Previous trials of antiplatelet therapy for the prevention of venous thromboembolism have individually been inconclusive, but a meta-analysis of their results indicated reductions in the risks of deep-vein thrombosis and of pulmonary embolism in various high-risk groups. The aim of this large randomised placebo-controlled trial was to confirm or refute these apparent benefits.During 1992-1998, 148 hospitals in Australia, New Zealand, South Africa, Sweden and the UK randomised 13,356 patients undergoing surgery for hip fracture, and 22 hospitals in New Zealand randomised a further 4088 patients undergoing elective arthroplasty. Study treatment was 160 mg daily aspirin or placebo, started preoperatively and continued for 35 days. Patients received any other thromboprophylaxis thought necessary. Follow-up was of mortality and of in-hospital morbidity up to day 35.Among the patients with hip fracture, allocation to aspirin produced proportional reductions in pulmonary embolism of 43% (95% CI 18-60; p=0.002) and in symptomatic deep-vein thrombosis of 29% (3-48; p=0.03). Pulmonary embolism or deep-vein thrombosis was confirmed in 105 (1.6%) of 6679 patients assigned aspirin compared with 165 (2.5%) of 6677 assigned placebo, which represents an absolute reduction of 9 (SE 2) per 1000 and a proportional reduction of 36% (19-50; p=0.0003). Similar proportional effects were seen in all major subgroups, including patients receiving subcutaneous heparin. Aspirin prevented 4 (1) fatal pulmonary emboli per 1000 patients (18 aspirin-group vs 43 placebo-group deaths), representing a proportional reduction of 58% (27-76; p=0.002), with no apparent effect on deaths from any other vascular cause (hazard ratio 1.04 [95% CI 0.86-1.26]) or non-vascular cause (1.01 [0.84-1.23]). Deaths due to bleeding were few (13 aspirin vs 15 placebo), but there was an excess of 6 (3) postoperative transfused bleeding episodes per 1000 patients assigned aspirin (p=0.04). Among elective-arthroplasty patients, rates of venous thromboembolism were lower, but the proportional effects of aspirin were compatible with those among patients with hip fracture.These results, along with those of the previous meta-analysis, show that aspirin reduces the risk of pulmonary embolism and deep-vein thrombosis by at least a third throughout a period of increased risk. Hence, there is now good evidence for considering aspirin routinely in a wide range of surgical and medical groups at high risk of venous thromboembolism.

BACKGROUND Patients who survive life-threatening ventricular arrhythmias are at risk for recurrent arrhythmias. They can be treated with either an implantable cardioverter-defibrillator or antiarrhythmic drugs, but the relative efficacy of these two treatment strategies is unknown. METHODS To address this issue, we conducted a randomized comparison of these two treatment strategies in patients who had been resuscitated from near-fatal ventricular fibrillation or who had undergone cardioversion from sustained ventricular tachycardia. Patients with ventricular tachycardia also had either syncope or other serious cardiac symptoms, along with a left ventricular ejection fraction of 0.40 or less. One group of patients was treated with implantation of a cardioverter-defibrillator; the other received class III antiarrhythmic drugs, primarily amiodarone at empirically determined doses. Fifty-six clinical centers screened all patients who presented with ventricular tachycardia or ventricular fibrillation during a period of nearly four years. Of 1016 patients (45 percent of whom had ventricular fibrillation, and 55 percent ventricular tachycardia), 507 were randomly assigned to treatment with implantable cardioverter-defibrillators and 509 to antiarrhythmic-drug therapy. The primary end point was overall mortality. RESULTS Follow-up was complete for 1013 patients (99.7 percent). Overall survival was greater with the implantable defibrillator, with unadjusted estimates of 89.3 percent, as compared with 82.3 percent in the antiarrhythmic-drug group at one year, 81.6 percent versus 74.7 percent at two years, and 75.4 percent versus 64.1 percent at three years (P<0.02). The corresponding reductions in mortality (with 95 percent confidence limits) with the implantable defibrillator were 39+/-20 percent, 27+/-21 percent, and 31+/-21 percent CONCLUSIONS Among survivors of ventricular fibrillation or sustained ventricular tachycardia causing severe symptoms, the implantable cardioverter-defibrillator is superior to antiarrhythmic drugs for increasing overall survival.

BACKGROUND TNK-tissue plasminogen activator (TNK-TPA) is a genetically engineered variant of TPA, which in experimental models has a slower plasma clearance and greater fibrin specificity and is 80-fold more resistant to plasminogen activator inhibitor-1 than alteplase TPA. METHODS AND RESULTS The thrombolysis in Myocardial Infarction (TIMI) 10A trial was a Phase 1, dose-ranging pilot trial designed to evaluate the pharmacokinetics, safety, and efficacy of TNK-TPA in patients with acute myocardial infarction. One hundred thirteen patients with acute ST-segment elevation myocardial infarction presenting within 12 hours and without contraindications to thrombolysis were enrolled and treated with a single bolus of TNK-TPA over 5 to 10 seconds with doses ranging from 5 to 50 mg. TNK-TPA demonstrated a plasma clearance of 151 +/- 55 mL/min and a half-life of 17 +/- 7 minutes. Comparable values for wild-type TPA are 572 +/- 132 mL/min and 3.5 +/- 1.4 minutes, respectively. Systemic fibrinogen and plasminogen levels fell by only 3% and 13%, respectively, at 1 hour after TNK-TPA administration. TIMI grade 3 flow at 90 minutes was achieved in 57% to 64% of patients at the 30- to 50-mg doses. Seven patients (6.2%) experienced a major hemorrhage, which occurred at a vascular access site in six patients. CONCLUSIONS TNK-TPA has a prolonged half-life so it can be administered as a single bolus. TNK-TPA appears to be very fibrin specific, and the initial patency and safety profiles are encouraging. Further study of this new thrombolytic agent is ongoing.

Background Cardiogenic shock remains the leading cause of death of patients hospitalized with acute myocardial infarction (MI). This study was conducted to examine (1) the current spectrum of cardiogenic shock, (2) the proportion of patients who are potential candidates for a trial of early revascularization, and (3) the apparent impact of early revascularization on mortality.Methods and Results Nineteen participating centers in the United States and Belgium prospectively registered all patients diagnosed with cardiogenic shock. Two hundred fifty-one patients were registered. The mean age was 67.5+/-11.7 years, and 43% were women. Acute mitral regurgitation or ventricular septal rupture was the cause of shock in 8%. Concurrent conditions contributing to the development of shock were noted in 5%, and 2% had isolated right ventricular shock. Among the remaining 214 patients, nonspecific findings on the ECG associated with ''nontransmural'' MI were seen in 14%. The median time to shock diagnosis after MI was 8 hours. The overall in-hospital mortality was 66%. Patients clinically selected to undergo cardiac catheterization were significantly younger and had a lower mortality than those not selected (51% versus 85%, P<.0001) even if they were not revascularized (58%). Mortality for patients undergoing percutaneous transluminal coronary angioplasty (PTCA) was 60% (n=55) and 19% (n=16) for coronary artery bypass graft surgery (CABG). Sixty percent (n=150) of registered patients were judged eligible for a trial of early revascularization. Trial-eligible patients were significantly younger (65.4+/-11.0 versus 70.6+/-11.9 years, P<.001), had an earlier median time to shock onset after MI (6.5 versus 17.5 hours, P=.003), and had lower mortality (62% versus 73%, P=.077) than ineligible patients.Conclusions Patients diagnosed with cardiogenic shock complicating acute MI are a heterogeneous group. Those eligible for a trial of early revascularization tended to have lower mortality. Patients selected to undergo cardiac catheterization had lower mortality whether or not they were revascularized. Emergent PTCA and CABG are promising treatment modalities for cardiogenic shock, but biased case selection for treatment may confound the data. Whether PTCA and CABG reduce mortality and which patient subgroups benefit most remain to be determined in a randomized clinical trial.

BACKGROUND Direct thrombin inhibitors are a new class of drugs that may offer a more effective and potentially simpler alternative to heparin. Hirulog is a synthetic peptide based on the leech-derived compound hirudin and, like hirudin, is a highly specific, direct inhibitor of free and clot-bound thrombin. METHODS AND RESULTS TIMI 7 was a randomized, double-blind study of Hirulog, given with 325 mg/d aspirin to 410 patients with unstable angina. Patients received a constant infusion of Hirulog for 72 hours at one of four doses: 0.02 (n = 160), 0.25 (n = 81), 0.5 (n = 88), and 1.0 (n = 81) mg.kg-1.h-1. The primary efficacy end point was "unsatisfactory outcome," defined as death, nonfatal myocardial infarction (MI), rapid clinical deterioration, or recurrent ischemic pain at rest with ECG changes by 72 hours. Unsatisfactory outcome was not different among the four dose groups: 8.1%, 6.2%, 11.4%, and 6.2% (P = NS). However, the secondary end point of death or nonfatal MI through hospital discharge occurred in 10.0% of patients treated with 0.02 mg.kg-1.h-1 compared with 3.2% of patients treated with the three higher doses of Hirulog (0.25, 0.5, and 1.0 mg.kg-1.h-1, P = .008). Only 2 of 410 patients (0.5%) experienced a major hemorrhage attributed to Hirulog. CONCLUSIONS The direct thrombin inhibitor Hirulog is a promising new antithrombotic agent that deserves further study. The results of TIMI 7 lend support to the use of an antithrombin agent with aspirin in patients with unstable angina.

Background Although coronary thrombosis plays a critical role in the pathogenesis of unstable angina and non-Q-wave myocardial infarction (NQMI), the effects of thrombolytic therapy in these disorders is not clear. Also, the role of routine early coronary arteriography followed by revascularization has not been established.Methods and Results Patients (n=1473) seen within 24 hours of ischemic chest discomfort at rest, considered to represent unstable angina or NQMI, were randomized using a 2x2 factorial design to compare (1) TPA versus placebo as initial therapy and (2) an early invasive strategy (early coronary arteriography followed by revascularization when the anatomy was suitable) versus an early conservative strategy (coronary arteriography followed by revascularization if initial medical therapy failed). All patients were treated with bed rest, anti-ischemic medications, aspirin, and heparin. The primary end point for the TPA-placebo comparison (death, myocardial infarction, or failure of initial therapy at 6 weeks) occurred in 54.2% of the TPA-treated patients and 55.5% of the placebo-treated patients (P=NS). Fatal and nonfatal myocardial infarction after randomization (reinfarction in NQMI patients) occurred more frequently in TPA-treated patients (7.4%) than in placebo-treated patients (4.9%, P=.04, Kaplan-Meier estimate). Four intracranial hemorrhages occurred in the TPA-treated group versus none in the placebo-treated group (P=.06). The end point for the comparison of the two strategies (death, myocardial infarction, or an unsatisfactory symptom-limited exercise stress test at 6 weeks) occurred in 18.1% of patients assigned to the early conservative strategy and 16.2% of patients assigned to the early invasive strategy (P=NS). In the latter, the average length of initial hospitalization, incidence of rehospitalization within 6 weeks, and days of rehospitalization all were significantly lower.Conclusions In the overall trial, patients with unstable angina and NQMI were managed with low rates of mortality (2.4%) and myocardial infarction or reinfarction (6.3%) at the time of the 6-week visit. These results can be achieved using either an early conservative or early invasive strategy, the latter resulting in a reduced incidence of days of hospitalization and of rehospitalization and in the use of antianginal drugs. The addition of a thrombolytic agent is not beneficial and may be harmful.