http://repub.eur.nl/res/aut/2320/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/38209/ 2012-02-16T00:00:00Z Background: Data are limited on whether clinical trials have randomized higher-risk patients over time and how trends in risk profiles and evidence-based pharmacotherapies have influenced trial outcomes. We quantified changes in baseline risk, treatment, and outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) randomized in 9 phase 3 clinical trials of antithrombotic therapy over 15 years. Methods: We studied 58,771 patients in GUSTO IIb, PURSUIT, PARAGON-A, PARAGON-B, PRISM, PRISM-PLUS, GUSTO IV-ACS, SYNERGY, and EARLY ACS. Patient-level data were mapped to 3 pre-specified 5-year randomization periods. Temporal trends in GRACE score-predicted mortality were compared with trends in observed mortality. Results: Over time, in-hospital and discharge use of thienopyridines (p = 0.001), statins (p < 0.0001), and angiotensin-converting enzyme inhibitors (p < 0.0001) increased, and hospital length-of-stay decreased (p = 0.024). Blood transfusion use increased (8.3% [1994-98], 10.7% [1999-2003], 13% [2004-08], p = 0.0002) despite stable rates of severe bleeding (0.9% [1994-98], 1.4% [1999-2003] and 1.1% [2004-08], p = 0.127) and coronary artery bypass grafting (12.4% [1994-98], 13.7% [1999-2003] 13.1% [2004-08], p = 0.880). Although predicted 6-month mortality increased (6.9% [1994-98], 9.0% [1999-2003], 7.9% [2004-08], p = 0.017), observed 6-month mortality decreased (6.7% [1994-98], 5.8% [1999-2003], 5.1% [2004-08], p = 0.025). Thirty-day myocardial infarction rates remained stable (9.2% [1994-98], 9.3% [1999-2003], 10% [2004-08], p = 0.539). Conclusions: Despite enrolling higher-risk patients into these NSTE ACS trials, with better treatment, observed mortality declined over the past 15 years. The appropriateness of increased blood transfusion despite unchanged bleeding rates deserves further study. http://repub.eur.nl/res/pub/30734/ 2011-10-01T00:00:00Z Background: Higher levels of lipoprotein-associated phospholipase A2(Lp-PLA2) are associated with a higher risk of cardiovascular events and may play a causal role in atherogenesis. Darapladib inhibits Lp-PLA2activity in plasma and in arterial plaques and may confer clinical benefit in preventing cardiovascular events. Study Design: The SOLID-TIMI 52 trial is a randomized, double-blind, placebo-controlled, multicenter, event-driven trial. Approximately 13,000 subjects are being randomized to darapladib (160 mg enteric-coated tablet daily) or matching placebo within 30 days of hospitalization with an acute coronary syndrome. The primary end point is the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary end points include major and total coronary events, individual components of the primary end point, and all-cause mortality. The study will continue until approximately 1,500 primary end point events have occurred to achieve 90% power to detect a 15.5% reduction in the primary end point. The median treatment duration is anticipated to be approximately 3 years, with a total study duration of approximately 4.1 years. Conclusions: The SOLID-TIMI 52 trial will determine the clinical benefit of direct inhibition of Lp-PLA2activity with darapladib in patients after an acute coronary syndrome. http://repub.eur.nl/res/pub/11676/ 2008-03-14T00:00:00Z Objective: To investigate whether the beneficial and harmful effects of platelet glycoprotein IIb/IIIa receptor blockers in non-ST elevation acute coronary syndromes (NSTE-ACS) depend on age. Methods: A meta-analysis of six trials of platelet glycoprotein IIb/IIIa receptor blockers in patients with NSTE-ACS (PRISM, PRISM-PLUS, PARAGON-A, PURSUIT, PARAGON-B, GUSTO IV-ACS; n = 31 402) was performed. We applied multivariable logistic regression analyses to evaluate the drug effects on death or non-fatal myocardial infarction at 30 days, and on major bleeding, by age subgroups (<60, 60–69, 70–79, >=80 years). We quantified the reduction of death or myocardial infarction as the number needed to treat (NNT), and the increase of major bleeding as the number needed to harm (NNH). Results: Subgroups had 11 155 (35%), 9727 (31%), 8468 (27%) and 2049 (7%) patients, respectively. The relative benefit of platelet glycoprotein IIb/IIIa receptor blockers did not differ significantly (p = 0.5) between age subgroups (OR (95% CI) for death or myocardial infarction: 0.86 (0.74 to 0.99), 0.90 (0.80 to 1.02), 0.97 (0.86 to 1.10), 0.90 (0.73 to 1.16); overall 0.91 (0.86 to 0.99). ORs for major bleeding were 1.9 (1.3 to 2.8), 1.9 (1.4 to 2.7), 1.6 (1.2 to 2.1) and 2.5 (1.5–4.1). Overall NNT was 105, and overall NNH was 90. The oldest patients had larger absolute increases in major bleeding, but also had the largest absolute reductions of death or myocardial infarction. Patients >=80 years had half of the NNT and a third of the NNH of patients <60 years. Conclusions: In patients with NSTE-ACS, the relative reduction of death or non-fatal myocardial infarction with platelet glycoprotein IIb/IIIa receptor blockers was independent of patient age. Larger absolute outcome reductions were seen in older patients, but with a higher risk of major bleeding. Close monitoring of these patients is warranted. http://repub.eur.nl/res/pub/13627/ 2005-01-01T00:00:00Z AIMS: We sought to characterize the outcomes of patients with a prior percutaneous coronary intervention (PCI) who presented with a non-ST-segment elevation acute coronary syndrome (ACS). METHODS AND RESULTS: We analysed the 30 and 180 day outcomes of 3012 patients with prior PCI and 21 154 patients without prior PCI enrolled in three randomized ACS trials (GUSTO IIb, PURSUIT, and PARAGON-B). The median (25th, 75th percentile) interval between the prior PCI and randomization was 647 (123, 1585) days. Patients with prior PCI had significantly more adverse baseline clinical characteristics, left ventricular dysfunction, and multi-vessel coronary artery disease. After adjusting for baseline characteristics and treatment, we found that patients with prior PCI had a significantly lower mortality rate at 30 days [hazard ratio (HR), 0.60; 95% confidence interval (CI), 0.45-0.80; P=0.0006] and 180 days (HR, 0.81; 95% CI, 0.66-0.98; P=0.029). However, no difference was observed in the composite of death or myocardial infarction (MI) at 30 days (HR, 0.95; 95% CI, 0.83-1.08; P=0.42) or 180 days (HR, 1.01; 95% CI, 0.90-1.13; P=0.90). Patients with prior PCI had a higher rate of MI at 180 days (13.3 vs. 12.0%; P=0.045). Prior-PCI patients had lower incidences of in-hospital cardiogenic shock, congestive heart failure (CHF), and atrial fibrillation. CONCLUSION: Patients with prior PCI who present with non-ST-segment elevation ACS have a lower mortality rate than those without prior PCI. http://repub.eur.nl/res/pub/5676/ 2002-01-19T00:00:00Z BACKGROUND: Platelet glycoprotein IIb/IIIa inhibitors have been shown to reduce cardiac complications in patients undergoing percutaneous coronary intervention. The clinical efficacy of these drugs in acute coronary syndromes, however, is still unclear. We did a meta-analysis of all large randomised trials designed to study the clinical efficacy and safety of glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes who were not routinely scheduled to undergo early coronary revascularisation. METHODS: Inclusion criteria were: randomisation of patients with acute coronary syndromes but without persistent ST elevation; comparison of a glycoprotein IIb/IIIa inhibitor with placebo or control therapy; non-recommendation of early coronary revascularisation during study-drug infusion; and enrollment of at least 1000 patients. Data on individual patients were obtained from all participants in these trials. FINDINGS: Six trials, enrolling 31402 patients, fulfilled the inclusion criteria. 30 days after randomisation, 3530 (11.2%) patients died or developed a myocardial infarction. At 30 days, a 9% reduction in the odds of death or myocardial infarction was seen with glycoprotein IIb/IIIa inhibitors compared with placebo or control (10.8% [1980/18297] vs 11.8% [1550/13105] events; odds ratio 0.91 [95% CI 0.84-0.98]; p=0.015). The relative treatment benefit was similar in subgroups of patients according to important clinical baseline characteristics; hence, the absolute treatment benefit was largest in high-risk patients. An unexpected and significant interaction was seen between sex and allocated treatment, with a treatment benefit in men (0.81 [0.75-0.89] but not in women (1.15 [1.01-1.30]). However, once patients were stratified according to troponin concentration, there was no evidence of a sex difference in treatment response, and a risk reduction was seen in men and women with raised troponin concentrations. Major bleeding complications were increased by glycoprotein IIb/IIIa inhibitors (2.4% [445/18297] vs 1.4% [180/13105]; p<0.0001), but intracranial bleeding was not (16 [0.09%] vs 8 [0.06%]; p=0.40). INTERPRETATION: Glycoprotein IIb/IIIa inhibitors reduce the occurrence of death or myocardial infarction in patients with acute coronary syndromes not routinely scheduled for early revascularisation. The event reduction is greatest in patients at high risk of thrombotic complications. Treatment with a glycoprotein IIb/IIIa inhibitor might therefore be considered especially in such patients early after admission, and continued until a decision about early coronary revascularisation has been made. http://repub.eur.nl/res/pub/9934/ 2002-01-01T00:00:00Z BACKGROUND: The prognosis of ventricular arrhythmias among patients with non-ST-elevation acute coronary syndromes is unknown. We studied the incidence, predictors, and outcomes of sustained ventricular arrhythmias in 4 large randomized trials of such patients. METHODS AND RESULTS: We pooled the datasets of the Global Use of Streptokinase and tPA for Occluded Arteries (GUSTO)-IIb, Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT), Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (PARAGON)-A, and PARAGON-B trials (n=26 416). We identified independent predictors of ventricular fibrillation (VF) and ventricular tachycardia (VT) and compared the 30-day and 6-month mortality rates of patients who did (n=552) and did not (n=25 864) develop these arrhythmias during the index hospitalization. Independent predictors of in-hospital VF included prior hypertension, chronic obstructive pulmonary disease, prior myocardial infarction, and ST-segment changes at presentation. Except for hypertension, these variables also independently predicted in-hospital VT. In Cox proportional-hazards modeling, in-hospital VF and VT were independently associated with 30-day mortality (hazard ratio [HR], 23.2 [95% CI, 18.1 to 29.8] for VF and HR, 7.6 [95% CI, 5.5 to 10.4] for VT) and 6-month mortality (HR, 14.8 [95% CI, 12.1 to 18.3] for VF and HR, 5.0 [95% CI, 3.8 to 6.5] for VT). These differences remained significant after excluding patients with heart failure or cardiogenic shock and those who died <24 hours after enrollment. CONCLUSIONS: Despite the use of effective therapies for non-ST-elevation acute coronary syndromes, ventricular arrhythmias in this setting are associated with increased 30-day and 6-month mortality. More effective therapies are needed to improve the survival of patients with these arrhythmias. http://repub.eur.nl/res/pub/9003/ 1999-01-01T00:00:00Z BACKGROUND: Stroke occurs concurrently with myocardial infarction (MI) in approximately 30 000 US patients each year. This number is expected to rise with the increasing use of thrombolytic therapy for MI. However, no data exist for the economic effect of stroke in the setting of acute MI (AMI). The purpose of this prospective study was to assess the effect of stroke on medical resource use and costs in AMI patients in the United States. METHODS AND RESULTS: Medical resource use and cost data were prospectively collected for 2566 randomly selected US GUSTO I patients (from 23 105 patients) and for the 321 US GUSTO I patients who developed non-bypass surgery-related stroke during the baseline hospitalization. Follow-up was for 1 year. All costs are expressed in 1993 US dollars. During the baseline hospitalization, stroke was associated with a reduction in cardiac procedure rates and an increase in length of stay, despite a hospital mortality rate of 37%. Together with stroke-related procedural costs of $2220 per patient, the baseline medical costs increased by 44% ($29 242 versus $20 301, P<0.0001). Follow-up medical costs were substantially higher for stroke survivors ($22 400 versus $5282, P<0.0001), dominated by the cost of institutional care. The main determinant for institutional care was discharge disability status. The cumulative 1-year medical costs for stroke patients were $15 092 higher than for no-stroke patients. Hemorrhagic stroke patients had a much higher hospital mortality rate than non-hemorrhagic stroke patients (53% versus 15%, P<0.001), which was associated with approximately $7200 lower mean baseline hospitalization cost. At discharge, hemorrhagic stroke patients were more likely to be disabled (68% versus 46%, P=0.002). CONCLUSIONS: In this first large prospective economic study of stroke in AMI patients, we found that strokes were associated with a 60% ($15 092) increase in cumulative 1-year medical costs. Baseline hospitalization costs were 44% higher because of longer mean lengths of stay. Stroke type was a key determinant of baseline cost. Follow-up costs were more than quadrupled for stroke survivors because of the need for institutional care. Disability level was the main determinant of institutional care and thus of follow-up costs. http://repub.eur.nl/res/pub/5748/ 1998-01-01T00:00:00Z Background—Limited information exists on risk factors for mortality after thrombolysis-related intracranial hemorrhage. We wished to determine the characteristics associated with 30-day mortality after thrombolysis-related intracranial hemorrhage. Methods and Results—We performed an observational analysis within a randomized trial of 4 thrombolytic therapies, conducted in 1081 hospitals in 15 countries. Patients presented with ST-segment elevation within 6 hours of symptom onset. Our population was composed of the 268 patients who had primary intracranial hemorrhage after thrombolysis. With univariable and multivariable analyses, we identified clinical and brain imaging characteristics that would predict 30-day mortality among these patients. CT or MRI were available for 240 patients (90%). The 30-day mortality rate was 59.7%. Glasgow Coma Scale score, age, time from thrombolysis to symptoms of intracranial hemorrhage, hydrocephalus, herniation, mass effect, intraventricular extension, and volume and location of intracranial hemorrhage were significant univariable predictors. Multivariable analysis of 170 patients with complete data, 98 of whom died, identified the following independent, significant predictors: Glasgow Coma Scale score (2, 19.3; P<0.001), time from thrombolysis to intracranial hemorrhage (2, 15.8; P<0.001), volume of intracranial hemorrhage (2, 11.6; P<0.001), and baseline clinical predictors of mortality in the overall GUSTO-I trial (2, 10.3; P=0.001). The final model had a C-index of 0.931. Conclusions—This model provides excellent discrimination between patients who are likely to live and those who are likely to die after thrombolytic-related intracranial hemorrhage; this may aid in making decisions about the appropriate level of care for such patients. http://repub.eur.nl/res/pub/8789/ 1998-01-01T00:00:00Z BACKGROUND: Nonhemorrhagic stroke occurs in 0.1% to 1.3% of patients with acute myocardial infarction who are treated with thrombolysis, with substantial associated mortality and morbidity. Little is known about the risk factors for its occurrence. METHODS AND RESULTS: We studied the 247 patients with nonhemorrhagic stroke who were randomly assigned to one of four thrombolytic regimens within 6 hours of symptom onset in the GUSTO-I trial. We assessed the univariable and multivariable baseline risk factors for nonhemorrhagic stroke and created a scoring nomogram from the baseline multivariable modeling. We used time-dependent Cox modeling to determine multivariable in-hospital predictors of nonhemorrhagic stroke. Baseline and in-hospital predictors were then combined to determine the overall predictors of nonhemorrhagic stroke. Of the 247 patients, 42 (17%) died and another 98 (40%) were disabled by 30-day follow-up. Older age was the most important baseline clinical predictor of nonhemorrhagic stroke, followed by higher heart rate, history of stroke or transient ischemic attack, diabetes, previous angina, and history of hypertension. These factors remained statistically significant predictors in the combined model, along with worse Killip class, coronary angiography, bypass surgery, and atrial fibrillation/flutter. CONCLUSIONS: Nonhemorrhagic stroke is a serious event in patients with acute myocardial infarction who are treated with thrombolytic, antithrombin, and antiplatelet therapy. We developed a simple nomogram that can predict the risk of nonhemorrhagic stroke on the basis of baseline clinical characteristics. Prophylactic anticoagulation may be an important treatment strategy for patients with high probability for nonhemorrhagic stroke, but further study is needed. http://repub.eur.nl/res/pub/5538/ 1997-01-20T00:00:00Z BACKGROUND: Use of aggressive and invasive interventions is more common in the USA than in other countries. We have compared use of resources for patients with cardiogenic shock after myocardial infarction in the USA and in other countries, and assessed the association between use of resources and clinical outcomes. METHODS: We analysed data for patients with cardiogenic shock after myocardial infarction who were enrolled in the GUSTO-I trial (1891 treated in the USA, 1081 treated in other countries). Patients were randomly assigned combinations of streptokinase, heparin, and accelerated tissue-plasminogen activator (t-PA), then decisions about further interventions were left to the discretion of the attending physician. The interventions included in our analysis were: pulmonary-artery catheterisation, cardiac catheterisation, intravenous inotropic agents, ventilatory support, intra-aortic balloon counterpulsation (IABP), percutaneous transluminal coronary angioplasty (PTCA), and coronary bypass graft surgery (CABG). The primary outcome measure was death from any cause at 30 days of follow-up. FINDINGS: Patients who were treated in the USA were significantly younger than those treated elsewhere (median 68 [IQR 59-75] vs 70 [62-76], p < 0.001), a smaller proportion had anterior infarction (49 vs 53%, p < 0.001), and they had a shorter time to treatment (mean 3.1 vs 3.3 h, p < 0.001). Aggressive diagnostic and therapeutic procedures were used more commonly in the USA than in the other countries: cardiac catheterisation (58 vs 23%); IABP (35 vs 7%); right-heart catheterisation (57 vs 22%); and ventilatory support (54 vs 38%). 483 (26%) of the patients treated in the USA underwent PTCA, compared with 82 (8%) patients in other countries. Patients who underwent revascularisation had better survival in all countries. Adjusted 30-day mortality was significantly lower among patients treated in the USA than among those treated elsewhere (50 vs 66%, p < 0.001). The difference in mortality remained at 1 year-56% of patients treated in the USA died versus 70% of patients treated elsewhere (hazard ratio 0.69 [95% CI 0.63-0.75], p < 0.001). INTERPRETATION: 30-day and 1-year mortality was significantly lower among patients treated in the USA than among those treated in other countries. This difference in mortality may be due to the greater use of invasive diagnostic and therapeutic interventions in the USA. http://repub.eur.nl/res/pub/5542/ 1997-01-01T00:00:00Z http://repub.eur.nl/res/pub/5550/ 1997-01-01T00:00:00Z We developed a logistic regression model with data from the GUSTO-I trial to predict mortality rate differences in individual patients who received accelerated tissue plasminogen activator (TPA) versus streptokinase treatment for acute myocardial infarction. A nomogram was developed from a reduced version of this model that approximated the underlying risk of patients treated with streptokinase, and thus the benefit of TPA. The 30-day mortality rate with accelerated TPA was 0.063 versus 0.073 with streptokinase and subcutaneously administered heparin and 0.074 with streptokinase and intravenously administered heparin. No baseline patient characteristics were significantly associated with a different relative effect of TPA. Older patients and those with anterior infarction, higher Killip classification (except Killip class IV), lower blood pressure, and increased heart rate had the greatest absolute benefit with accelerated TPA. Patients with acute myocardial infarction who had more high-risk characteristics derived a greater absolute benefit from treatment with accelerated TPA versus streptokinase. http://repub.eur.nl/res/pub/5489/ 1995-01-01T00:00:00Z BACKGROUND. Patients with acute myocardial infarction who were treated with accelerated tissue plasminogen activator (t-PA) (given over a period of 1 1/2 hours rather than the conventional 3 hours, and with two thirds of the dose given in the first 30 minutes) had a 30-day mortality that was 15 percent lower than that of patients treated with streptokinase in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) study. This was equivalent to an absolute decrease of 1 percent in 30-day mortality. We sought to assess whether the use of t-PA, as compared with streptokinase, is cost effective. METHODS. Our primary, or base-case, analysis of cost effectiveness used data from the GUSTO study and life expectancy projected on the basis of the records of survivors of myocardial infarction in the Duke Cardiovascular Disease Database. In the primary analysis, we assumed that there were no additional treatment costs due to the use of t-PA after the first year and that the comparative survival benefit of t-PA was still evident one year after enrollment. RESULTS. One year after enrollment, patients who received t-PA had both higher costs ($2,845) and a higher survival rate (an increase of 1.1 percent, or 11 per 1000 patients treated) than streptokinase-treated patients. On the basis of the projected life expectancy of each treatment group, the incremental cost-effectiveness ratio--with both future costs and benefits discounted at 5 percent per year--was$32,678 per year of life saved. The use of t-PA was least cost effective in younger patients and most cost effective in older patients. At all ages, the use of t-PA in patients with anterior infarctions yielded more favorable cost-effectiveness values. In our secondary analyses, the cost-effectiveness values were most sensitive to a lowering of the projected long-term survival benefits of t-PA and to moderate or greater increases in the projected medical costs for patients in the t-PA group after the first year. In contrast, our results were not sensitive to even very unfavorable assumptions about the additional costs associated with the higher rate of disabling stroke that was noted in patients treated with t-PA in the GUSTO study. CONCLUSIONS. The cost effectiveness of treatment with accelerated t-PA rather than streptokinase compares favorably with that of other therapies whose added medical benefit for dollars spent is judged by society to be worthwhile. http://repub.eur.nl/res/pub/5496/ 1995-01-01T00:00:00Z BACKGROUND: The Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries (GUSTO-I) trial was designed to test whether thrombolytic strategies achieving more complete, early, sustained coronary artery patency would lead to further reductions in mortality in patients with acute myocardial infarction. An angiographic substudy within GUSTO-I provided a unique opportunity to examine the relation between mortality and degrees of patency among the regimens. METHODS AND RESULTS: Four thrombolytic strategies were compared in 41,021 patients in GUSTO-I: streptokinase with subcutaneous or intravenous heparin, accelerated tissue plasminogen activator (TPA) with intravenous heparin, and combination streptokinase plus TPA with intravenous heparin. Accelerated TPA was associated with lower 30-day mortality (6.3%) than the other strategies (7.2%, 7.4%, and 7.0%, respectively). Among the 1210 patients in the angiographic substudy randomized to angiography 90 minutes after starting treatment, there was improved patency, particularly Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow, with accelerated TPA over the other regimens (P < .0001). Coronary artery perfusion (TIMI grade 3) at 90 minutes was also a significant predictor of 30-day survival (P < .01). To determine whether differences in mortality among the four strategies matched differences in 90-minute patency, a model was developed for predicting mortality differences in the main trial from the angiographic substudy. The model assumed that any differences in treatment effects on 30-day mortality were mediated through differences in 90-minute patency for the four treatments. The predicted rates were then compared with observed mortality rates of the remaining patients in the main trial for each treatment group. The predicted and observed 30-day mortality rates of the four treatments were streptokinase with subcutaneous heparin, 7.46% versus 7.28%; streptokinase with intravenous heparin, 7.26% versus 7.39%; accelerated TPA, 6.31% versus 6.37%; and streptokinase plus TPA, 6.98% versus 6.96%. The correlation between predicted and observed results was .97, and the proportion of squared error explained (R2) was .92. CONCLUSIONS: The close relation between the predicted and observed 30-day mortality rates supports the concept that an important mechanism for improved survival with thrombolytic therapy is achievement of early, complete perfusion. The close match provides a strong biological explanation for the mortality differences seen in GUSTO-I and a sound rationale for the additional survival advantage of the accelerated TPA regimen. Irrespective of which treatment is used, early and complete restoration of infarct artery perfusion represents an essential goal of myocardial reperfusion therapy. http://repub.eur.nl/res/pub/5433/ 1992-01-01T00:00:00Z The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial is a large scale international trial of new myocardial reperfusion strategies. The primary hypothesis is that early and sustained coronary artery recanalization will be associated with a significant reduction in mortality. The four regimens that are being tested are 1) streptokinase with subcutaneous heparin; 2) streptokinase with intravenous heparin; 3) accelerated recombinant tissue-type plasminogen activator (rt-PA) with intravenous heparin; and 4) combination streptokinase, rt-PA and intravenous heparin. The planned recruitment of 41,600 patients in 1,500 sites from 15 countries is expected to be completed by December 1992 and will enable detection of a 15% reduction or 1% absolute difference in mortality compared with that associated with standard therapy (streptokinase and subcutaneous heparin). In designing the trial, two important issues were directly addressed. First, a strategy was developed to provide assurance of patient safety during large scale investigational use of an aggressive thrombolytic regimen. This includes fascimile transmission of a one-page safety summary form to the Data Coordinating Center within 24 h of death or discharge, acceptance of the concept of "net clinical benefit" and close surveillance of the trial's progress by the independent Data and Safety Monitoring Committee. Second, to avoid potential conflict of interest beyond elimination of any position of financial equity, the Steering Committee unanimously voted to prohibit any honoraria for speaking engagements, payment for consultancy or travel or reimbursement of any kind from any of the five corporate sponsors until 1 year after publication of the results. Incorporation of these approaches may facilitate the design of future large scale randomized trials in cardiovascular medicine.