Physical activity as a determinant of fasting and 2-h post-challenge glucose: a prospective cohort analysis of the NAVIGATOR trial.

AIM: To investigate whether previous physical activity levels are associated with blood glucose levels in individuals with impaired glucose tolerance in the context of an international pharmaceutical trial. METHODS: Data were analysed from the NAVIGATOR trial, which involved 9306 individuals with impaired glucose tolerance and high cardiovascular risk from 40 different countries, recruited in the period 2002-2004. Fasting glucose, 2-h post-challenge glucose and physical activity (pedometer) were assessed annually. A longitudinal regression analysis was used to determine whether physical activity levels 2 years (t-2 ) and 1 year (t-1 ) previously were associated with levels of glucose, after adjusting for previous glucose levels and other patient characteristics. Those participants with four consecutive annual measures of glucose and two consecutive measures of physical activity were included in the analysis. RESULTS: The analysis included 3964 individuals. Change in physical activity from t-2 to t-1 and activity levels at t-2 were both associated with 2-h glucose levels after adjustment for previous glucose levels and baseline characteristics; however, the associations were weak: a 100% increase in physical activity was associated with a 0.9% reduction in 2-h glucose levels. In addition, previous physical activity only explained an additional 0.05% of the variance in 2-h glucose over the variance explained by the history of 2-h glucose alone (R(2)  = 0.3473 vs. 0.3468). There was no association with fasting glucose. CONCLUSIONS: In the context of a large international clinical trial, previous physical activity levels did not meaningfully influence glucose levels in those with a high risk of chronic disease, after taking into account participants' previous trajectory of glucose control.

Regional, age and sex differences in baseline characteristics of patients enrolled in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS).

AIMS: To report baseline characteristics and cardiovascular (CV) risk management by region, age, sex and CV event type for 14 724 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a randomized, double-blind, placebo-controlled trial exploring whether sitagliptin added to usual type 2 diabetes (T2DM) care affects time to first event in the composite endpoint of CV death, non-fatal myocardial infarction (MI), non-fatal stroke or unstable angina hospitalization. METHODS: TECOS enrolled patients aged ≥50 years, with T2DM and CV disease from 38 countries in five regions: North America, Eastern Europe, Western Europe, Asia Pacific and Latin America. Participants had a glycated haemoglobin concentration of 6.5-8.0% (48-64 mmol/mol) and were receiving oral and/or insulin-based antihyperglycaemic therapy. Analysis of variance or logistic regression was used to compare regional CV risk factors and treatments, referenced to North America. RESULTS: Patients had a mean [1 standard deviation (SD)] age of 66 (8) years, a median (interquartile range) diabetes duration of 9.4 (4.9, 15.3) years, and a mean (SD) body mass index 30.2 (5.7) kg/m² . Compared with North America, blood pressure and lipids were higher in all regions. Statin use was lowest in Latin America (68%) and Eastern Europe (70%) and aspirin use was lower compared with North America in all regions except Asia Pacific. Achievement of treatment targets did not differ by age group or insulin usage, but men and participants with previous MI were more likely than women or those with previous stroke or peripheral arterial disease to reach most treatment goals. CONCLUSION: The CV risk factors of participants in TECOS are reasonably controlled, but differences in CV risk management according to region, sex and history of disease exist. This diversity will enhance the generalizability of the trial results.

Change in levels of physical activity after diagnosis of type 2 diabetes: an observational analysis from the NAVIGATOR study.

Increased physical activity is known to be beneficial in people with type 2 diabetes mellitus (T2DM), but it is not known whether individuals change their activity levels after T2DM diagnosis. The present Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, conducted in participants with impaired glucose tolerance at high cardiovascular risk, assessed ambulatory activity annually using research-grade pedometers. Oral glucose tolerance tests were performed annually and repeated to confirm T2DM diagnosis. This observational analysis used general linear models to compare step counts before and after T2DM diagnosis in the 2816 participants with the requisite data. Participants were relatively inactive at baseline, taking a median (interquartile range) of 5488 (3258-8361) steps/day, which decreased after T2DM diagnosis by a mean (s.e.) of 258 (64) steps/day (p < 0.0001); however, after adjusting for background trend for activity, step count after T2DM diagnosis was unchanged [mean (s.e.) of 103 (87) fewer steps/day; p = 0.23]. Awareness of T2DM diagnosis had no impact on the trajectory of activity established before the diagnosis.

Digitizing clinical trials.

Clinical trials are a fundamental tool used to evaluate the efficacy and safety of new drugs and medical devices and other health system interventions. The traditional clinical trials system acts as a quality funnel for the development and implementation of new drugs, devices and health system interventions. The concept of a "digital clinical trial" involves leveraging digital technology to improve participant access, engagement, trial-related measurements, and/or interventions, enable concealed randomized intervention allocation, and has the potential to transform clinical trials and to lower their cost. In April 2019, the US National Institutes of Health (NIH) and the National Science Foundation (NSF) held a workshop bringing together experts in clinical trials, digital technology, and digital analytics to discuss strategies to implement the use of digital technologies in clinical trials while considering potential challenges. This position paper builds on this workshop to describe the current state of the art for digital clinical trials including (1) defining and outlining the composition and elements of digital trials; (2) describing recruitment and retention using digital technology; (3) outlining data collection elements including mobile health, wearable technologies, application programming interfaces (APIs), digital transmission of data, and consideration of regulatory oversight and guidance for data security, privacy, and remotely provided informed consent; (4) elucidating digital analytics and data science approaches leveraging artificial intelligence and machine learning algorithms; and (5) setting future priorities and strategies that should be addressed to successfully harness digital methods and the myriad benefits of such technologies for clinical research.

Metabolic syndrome and alanine aminotransferase: a global perspective from the NAVIGATOR screening population.

AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with features of the metabolic syndrome (MetS) and may be an expression of the syndrome within the liver. Using screening data from the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study (n = 42 149), we examined whether alanine aminotransferase (ALT), a biomarker for NAFLD, clustered with features of MetS and whether the clusters differed across global geographic regions. METHODS: Exploratory factor analysis using principle components analysis was applied to data drawn from the NAVIGATOR screening population (n = 41 111). Demographic data, anthropomorphic measurements and blood pressure (BP) collected during the screening visit, as well as blood samples analysed for ALT, total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, and fasting and 2-h glucose measures after an oral glucose tolerance test were used for our analysis. RESULTS: Two factors, interpreted as lipid (Factor 1), and BP/obesity (Factor 2) were identified, explaining approximately 50% of the variance in the overall population. Similar patterns of aggregation were reproducible across all geographic regions except Asia, where fasting glucose loaded more consistently on Factor 1. ALT loaded with mean arterial pressure, fasting glucose and waist circumference except in Asia, where it loaded only with mean arterial pressure and waist circumference. CONCLUSIONS: ALT aggregated with components of MetS, and the pattern of aggregation of ALT with other features of MetS was similar across regions except Asia, possibly indicating a different pathophysiology for NAFLD in Asia. Predictive models of NAFLD may need to be adjusted for regional and ethnic differences.

Role of the centers for education and research on therapeutics (CERTs) in pharmacovigilance and proper use of therapeutics.

According to the Institute of Medicine (IOM) Committee on the Assessment of the U.S. Drug Safety System, "The recent highly publicized controversies surrounding the safety of some drugs have contributed to a public perception that the drug safety system is in crisis. It seems fair to say that this perception has created an opportunity for a thorough evaluation of the U.S. drug safety system." The evaluation was focused on the U.S. Food and Drug Administration (FDA). To improve the FDA and its function in the public health system to improve therapeutics, it is critical to understand the contributions of other components.

Platelet glycoprotein IIb/IIIa receptor inhibition in non-ST-elevation acute coronary syndromes: early benefit during medical treatment only, with additional protection during percutaneous coronary intervention.

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.

Canadian-American differences in the management of acute coronary syndromes in the GUSTO IIb trial: one-year follow-up of patients without ST-segment elevation. Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) II Investigators.

BACKGROUND: Little information exists concerning practice patterns between Canada and the United States in the management of myocardial infarction (MI) patients without ST-segment elevation and unstable angina. METHODS AND RESULTS: We examined the practice patterns and 1-year outcomes of 2250 US and 922 Canadian patients without ST-elevation acute coronary syndromes in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb trial. The US hospitals more commonly had on-site facilities for angiography and revascularization. These procedures were performed more often and sooner in the United States than Canada, whereas Canadian patients were more likely to undergo noninvasive stress testing. The length of initial hospital stay was 1 day longer for Canadian than US patients. Recurrent and refractory ischemia was more common in Canada. One-year mortality was comparable between the 2 countries. However, at 6 months, even after baseline differences were accounted for, the (re)MI rate was significantly higher in Canadian than US patients with unstable angina (8.8% versus 5.8%, P:=0.039), as was the composite rate of death or (re)MI (13.1% versus 9.1%, P:=0.016). CONCLUSIONS: One-year mortality was comparable between Canada and the United States in both MI and unstable angina cohorts despite higher intervention rates in the United States. However, outcomes at 6 months among patients with unstable angina differed. Whereas more frequent coronary interventions were not associated with reduced recurrent MI or death among MI patients without ST elevation, they may favorably affect outcomes in patients with unstable angina.

Prediction of 1-year survival after thrombolysis for acute myocardial infarction in the global utilization of streptokinase and TPA for occluded coronary arteries trial.

BACKGROUND: When a patient survives thrombolysis for acute myocardial infarction, little information from large studies exists from which to estimate prognosis during follow-up visits. METHODS AND RESULTS: Baseline, in-hospital, and later survival data were collected from 41 021 patients enrolled in Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries, a randomized trial of 4 thrombolytic-heparin regimens with standard aspirin and beta-blockade. Cox proportional hazards models were developed to predict 1-year survival in 30-day survivors (n=37 869) from baseline clinical and ECG factors and in-hospital factors; a combined model then was developed (C-index 0.800). The model was simplified into a nomogram to predict individual outcomes (C-index 0.754). Factors reflecting demographics (advanced age, lighter weight), larger infarctions (higher Killip class, lower blood pressure, faster heart rate, longer QRS duration), cardiac risk (smoking, hypertension, prior cerebrovascular disease), and arrhythmia were important predictors of death between 30 days and 1 year. Black race was associated with a substantial increase in risk after considering other factors. Revascularization was associated with reduced risk between 30 days and 1 year. CONCLUSIONS: When evaluating a patient who has survived acute infarction treated with thrombolysis, clinicians can estimate the likelihood of survival from factors easily measured during admission. Although many risk factors clearly relate to age, left ventricular dysfunction, or clinical instability, black race is an unexplained risk factor requiring further examination.

Relationship between delay in performing direct coronary angioplasty and early clinical outcome in patients with acute myocardial infarction: results from the global use of strategies to open occluded arteries in Acute Coronary Syndromes (GUSTO-IIb) trial.

BACKGROUND: Time to treatment with thrombolytic therapy is a critical determinant of mortality in acute myocardial infarction. Little is known about the relationship between the time to treatment with direct coronary angioplasty and clinical outcome. The objectives of this study were to determine both the time required to perform direct coronary angioplasty in the Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-IIb) trial and its relationship to clinical outcome. METHODS AND RESULTS: Patients randomized to direct coronary angioplasty (n=565) were divided into groups based on the time between study enrollment and first balloon inflation. Patients randomized to angioplasty who did not undergo the procedure were also analyzed. The median time from study enrollment to first balloon inflation was 76 minutes; 19% of patients assigned to angioplasty did not undergo an angioplasty procedure. The 30-day mortality rate of patients who underwent balloon inflation /=91 minutes after enrollment, 6.4%. The mortality rate of patients assigned to angioplasty who never underwent the procedure was 14.1% (P=0.001). Logistic regression analysis revealed that the time from enrollment to first balloon inflation was a significant predictor of mortality within 30 days; after adjustment for differences in baseline characteristics, the odds of death increased 1.6 times (P=0.008) for a movement from each time interval to the next. CONCLUSIONS: The time to treatment with direct PTCA, as with thrombolytic therapy, is a critical determinant of mortality.

Clinical outcomes of bivalirudin for ischemic heart disease.

BACKGROUND: Current treatment strategies for percutaneous coronary revascularization and acute coronary syndromes incorporate thrombin inhibition with either unfractionated or fractionated heparin. The peptide bivalirudin (Hirulog) is a direct thrombin inhibitor whose pharmacological properties differ from those of heparin. We conducted a systematic overview (meta-analysis) to assess the effect of bivalirudin on 4 end points: death, myocardial infarction, major hemorrhage, and the composite of death or infarction. METHODS AND RESULTS: Six trials (5674 patients) represent the randomized, controlled bivalirudin experience, including 4603 patients undergoing elective percutaneous coronary revascularization and 1071 patients with acute coronary syndromes. ORs for the 4 clinical end points were calculated for each trial. Four trials (4973 patients) that compared bivalirudin with heparin were combined with the use of a random-effects model. In these trials, bivalirudin was associated with a significant reduction in the composite of death or infarction (OR 0.73, 95% CI 0.57 to 0.95; P=0.02) at 30 to 50 days, or 14 fewer events per 1000 patients so treated. There also was a significant reduction in major hemorrhage for the same trials (OR 0.41, 95% CI 0. 32 to 0.52; P<0.001, or 58 fewer events per 1000 patients so treated). A similar analysis combined 2 dose-ranging trials (701 patients) that compared therapeutic (activated partial thromboplastin time more than twice the control time) with subtherapeutic bivalirudin anticoagulation (activated partial thromboplastin time less than twice the control time). CONCLUSIONS: Bivalirudin is at least as effective as heparin, with clearly superior safety. Thus, it provides an unprecedented net clinical benefit over heparin in patients with ischemic heart disease.

Cardiogenic shock in patients with acute ischemic syndromes with and without ST-segment elevation.

BACKGROUND: Cardiogenic shock is usually considered a sequela of ST-segment elevation myocardial infarction. There are limited prospective data on the incidence and significance of shock in non-ST-segment elevation patients. This study assessed the incidence and outcomes of cardiogenic shock developing after enrollment among patients with and without ST-segment elevation in the Global Use of Strategies To Open Occluded Coronary Arteries (GUSTO)-IIb trial. METHODS AND RESULTS: Among 12,084 patients in GUSTO-IIb who did not present with cardiogenic shock, 4092 (34%) had and 7991 (66%) did not have ST-segment elevation on the enrollment ECG. Cardiogenic shock developed in 4.2% of ST-segment elevation patients compared with 2.5% of patients without ST-segment elevation (odds ratio, 0. 581; 95% CI, 0.472 to 0.715; P<0.001). Shock developed significantly later among patients without ST-segment elevation. There were significant differences in baseline characteristics between shock patients with and without ST-segment elevation: Patients without ST-segment elevation were older, more frequently had diabetes mellitus and 3-vessel disease, but had less TIMI grade 0 flow at angiography. Regardless of the initial ECG, mortality was high: 63% among patients with ST-segment elevation and 73% in those without ST-segment elevation. CONCLUSIONS: Cardiogenic shock occurs in the setting of acute ischemic syndromes regardless of whether ST-segment elevation is present. The incidence, patient characteristics, timing, clinical course, and angiographic findings differ between the 2 groups. Mortality from cardiogenic shock is similarly high among patients with and without ST-segment elevation.

Dose-finding, safety, and tolerability study of an oral platelet glycoprotein IIb/IIIa inhibitor, lotrafiban, in patients with coronary or cerebral atherosclerotic disease.

BACKGROUND: Antiplatelet therapy is the mainstay of the treatment and secondary prevention of cardiovascular and cerebrovascular ischemic events. We assessed the safety, tolerability, and pharmacodynamics of lotrafiban, an oral platelet glycoprotein IIb/IIIa inhibitor, as a secondary prevention strategy in patients with cerebrovascular or cardiovascular disease. METHODS AND RESULTS: Overall, 451 patients with a recent cardiovascular or cerebrovascular acute ischemic event were randomized in a double-blind fashion to 1 of 5 dosing regimens for 12 weeks: placebo or 5, 20, 50, or 100 mg lotrafiban, both twice daily with 300 to 325 mg/d aspirin. The primary end point was the incidence and tolerability of major and minor bleeding during treatment. Secondary end points included inhibition of platelet aggregation and clinical events. The placebo and lotrafiban 5-mg groups had similarly low rates of minor and major bleeding, but the 100-mg arm was terminated early because of excess major bleeding. Protocol-defined thrombocytopenia (<100 000 platelets/microL) occurred in 5 lotrafiban-treated patients (1.4%, 95% CI 0.2% to 2.7%) and 1 placebo patient (1.1%, 95% CI 0% to 3.1%). Three lotrafiban-treated patients had a nadir platelet count <20 000/microL (0.9%, 95% CI 0% to 1.8%). Lotrafiban produced dose-dependent inhibition of platelet aggregation; 5 mg lotrafiban did not differ significantly from placebo, whereas 100 mg inhibited aggregation by nearly 100%. CONCLUSIONS: -Lotrafiban provides dose-dependent platelet inhibition when administered to a range of patients with atherosclerosis. The level of platelet inhibition appears to correlate with bleeding risk and drug tolerability.

Economic assessment of platelet glycoprotein IIb/IIIa receptor blockade with abciximab and low-dose heparin during percutaneous coronary revascularization: results from the EPILOG randomized trial. Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade.

BACKGROUND: In the EPILOG trial (Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade), abciximab administered with weight-adjusted heparin diminished the risk of ischemic complications within 30 days by 56% among patients undergoing percutaneous coronary revascularization, without increased bleeding complications. METHODS AND RESULTS: A prospective economic assessment was performed in the 2792 patients enrolled in EPILOG. Patients were randomized to receive placebo with standard-dose weight-adjusted heparin, abciximab with low-dose weight-adjusted heparin, or abciximab with standard-dose weight-adjusted heparin during percutaneous coronary intervention. Hospital billing data for the baseline hospitalization were collected for 2581 patients (92.4% of total) and imputed for the remainder, with physician fees estimated from the Medicare Fee Schedule. For the baseline hospitalization, medical costs (hospitalization and physician fees) averaged $9632 for the placebo arm compared with $8758 (P:=0.005) and $9092 (P:=0.176) for the abciximab with low-dose and standard-dose heparin arms, respectively. Inclusive of average drug cost ($1454 to $1457), the net incremental baseline cost of these 2 abciximab strategies was $583 with low-dose weight-adjusted heparin and $914 with standard-dose weight-adjusted heparin. During 6-month follow-up, average hospital costs were not significantly different in the 3 treatment groups; cumulative net incremental costs were $1236 and $1268 in the abciximab with low-dose and standard-dose heparin groups, respectively. CONCLUSIONS: Treatment with abciximab and low-dose, weight-adjusted heparin during percutaneous coronary revascularization reduces ischemic events and associated costs, thereby offsetting some of the cost of the drug. The suppression of bleeding complications associated with this agent by heparin dose reduction optimizes the economic attractiveness of this treatment strategy.

Enhanced efficacy of eptifibatide administration in patients with acute coronary syndrome requiring in-hospital coronary artery bypass grafting. PURSUIT Investigators.

BACKGROUND: Patients with a recent episode of non-ST-segment elevation acute coronary syndrome before CABG have higher rates of operative morbidity and mortality than patients with stable coronary syndromes. The efficacy of administering eptifibatide to these patients undergoing in-hospital CABG is unknown. METHODS AND RESULTS: The Platelet Glycoprotein IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial randomized 10 948 patients to receive either eptifibatide or placebo. There were 1558 study participants who underwent in-hospital CABG: 692 received placebo, and 866 received eptifibatide. The main substudy analysis end point was death or myocardial infarction (MI) rates at the 6-month follow-up. The 30-day death or MI rates were 30. 8% and 26.1% for the placebo and eptifibatide groups, respectively (P:=0.041). The benefit of eptifibatide administration persisted through 6-months of follow-up (32.7% versus 27.6% for placebo versus eptifibatide, respectively; P:=0.029). There was a greater reduction in the 6-month death or MI rate for patients who received eptifibatide within 72 hours of CABG (33.6% versus 23.8%; P:=0.002) compared with the >72-hour group (31.6% versus 32%; P:=1.0). The incidence of major bleeding was 56.6% for placebo-treated patients versus 58.2% for eptifibatide-treated patients (P:=0.7). CONCLUSIONS: Eptifibatide administration in patients undergoing in-hospital CABG with a recent episode of a non-ST-segment elevation acute coronary syndrome results in a significant reduction in death or MI that is evident at 7 days and persists through the 6-month follow-up without a significant increase in perioperative bleeding rates.

Cost-effectiveness of platelet glycoprotein IIb/IIIa inhibition with eptifibatide in patients with non-ST-elevation acute coronary syndromes.

BACKGROUND: In the PURSUIT trial, eptifibatide significantly reduced the 30-day incidence of death and myocardial infarction relative to placebo in 9461 patients with an acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction). METHODS AND RESULTS: We conducted a 2-part prospective economic substudy of the 3522 US patients enrolled in PURSUIT: (1) an empirical intention-to-treat comparison of medical costs (hospital plus physician) up to 6 months after hospitalization and (2) a lifetime cost-effectiveness analysis. The base-case cost-effectiveness ratio was expressed as the 1996 US dollars required to add 1 life-year with eptifibatide therapy. The 2 treatment arms had equivalent resource consumption and medical costs (exclusive of the cost of the eptifibatide regimen) during the index (enrollment) hospitalization (P=0.78) and up to 6 months afterward (P=0.60). The average wholesale price of the eptifibatide regimen was $1217, but a typical hospital discounted price was $1014. The estimated life expectancy from randomization in the US patients was 15.96 years for eptifibatide and 15.85 years for placebo, an incremental difference of 0.111. The incremental cost-effectiveness ratio for eptifibatide therapy in US PURSUIT patients was $16 491 per year of life saved. This result was robust through a wide range of sensitivity analyses. The cost-utility ratio for eptifibatide (using time trade-off defined utilities) was $19 693 per added quality-adjusted life-year. CONCLUSIONS: Based on the results observed in the US PURSUIT patients, the routine addition of eptifibatide to standard care for non-ST-elevation acute coronary syndrome patients is economically attractive by conventional standards.

Predictors of mortality and mortality from cardiac causes in the bypass angioplasty revascularization investigation (BARI) randomized trial and registry. For the BARI Investigators.

BACKGROUND: The impact of percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG) on long-term mortality rates in the presence of various demographic, clinical, and angiographic factors is uncertain in the population of patients suitable for both procedures. METHODS AND RESULTS: In the Bypass Angioplasty Revascularization Investigation (BARI) randomized trial and registry, 3610 patients who were eligible to receive PTCA and CABG were revascularized between 1989 and 1992. Multivariate Cox models were used to identify factors associated with 5-year mortality and cardiac mortality, with particular attention to factors that interact with treatment. Diabetic patients receiving insulin had higher mortality and cardiac mortality rates with PTCA compared with CABG (relative risk [RR] 1.78 and 2.63, respectively, P<0.001), and patients with ST elevation had higher cardiac mortality rates with CABG than with PTCA (RR 4.08, P<0.001). Factors most strongly associated with high overall mortality rates were insulin-treated diabetes, congestive heart failure, kidney failure, and older age. Black race was also associated with higher mortality rates (RR 1.49, P=0.019). CONCLUSIONS: A set of variables was identified that could be used to help select a revascularization procedure and to evaluate risk of long-term mortality in the population of patients considering revascularization.

Gender differences in survival in advanced heart failure. Insights from the FIRST study.

BACKGROUND: Previous natural history studies in broad populations of heart failure patients have associated female gender with improved survival, particularly in patients with a nonischemic etiology of ventricular dysfunction. This study investigates whether a similar survival advantage for women would be evident among patients with advanced heart failure. METHODS AND RESULTS: The study analysis is based on the Flolan International Randomized Survival Trial (FIRST) study which enrolled 471 patients (359 men and 112 women) who had evidence of end-stage heart failure with marked symptoms (60% NYHA class IV) and severe left ventricular dysfunction (left ventricular ejection fraction 18+/-4.9%). A Cox proportional-hazards model, adjusted for age, gender, 6-minute walk, dobutamine use at randomization, mean pulmonary artery blood pressure, and treatment assignment, showed a significant association between female gender and better survival (relative risk of death for men versus women was 2.18, 95% CI 1.39 to 3.41; P<0.001). Although formal interaction testing was negative (P=0.275), among patients with a nonischemic etiology of heart failure, the relative risk of death for men versus women was 3.08 (95% CI 1.56 to 6.09, P=0.001), whereas among those with ischemic heart disease, the relative risk of death for men versus women was 1.64 (95% CI 0.87 to 3.09, P=0.127). CONCLUSIONS: Women with advanced heart failure appear to have better survival than men. Subgroup analysis suggests this finding is strongest among patients with a nonischemic etiology of heart failure.

Treatment of reinfarction after thrombolytic therapy for acute myocardial infarction: an analysis of outcome and treatment choices in the global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries (gusto I) and assessment of the safety of a new thrombolytic (assent 2) studies.

BACKGROUND: Early reinfarction after thrombolytic therapy is associated with adverse outcomes and increased mortality. Among patients with reinfarction in the 1992 Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO I) and the 1998 Assessment of the Safety of a New Thrombolytic (ASSENT 2) trials, we investigated temporal and regional differences in the use of repeat thrombolysis, revascularization (angioplasty and/or bypass surgery), or conservative measures and the outcomes of each management strategy. METHODS AND RESULTS: Data from the 4% of patients (n=2301) who experienced reinfarction after thrombolytic therapy were studied. Baseline characteristics, 30-day mortality, and incidence of total and hemorrhagic strokes were compared among the 3 treatment groups. The 30-day mortality did not differ between the repeat thrombolysis and revascularization groups (P=0.72), and it was significantly lower among patients treated by these 2 strategies than in those treated conservatively (11% and 11% versus 28%, respectively; P<0.001). Stroke rates did not differ significantly between the 3 treatment strategies (P=0.49). From 1992 to 1998, the percentage of reinfarction patients treated with repeat thrombolysis decreased from 29.3% to 18.5% in US centers and from 51.4% to 41.9% in all other centers (P<0.001). In contrast, use of revascularization procedures increased from 33.5% to 47.9% in US centers and from 8.1% to 23.0% in all other centers (P<0.001). CONCLUSIONS: Repeat thrombolysis and revascularization are associated with significantly lower mortality among reinfarction patients. Randomized trials are necessary to assess the exact risks and benefits of rethrombolysis versus interventional revascularization in this subset of high-risk patients presenting with reinfarction after thrombolytic therapy.

Early reinfarction after fibrinolysis: experience from the global utilization of streptokinase and tissue plasminogen activator (alteplase) for occluded coronary arteries (GUSTO I) and global use of strategies to open occluded coronary arteries (GUSTO III) trials.

BACKGROUND: Trials report a 2% to 6% incidence of reinfarction after fibrinolysis for acute myocardial infarction (MI). We combined the Global Utilization of Streptokinase and Tissue plasminogen activator (alteplase) for Occluded coronary arteries (GUSTO I) and Global Use of Strategies To Open occluded coronary arteries (GUSTO III) populations to better define frequency, timing, and clinical predictors of in-hospital reinfarction. METHODS AND RESULTS: In 55 911 patients with ST-segment elevation myocardial infarction (MI) who were receiving fibrinolysis, we compared baseline characteristics and mortality rate by reinfarction incidence and developed multivariable logistic regression models to predict in-hospital reinfarction and composite of death or reinfarction. Reinfarction occurred in 2258 patients (4.3%) a median of 3.8 days after fibrinolysis; rates did not differ between GUSTO I (4.0%) and GUSTO III (4.2%) or by fibrinolytic assignment (streptokinase, 4.1%; alteplase, 4.3%; reteplase, 4.5%; combined streptokinase and alteplase, 4.4%; P=0.55). Advanced age, shorter time to fibrinolysis, non-US enrollment, nonsmoking status, prior MI or angina, female sex, anterior MI, and lower systolic blood pressure were associated significantly with reinfarction. Patients with reinfarction had higher mortality at 30 days (11.3% versus 3.5% without reinfarction; odds ratio, 3.5; P<0.001) and from 30 days to 1 year (4.7% versus 3.2%; hazard ratio, 1.5; P<0.001). Significant multivariate predictors of in-hospital death or reinfarction included age, Killip class, systolic and diastolic blood pressures, heart rate, anterior MI, smoking status, prior MI, sex, and country of enrollment (all P<0.001). CONCLUSIONS: Reinfarction occurs infrequently after fibrinolysis but confers increased risk of 30-day and 1-year mortality. Some predictors of reinfarction differ from known predictors of death after MI. Improved treatment and prevention strategies for reinfarction deserve study.