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Robert M Califf

Publications and source records attributed to Robert M Califf.

At least 199 records · Page 11Linked to original sources
PubMed2002

Integrating quality into the cycle of therapeutic development.

The quality of healthcare, particularly as reflected in current practice versus the available evidence, has become a major focus of national health policy discussions. Key components needed to provide quality care include: 1) development of quality indicators and performance measures from specific practice guidelines, 2) better ways to disseminate such guidelines and measures, and 3) development of support tools to promote standardized practice. Although rational decision-making and development of practice guidelines have relied upon results of randomized trials and outcomes studies, not all questions can be answered by randomized trials, and many treatment decisions necessarily reflect physiology, intuition, and experience when treating individuals. Debate about the role of "evidence-based medicine" also has raised questions about the value of applying trial results in practice, and some skepticism has arisen about whether advocated measures of clinical effectiveness, the basic definition of quality, truly reflect a worthwhile approach to improving medical practice. We provide a perspective on this issue by describing a model that integrates quantitative measurements of quality and performance into the development cycle of existing and future therapeutics. Such a model would serve as a basic approach to cardiovascular medicine that is necessary, but not sufficient, to those wishing to provide the best care for their patients.

Clinical Trials as Topic↗
PubMed2002

Mortality at 1 year with combination platelet glycoprotein IIb/IIIa inhibition and reduced-dose fibrinolytic therapy vs conventional fibrinolytic therapy for acute myocardial infarction: GUSTO V randomized trial.

CONTEXT: Among patients with acute myocardial infarction, combination reperfusion therapy with a platelet glycoprotein IIb/IIIa receptor inhibitor (abciximab) and a half dose of a plasminogen activator (reteplase) did not significantly reduce mortality at 30 days compared with a full dose of reteplase. Rates of nonfatal ischemic complications were significantly diminished. OBJECTIVE: To determine if the beneficial effects of abciximab and reteplase (combination therapy) on early nonfatal complications would translate into a reduction in the risk of death by 1 year. DESIGN, SETTING, AND PATIENTS: One-year follow-up of a randomized controlled trial (Global Use of Strategies To Open Coronary Arteries [GUSTO] V). Of 16 588 patients who had been treated in 820 community and referral hospitals in 20 countries between July 1999 and February 2001, mortality data were available for 16 453 (99.2%). INTERVENTION: Patients were randomly assigned to receive (intravenously) a standard dose of reteplase (two 10-U boluses, 30 minutes apart) or the combination of a standard dose of abciximab (0.25 mg/kg bolus, 0.125 microg/kg per minute infusion [maximum 10 micro g/min for 12 hours]) and a half dose of reteplase (two 5-U boluses, 30 minutes apart). MAIN OUTCOME MEASURE: One-year all-cause mortality rates. RESULTS: All-cause mortality at 1 year occurred in 692 (8.38%) of 8260 patients in the reteplase group and 698 (8.38%) of the 8328 patients in the combination therapy group (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.90-1.11; P>.99). Reinfarction within the first 7 days occurred in 3.5% of patients in the reteplase group and 2.3% of patients in the combination therapy group, and was significantly associated with 1-year mortality (22.6% in patients with reinfarction vs 8.0% in patients without reinfarction; HR, 3.08; 95% CI, 2.53-3.75; P<.001). However, treatment assignment did not significantly influence time of mortality regardless of reinfarction status. CONCLUSION: Combination therapy (abciximab and reteplase) did not reduce mortality over 1 year compared with fibrinolytic therapy with reteplase alone.

Abciximab↗
PubMed2002

Effect of abciximab on angiographic complications during percutaneous coronary stenting in the Evaluation of Platelet IIb/IIIa Inhibition in Stenting Trial (EPISTENT).

In the Evaluation of Platelet IIb/IIIa Inhibition in Stenting Trial (EPISTENT), abciximab reduced ischemic complications of stent implantation at 30 days and 6 months. The responsible mechanisms remain unclear. We sought to determine if abciximab decreases ischemic complications by decreasing the incidence of angiographic complications during coronary stenting. In EPISTENT, patients were randomized to stenting with abciximab (abciximab group), stenting with placebo (placebo group), or balloon angioplasty with abciximab. Angiographic complications (including major or minor dissection, distal embolization, thrombus postprocedure, side branch or other vessel occlusion, residual stenosis >50%, transient coronary occlusion, and Thrombolysis In Myocardial Infarction final flow <3) were recorded prospectively. Creatine kinase (CK)-MB enzyme levels after intervention were measured at 6-hour intervals. We analyzed angiographic complications and CK-MB elevations in the abciximab group (n = 784) and the placebo group (n = 803). Angiographic complications were 29% less frequent in the abciximab group compared with the placebo group (17.0% vs 23.8%; p = 0.001). In patients with angiographic complications, there was a nonsignificant reduction in the incidence of CK-MB elevation >3 times normal with abciximab therapy (19.7% vs 24.5% in placebo group; p = 0.314). Abciximab (compared with placebo) significantly reduced the incidence of CK-MB elevation >3 times normal in those without any angiographic complications (6.5% vs 10.7%; p = 0.007). In summary, abciximab (compared with placebo) significantly reduced angiographic complications during coronary stenting. Abciximab also prevented CK-MB elevations in patients without angiographic complications.

Abciximab↗
PubMed2002

A national survey of provisions in clinical-trial agreements between medical schools and industry sponsors.

BACKGROUND: Concerned about threats to the integrity of clinical trials in a research environment increasingly controlled by private interests, the International Committee of Medical Journal Editors (ICMJE) has issued revised guidelines for investigators' participation in the study design, access to data, and control over publication. It is unclear whether research conducted at academic institutions adheres to these new standards. METHODS: From November 2001 through January 2002, we interviewed officials at U.S. medical schools about provisions in their institutions' agreements with industry sponsors of multicenter clinical trials. A subgroup of the respondents were also asked about coordinating-center agreements for such trials. RESULTS: Of the 122 medical schools that are members of the Association of American Medical Colleges, 108 participated in the survey. The median number of site-level agreements executed per institution in the previous year was 103 (interquartile range, 50 to 210). Scores for compliance with a wide range of provisions--from ensuring that authors of reports on multicenter trials have access to all trial data (1 percent [interquartile range, 0 to 21]) to addressing the plan for data collection and monitoring (10 percent [interquartile range, 1 to 50])--demonstrated limited adherence to the standards embodied in the new ICMJE guidelines. Scores for coordinating-center agreements were somewhat higher for most survey items. CONCLUSIONS: Academic institutions routinely engage in industry-sponsored research that fails to adhere to ICMJE guidelines regarding trial design, access to data, and publication rights. Our findings suggest that a reevaluation of the process of contracting for clinical research is urgently needed.

Clinical Trials as Topic↗
PubMed2002

Evaluating the costs and effectiveness of cardiovascular therapies: who cares about economic analyses?

The field of cardiovascular medicine is providing important insights about how the costs and effectiveness of diagnostic and therapeutic technologies are managed. As health-care budgets have taken up more of the economy and as employers and patients have become concerned about the escalating costs of health care, we have entered an era in which individual practitioners must become concerned with the costs of a service relative to its benefits. Further, increasing numbers of effective therapies in a time when finances are notably constrained, we clearly cannot use all effective therapies in all patients. Increasingly, therefore, we must assess the value derived from spending incremental money on health care products and services. This exercise has been termed cost-effectiveness analysis. The case of the platelet glycoprotein IIb/IIIa inhibitor, abciximab, is used to illustrate many of the issues surrounding the collection, interpretation, and (mis) application of cost-effectiveness data.

Abciximab↗
PubMed2002

Patient outcomes after fibrinolytic therapy for acute myocardial infarction at hospitals with and without coronary revascularization capability.

OBJECTIVES: This study evaluated clinical outcomes in patients with acute myocardial infarction (MI) treated with fibrinolytic therapy in hospitals with and without coronary revascularization capability. BACKGROUND: Patients with MI may have better outcomes when admitted to certain hospitals with coronary revascularization capability. Development of regional heart care centers for the treatment of MI has been proposed. METHOD: We performed a retrospective analysis of 25,515 U.S. patients enrolled in the Global Use of Streptokinase and TPA (alteplase) for Occluded Coronary arteries (GUSTO)-I trial. Outcomes of patients admitted to hospitals with and without coronary revascularization capability were analyzed. We also analyzed patients who remained in hospitals without coronary revascularization capability compared with those transferred to hospitals with revascularization capability. RESULTS: Baseline characteristics and complications were similar between patients in the two hospital types. Patients in hospitals with coronary revascularization capability more often underwent cardiac catheterization (78.1% vs. 59.2%; p < 0.001), angioplasty (34.6% vs. 22.6%; p < 0.001), or bypass surgery (14.1% vs. 10.4%; p < 0.001) but had a similar adjusted 30-day (odds ratio [OR] 0.91, 95% confidence interval [CI] 82 to 1.02) and one-year (OR 0.98, 95% CI 0.90 to 1.07) mortality. Forty percent of patients admitted to hospitals without revascularization capability were transferred, with 94% of transfer patients undergoing angiography. Almost 80% of transfers occurred >48 h after hospital admission. CONCLUSION: Patients receiving fibrinolytic therapy for acute MI admitted to hospitals without coronary revascularization capability appear to have outcomes similar to those of patients admitted to hospitals with such capability when aspirin and beta-adrenergic blocking agents are given appropriately and transfer is available for angiography and angioplasty as needed.

Aged↗
PubMed2002

Randomized COMparison of platelet inhibition with abciximab, tiRofiban and eptifibatide during percutaneous coronary intervention in acute coronary syndromes: the COMPARE trial. Comparison Of Measurements of Platelet aggregation with Aggrastat, Reopro, and Eptifibatide.

BACKGROUND: The relative anti-aggregatory effects of currently prescribed platelet glycoprotein IIb/IIIa receptor antagonists during and after percutaneous coronary intervention for acute coronary syndromes have not been established. METHODS AND RESULTS: We randomized 70 acute coronary syndrome patients undergoing percutaneous coronary intervention to receive abciximab, eptifibatide, or tirofiban at doses used in the Evaluation of Platelet IIb/IIIa Inhibitor for STENTing (EPISTENT), Platelet glycoprotein IIb/IIIa in Unstable angina Receptor Suppression Using Integrilin Therapy (PURSUIT), and Platelet Receptor Inhibition in ischemic Syndrome Management in Patients Limited by Unstable Signs and symptoms (PRISM-PLUS)/Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis (RESTORE) trials, respectively. Platelet aggregation (PA) in response to 20 micro mol/L of adenosine diphosphate was measured with turbidimetric aggregometry in both D-phenylalanyl-L-prolyl-L-arginine chloromethylketone and citrate-anticoagulated blood early (15 and 30 minutes) and late (4, 12, and 18 to 24 hours) after drug initiation. At 15 and 30 minutes, PA was significantly less inhibited by the tirofiban-RESTORE regimen compared with abciximab (P=0.028) and eptifibatide regimens (P=0.0001). The abciximab regimen, however, showed increasingly varied anti-aggregatory effects during continued infusion for > or =4 hours. Citrate exaggerated ex vivo platelet inhibition after eptifibatide and tirofiban, but had the opposite effect on abciximab. Of all regimens evaluated, the eptifibatide regimen inhibited PA most consistently throughout both the early and late periods. CONCLUSIONS: Currently recommended drug regimens to inhibit the platelet glycoprotein IIb/IIIa receptor have distinct pharmacodynamic profiles that might affect their relative efficacy in acute coronary syndromes and percutaneous coronary intervention.

Abciximab↗
PubMed2002

Comparison of one-year outcomes following coronary artery stenting in diabetic versus nondiabetic patients (from the Enhanced Suppression of the Platelet IIb/IIIa Receptor With Integrilin Therapy [ESPRIT] Trial).

For patients undergoing nonurgent coronary stent implantation, blockade of the glycoprotein IIb/IIIa receptor with eptifibatide reduces the incidence of ischemic complications. We evaluated the interaction of eptifibatide with diabetes in patients who underwent this procedure by analyzing the 1-year outcomes of those enrolled in the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial (466 diabetic and 1,595 nondiabetic patients). At 1 year, the composite end point of death, myocardial infarction (MI), or target vessel revascuarlization (TVR) was higher in diabetic patients (24.5% vs 18.4%; p = 0.008). At 1 year, eptifibatide had a similar effect on the composite end point of death, MI, or TVR in diabetic (hazards ratio [HR] 0.71, 95% confidence interval [CI] 0.49 to 1.04) and nondiabetic patients (HR 0.80, 95% CI 0.63 to 0.99). A similar treatment effect was also seen on death or MI in both groups. The 1-year mortality rate for diabetic patients assigned to placebo was 3.5% versus 1.3% for patients receiving eptifibatide (HR 0.37, 95% CI 0.10 to 1.41); the latter rate was similar to the mortality rate of 1.4% for nondiabetic patients in the eptifibatide group. However, eptifibatide did not have a significant effect on TVR in diabetic patients (HR 0.90, 95% CI 0.57 to 1.41). Our data suggest that treatment with eptifibatide is associated with a similar relative reduction in adverse ischemic complications in diabetic and nondiabetic patients undergoing coronary stent implantation. There is no evidence of a statistical interaction in the treatment effect of eptifibatide between patients with and without diabetes.

Administration, Oral↗
PubMed2002

Prognostic implications of abnormalities in renal function in patients with acute coronary syndromes.

BACKGROUND: Outcomes in patients with mild to moderate renal function (RF) abnormalities presenting with acute coronary syndromes (ACS) are not well defined. METHODS AND RESULTS: A convenience sample of 4 ACS trial databases including all enrolled patients was assessed to determine 30- and 180-day outcomes. The 4 trials were Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb, GUSTO-III, Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT), and Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON-A). Patients were stratified into ST-segment elevation (STE) and non-ST-segment elevation (NSE) groups and by the presence or absence of abnormal RF (creatinine clearance <70 mL/min). In the STE group, 7670 of 18 621 patients (41%) had abnormal RF. In the NSE group, 8152 of 19 304 (42%) had abnormal RF. Patients with abnormal RF were older, more often female, and more likely to have adverse baseline characteristics. They had higher mortality and higher mortality/nonfatal myocardial infarction (MI) at both 30 and 180 days, regardless of ST-segment status. Creatinine clearance was independently associated with risk of mortality (hazard ratio 0.79 in the STE group and 0.81 in the NSE group) and with risk of mortality/MI (hazard ratio 0.93) in the NSE group at 180 days. CONCLUSIONS: Patients presenting with ACS frequently have abnormal RF. Abnormal RF is a marker of adverse baseline clinical characteristics and is independently associated with increased risk of death and death/MI.

Acute Disease↗
PubMed2002

Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE).

BACKGROUND: Combined inhibition of the angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) may produce greater benefits in heart failure than ACE inhibition alone. METHODS AND RESULTS: We randomly assigned 5770 patients with New York Heart Association class II to IV heart failure to double-blind treatment with either the ACE inhibitor enalapril (10 mg BID, n=2884) or to the ACE-NEP inhibitor omapatrilat (40 mg once daily, n=2886) for a mean of 14.5 months. The primary end point-the combined risk of death or hospitalization for heart failure requiring intravenous treatment--was used prospectively to test both a superiority and noninferiority hypothesis (based on the effect of enalapril in the Studies of Left Ventricular Dysfunction [SOLVD] Treatment Trial). A primary end point was achieved in 973 patients in the enalapril group and in 914 patients in the omapatrilat group (hazard ratio 0.94; 95% CI: 0.86 to 1.03, P=0.187)--a result that fulfilled prespecified criteria for noninferiority but not for superiority. The omapatrilat group also had a 9% lower risk of cardiovascular death or hospitalization (P=0.024) and a 6% lower risk of death (P=0.339). Post hoc analysis of the primary end point with the definition used in the SOLVD Treatment Trial (which included all hospitalizations for heart failure) showed an 11% lower risk in patients treated with omapatrilat (nominal P=0.012). CONCLUSION: Omapatrilat reduces the risk of death and hospitalization in chronic heart failure but was not more effective than ACE inhibition alone in reducing the risk of a primary clinical event. Between-group differences in favor of omapatrilat observed in secondary and post hoc analyses warrant further study.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Sertraline treatment of major depression in patients with acute MI or unstable angina.

CONTEXT: Major depressive disorder (MDD) occurs in 15% to 23% of patients with acute coronary syndromes and constitutes an independent risk factor for morbidity and mortality. However, no published evidence exists that antidepressant drugs are safe or efficacious in patients with unstable ischemic heart disease. OBJECTIVE: To evaluate the safety and efficacy of sertraline treatment of MDD in patients hospitalized for acute myocardial infarction (MI) or unstable angina and free of other life-threatening medical conditions. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled trial conducted in 40 outpatient cardiology centers and psychiatry clinics in the United States, Europe, Canada, and Australia. Enrollment began in April 1997 and follow-up ended in April 2001. PATIENTS: A total of 369 patients with MDD (64% male; mean age, 57.1 years; mean 17-item Hamilton Depression [HAM-D] score, 19.6; MI, 74%; unstable angina, 26%). INTERVENTION: After a 2-week single-blind placebo run-in, patients were randomly assigned to receive sertraline in flexible dosages of 50 to 200 mg/d (n = 186) or placebo (n = 183) for 24 weeks. MAIN OUTCOME MEASURES: The primary (safety) outcome measure was change from baseline in left ventricular ejection fraction (LVEF); secondary measures included surrogate cardiac measures and cardiovascular adverse events, as well as scores on the HAM-D scale and Clinical Global Impression Improvement scale (CGI-I) in the total randomized sample, in a group with any prior history of MDD, and in a more severe MDD subgroup defined a priori by a HAM-D score of at least 18 and history of 2 or more prior episodes of MDD. RESULTS: Sertraline had no significant effect on mean (SD) LVEF (sertraline: baseline, 54% [10%]; week 16, 54% [11%]; placebo: baseline, 52% [13%]; week 16, 53% [13%]), treatment-emergent increase in ventricular premature complex (VPC) runs (sertraline: 13.1%; placebo: 12.9%), QTc interval greater than 450 milliseconds at end point (sertraline: 12%; placebo: 13%), or other cardiac measures. All comparisons were statistically nonsignificant (P> or = .05). The incidence of severe cardiovascular adverse events was 14.5% with sertraline and 22.4% with placebo. In the total randomized sample, the CGI-I (P =.049), but not the HAM-D (P =.14), favored sertraline. The CGI-I responder rates for sertraline were significantly higher than for placebo in the total sample (67% vs 53%; P =.01), in the group with at least 1 prior episode of depression (72% vs 51%; P =.003), and in the more severe MDD group (78% vs 45%; P =.001). In the latter 2 groups, both CGI-I and HAM-D measures were significantly better in those assigned to sertraline. CONCLUSION: Our results suggest that sertraline is a safe and effective treatment for recurrent depression in patients with recent MI or unstable angina and without other life-threatening medical conditions.

Angina, Unstable↗