http://repub.eur.nl/res/aut/199/ 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/27540/ 2010-05-01T00:00:00Z Background: ST2 is a member of the interleukin-1 receptor family that is up-regulated in conditions associated with increased myocardial strain. ST2 has been shown to be independently predictive of adverse outcome in heart failure and ST-segment elevation myocardial infarction, but its prognostic value in non-ST-elevation acute coronary syndrome (NSTE-ACS) has not been established. Methods: We measured ST2 at randomization and after 24, 48, and 72 hours in 403 NSTE-ACS patients from the GUSTO IV study, and studied its kinetics and its associations to clinical baseline factors and 1-year mortality. Results: Median ST2 levels decreased from 28.4 U/mL at randomization to 21.8 U/mL at 72 hours (P < .001). Peak levels were noted 6 to 17 hours after symptom onset. Randomization ST2 levels were independently associated to N-terminal pro-B-type natriuretic peptide but otherwise exhibited only weak relations to cardiovascular risk factors and comorbidities, and biomarkers of myocardial necrosis or inflammation. ST2 was related to 1-year mortality independently of clinical risk indicators (odds ratio 2.3 [95% CI 1.1-4.6], P = .03) but lost its predictive value after additional adjustment for prognostic biomarkers, in particular N-terminal pro-B-type natriuretic peptide. Conclusions: ST2 levels are elevated early in NSTE-ACS and predict 1-year mortality. Our data indicate that ST2 represents an interesting novel pathophysiologic pathway in the setting of ischemia-related myocardial dysfunction. However, future prospective evaluations in larger populations are needed before the clinical utility of ST2 can be determined. http://repub.eur.nl/res/pub/29202/ 2008-11-15T00:00:00Z Despite aspirin's established role in the treatment of atherosclerotic vascular disease, considerable controversy exists regarding its most effective dosing strategy. In a retrospective observational study, we examined the relation between prescribed aspirin dose (<162 mg vs ≥162 mg/day aspirin) and clinical outcome in 4,589 placebo-treated patients enrolled in the Blockage of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial over a median follow-up of 366 days. Standard Cox regression analysis was employed because propensity analysis was not feasible. Compared with lower aspirin doses, higher doses were associated with lower unadjusted all-cause mortality (2.9 vs 1.6%, respectively; log rank chi-square 8.6, p = 0.0034). Higher aspirin dose remained independently predictive of lower all-cause mortality in a multivariable Cox proportional hazards model (hazard ratio 0.64, 95% confidence interval 0.42 to 0.97, p = 0.037). However, there was no significant difference in the incidence of the composite endpoint death, nonfatal myocardial infarction, or nonfatal stroke (6.1% vs 6.2%, p = 0.74). Higher aspirin dose was a significant independent predictor of any (hazard ratio 1.32, 95% confidence interval 1.12 to 1.55, p = 0.001) but not serious bleeding. In conclusion, our findings suggest that aspirin doses of ≥162 mg/day may be more beneficial than those <162 mg/day at preventing death. 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/35306/ 2007-08-01T00:00:00Z Background: Although relationships between chronic Chlamydia pneumoniae (Cpn) infection and the risk of coronary events in stable coronary artery disease patients have been reported, a similar link in acute coronary syndrome (ACS) patients has not been consistently observed. Methods: In a nested case-control substudy of the Global Utilization of Strategies to Open Occluded Arteries IV Acute Coronary Syndromes trial, 295 cases (30-day death/myocardial infarction [MI]) were matched by age, sex, baseline creatine kinase-myocardial kinase, and smoking status with 295 control subjects. To test the hypothesis on 1-year mortality, another subset (n = 276) was drawn from the 590-patient cohort; 138 patients who died at 1 year plus the matching controls who survived at 1 year. We measured Cpn IgG and IgA antibody titers in baseline serum with microimmunofluorescence. Conditional logistic regression was used to quantify the prognostic relevance seropositivity (IgG ≥1:32; IgA ≥1:16) and elevated titer levels. Results: The prevalence of Cpn IgG and IgA was similar between cases and controls (30-day death/MI: IgG, 80% vs 85%, P = .126; IgA, 45% vs 37%, P = .079), and were not statistically significant predictors of 30-day death/MI after baseline adjustment. Likewise, the 1-year death cohort had comparable proportions of Cpn IgG and IgA among cases and controls (86% vs 91% [P = .265] and 49% vs 43% [P = .334], respectively), and did not add prognostic value. Conclusions: These findings are in concert with study results suggesting that chronic Cpn infection is not associated with 30-day death/MI or 1-year mortality in non-ST elevation ACS. http://repub.eur.nl/res/pub/35621/ 2007-02-01T00:00:00Z BACKGROUND - Growth-differentiation factor-15 (GDF-15) is a member of the transforming growth factor-β cytokine superfamily that is induced in the heart after ischemia-and-reperfusion injury. Circulating levels of GDF-15 may provide prognostic information in patients with non-ST-elevation acute coronary syndrome. METHODS AND RESULTS - Blood samples were obtained on admission from 2081 patients with acute chest pain and either ST-segment depression or troponin elevation who were included in the Global Utilization of Strategies to Open Occluded Arteries (GUSTO)-IV Non-ST-Elevation Acute Coronary Syndrome trial and from a matching cohort of 429 apparently healthy individuals. GDF-15 levels were determined by immunoradiometric assay. Approximately two thirds of patients presented with GDF-15 levels above the upper limit of normal in healthy controls (1200 ng/L); one third presented with levels >1800 ng/L. Increasing tertiles of GDF-15 were associated with an enhanced risk of death at 1 year (1.5%, 5.0%, and 14.1%; P<0.001). By multiple Cox regression analysis, only the levels of GDF-15 and N-terminal pro-B-type natriuretic peptide, together with age and a history of previous myocardial infarction, contributed independently to 1-year mortality risk. Receiver operating characteristic curve analyses further illustrated that GDF-15 is a strong marker of 1-year mortality risk (area under the curve, 0.757; best cutoff, 1808 ng/L). At this cutoff value, GDF-15 added significant prognostic information in patient subgroups defined by age; gender; time from symptom onset to admission; cardiovascular risk factors; previous cardiovascular disease; and the risk markers ST-segment depression, troponin T, N-terminal pro-B-type natriuretic peptide, C-reactive protein, and creatinine clearance. CONCLUSIONS - GDF-15 is a new biomarker of the risk for death in patients with non-ST-elevation acute coronary syndrome that provides prognostic information beyond that provided by established clinical and biochemical markers. http://repub.eur.nl/res/pub/35852/ 2007-02-01T00:00:00Z Aims: To assess the significance of creatine kinase (CK)-MB elevations in outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) who have undergone coronary artery bypass grafting (CABG) surgery. Methods and results: This analysis includes data from 26 465 patients with NSTE ACS enrolled in four major trials. In total, 4626 (17.5%) of patients had CABG within 30 days. Patients were excluded if CK-MB was elevated within 24 h before surgery and there was no CK-MB measured after surgery. Overall, 4401 patients were included in these analyses. The incidence of mortality increased with peak CK-MB ratios of 0-1, > 1-3, > 3-5, > 5-10, and > 10 x the upper limit of normal measured at the local lab (P < 0.001 across categories): 1.1, 2.8, 2.4, 3.1, and 10.8% in hospital; 1.1, 3.0, 2.9, 3.5, and 10.2% at 30 days; and 1.6, 4.4, 4.7, 6.0, and 10.9% at 180 days. Multivariable predictors of 6-month mortality included age, heart rate and randomization, peak CK-MB ratio, time to CABG, prior angina, signs of congestive heart failure and randomization, three- and two-vessel coronary disease, enrolment infarction, ST-segment depression at enrolment, female sex, experimental treatment, and systolic blood pressure. Conclusion: CK-MB elevations after CABG are independently associated with increased risk of mortality in patients with NSTE ACS. 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/13312/ 2004-02-01T00:00:00Z AIM: To study the relationship between outcomes and peak creatine kinase (CK)-MB levels after percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). METHODS AND RESULTS: Peak CK-MB ratios (peak CK-MB level/upper limit of normal [ULN]) after PCI were analysed in 6164 patients with NSTE ACS from four randomized trials who underwent in-hospital PCI. We excluded 696 patients with elevated CK or CK-MB levels <24h before PCI; the primary analysis included 2384 of the remaining 5468 patients (43.6%) with CK-MB levels measured <==24h after PCI. The incidence of in-hospital heart failure (0.1%, 0.8%, 3.4%, 4.1%, and 6.1%; P<0.001), arrhythmias (0.8%, 1.9%, 6.9%, 4.1%, and 7.9%; P<0.001), cardiogenic shock (0.1%, 1.3%, 2.0%, 2.3%, and 2.6%; P=0.004), and mortality through 6 months (2.1%, 2.4%, 4.9%, 4.1%, and 5.7%, P=0.005) was increased with peak CK-MB ratios of 0-1, 1-3, 3-5, 5-10, and >10xULN, respectively. The continuous peak CK-MB ratio after PCI significantly predicted adjusted 6-month mortality (risk ratio, 1.06 per unit increase above ULN; 95% confidence interval, 1.01-1.11; P=0.017). CONCLUSIONS: Greater CK-MB elevation after PCI is independently associated with adverse outcomes in NSTE ACS. These results underscore the adverse implications of elevated CK-MB levels after PCI in this high-risk population. http://repub.eur.nl/res/pub/5719/ 2004-02-01T00:00:00Z BACKGROUND: Troponin is a specific marker of myocardial damage. For early prediction of coronary events in patients with suspicion of acute coronary syndromes the assay also needs to be highly sensitive. METHODS AND RESULTS: A rapid troponin I assay was performed prior to inclusion in 4447 acute coronary syndrome patients in the GUSTO-IV trial. A quantitative troponin T analysis was later performed on blood samples obtained at randomization by a central laboratory. There was an agreement between the rapid troponin I assay and troponin T (< or =/>0.1 microg/l) in 3596 (80.9%) patients. A positive rapid troponin I was identifying any elevation of troponin T (>0.01 microg/l) in 1990 patients (90.4%) whereas a negative rapid troponin I was corresponding to negative troponin T (< or =0.01 microg/l) in only 1217 patients (54.2%). Patients with a positive versus negative rapid troponin I had an increased risk of death or myocardial infarction at 30 days (9.3 vs. 5.9%; odds ratio, O.R. 1.64; 95% confidence interval, 1.31-2.06). Troponin T elevation (>0.1 microg/l) provided a better (10.5 v. 4.9%, O.R. 2.26; C.I. 1.79-2.85) risk stratification. Regardless of a positive or a negative rapid troponin I, the troponin T result (>0.1 vs. < or =0.1 microg/l) stratified the patients into high and low risk of events at 30 days, (10.3 vs. 5.7%, P=0.002) and (11.5 vs. 4.8%, P<0.001), respectively. CONCLUSION: In a population with non-ST elevation acute coronary syndrome a positive rapid troponin I assay is a specific indicator of troponin elevation and a predictor of early outcome. However, a negative rapid troponin I is not a reliable indicator of the absence of myocardial damage and does not indicate a low risk of subsequent cardiac events. A rapid troponin I assay was performed prior to inclusion in 4447 acute coronary syndrome patients in the GUSTO-IV trial and related to a centrally analyzed quantitative troponin T test. A positive rapid troponin I was well corresponding to any elevation of troponin T (>0.01 microg/l) and predicted an unfavorable outcome at 30 days. However, a negative rapid troponin I was corresponding to troponin T < or =0.01 microg/l in only half of the patients. Troponin T >0.1 microg/l vs. < or =0.1 microg/l provided a better risk stratification than the rapid troponin I result. For patients with troponin T elevation (>0.1 microg/l) the 30 day event rate was high regardless of the rapid troponin I result. http://repub.eur.nl/res/pub/5720/ 2004-02-01T00:00:00Z BACKGROUND: In acute coronary syndromes, the inflammation and the coagulation systems are activated, implying an impaired outcome. In addition to platelet inhibition, recent evidence suggests that the glycoprotein IIb/IIIa receptor inhibitor abciximab attenuates inflammation and coagulation activity. METHODS: The Swedish Global Utilization of Strategies To open Occluded arteries-IV (GUSTO-IV) substudy included 404 patients with non-ST-elevation acute coronary syndromes. In addition to aspirin and dalteparin, all patients were randomized to receive abciximab infusion for 24 hours or 48 hours or corresponding placebo without early coronary revascularization. Plasma samples were obtained at baseline and 24, 48, and 72 hours. RESULTS: The median levels of the coagulation markers thrombin/antithrombin complex and soluble fibrin increased significantly from 3.1 to 3.7 ug/L (baseline to peak; P <.001) and from 20 to 23 nmol/L (P <.001), respectively. The fibrinolysis marker, tissue plasminogen-activator, also increased its median levels, from 11.7 to 17.5 ug/L (P <.001), whereas the median level of plasminogen-activator-inhibitor was unchanged. The inflammatory markers interleukin-6, C-reactive protein, and fibrinogen also increased their median levels (5.4-7.8 ng/L, P <.001; 4.4-8.7 mg/L, P <.001; 3.3-3.9 g/L, P <.001). However, there were no differences in median levels or in changes of median levels of any marker at any point between the placebo group and any of the abciximab groups. CONCLUSIONS: In non-ST-elevation acute coronary syndrome, there was a simultaneous activation of the inflammation, coagulation, and fibrinolysis systems, despite aspirin and dalteparin treatment. Prolonged treatment with abciximab had no influence of the activation of these systems. http://repub.eur.nl/res/pub/5712/ 2003-08-15T00:00:00Z BACKGROUND: A third-generation troponin T assay with improved precision and a lower detection limit has been developed. However, the appropriate cutoff for identifying patients with the acute coronary syndrome who are at low risk of subsequent mortality has not been established. METHODS: A retrospective evaluation of data from the Fragmin and fast Revascularization during InStability in Coronary artery disease II (FRISC-II) trial suggested that a cutoff below 0.1 microg/L for troponin T levels might be more useful in risk stratification. A prospective validation of two cutoff levels (0.03 microg/L and 0.01 microg/L) was performed in 7115 patients with non-ST-elevation acute coronary syndrome from the Global Utilization of Strategies To open Occluded arteries IV (GUSTO-IV) trial. RESULTS: Patients with troponin T levels >0.1 microg/L had greater 30-day mortality (5.5% [201/3679]) than did those with levels <or=0.1 microg/L (2.2% [75/3436], P <0.001). A cutoff value of 0.03 microg/L provided better discrimination between high and low risk: 5.1% (234/4552) versus 1.6% (42/2563). However, a cutoff value at the lower limit of detection, 0.01 microg/L, provided the best discrimination: 5.0% (254/5123) versus 1.1% (22/1992) (P<0.001). This cutoff level had the highest negative predictive value; it also discriminated best for the combined endpoint of death and myocardial infarction. CONCLUSION: Using a cutoff of <or=0.01 microg/L for the third-generation troponin T assay, the detection level of the assay, is useful for identifying patients with the acute coronary syndrome who are at low risk of subsequent mortality. http://repub.eur.nl/res/pub/13175/ 2003-07-22T00:00:00Z BACKGROUND: Biochemical markers are useful for prediction of cardiac events in patients with non-ST-segment-elevation acute coronary syndrome (ACS). The associations between N-terminal pro-brain natriuretic peptide (NT-proBNP) and other biochemical and clinical risk indicators, as well as their prognostic value concerning the individual end points of death and myocardial infarction (MI), were elucidated in a large cohort of ACS patients. METHODS AND RESULTS: NT-proBNP, troponin T, and C-reactive protein (CRP) were analyzed in blood samples obtained at a median of 9.5 hours from symptom onset in 6809 of 7800 ACS patients in the Global Utilization of Strategies To Open occluded arteries-IV (GUSTO-IV) trial. Levels of NT-proBNP were correlated independently with age, female gender, low body weight, diabetes, renal dysfunction, history of MI, heart failure, heart rate, ongoing myocardial damage, and time since onset of ischemia. Increasing quartiles of NT-proBNP were related to short- and long-term mortality that reached 1.8%, 3.9%, 7.7%, and 19.2%, (P<0.001), respectively, at 1 year. Levels of troponin T, CRP, heart rate, and creatinine clearance, in addition to ST-segment depression, were also correlated independently with 1-year mortality, but NT-proBNP was the marker with the strongest relation. In contrast, only troponin T, creatinine clearance, and ST-segment depression were independently related to future MI. The combination of NT-proBNP and creatinine clearance provided the best prediction, with a 1-year mortality of 25.7% with both markers in the top quartile vs 0.3% with both markers in the bottom quartile. CONCLUSIONS: The use of NT-proBNP appears to add critical prognostic insight to the assessment of patients with ACS. http://repub.eur.nl/res/pub/22493/ 2003-07-01T00:00:00Z BACKGROUND: This is the primary report of the large-scale evaluation of lotrafiban, an orally administered IIb/IIIa receptor antagonist, a unique trial with respect to the platelet antagonist, protocol design, and inclusion of cerebrovascular disease in a significant proportion of patients. METHODS AND RESULTS: Patients with vascular disease were randomized to lotrafiban 30 or 50 mg BID on the basis of age and predicted creatinine clearance or placebo in addition to aspirin at a dose ranging from 75 to 325 mg/d at the discretion of the physician-investigator. Follow-up was for up to 2 years. The primary end point was the composite of all-cause mortality, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, and urgent revascularization. Of 9190 patients enrolled from 23 countries and 690 hospitals, 41% had cerebrovascular disease at the time of entry, and 59% had coronary artery disease. Death occurred in 2.3% of placebo-assigned patients and 3.0% of lotrafiban-group patients (hazard ratio 1.33, 95% CI 1.03 to 1.72, P=0.026), and the cause of excess death was vascular related. There was no significant difference in the primary end point (17.5% compared with 16.4%, respectively; hazard ratio 0.94, 95% CI 0.85 to 1.03, P=0.19). Serious bleeding was more frequent in the lotrafiban group (8.0% compared with 2.8%; P<0.001). Serious bleeding was more common among patients who received higher doses of aspirin (>162 mg/d), with or without lotrafiban. CONCLUSIONS: Lotrafiban, an orally administered platelet glycoprotein IIb/IIIa blocker, induced a 33% increase in death rate, which was vascular in origin and not affected by the type of atherosclerotic involvement at entry to the trial. Although the dose of aspirin was not randomly assigned, the finding of increased bleeding with doses >162 mg/d is noteworthy. http://repub.eur.nl/res/pub/13154/ 2003-05-13T00:00:00Z BACKGROUND: We postulated that antibodies to platelet factor 4/heparin complex might contribute to recurrent ischemic events in patients with acute coronary syndrome. METHODS AND RESULTS: We analyzed serum from patients enrolled in the placebo/unfractionated heparin arm of the GUSTO IV-ACS trial who had high likelihood of prior heparin exposure. We selected 109 patients without thrombocytopenia with the 30-day primary end point (death, myocardial infarction [MI], or revascularization) and 109 age-, gender-, and race-matched controls who did not achieve the primary end point. An ELISA for anti-platelet factor 4/heparin antibodies was performed using 48-hour serum samples. The analyses were done by blinded investigators, and the results were correlated with clinical outcomes. Twenty-three of 218 patients (10.6%) had anti-PF4/heparin antibodies. Patients with anti-PF4/heparin antibodies were more likely to have death or MI (30.4% versus 11.3%, P=0.011) or MI (21.7% versus 6.2%, P=0.008) than patients who were negative for the antibody. After multiple logistic regression analysis, anti-PF4/heparin antibodies remained a predictor of 30-day death or MI (odds ratio, 4.0; 95% CI, 1.4 to 11.3; P=0.0093) and MI (odds ratio, 4.6; 95% CI, 1.4 to 15.0; P=0.0108). The antibody was not associated with the composite end point (death, MI, or revascularization) or with death or revascularization alone. CONCLUSIONS: Antibodies to the platelet factor 4/heparin complex are a novel, independent predictor of myocardial infarction at 30 days in patients presenting with acute coronary ischemic syndromes. This finding may explain the previous association between thrombocytopenia and adverse events in patients with acute coronary syndrome and may have important implications for the choice of anticoagulant regimens. http://repub.eur.nl/res/pub/5707/ 2003-03-19T00:00:00Z OBJECTIVES: We sought to evaluate C-reactive protein (CRP) and troponin T (TnT) as predictors of risk of the individual end points of mortality and myocardial infarction (MI) in a large cohort of patients with acute coronary syndrome (ACS). BACKGROUND: Both CRP and TnT predict risk of future coronary events in patients with ACS. However, the relationships between the levels of the markers and the individual end points are still unclear. METHODS: Baseline levels of CRP and TnT were determined in 7,108 patients with ACS not undergoing early revascularization in the Global Use of Strategies To Open occluded arteries trial IV (GUSTO-IV) trial and related to outcome at 30 days. RESULTS: Quartiles of TnT related to 30-day mortality, which was 1.1%, 3.7%, 3.7%, and 7.4% (p < 0.001) and to the rate of MI: 2.5%, 6.7%, 7.2%, and 5.6% (p < 0.001). Quartiles of CRP also related to 30-day mortality, which was 2.0%, 3.3%, 3.9%, and 6.3% (p < 0.001), whereas there was no relationship to the 30-day rate of MI: 5.6%, 4.7%, 5.2%, and 5.9% (p = 0.48). On multivariable analysis, both TnT and CRP were independent predictors of mortality, but only TnT was a predictor of MI. The combination of CRP and TnT provides an even better risk stratification of mortality, with 0.3% and 9.1% death rates, respectively, when both markers are in the bottom versus top quartiles. CONCLUSIONS: In ACS, baseline levels of TnT and CRP are independently related to 30-day mortality. Any detectable elevation of TnT, but not of CRP, is also associated with an increased risk of subsequent MI. Regarding mortality, the combination of both markers provides a better risk stratification than either one alone. http://repub.eur.nl/res/pub/5696/ 2002-12-01T00:00:00Z BACKGROUND: The 6-month clinical outcome of patients with multivessel disease enrolled in PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) is described. Patients with complete angiography data were included; multivessel disease was stratified according to the treatment strategy applied early during hospitalization, i.e. medical treatment, percutaneous coronary intervention (PCI) (balloon), PCI (stent), or coronary artery bypass grafting (CABG). METHODS: Patients were divided into three groups according to the treatment strategy applied during the first 30 days of enrolment. Patients who did not undergo a percutaneous or surgical coronary intervention were classified as medically treated. Patients who underwent a PCI (prior to a possible CABG) were separated from those who underwent a CABG (prior to a possible PCI). The PCI group was further subdivided: patients receiving >/=1 coronary stents were separated from those in whom no stents were used. RESULTS: The mortality rate at 30 days was 6.7, 3.9, 2.4 and 4.8% for the medical treatment, PCI (balloon), PCI (stent) and CABG groups, respectively (p value = 0.002). Differences as observed at 30 days were still present at 6-month follow-up with 11.1, 5.8, 5.5 and 6.5% mortality event rates for the aforementioned groups (p value = 0.002). The 30-day myocardial infarction (MI) rate according to the opinion of the Clinical Events Committee was lower among medically than non-medically treated patients, with the highest event rate observed in the CABG group (27.7%). Approximately half of the MIs in the PCI and CABG subgroups occurred within 48 h after the procedure. CONCLUSIONS: The observed differences in clinical outcomes are explained by an imbalance in baseline characteristics and comorbid conditions between the analyzed groups of patients. http://repub.eur.nl/res/pub/13065/ 2002-07-01T00:00:00Z AIMS: To evaluate the differential effects of eptifibatide therapy on unstable angina vs non-ST elevation myocardial infarction at enrollment, since the separate impact on these two major diagnostic subsets of acute coronary syndrome patients has not been fully investigated. METHODS AND RESULTS: We examined the 9461 patients in the PURSUIT trial (conducted between 1995 and 1997) to compare the effects of eptifibatide on unstable angina and myocardial infarction. The study showed greater and more consistent effects of eptifibatide therapy on unstable angina than non-ST elevation myocardial infarction in reducing 30-day death/(re)infarction (from the unadjusted rate of 13.0% to 11.2%, P=0.059 for unstable angina; and 18.9% to 17.9%, P=0.387 for myocardial infarction), especially among patients who underwent early percutaneous coronary intervention (odds ratios=0.49 and 0.86, 95% confidence intervals=0.30-0.80 and 0.53-1.42, respectively, for unstable angina and myocardial infarction). The only subgroup for whom the benefit of eptifibatide was not evident was female myocardial infarction patients who did not undergo early percutaneous coronary intervention. CONCLUSIONS: These data suggest that eptifibatide benefited unstable angina patients more than myocardial infarction patients, especially among those who underwent early percutaneous coronary intervention, and support its use as concomitant therapy with early percutaneous coronary intervention especially in female myocardial infarction patients. http://repub.eur.nl/res/pub/13008/ 2002-02-01T00:00:00Z BACKGROUND: Many patients with acute coronary syndromes are offered percutaneous coronary intervention. However, the appropriate indications for, and optimal timing of, such procedures are uncertain. We analysed timing of intervention and associated events (death and myocardial infarction) in the PURSUIT trial in which 9461 patients received a platelet glycoprotein IIb/IIIa inhibitor, eptifibatide, or placebo for 72 h. Other treatment was left to the investigators. 2430 patients underwent percutaneous coronary intervention within 30 days. Four groups were distinguished, who underwent percutaneous coronary intervention on day 1; on days 2 or 3; at 4 to 7 days; or between 8 until 30 days, for eptifibatide- and placebo-treated patients. RESULTS: The four groups treated with placebo demonstrated total 30-day events of 15.9% for day 1 percutaneous coronary intervention, 17.7%, 15.0% and 18.2%, respectively, for successive intervals of later intervention. Later intervention was associated with more pre-procedural events (2.2% to 13.7%, P=0.001) which was balanced by a decrease in procedure-related events (12.1 to 3.1%, P=0.001), while the overall 30-day event rates were similar. Eptifibatide-treated patients with percutaneous coronary intervention on day 1 had the lowest rate of 30-day events (9.2%, P<0.05 vs other groups). In this group, pre-procedural risk was only 0.3%, while percutaneous coronary intervention on eptifibatide treatment was associated with low procedural risk (7.2%). The total 30-day event rate for later percutaneous coronary intervention in patients receiving eptifibatide was 14.0 on days 2 and 3, 15.0% for days 4 to 7 and 17.4% for days 7 to 30, respectively. CONCLUSION: Patients treated with a platelet glycoprotein IIb/IIIa receptor blocker, and early percutaneous coronary intervention (within 24 h) had the lowest event rate in this post hoc analysis. Thus 'watchful waiting' may not be the optimal strategy. Rather an early invasive strategy with percutaneous coronary intervention under protection of a platelet glycoprotein IIb/IIIa receptor blocker should be considered in selected patients. Randomized trials are warranted to verify this issue. http://repub.eur.nl/res/pub/9825/ 2002-01-22T00:00:00Z BACKGROUND: Patients with prior CABG with a subsequent non-ST-segment elevation acute coronary syndrome (ACS) pose an increasingly important clinical problem. Although GP IIb/IIIa inhibitors have improved the outcome of patients with ACS, their efficacy in patients with prior CABG has not been previously evaluated. Methods and Results- We analyzed the 30- and 180-day outcomes of patients with prior CABG enrolled in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial. In this trial, which evaluated the efficacy of eptifibatide in patients with ACS, 1134 patients (12%) with prior CABG and 8321 without prior CABG were enrolled. After adjusting for differences in baseline characteristics and treatment, patients with prior CABG had a significantly higher mortality rates at 30 days (hazard ratio [HR], 1.45 [95% CI, 1.06 to 1.98]; P=0.019) and at 180 days (HR, 1.32 [95% CI, 1.04 to 1.67]; P=0.021). At 30 days, there was a similar effect on the primary end point of death or myocardial infarction in the eptifibatide group versus the placebo group in prior CABG patients (unadjusted HR, 0.90 [95% CI, 0.67 to 1.20]) and in patients without a history of CABG (unadjusted HR, 0.89 [95% CI, 0.80 to 0.99]). CONCLUSIONS: Patients with prior CABG with non-ST-segment elevation ACS have a significantly worse prognosis than do patients without a history of CABG. The treatment effect of eptifibatide in the prior CABG group was similar to the effect seen in patients without prior CABG. 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/8453/ 2002-01-01T00:00:00Z BACKGROUND: Among patients with suspected acute coronary syndromes, cardiac troponin T levels have prognostic value. However, there is concern that renal dysfunction may impair the prognostic value, because cardiac troponin T may be cleared by the kidney. METHODS: We analyzed the outcomes in 7033 patients enrolled in the Global Use of Strategies to Open Occluded Coronary Arteries IV trial who had complete base-line data on troponin T levels and creatinine clearance rates. The troponin T level was considered abnormal if it was 0.1 ng per milliliter or higher, and creatinine clearance was assessed in quartiles. The primary end point was a composite of death or myocardial infarction within 30 days. RESULTS: Death or myocardial infarction occurred in 581 patients. Among patients with a creatinine clearance above the 25th percentile value of 58.4 ml per minute, an abnormally elevated troponin T level was predictive of an increased risk of myocardial infarction or death (7 percent vs. 5 percent; adjusted odds ratio, 1.7; 95 percent confidence interval, 1.3 to 2.2; P<0.001). Among patients with a creatinine clearance in the lowest quartile, an elevated troponin T level was similarly predictive of increased risk (20 percent vs. 9 percent; adjusted odds ratio, 2.5; 95 percent confidence interval, 1.8 to 3.3; P<0.001). When the creatinine clearance rate was considered as a continuous variable and age, sex, ST-segment depression, heart failure, previous revascularization, diabetes mellitus, and other confounders had been accounted for, elevation of the troponin T level was independently predictive of risk across the entire spectrum of renal function. CONCLUSIONS: Cardiac troponin T levels predict short-term prognosis in patients with acute coronary syndromes regardless of their level of creatinine clearance. 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/9977/ 2002-01-01T00:00:00Z AIMS: The safety and efficacy of abciximab in addition to low-molecular-weight-heparin as the primary medical treatment of acute coronary syndromes has not previously been investigated. METHODS AND RESULTS: The GUSTO IV-ACS trial included 7800 patients with chest pain and either ST-segment depression or a positive troponin test. They were randomized to abciximab for 24 h, 48 h or placebo. In the dalteparin substudy, 974 patients received 5 days of s.c. dalteparin, instead of a 48 h infusion of unfractionated heparin (UFH). Major and minor bleedings were more frequent for abciximab (24 and 48 h combined) than placebo both in the dalteparin (abciximab 5.0% vs placebo 1.8% P<0.05) and in the UFH cohort (3.8% vs 1.8% P<0.001). However, stroke rates were low, < or = 0.6%. At 30 days there were no significant differences in the rate of death or MI, either in the dalteparin (abciximab 9.6% vs placebo 11.3%: O.R. 0.85; 95% C.I. 0.58-1.25) or in the UFH cohort (8.5% vs 7.6%: O.R.; 1.12: 0.95-1.34). CONCLUSION: Treatment with abciximab, aspirin and s.c. dalteparin is associated with a low risk of major side effects and is as safe as the combination of abciximab and UFH. Without early coronary intervention there is no indication for abciximab treatment. http://repub.eur.nl/res/pub/13016/ 2001-09-04T00:00:00Z BACKGROUND: Clinical events committees (CEC) are used routinely to adjudicate suspected end-points in cardiovascular trials, but little information has been published about the various processes used. We reviewed results of the CEC process used to identify and adjudicate suspected end-point (post-enrolment) myocardial infarction (MI) in the large Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin (Eptifibatide) Therapy (PURSUIT) trial. METHODS: The PURSUIT trial randomised 10,948 patients with acute coronary syndromes to receive eptifibatide or placebo. A central adjudication process was established prospectively to identify all suspected MIs and adjudicate events based on protocol definitions of MI. Suspected MIs were identified by systematic review of data collection forms, cardiac enzyme results, and electrocardiograms. Two physicians independently reviewed all suspected events. If they disagreed whether a MI had occurred, a committee of cardiologists adjudicated the case. RESULTS: The CEC identified 5005 patients with suspected infarction (46%), of which 1415 (28%) were adjudicated as end-point infarctions. As expected, the process identified more end-point events than did the site investigators. Absolute and relative treatment effects of eptifibatide were smaller when using CEC-determined MI rates rather than site investigator-determined rates. The site-investigator reporting of MI and the CEC assessment of MI disagreed in 20% of the cases reviewed by the CEC. CONCLUSIONS: End-point adjudication by a CEC is important, to provide standardised, systematic, independent, and unbiased assessment of end-points, particularly in trials that span geographic regions and clinical practice settings. Understanding the CEC process used is important in the interpretation of trial results and event rates. http://repub.eur.nl/res/pub/5742/ 2001-09-04T00:00:00Z Abstract: Background Limited information has been published regarding how specific processes for event adjudication can affect event rates in trials. We reviewed nonfatal myocardial infarctions (MIs) reported by site investigators in the international Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin (Eptifibatide) Therapy (PURSUIT) trial and those adjudicated by a central clinical events committee (CEC) to determine the reasons for differences in event rates. Methods The PURSUIT trial randomised 10,948 patients with acute coronary syndromes to receive eptifibatide or placebo. The primary end-point was death or post-enrolment MI at 30 days as assessed by the CEC; this end-point was also constructed using site-reported events. The CEC identified suspected MIs by systematic review of clinical, cardiac enzyme, and lectrocardiographic data. Results The CEC identified 5005 (46%) suspected events, of which 1415 (28%) were adjudicated as MI. The site investigator and CEC assessments of whether a MI had occurred disagreed in 983 (20%) of the 5005 patients with suspected MI, mostly reflecting site misclassification of post-enrolment MIs (as enrolment MIs) or underreported periprocedural MIs. Patients for whom the CEC and site investigator agreed that no end-point MI had occurred had the lowest mortality at 30 days and between 30 days and 6 months, and those with agreement that a MI had occurred had the highest mortality. Conclusion CEC adjudication provides a standard, systematic, independent, and unbiased assessment of end-points, particularly for trials that span geographic regions and clinical practice settings. Understanding the review process and reasons for disagreement between CEC and site investigator assessments of MI is important to design future trials and interpret event rates between trials. http://repub.eur.nl/res/pub/5659/ 2001-07-01T00:00:00Z http://repub.eur.nl/res/pub/9668/ 2001-01-01T00:00:00Z CONTEXT: Abciximab, a potent inhibitor of the platelet glycoprotein IIb/IIIa receptor, reduces thrombotic complications in patients undergoing percutaneous coronary intervention (PCI). Because of its potent inhibition of platelet aggregation, the effect of abciximab on risk of stroke is a concern. OBJECTIVE: To determine whether abciximab use among patients undergoing PCI is associated with an increased risk of stroke. DESIGN: Combined analysis of data from 4 double-blind, placebo-controlled, randomized trials (EPIC, CAPTURE, EPILOG, and EPISTENT) conducted between November 1991 and October 1997 at a total of 257 academic and community hospitals in the United States and Europe. PATIENTS: A total of 8555 patients undergoing PCI with or without stent deployment for a variety of indications were randomly assigned to receive a bolus and infusion of abciximab (n = 5476) or matching placebo (n = 3079). One treatment group in EPIC received a bolus of abciximab only. MAIN OUTCOME MEASURE: Risk of hemorrhagic and nonhemorrhagic stroke within 30 days of treatment among abciximab and placebo groups. RESULTS: No significant difference in stroke rate was observed between patients assigned abciximab (n = 22 [0.40%]) and those assigned placebo (n = 9 [0.29%]; P =.46). Excluding the EPIC abciximab bolus-only group, there were 9 strokes (0.30%) among 3023 patients who received placebo and 15 (0.32%) in 4680 patients treated with abciximab bolus plus infusion, a difference of 0.02% (95% confidence interval [CI], -0.23% to 0.28%). The rate of nonhemorrhagic stroke was 0.17% in patients treated with abciximab and 0.20% in patients treated with placebo (difference, -0.03%; 95% CI, -0.23% to 0.17%), and the rates of hemorrhagic stroke were 0.15% and 0.10%, respectively (difference, 0.05%; 95% CI, -0.11% to 0.21%). Among patients treated with abciximab, the rate of hemorrhagic stroke in patients receiving standard-dose heparin in EPIC, CAPTURE, and EPILOG was higher than in those receiving low-dose heparin in the EPILOG and EPISTENT trials (0.27% vs 0.04%; P =.057). CONCLUSIONS: Abciximab in addition to aspirin and heparin does not increase the risk of stroke in patients undergoing PCI. Patients undergoing PCI and treated with abciximab should receive low-dose, weight-adjusted heparin. http://repub.eur.nl/res/pub/12827/ 2000-03-04T00:00:00Z AIMS: Variations in outcome of patients from different geographic regions have been observed in many large international trials. We analysed the factors that might contribute to the geographic variations in patient outcome and treatment effect as observed in the PURSUIT trial. METHODS: In PURSUIT, 9461 patients with acute coronary syndromes without persistent ST-elevation were randomized to the platelet inhibitor eptifibatide or placebo for 72 h in 27 countries in four geographic regions: Western (n=3697) and Eastern Europe (n=1541) as well as North (n=3827) and Latin America (n=396). The primary end-point was the 30-day composite of death or myocardial infarction. In the initial univariate analysis, the treatment effect appeared greater in N. America than in W. Europe, while no benefit was apparent in L. America and E. Europe. However, the confidence intervals were wide and overlapping. To study these differences, a subdivision in an early and late patient outcome and treatment effect was made. Accordingly, we analysed the rate of death or infarction at 72 h censored for percutaneous coronary intervention and the rate between 3 and 30 days, respectively. Additional analyses were performed with different definitions of myocardial infarction using progressively higher thresholds of CK(-MB) elevation. Multivariable analysis was used to evaluate the relation between region and outcome and to determine the adjusted odds ratios for the eptifibatide treatment effect. RESULTS: Major differences in baseline demographics were apparent among the four regions; in particular, more patients from E. Europe had characteristics associated with impaired outcome. Interventional treatment also varied considerably, with more patients from N. America undergoing revascularization. Despite differences in the 72 h event rate, eptifibatide showed a consistent trend towards a reduction in the composite end-point among all four regions and for all definitions of infarction. Relative reductions ranged from 17-42% in W. Europe, 23-35% in N. America, 0-33% in E. Europe, and 55-82% in L. America. After multivariable adjustment, the pattern of benefit with eptifibatide was consistent among the regions. In patients undergoing percutaneous coronary intervention during study drug infusion in W. Europe (n=266) and N. America (n=931), the relative reduction in myocardial infarction during medical therapy ranged from 56-75% in W. Europe and 14-67% in N. America, while the reduction in procedure-related events ranged from 12-44% and 25-61% for different definitions of infarction. After multivariable adjustment neither benefit nor rebound were apparent after study drug discontinuation, or after 3 days in all regions, except in L. America. In general, the differences in outcome and treatment effect were greatest when the protocol definition of myocardial infarction (CK(-MB) >1 upper normal limit) was applied. Under stricter definitions, these differences became smaller and disappeared with the investigator's assessment. CONCLUSION: The analysis suggests that the apparent differences in patient outcome and eptifibatide treatment effect can be explained largely by differences in baseline demographics and adjunctive treatment strategies as well as by the methodology of myocardial infarction definition and the adjudication process. http://repub.eur.nl/res/pub/5739/ 2000-01-01T00:00:00Z BACKGROUND: Studies have shown that cigarette smokers constitute a substantial proportion of patients with acute coronary syndromes (ACS) and have platelet-rich coronary thrombi. We characterized the influence of smoking status on outcome of patients with ACS without persistent ST-segment elevation and tested the hypothesis that selective inhibition of the platelet glycoprotein IIb/IIIa receptor with eptifibatide would improve outcomes among cigarette smokers. METHODS: The study population included patients enrolled in the PURSUIT trial (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) with known smoking status presenting with ischemic chest pain </=24 hours and having either ischemic electrocardiographic changes without persistent ST-segment elevation or elevated creatine kinase MB levels. Patients were randomly assigned to receive a bolus and infusion of either eptifibatide or placebo in addition to standard therapy. The primary end point was a composite of death or nonfatal myocardial infarction within 30 days. RESULTS: Of the 9406 patients with known smoking status, 2677 were current smokers, 3086 were former smokers, and 3643 were nonsmokers. Cigarette smokers had better 30-day outcomes (12.3%, 16.8%, and 15.4% for smokers, former smokers, and nonsmokers, respectively; P =.001). However, after adjusting for differences in baseline clinical variables, smoking status was not a predictor of 30-day outcome (P =.45). There was a reduction in the composite end point overall with eptifibatide compared with placebo (14.3% vs 15. 7%, P =.054) but no interaction between smoking status and treatment strategy (P =.68). CONCLUSIONS: Among patients with ACS without persistent ST-segment elevation, cigarette smokers had better short-term outcomes because of their more favorable clinical profile. Although prior studies have suggested that smokers more commonly have platelet-rich thrombi than nonsmokers, eptifibatide did not result in more improvement in their outcome compared with former smokers or nonsmokers. http://repub.eur.nl/res/pub/9233/ 2000-01-01T00:00:00Z CONTEXT: Controversy surrounds the diagnostic and prognostic importance of slightly elevated cardiac markers in patients with acute coronary syndromes without ST-segment elevation. OBJECTIVES: To investigate the relationship between peak creatine kinase (CK)-MB level and outcome and to determine whether a threshold CK-MB level exists below which risk is not increased. DESIGN AND SETTING: Retrospective observational analysis of data from the international Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, conducted from November 1995 to January 1997. PATIENTS: A total of 8250 patients with acute coronary syndromes without ST-segment elevation who had at least 1 CK-MB sample collected during their index hospitalization. MAIN OUTCOME MEASURE: Mortality at 30 days and 6 months, was assessed by category of index-hospitalization peak CK-MB level (0-1, >1-2, >2-3, >3-5, >5-10, or >10 times the upper limit of normal). Multivariable logistic regression was used to determine the independent prognostic significance of peak CK-MB level after adjustment for baseline predictors of 30-day and 6-month mortality. RESULTS: Mortality at 30 days and 6 months increased from 1.8% and 4.0%, respectively, in patients with normal peak CK-MB levels, to 3.3% and 6.2 % at peak CK-MB levels 1 to 2 times normal, to 5.1% and 7.5% at peak CK-MB levels 3 to 5 times normal, and to 8.3% and 11.0% at peak CK-MB levels greater than 10 times normal. Log-transformed peak CK-MB levels were predictive of adjusted 30-day and 6-month mortality (P<.001 for both). CONCLUSIONS: Our data show that elevation of CK-MB level is strongly related to mortality in patients with acute coronary syndromes without ST-segment elevation, and that the increased risk begins with CK-MB levels just above normal. In the appropriate clinical context, even minor CK-MB elevations should be considered indicative of myocardial infarction. http://repub.eur.nl/res/pub/9261/ 2000-01-01T00:00:00Z BACKGROUND: Platelet glycoprotein (GP) IIb/IIIa antagonists prevent the composite end point of death or myocardial infarction (MI) in patients with acute coronary syndromes. There is uncertainty about whether this effect is confined to patients who have percutaneous coronary interventions (PCIs) and whether PCIs further prevent death or MI in patients already treated with GP IIb/IIIa antagonists. METHODS AND RESULTS: PURSUIT patients were treated with the GP IIb/IIIa antagonist eptifibatide or placebo; PCIs were performed according to physician practices. In 2253 of 9641 patients (23.4%), PCI was performed by 30 days. Early (<72 hours) PCI was performed in 1228 (12.7%). In 34 placebo patients (5.5%) and 10 treated with eptifibatide (1.7%) (P=0.001), MI preceded early PCI. In patients censored for PCI across the 30-day period, there was a significant reduction in the primary composite end point in eptifibatide patients (P=0.035). Eptifibatide reduced 30-day events in patients who had early PCI (11.6% versus 16.7%, P=0.01) and in patients who did not (14.6% versus 15.6%, P=0.23). After adjustment for PCI propensity, there was no evidence that eptifibatide treatment effect differed between patients with or without early PCI (P for interaction=0.634). PCI was not associated with a reduction of the primary composite end point but was associated with a reduced (nonspecified) composite of death or Q-wave MI. This association disappeared after adjustment for propensity for early PCI. CONCLUSIONS: Eptifibatide reduced the composite rates of death or MI in PCI patients and those managed conservatively. http://repub.eur.nl/res/pub/9378/ 2000-01-01T00:00:00Z BACKGROUND: Appropriate treatment policies should include an accurate estimate of a patient's baseline risk. Risk modeling to date has been underutilized in patients with acute coronary syndromes without persistent ST-segment elevation. METHODS AND RESULTS: We analyzed the relation between baseline characteristics and the 30-day incidence of death and the composite of death or myocardial (re)infarction in 9461 patients with acute coronary syndromes without persistent ST-segment elevation enrolled in the PURSUIT trial [Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin (eptifibatide) Therapy]. Variables examined included demographics, history, hemodynamic condition, and symptom duration. Risk models were created with multivariable logistic regression and validated by bootstrapping techniques. There was a 3.6% mortality rate and 11.4% infarction rate by 30 days. More than 20 significant predictors for mortality and for the composite end point were identified. The most important baseline determinants of death were age (adjusted chi(2)=95), heart rate (chi(2)=32), systolic blood pressure (chi(2)=20), ST-segment depression (chi(2)=20), signs of heart failure (chi(2)=18), and cardiac enzymes (chi(2)=15). Determinants of mortality were generally also predictive of death or myocardial (re)infarction. Differences were observed, however, in the relative prognostic importance of predictive variables for mortality alone or the composite end point; for example, sex was a more important determinant of the composite end point (chi(2)=21) than of death alone (chi(2)=10). The accuracy of the prediction of the composite end point was less than that of mortality (C-index 0.67 versus 0.81). CONCLUSIONS: The occurrence of adverse events after presentation with acute coronary syndromes is affected by multiple factors. These factors should be considered in the clinical decision-making process. http://repub.eur.nl/res/pub/9448/ 2000-01-01T00:00:00Z BACKGROUND: A multinational, randomized, placebo-controlled trial (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy, PURSUIT) demonstrated that the platelet glycoprotein IIb/IIIa receptor antagonist eptifibatide reduced the incidence of death or myocardial infarction among patients with acute ischemic syndromes without ST-segment elevation. Because of expected differences in practice patterns, a prospectively planned analysis of outcomes as a function of regions of the world was performed. The current study provides a detailed assessment of eptifibatide among the subgroup of patients enrolled within the United States. METHODS AND RESULTS: Patients presenting with chest pain within the previous 24 hours and ischemic ECG changes or creatine kinase-MB elevation were eligible for enrollment. Of the 10 948 patients randomized worldwide, 4035 were enrolled within the United States. Patients were allocated to placebo or eptifibatide infusion for up to 72 to 96 hours. Other medical therapies and revascularization strategies were at the discretion of the treating physician. Eptifibatide reduced the rate of the primary end point of death or myocardial infarction by 30 days from 15.4% to 11.9% (P=0.003) among patients in the United States. The treatment effect was achieved early and maintained over a period of 6 months (18.9% versus 15.2%; P=0.004). Bleeding events were more common in patients receiving eptifibatide but were predominantly associated with invasive procedures. The magnitude of clinical benefit from eptifibatide was greater among patients in the United States than elsewhere in the world. CONCLUSIONS: Platelet glycoprotein IIb/IIIa receptor blockade with eptifibatide reduces the incidence of death or myocardial infarction among patients treated for acute ischemic syndromes without ST-segment elevation within the United States. http://repub.eur.nl/res/pub/9449/ 2000-01-01T00:00:00Z BACKGROUND: A proportion of patients who present with suspected acute coronary syndrome (ACS) are found to have insignificant coronary artery disease (CAD) during coronary angiography, but these patients have not been well characterized. METHODS AND RESULTS: Of the 5767 patients with non-ST-segment elevation ACS who were enrolled in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin (Eptifibatide) Therapy (PURSUIT) trial and who underwent in-hospital angiography, 88% had significant CAD (any stenosis >50%), 6% had mild CAD (any stenosis >0% to </=50%), and 6% had no CAD (no stenosis identified). The frequency of death or nonfatal myocardial infarction at 30 days was reduced with eptifibatide treatment in patients with significant CAD (18.3% versus 15.6% for placebo, P=0.006) but not in those with mild CAD (6.6% versus 5.4%, P=0.62) and with no CAD (3.0% versus 1. 2%, P=0.28). We identified independent baseline predictors of insignificant CAD (mild or no CAD) and used them to develop a simple predictive nomogram of the probability of insignificant CAD for use at hospital presentation. This nomogram was validated in a separate population of patients with non-ST-segment elevation ACS. CONCLUSIONS: Patients with suspected ACS found to have insignificant CAD have a low risk of adverse outcomes, do not appear to benefit from treatment with eptifibatide, and can be predicted with a simple nomogram drawn from baseline characteristics. Because patients with significant CAD appear to have an enhanced benefit from eptifibatide treatment, the predictive nomogram developed can be used to determine indications for glycoprotein IIb/IIIa blockade. http://repub.eur.nl/res/pub/5597/ 1999-08-01T00:00:00Z AIMS: Studies on the glycoprotein IIb-IIIa receptor blocker abciximab in patients undergoing percutaneous coronary intervention consistently show a reduction in procedure-related myocardial infarction. Some such infarcts are characterized by elevated creatine kinase or creatine kinase-MB, without apparent clinical symptoms. The clinical relevance of such 'creatine kinase leaks' has been questioned. Therefore we investigated the relationship between post-procedural creatine kinase-MB elevation and outcome at the 6 month follow-up. METHODS AND RESULTS: Creatine kinase-MB, or total creatine kinase values were analysed in 5025 out of 6156 patients enrolled in the CAPTURE, EPIC and EPILOG studies. A consistent gradual increase in 6 month mortality was observed as creatine kinase-MB or creatine kinase levels increased: 1.1%, 2.1%, 1.8%, 3. 6% and 6.7% for creatine-MB or creatine ratios (relative to upper limit of normal) <1, 1-3, 3-5, 5-10 and >/=10, respectively. Also the incidence of death or (recurrent) myocardial infarction was related to creatine kinase-MB or creatine kinase ratios. Subsequent revascularization was not related to periprocedural myocardial infarction. By multivariable analysis, correcting for clinical and angiographic characteristics, mortality at 6 months was related to the enzyme (creatine kinase, creatine kinase-MB) ratio, a history of heart failure and age. The combined end-point of death and myocardial infarction was also related to these factors, as well as to a history of bypass surgery and unstable angina. CONCLUSION: Modest elevation of cardiac enzymes (creatine kinase-MB, creatine kinase) after percutaneous coronary intervention is associated with an increased risk of mortality and reinfarction during the 6 month follow-up. Measures to reduce such periprocedural infarcts are warranted. http://repub.eur.nl/res/pub/5656/ 1999-01-01T00:00:00Z BACKGROUND: The significance of thrombocytopenia in patients experiencing an acute coronary syndrome (ACS) has not been examined systematically. We evaluated this condition in a large non-ST-elevation ACS clinical trial, with particular interest paid to its correlation with clinical outcomes. METHODS AND RESULTS: Patients presenting without persistent ST elevation during an ACS were randomized to receive a double-blind infusion of the platelet glycoprotein (GP) IIb/IIIa inhibitor eptifibatide or placebo in addition to other standard therapies including heparin and aspirin. The primary end point was death/nonfatal myocardial infarction (MI) at 30 days, whereas bleeding and stroke were the main safety outcomes. Thrombocytopenia (nadir platelet count <100x10(9)/L or <50% of baseline) occurred in 7.0% of enrolled patients. The time to onset was a median of 4 days in both treatment arms. Patients with thrombocytopenia were older, weighed less, were more likely nonwhite, and had more cardiac risk factors. These patients experienced significantly more bleeding events: they were more than twice as likely to experience moderate/severe bleeding after adjustment for confounders. Univariably, ischemic events (stroke, MI, and death) occurred significantly (P<0.001) more frequently in patients with thrombocytopenia; multivariable regression modeling preserved this association with death/nonfatal MI at 30 days. Neither the use of heparin or eptifibatide was found to independently increase thrombocytopenic risk. CONCLUSIONS: Although causality between thrombocytopenia and adverse clinical events could not be established definitively, thrombocytopenia was highly correlated with both bleeding and ischemic events, and the presence of this condition identified a more-at-risk patient population. 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/9090/ 1999-01-01T00:00:00Z BACKGROUND: The incidence of stroke in patients with acute coronary syndromes has not been clearly defined because few trials in this patient population have been large enough to provide stable estimates of stroke rates. METHODS AND RESULTS: We studied the 10 948 patients with acute coronary syndromes without persistent ST-segment elevation who were randomly assigned to placebo or the platelet glycoprotein IIb/IIIa receptor inhibitor eptifibatide in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial to determine stroke rates, stroke types, clinical outcomes in patients with stroke, and independent baseline clinical predictors for nonhemorrhagic stroke. Stroke occurred in 79 (0.7%) patients, with 66 (0.6%) nonhemorrhagic, 6 intracranial hemorrhages, 3 cerebral infarctions with hemorrhagic conversion, and 4 of uncertain cause. There were no differences in stroke rates between patients who received placebo and those assigned high-dose eptifibatide (odds ratios and 95% confidence intervals 0.82 [0.59, 1.14] and 0.70 [0.49, 0.99], respectively). Of the 79 patients with stroke, 17 (22%) died within 30 days, and another 26 (32%) were disabled by hospital discharge or 30 days, whichever came first. Higher heart rate was the most important baseline clinical predictor of nonhemorrhagic stroke, followed by older age, prior anterior myocardial infarction, prior stroke or transient ischemic attack, and diabetes mellitus. These factors were used to develop a simple scoring nomogram that can predict the risk of nonhemorrhagic stroke. CONCLUSIONS: Stroke was an uncommon event in patients with acute coronary syndromes in the PURSUIT trial. These strokes are, however, associated with substantial morbidity and mortality rates. The majority of strokes were of nonhemorrhagic causes. Eptifibatide was not associated with an increase in intracranial hemorrhage, and no significant effect on nonhemorrhagic stroke was observed. We developed a useful nomogram for assigning baseline nonhemorrhagic stroke risk in this patient population. http://repub.eur.nl/res/pub/9193/ 1999-01-01T00:00:00Z BACKGROUND: Glycoprotein (GP) IIb/IIIa receptor blockers prevent life-threatening cardiac complications in patients with acute coronary syndromes without ST-segment elevation and protect against thrombotic complications associated with percutaneous coronary interventions (PCIs). The question arises as to whether these 2 beneficial effects are independent and additive. METHODS AND RESULTS: We analyzed data from the CAPTURE, PURSUIT, and PRISM-PLUS randomized trials, which studied the effects of the GP IIb/IIIa inhibitors abciximab, eptifibatide, and tirofiban, respectively, in acute coronary syndrome patients without persistent ST-segment elevation, with a period of study drug infusion before a possible PCI. During the period of pharmacological treatment, each trial demonstrated a significant reduction in the rate of death or nonfatal myocardial infarction in patients randomized to the GP IIb/IIIa inhibitor compared with placebo. The 3 trials combined showed a 2.5% event rate in this period in the GP IIb/IIIa inhibitor group (N=6125) versus 3.8% in placebo (N=6171), which implies a 34% relative reduction (P<0.001). During study medication, a PCI was performed in 1358 patients assigned GP IIb/IIIa inhibition and 1396 placebo patients. The event rate during the first 48 hours after PCI was also significantly lower in the GP IIb/IIIa inhibitor group (4. 9% versus 8.0%; 41% reduction; P<0.001). No further benefit or rebound effect was observed beyond 48 hours after the PCI. CONCLUSIONS: There is conclusive evidence of an early benefit of GP IIb/IIIa inhibitors during medical treatment in patients with acute coronary syndromes without persistent ST-segment elevation. In addition, in patients subsequently undergoing PCI, GP IIb/IIIa inhibition protects against myocardial damage associated with the intervention. http://repub.eur.nl/res/pub/5562/ 1998-01-01T00:00:00Z Background—Reperfusion therapy for myocardial infarction, understood to reduce mortality by preserving left ventricular function, was initially expected to provide increasing benefits over time. Surprisingly, large controlled thrombolysis trials demonstrated maximum benefit at 4 to 6 weeks with no subsequent increased treatment advantage. Such studies, however, compared groups by assigned treatment, not physiological effectiveness. Methods and Results—We calculated 2-year survival differences among 2431 myocardial infarction patients according to early infarct artery patency and outcome left ventricular ejection fraction using Kaplan-Meier curves. Hazard ratios for significant survival determinants were derived from Cox regression models. Two-year vital status (minimum, 688 days) was determined in 2375 patients (97.7%). A substantial mortality advantage for early complete reperfusion (Thrombolysis in Myocardial Infarction [TIMI] grade 3) and for preserved ejection fraction occurred beyond 30 days. The unadjusted hazard ratio for the TIMI 3 group compared with lesser grades at 30 days was 0.57 (95% confidence interval [CI], 0.35 to 0.94) and 30 days to 688 days was 0.39 (95% CI, 0.22 to 0.69). Consequently, early TIMI 3 flow was associated with approximately a 3 patient per 100 mortality reduction the first month with an additional 5 lives per 100 from 30 days to 2 years. For ejection fraction >40% compared with 40%, the unadjusted hazard ratio was 0.25 (95% CI, 0.16 to 0.37) at 30 days and 0.22 (95% CI, 0.15 to 0.33) after 30 days through 2 years (lives saved, 9 and 11 per 100, respectively). Conclusions—Successful reperfusion and myocardial salvage produce significant mortality benefits that are amplified beyond the initial 30 days. http://repub.eur.nl/res/pub/5747/ 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/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/8784/ 1998-01-01T00:00:00Z BACKGROUND: Although the stratification of patients with myocardial infarction into ECG subsets based on the presence or absence of new Q waves has important clinical and prognostic utility, systematic evaluation of the impact of thrombolytic therapy on the subsequent development and prognosis of non-Q-wave infarction has been limited to date. METHODS AND RESULTS: We examined 12-lead ECG, coronary anatomy, left ventricular function, and mortality among 2046 patients with ST-segment elevation infarction from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries angiographic subset to gain further insight into the pathophysiology and prognosis of Q- versus non-Q-wave infarction in the thrombolytic era. Non-Q-wave infarction developed in 409 patients (20%) after thrombolytic therapy. Compared with Q-wave patients, non-Q-wave patients were more likely to present with lesser ST-segment elevation in a nonanterior location. The infarct-related artery in non-Q-wave patients was more likely to be nonanterior (67% versus 58%, P=.012) and distally located (33% versus 39%, P=.021). Early (90-minute, 77% versus 65%, P=.001) and complete (54% versus 44%, P<.001) infarct-related artery patency was greater among the non-Q-wave group. Non-Q-wave patients had better global (ejection fraction, 66% versus 57%; P<.0001) and regional left ventricular function (10 versus 24 abnormal chords, P=.0001). In-hospital, 30-day, 1-year, and 2-year (6.3% versus 10.1%, P=.02) mortality rates were lower among non-Q-wave patients. CONCLUSIONS: The excellent prognosis among the subgroup of patients who develop non-Q-wave infarction after thrombolysis is related to early, complete, and sustained infarct-related artery patency with resultant limitation of left ventricular infarction and dysfunction. 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/5553/ 1997-01-01T00:00:00Z BACKGROUND: Although the benefit of thrombolytic therapy in reducing mortality in acute myocardial infarction is well established, the types of bleeding and risk factors for bleeding are less well described in large trials. METHODS AND RESULTS: We analyzed the baseline characteristics, outcomes, and incidence of bleeding by location, severity, and treatment assignment among 41,021 patients in the GUSTO-I trial of thrombolysis for acute myocardial infarction. Of the 40,903 patients for whom there were complete data, 1.2% suffered severe bleeding and 11.4% experienced moderate hemorrhage at a variety of sites. The most common sources of bleeding were procedure related. The thrombolytic regimen was strongly related to the incidence of bleeding; comparatively more bleeding was seen with the therapies of streptokinase plus intravenous heparin and the streptokinase and tissue plasminogen activator plus intravenous heparin combination. In multivariate analysis, the four most powerful independent predictors of hemorrhage were older age, lighter body weight, female sex, and African ancestry; they remained the most important predictors of bleeding when multivariate analysis was performed on patients who did not undergo invasive procedures. The presence of serious hemorrhage was associated with other undesirable outcomes (recurrent events, left ventricular dysfunction, arrhythmia, or stroke). CONCLUSIONS: Important predictors of bleeding in this population are increased age, lighter weight, female sex, African ancestry, and experiencing invasive procedures. Other nonhemorrhagic adverse clinical outcomes were associated with moderate and severe bleeding, which was in turn associated with increased length of hospital stay and mortality at 30 days. http://repub.eur.nl/res/pub/5525/ 1996-06-01T00:00:00Z OBJECTIVES: This study sought to examine the relations among patient characteristics, time to thrombolysis and outcomes in the international GUSTO-I trial. BACKGROUND: Studies have shown better left ventricular function and decreased infarct size as well as increased survival with earlier thrombolysis, but the relative benefits of various thrombolytic agents with earlier administration are uncertain. METHODS: We evaluated the relations of baseline characteristics to three prospectively defined time variables: symptom onset to treatment, symptom onset to hospital arrival (presentation delay) and hospital arrival to treatment (treatment delay). We also examined the relations of delays to clinical outcomes and to the relative 30-day mortality benefit with accelerated tissue-type plasminogen activator (t-PA) versus streptokinase. RESULTS: Female, elderly, diabetic and hypertensive patients had longer delays at all stages. Previous infarction or bypass surgery was an additional risk factor for treatment delay. Early thrombolysis was associated with lower overall mortality rate (< 2 h, 5.5%; > 4 h, 9.0%), but no additional relative benefit resulted from earlier treatment with accelerated t-PA versus streptokinase (p = 0.38). Longer presentation and treatment delays were both associated with increased mortality rate (presentation delay < 1 h, 5.6% and > 4 h, 8.6%; treatment delay < 1 h, 5.4%, and > 90 min, 8.1%). As time to treatment increased, the incidence of recurrent ischemia or reinfarction decreased, but the rates of shock, heart failure and stroke increased. CONCLUSIONS: Earlier treatment resulted in better outcomes, regardless of thrombolytic strategy. Elderly, female and diabetic patients were treated later, adding to their already substantial risk. http://repub.eur.nl/res/pub/5537/ 1996-01-01T00:00:00Z OBJECTIVES: This study sought to determine whether diabetes mellitus, in the setting of thrombolysis for acute myocardial infarction, affects 1) early infarct-related artery patency and reocclusion rates; and 2) global and regional ventricular function indexes. We also sought to assess whether angiographic or baseline clinical variables, or both, can account for the known excess mortality after myocardial infarction in the diabetic population. BACKGROUND: Mortality after acute myocardial infarction in patients with diabetes is approximately twice that of nondiabetic patients. It is uncertain whether this difference in mortality is due to a lower rate of successful thrombolysis, increased reocclusion after successful thrombolysis, greater ventricular injury or a more adverse angiographic or clinical profile in diabetic patients. METHODS: Patency rates and global and regional left ventricular function were determined in patients enrolled in the GUSTO-I Angiographic Trial. Thirty-day mortality differences between those with and without diabetes were compared. RESULTS: The diabetic cohort had a significantly higher proportion of female and elderly patients, and they were more often hypertensive, came to the hospital later and had more congestive heart failure and a higher number of previous myocardial infarctions and bypass surgery procedures. Ninety-minute patency (Thrombolysis in Myocardial Infarction [TIMI] flow grade 3) rates in patients with and without diabetes were 40.3% and 37.6%, respectively (p = 0.7). Reocclusion rates were 9.2% vs. 5.3% (p = 0.17). Ejection fraction at 90 min after thrombolysis was similar in diabetic and nondiabetic patients ([mean +/- SEM] 6.10 +/- 1.6% vs. 60.1 +/- 0.7%, p = 0.7), as was regional ventricular function (number of abnormal chords: 19.1 +/- 2.0 vs. 17.5 +/- 0.8, p = 0.3; SD/chord: -2.3 +/- 0.2 vs. -2.4 +/- 0.1, p = 0.6). Diabetic patients had less compensatory hyperkinesia in the noninfarct zone (SD/ chord: 1.3 +/- 0.2 vs. 1.7 +/- 0.1, p < or = 0.01). No significant difference in ventricular function was noted at 5- to 7-day follow-up. The 30-day mortality rate was 11.3% in diabetic versus 5.9% in nondiabetic patients (p < or = 0.0001). After adjustment for clinical and angiographic variables, diabetes remained an independent determinant of 30-day mortality (p = 0.02). CONCLUSIONS: Early (90-min) infarct-related artery patency as well as regional and global ventricular function do not differ between patients with and without diabetes after thrombolytic therapy, except for reduced compensatory hyperkinesia in the noninfarct zone among patients with diabetes. Diabetes remained an independent determinant of 30-day mortality after correction for clinical and angiographic variables. 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/5495/ 1995-01-01T00:00:00Z BACKGROUND: Despite remarkable advances in the treatment of acute myocardial infarction, substantial early patient mortality remains. Appropriate choices among alternative therapies and the use of clinical resources depend on an estimate of the patient's risk. Individual patients reflect a combination of clinical features that influence prognosis, and these factors must be appropriately weighted to produce an accurate assessment of risk. Prior studies to define prognosis either were performed before widespread use of thrombolysis or were limited in sample size or spectrum of data. Using the large population of the GUSTO-I trial, we performed a comprehensive analysis of relations between baseline clinical data and 30-day mortality and developed a multivariable statistical model for risk assessment in candidates for thrombolytic therapy. METHODS AND RESULTS: For the 41,021 patients enrolled in GUSTO-I, a randomized trial of four thrombolytic strategies, relations between clinical descriptors routinely collected at initial presentation, and death within 30 days (which occurred in 7% of the population) were examined with both univariable and multivariable analyses. Variables studied included demographics, history and risk factors, presenting characteristics, and treatment assignment. Risk modeling was performed with logistic multiple regression and validated with bootstrapping techniques. Multivariable analysis identified age as the most significant factor influencing 30-day mortality, with rates of 1.1% in the youngest decile (< 45 years) and 20.5% in patients > 75 (adjusted chi 2 = 717, P < .0001). Other factors most significantly associated with increased mortality were lower systolic blood pressure (chi 2 = 550, P < .0001), higher Killip class (chi 2 = 350, P < .0001), elevated heart rate (chi 2 = 275, P < .0001), and anterior infarction (chi 2 = 143, P < .0001). Together, these five characteristics contained 90% of the prognostic information in the baseline clinical data. Other significant though less important factors included previous myocardial infarction, height, time to treatment, diabetes, weight, smoking status, type of thrombolytic, previous bypass surgery, hypertension, and prior cerebrovascular disease. Combining prognostic variables through logistic regression, we produced a validated model that stratified patient risk and accurately estimated the likelihood of death. CONCLUSIONS: The clinical determinants of mortality in patients treated with thrombolytic therapy within 6 hours of symptom onset are multifactorial and the relations complex. Although a few variables contain most of the prognostic information, many others contribute additional independent prognostic information. Through consideration of multiple characteristics, including age, medical history, physiological significance of the infarction, and medical treatment, the prognosis of an individual patient can be accurately estimated. 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/4519/ 1993-01-01T00:00:00Z BACKGROUND. Directional coronary atherectomy is a new technique of coronary revascularization by which atherosclerotic plaque is excised and retrieved from target lesions. With respect to the rate of restenosis and clinical outcomes, it is not known how this procedure compares with balloon angioplasty, which relies on dilation of the plaque and vessel wall. We compared the rate of restenosis after angioplasty with that after atherectomy. METHODS. At 35 sites in the United States and Europe, 1012 patients were randomly assigned to either atherectomy (512 patients) or angioplasty (500 patients). The patients underwent coronary angiography at base line and again after six months; the paired angiograms were quantitatively assessed at one laboratory by investigators unaware of the treatment assignments. RESULTS. Stenosis was reduced to 50 percent or less more often with atherectomy than with angioplasty (89 percent vs. 80 percent; P < 0.001), and there was a greater immediate increase in vessel caliber (1.05 vs. 0.86 mm, P < 0.001). This was accompanied by a higher rate of early complications (11 percent vs. 5 percent, P < 0.001) and higher in-hospital costs ($11,904 vs $10,637; P = 0.006). At six months, the rate of restenosis was 50 percent for atherectomy and 57 percent for angioplasty (P = 0.06). However, the probability of death or myocardial infarction within six months was higher in the atherectomy group (8.6 percent vs. 4.6 percent, P = 0.007). CONCLUSIONS. Removing coronary artery plaque with atherectomy led to a larger luminal diameter and a small reduction in angiographic restenosis, the latter being confined largely to the proximal left anterior descending coronary artery. However, atherectomy led to a higher rate of early complications, increased cost, and no apparent clinical benefit after six months of follow-up. http://repub.eur.nl/res/pub/5468/ 1993-01-01T00:00:00Z BACKGROUND: The relative efficacy of streptokinase and tissue plasminogen activator and the roles of intravenous as compared with subcutaneous heparin as adjunctive therapy in acute myocardial infarction are unresolved questions. The current trial was designed to compare new, aggressive thrombolytic strategies with standard thrombolytic regimens in the treatment of acute myocardial infarction. Our hypothesis was that newer thrombolytic strategies that produce earlier and sustained reperfusion would improve survival. METHODS: In 15 countries and 1081 hospitals, 41,021 patients with evolving myocardial infarction were randomly assigned to four different thrombolytic strategies, consisting of the use of streptokinase and subcutaneous heparin, streptokinase and intravenous heparin, accelerated tissue plasminogen activator (t-PA) and intravenous heparin, or a combination of streptokinase plus t-PA with intravenous heparin. ("Accelerated" refers to the administration of t-PA over a period of 1 1/2 hours--with two thirds of the dose given in the first 30 minutes--rather than the conventional period of 3 hours.) The primary end point was 30-day mortality. RESULTS: The mortality rates in the four treatment groups were as follows: streptokinase and subcutaneous heparin, 7.2 percent; streptokinase and intravenous heparin, 7.4 percent; accelerated t-PA and intravenous heparin, 6.3 percent, and the combination of both thrombolytic agents with intravenous heparin, 7.0 percent. This represented a 14 percent reduction (95 percent confidence interval, 5.9 to 21.3 percent) in mortality for accelerated t-PA as compared with the two streptokinase-only strategies (P = 0.001). The rates of hemorrhagic stroke were 0.49 percent, 0.54 percent, 0.72 percent, and 0.94 percent in the four groups, respectively, which represented a significant excess of hemorrhagic strokes for accelerated t-PA (P = 0.03) and for the combination strategy (P < 0.001), as compared with streptokinase only. A combined end point of death or disabling stroke was significantly lower in the accelerated-tPA group than in the streptokinase-only groups (6.9 percent vs. 7.8 percent, P = 0.006). CONCLUSIONS: The findings of this large-scale trial indicate that accelerated t-PA given with intravenous heparin provides a survival benefit over previous standard thrombolytic regimens 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.