more effective and safer than intravenous heparin in treating deep-vein thrombosis. Several studies have evaluated LMW heparins in unstable angina. In a small open trial, LMW heparin (nadroparin) reduced the risk of acute myocardial infarction compared with aspirin alone or a combination of aspirin and standard heparin. In 2 large clinical trials, LMW heparin (dalteparin) has been shown to be effective in the management of unstable angina with a 63% reduction in risk of death or acute myocardial infarction over patients treated with aspirin alone (Fragmin during Instability in Coronary Artery Disease; FRISC) and to be as effective as intravenous heparin (Fragmin in Unstable Coronary Artery Disease; FRIC).
Angina, Unstable↗
Fragmin in unstable angina pectoris or in non-Q-wave acute myocardial infarction (the FRIC study). Fragmin in Unstable Coronary Artery Disease.
The safety and efficacy of weight-adjusted, low-molecular-weight heparin (dalteparin) was compared with that of unfractionated heparin during 6 days of treatment in 1,482 patients with unstable angina or non-Q-wave myocardial infarction. Dalteparin, at a lower dose, was compared with placebo during the following 39 days. No significant outcome difference was found between the 2 treatment regimens in the unblinded phase (days 1-6). Between days 6-45 the rates of death, myocardial infarction, and recurrence of angina were comparable between the active treatment and placebo groups. The results suggest that twice-daily administration of subcutaneous dalteparin may be an effective and safe alternative to unfractionated heparin during the acute phase of unstable coronary artery disease. Prolonged treatment with dalteparin at a lower once-daily dose did not confer any additional benefit over aspirin (75-165 mg) alone.
Angina, Unstable↗
A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group.
BACKGROUND: Antithrombotic therapy with heparin plus aspirin reduces the rate of ischemic events in patients with unstable coronary artery disease. Low-molecular-weight heparin has a more predictable anticoagulant effect than standard unfractionated heparin, is easier to administer, and does not require monitoring. METHODS: In a double-blind, placebo-controlled study, we randomly assigned 3171 patients with angina at rest or non-Q-wave myocardial infarction to receive either 1 mg of enoxaparin (low-molecular-weight heparin) per kilogram of body weight, administered subcutaneously twice daily, or continuous intravenous unfractionated heparin. Therapy was continued for a minimum of 48 hours to a maximum of 8 days, and we collected data on important coronary end points over a period of 30 days. RESULTS: At 14 days the risk of death, myocardial infarction, or recurrent angina was significantly lower in the patients assigned to enoxaparin than in those assigned to unfractionated heparin (16.6 percent vs. 19.8 percent, P=0.019). At 30 days, the risk of this composite end point remained significantly lower in the enoxaparin group (19.8 percent vs. 23.3 percent, P=0.016). The need for revascularization procedures at 30 days was also significantly less frequent in the patients assigned to enoxaparin (27.1 percent vs. 32.2 percent, P=0.001). The 30-day incidence of major bleeding complications was 6.5 percent in the enoxaparin group and 7.0 percent in the unfractionated-heparin group, but the incidence of bleeding overall was significantly higher in the enoxaparin group (18.4 percent vs. 14.2 percent, P=0.001), primarily because of ecchymoses at injection sites. CONCLUSIONS: Antithrombotic therapy with enoxaparin plus aspirin was more effective than unfractionated heparin plus aspirin in reducing the incidence of ischemic events in patients with unstable angina or non-Q-wave myocardial infarction in the early phase. This benefit of enoxaparin was achieved with an increase in minor but not in major bleeding.
Aged↗