Metabolic syndrome: definition, pathophysiology, and mechanisms.
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Albuminuria↗
Biomedical subjects
Robert M Califf
Publications and source records attributed to Robert M Califf.
Incidence, predictors, and outcomes of high-degree atrioventricular block complicating acute myocardial infarction treated with thrombolytic therapy.
BACKGROUND: In the fibrinolytic era, several studies have suggested that the rate of atrioventricular block (AVB) in the setting of acute myocardial infarction (MI) is high and is associated with increased short-term mortality. We sought to delineate predictors of AVB and determine long-term mortality of patients developing AVB in the setting of ST-segment elevation MI (STEMI) treated with thrombolytic therapy. METHODS: We combined data on patients from 4 similar studies of STEMI. We identified independent predictors of AVB and compared the 6-month and 1-year mortality rates of patients with AVB (5251) to the rates of patients without AVB (70 742). RESULTS: The incidence of AVB was 6.9%. Significant independent predictors of AVB included inferior MI, older age, worse Killip class at presentation, female sex, enrollment in the United States, current smoking, hypertension, and diabetes. Adjusted mortality was significantly higher in patients with AVB than in patients without AVB within 30 days (OR 3.2, 95% CI 2.7-3.7), 6 months (OR 1.6, 95% CI 1.5-1.8), and 1 year (OR 1.5, 95% CI 1.3-1.6). For patients with AVB and inferior MI, mortality odds ratios (ORs) were 2.2 (95% CI 1.7-2.7), 2.6 (95% CI 2.4-2.9), and 2.4 (95% CI 2.2-2.6) within 30 days, 6 months, and 1 year, respectively. For patients with AVB and anterior MI, mortality ORs were 3.0 (95% CI 2.2-4.1), 3.5 (95% CI 3.1-3.8), and 3.3 (95% CI 3.0-3.7) within 30 days, 6 months, and 1 year, respectively. CONCLUSIONS: In the thrombolytic era, AVB in the setting of STEMI is common and associated with higher mortality. Future studies should focus on determining therapies that are effective at reducing mortality rates in such patients.
Aged↗
Resource use, costs, and quality of life among patients in the multinational Valsartan in Acute Myocardial Infarction Trial (VALIANT).
BACKGROUND: In a multinational clinical trial, valsartan was statistically not inferior to captopril in reducing mortality and cardiovascular morbidity after myocardial infarction (MI) in patients with signs of heart failure and/or left ventricular dysfunction. We conducted a prospective economic evaluation to compare within-trial resource use, costs, and quality of life in patients receiving valsartan, captopril, or both after MI. METHODS: We assigned country-specific unit costs to resource use data for 14703 patients and measured health-related quality of life in a subset of 4524 patients. We used the nonparametric bootstrap method to compare rates of resource use and costs, and a piecewise linear mixed-effects regression analysis to compare longitudinal measures of quality of life. RESULTS: There were no significant differences in rates of resource use between the valsartan and captopril groups. During an average follow-up of 2 years, total costs for patients receiving valsartan were significantly higher than for patients receiving captopril (USD 14103 vs USD 13038; 95% CI USD 369-USD 1875). The cost differential was caused primarily by the cost of the study medications (USD 1056 for valsartan vs USD 165 for captopril; 95% CI USD 867 to USD 912). Quality of life did not differ significantly between groups. CONCLUSIONS: For most patients at high risk after MI, the availability of generic captopril confers a cost advantage over valsartan because of lower medication costs. The difference will be smaller or nonexistent in settings where brand-name ACE inhibitors are prescribed.
Ambulatory Care↗
Coronary drug-eluting stent development: issues in trial design.
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Animals↗
Electrocardiographic infarct size assessment after thrombolysis: insights from the Acute Myocardial Infarction STudy ADenosine (AMISTAD) trial.
BACKGROUND: Noninvasive methods are needed to evaluate reperfusion success in patients with acute myocardial infarction (MI). The AMISTAD trial was analyzed to compare MI size and myocardial salvage determined by electrocardiogram (ECG) with technetium Tc 99m sestamibi single-photon emission computerized tomography (SPECT) imaging. METHODS: Of 236 patients enrolled in AMISTAD, 166 (70 %) with no ECG confounding factors and no prior MI were included in this analysis. Of these, group 1 (126 patients, 53%) had final infarct size (FIS) available by both ECG and SPECT. Group 2 (56 patients, 24%) had myocardium at risk, FIS, and salvage index (SI) assessed by both SPECT and ECG techniques. Aldrich/Clemmensen scores for myocardium at risk and the Selvester QRS score for final MI size were used. Salvage index was calculated as follows: SI = (myocardium at risk-FIS)/(myocardium at risk). RESULTS: In group 1, FIS was 15% (6, 24) as measured by ECG and 11% (2, 27) as measured by SPECT. In the adenosine group, FIS was 12% (6, 21) and 11% (2, 22). In the placebo group, FIS was 16.5% (7.5, 24) and 11.5% (3.0, 38.5) by ECG and SPECT, respectively. The overall correlation between SPECT and ECG for FIS was 0.58 (P = .0001): 0.60 in the placebo group (P = .0001) and 0.54 (P = .0001) in the adenosine group. In group 2, myocardium at risk was 23% (17, 30) and 26% (10, 50) with ECG and SPECT, respectively (P = .0066). Final infarct size was 17% (6, 21) and 12% (1, 24) (P < .0001). The SI was 29% (-7, 57) and 46% (15, 79) with ECG and SPECT, respectively (P = .0510). CONCLUSIONS: The ECG measurement of infarct size has a moderate relationship with SPECT infarct size measurements in the population with available assessments. This ECG algorithm must further be validated on clinical outcomes.
Adenosine↗
Conducting economic evaluations alongside multinational clinical trials: toward a research consensus.
Demand for economic evaluations in multinational clinical trials is increasing, but there is little consensus about how such studies should be conducted and reported. At a workshop in Durham, North Carolina, we sought to identify areas of agreement about how the primary findings of economic evaluations in multinational clinical trials should be generated and presented. In this paper, we propose a framework for classifying multinational economic evaluations according to (a) the sources of an analyst's estimates of resource use and clinical effectiveness and (b) the analyst's method of estimating costs. We review existing studies in the cardiology literature in the context of the proposed framework. We then describe important methodological and practical considerations in conducting multinational economic evaluations and summarize the advantages and disadvantages of each approach. Finally, we describe opportunities for future research. Delineation of the various approaches to multinational economic evaluation may assist researchers, peer reviewers, journal editors, and decision makers in evaluating the strengths and limitations of particular studies.
Clinical Trials as Topic↗
Testing new targets of therapy in advanced heart failure: the design and rationale of the Strategies for Tailoring Advanced Heart Failure Regimens in the Outpatient Setting: BRain NatrIuretic Peptide Versus the Clinical CongesTion ScorE (STARBRITE) trial.
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Clinical Trials as Topic↗
Tenecteplase and tirofiban in ST-segment elevation acute myocardial infarction: results of a randomized trial.
BACKGROUND: The combination of older reduced-dose fibrinolytic agents and platelet glycoprotein IIb/IIIa inhibitors has shown modest improvements in reperfusion and more striking improvements in ST-segment resolution after acute myocardial infarction. We performed a multicenter dose-ranging study of reduced doses of a newer fibrinolytic (tenecteplase) combined with tirofiban, a glycoprotein IIb/IIIa inhibitor. METHODS: The first goal of the trial was to identify a dose or doses of tirofiban that, when combined with reduced-dose tenecteplase, would result in a higher incidence of Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow at 60 minutes versus full-dose tenecteplase alone. The second goal was to assess whether the optimum dose(s) from the first stage also would result in greater resolution of ST-segment elevation. RESULTS: In all, 409 patients aged 18 to 75 years with myocardial infarction were enrolled. The incidence of TIMI grade 3 flow at 60 minutes did not differ significantly among dose groups, ranging from 50% to 68%. The corrected TIMI frame count likewise did not differ substantially (range 34-42). More patients given combined therapy had complete resolution of ST-segment elevation at 60 minutes compared with patients given tenecteplase alone. Major bleeding was infrequent, and no strokes occurred. Based on angiographic results of the first stage, the second planned stage of the study was not performed. CONCLUSIONS: Although combination therapies were not associated with increased reperfusion compared with full-dose tenecteplase alone, similar TIMI flow grades were achieved despite reductions in tenecteplase doses. ST-segment resolution was more rapid and complete with combination therapy versus full-dose tenecteplase, suggesting enhanced microcirculatory perfusion to the infarct zone in this dose-ranging trial.
Adolescent↗
Implantable cardioverter defibrillators and cardiac resynchronization therapy in patients with left ventricular dysfunction: randomized trial evidence through 2004.
Although many studies have shown that implantable cardioverter defibrillator (ICD) therapy improves the survival of patients with significant left ventricular dysfunction, the magnitude of effectiveness of ICD therapy in clinically defined subgroups remains uncertain. Similarly, although studies have shown an improvement in patients' hemodynamics and quality of life with cardiac resynchronization therapy (CRT), there is a continuing uncertainty about the effect of CRT on patients' survival and the magnitude of improvement in quality of life with this therapy. On August 24, 2004, an ad hoc group of experts representing clinical cardiovascular medicine, biostatistics, economics, and health policy were joined by representatives of the Food and Drug Administration, Centers for Medicare and Medicaid Services (Baltimore, Md), Agency for Healthcare Research and Quality (Rockville, Md), and the device industry for a 1-day round table to review the available clinical trial evidence on the effect of ICD therapy in the primary prevention of sudden cardiac death and the effect of CRT in patients with congestive heart failure. The meeting was organized by the Duke Clinical Research Institute, Durham, NC, and funded in part by the Agency for Healthcare Research and Quality. This document summarizes the evidence reviewed at that meeting and the discussions of that evidence.
Death, Sudden, Cardiac↗
A perspective on trials comparing enoxaparin and unfractionated heparin in the treatment of non-ST-elevation acute coronary syndromes.
BACKGROUND: Non-ST-elevation (NSTE) acute coronary syndrome (ACS) is a serious, acute illness characterized by a high rate of death and morbid events, and antithrombin therapy is integral to its management. Contemporary guidelines from the American College of Cardiology/American Heart Association call for use of low-molecular-weight heparin or unfractionated heparin (UFH). METHODS: A systematic overview of six randomized, controlled trials comparing enoxaparin to UFH in the treatment of NSTE ACS was performed using a random-effects empirical Bayes model. Efficacy end points included the incidence of death or the composite of death and myocardial infarction (MI) at 30 days. Safety end points included major bleeding and transfusion at 7 days. RESULTS: For the aggregate of 21,946 patients, the incidence of the composite of death and MI at 30 days was lower in enoxaparin-treated patients (10.1% vs 11.0% for UFH, OR 0.91, 95% CI 0.83-0.99, number need to treat 107). For the 9,835 patients in these trials who received no prerandomization antithrombin therapy, the composite of death and MI at 30 days occurred in 8.0% and 9.4% of enoxaparin- and UFH-treated patients, respectively (OR 0.81, 95% CI 0.70-0.94, number need to treat 94). There was no significant difference in the incidence of death at 30 days in either population. A nonsignificant trend toward higher rates of major bleeding was seen at 7 days for enoxaparin-treated patients, in both the overall safety population and the population of patients who did not receive antithrombin treatment before randomization, but there was no difference in blood transfusions. CONCLUSION: In a systematic overview of six randomized, controlled trials comparing enoxaparin to UFH in the treatment of NSTE ACS in approximately 22,000 patients, the use of enoxaparin rather than UFH was associated with a modest reduction in the incidence of the composite of death and MI at 30 days without a significant increase in the rate of major bleeding or transfusion at 7 days.
Aged↗
The early glycoprotein IIb/IIIa inhibition in non-ST-segment elevation acute coronary syndrome (EARLY ACS) trial: a randomized placebo-controlled trial evaluating the clinical benefits of early front-loaded eptifibatide in the treatment of patients with non-ST-segment elevation acute coronary syndrome--study design and rationale.
BACKGROUND: The recent North American and European practice guidelines in patients with non-ST-segment elevation acute coronary syndrome (nSTE ACS) recommend glycoprotein IIb/IIIa (GpIIb-IIIa) inhibition in patients undergoing an early invasive treatment strategy. However, the guidelines are not explicit regarding the timing of initiation of GpIIb-IIIa antagonists, and there is marked variation in clinical practice regarding their use. STUDY DESIGN: The EARLY ACS trial will enroll 10,500 patients in a prospective, randomized, double blind, international, multicenter investigation of early eptifibatide compared with placebo (with provisional eptifibatide in the catheterization laboratory) in patients with high-risk nSTE ACS in whom an invasive strategy is planned no sooner than the next calendar day. The primary efficacy end point is the 96-hour composite of all-cause mortality, nonfatal myocardial infarction, recurrent ischemia requiring urgent revascularization, or need for thrombotic bailout with GpIIb-IIIa inhibitor during percutaneous coronary intervention. The key secondary end point is the composite of death or nonfatal myocardial infarction within 30 days of enrollment. IMPLICATIONS: The EARLY ACS trial will be the largest study to date to evaluate the utility of early GpIIb-IIIa inhibition in patients with nSTE ACS in whom an invasive approach is planned. This trial will provide important evidence regarding the benefit of initiating eptifibatide early after presentation with high-risk ACS versus delayed provisional use after coronary angiography. Furthermore, it will explore the ability of biomarkers to identify high-risk patients who may benefit from such an early aggressive approach.
Acute Disease↗
Depression and ischemic heart disease: what have we learned so far and what must we do in the future?
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Antidepressive Agents↗
The PRoject of Ex-vivo Vein graft ENgineering via Transfection IV (PREVENT IV) trial: study rationale, design, and baseline patient characteristics.
BACKGROUND: Coronary artery bypass graft (CABG) surgery with autologous vein graft (VG) conduit is one of the most frequently performed operations in the United States. Unfortunately, many VGs become occluded during long-term follow-up largely because of neointimal hyperplasia. A novel approach to preventing neointimal hyperplasia is with the double-stranded oligonucleotide edifoligide (Corgentech Inc, South San Francisco, Calif). Edifoligide inhibits E2F, a transcription factor that activates cell-cycle genes responsible for neointimal hyperplasia. METHODS: PREVENT IV is a phase-III, multicenter, randomized double-blind placebo-controlled trial of ex vivo treatment of autologous VGs with edifoligide in patients undergoing initial CABG surgery. The primary end point is VG failure, defined as death or > or =75% stenosis in a treated VG at 12- to 18-month angiographic follow-up. Secondary end points include major adverse cardiac events through at least 5 years and adverse events through 30 days. RESULTS: Enrollment of 3014 patients from 107 sites was completed on October 22, 2003. The baseline and procedural characteristics of the PREVENT IV population are generally well matched to a contemporary population of patients undergoing initial CABG from the Society of Thoracic Surgeons National Database. Angiographic follow-up is ongoing and scheduled to be completed in March 2005. CONCLUSIONS: The PREVENT IV data will establish whether VG pretreatment with an E2F transcription factor decoy, edifoligide, can improve graft patency and reduce the long-term morbidity and mortality of patients undergoing CABG surgery.
Aged↗
Pulmonary artery catheterization in acute coronary syndromes: insights from the GUSTO IIb and GUSTO III trials.
PURPOSE: To correlate pulmonary artery catheterization (PAC) use and 30-day outcomes and to characterize the use of pulmonary artery catheters among patients with acute coronary syndromes (ACS). SUBJECTS AND METHODS: We retrospectively studied 26437 ACS patients from two large multicenter, international randomized clinical trials. Multivariable and causal inference analyses were applied to adjust for differences in baseline risk. RESULTS: PAC was performed in 735 patients (2.8%), with a median time to insertion of 24 hours. Patients undergoing PAC were older (median, 67 vs. 64 years), more often diabetic (25.7% vs.16.2%), and more likely to present with ST-segment elevation (81.6% vs. 70.2%) or Killip class III or IV (7.9% vs. 1.4%). US patients were 3.8 times more likely than non-US patients to undergo PAC. Patients managed with PAC also underwent more procedures, including percutaneous intervention (40.7% vs. 18.1%), coronary artery bypass grafting (12.5% vs. 7.7%), and endotracheal intubation (29.3% vs. 2.2%). Mortality at 30 days was substantially higher among patients with PAC for both unadjusted (odds ratio [OR] 8.7; 95% confidence interval [CI] 7.3-10.2) and adjusted analyses (OR 6.4; 95% CI 5.4-7.6) in all groups except in patients with cardiogenic shock (OR 0.99; 95% CI 0.80-1.23). CONCLUSIONS: PAC was associated with increased mortality, both before and after adjustment for baseline patient differences and subsequent events that may have led to PAC use, except in patients with cardiogenic shock. The definitive role of PAC in managing patients with ACS is still to be determined.
Acute Disease↗
Elevated body mass index and intermediate-term clinical outcomes after acute coronary syndromes.
PURPOSE: Obesity is a coronary disease risk factor, but its independent effect on clinical outcomes following acute coronary syndromes has not been quantified. We evaluated the relationship between elevated body mass index (BMI) and 30-day, 90-day, and 1-year clinical outcomes postacute coronary syndromes. SUBJECTS AND METHODS: Using 15 071 patients (normal weight [BMI = 18.5-24.9 kg/m(2)], overweight [BMI = 25-29.9 kg/m(2)], obese [BMI = 30-34.9 kg/m(2)] or very obese [BMI > or =35 kg/m(2)]) randomized from 1997-1999 in the SYMPHONY (Sibrafiban vs aspirin to Yield Maximum Protection from ischemic Heart events postacute cOroNary sYndromes) and 2nd SYMPHONY trials, we evaluated the relationships between BMI and 30-day, 90-day, and 1-year mortality and 30-day and 90-day death or myocardial infarction. RESULTS: Increasing BMI was associated with younger age, multiple comorbidities, and greater cardiac medication and procedure use; however, systolic function and coronary disease extent were similar for all BMI categories. Unadjusted Kaplan-Meier mortality estimates were higher for normal-weight patients than for all other BMI groups. After multivariable adjustment, the 30-day mortality hazard ratios (95% confidence interval [CI]) were: overweight, 0.66 (95% CI: 0.47 to 0.94); obese, 0.61 (95% CI: 0.39 to 0.97); very obese, 0.89 (95% CI: 0.48 to 1.64). Adjusted hazard ratios were similar for 90-day and 1-year mortality. There were no statistically significant differences among BMI groups in 30-day and 90-day death or myocardial infarction (unadjusted or adjusted). CONCLUSION: Overweight and obese BMI classifications were associated with better intermediate-term survival after acute coronary syndromes than normal weight and very obese, but death or myocardial infarction rates were similar. Further study is required to understand the apparent association of overweight and moderate obesity with better intermediate-term outcomes.
Acute Disease↗
A survey of health care practitioners' knowledge of the QT interval.
OBJECTIVE: To assess health care practitioners' ability to correctly measure the QT interval, and to identify factors and medications that may increase the risk of QT-interval prolongation and torsades de pointes. DESIGN: A cross-sectional analysis of a survey administered between April 2002 and March 2003. PARTICIPANTS AND SETTING: Health care practitioners attending Grand Rounds Conferences at 6 academic institutions in the United States in internal medicine and psychiatry and at 6 community hospitals in the same geographical areas as the academic institutions. INTERVENTION: Anonymous, self-administered questionnaire that included 20 questions on the QT interval. MEASUREMENTS AND MAIN RESULTS: Of approximately 826 attendees, 517 (63%) completed the survey. Of about 608 attendees of internal medicine conferences, 371 (61%) responded, and of about 208 attendees of psychiatry conferences, 146 (67%) responded. Of a total number of 20 questions, the median number of correct answers for the whole group was 10 (interquartile range 7-13). The median number of correct answers for internists was 12 (interquartile range 9-13), for psychiatrists 10 (interquartile range 7-13), and for other specialists 10 (interquartile range 5-13). Respondents who graduated between 1990 and 1999 and academicians performed significantly better overall than other respondents. Of the 517 respondents, 224 (43%) measured the QT interval correctly. Physicians in training and academicians were more likely to measure the QT interval correctly. CONCLUSION: The majority of health care practitioners cannot correctly measure the QT interval and cannot correctly identify factors and medications that can prolong the QT interval. Our findings suggest that greater attention to the QT interval is warranted to ensure safer use of QT prolonging medications.
Adult↗
Outcomes of patients with acute coronary syndromes and prior percutaneous coronary intervention: a pooled analysis of three randomized clinical trials.
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.
Aged↗
Lessons learned from a clinical trial.
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Aspirin↗