Diets and clinical coronary events: the truth is out there.
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Coronary Angiography↗
Biomedical subjects
Robert M Califf
Publications and source records attributed to Robert M Califf.
Outpatient prescribing of antiarrhythmic drugs from 1995 to 2000.
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Ambulatory Care↗
Translation of academic discovery into societal benefit: proposal for a balanced approach--part 1.
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Academic Medical Centers↗
International variation in the use of evidence-based medicines for acute coronary syndromes.
AIMS: We sought to evaluate international patterns of use and factors influencing use of evidence-based medications early after ACS. METHODS AND RESULTS: Using a database of 15904 ACS patients enrolled in the SYMPHONY and 2nd SYMPHONY trials in 37 countries, we performed descriptive and logistic regression analyses. After controlling for other factors, region was significantly associated with the use of every class of evidence-based medication, most pronounced for intravenous unfractionated heparin (IV UFH), low-molecular-weight heparin (LMWH), angiotensin II converting enzyme inhibitors (ACEI) and discharge use of lipid-lowering agents. Latin America and Eastern Europe were among the highest users of early ACEI, yet the lowest users of discharge lipid-lowering therapy. Relative to the United States, all regions except Canada had greater use of LMWH and lower use of IV UFH. Compared with patients with acute myocardial infarction, those with unstable angina less often received aspirin, beta-blockers, ACEI, or IV UFH. Older age was associated with lower use of aspirin, beta-blockers, IV UFH, and lipid-lowering agents. CONCLUSIONS: Use of evidence-based therapies for management of ACS patients is strongly associated with region. To improve patient outcomes, more research is needed to understand this variation, and to institute appropriate solutions.
Aged↗
Changing the model of care for patients with acute coronary syndromes.
Acute coronary syndromes (ACS) represent a major cause of morbidity and mortality for patients with cardiovascular disease, but evidence-based therapies shown to improve outcomes for ACS are often underused in clinically eligible patients. Although clinical practice guidelines have been developed to provide standards for the diagnosis and treatment of patients with ACS and to provide physicians with a framework for clinical decision-making, multiple obstacles have hindered their implementation and questions remain about the applicability of guidelines for diverse clinical situations. Systematic reviews of quality-improvement studies have shown that multifaceted approaches using targeted educational interventions, creation of quality standards, and regular performance feedback are needed to ensure sustained improvements in care. Approaches to quality improvement thus are being redirected to focus on multidisciplinary collaborations designed to improve the entire process of care for patients with ACS. Multiple large observational registries and quality-improvement initiatives now are capturing data regarding adherence to practice guidelines and contemporary patterns of care for ACS. This comprehensive evaluation of ACS treatment will help guide efforts designed to promote evidence-based care and ultimately determine the effect of widespread implementation of practice guidelines on clinical outcomes. The shifting model of care for ACS therefore suggests that quality improvement and monitoring of adherence to practice guidelines should be considered components of optimal clinical practice.
Angina, Unstable↗
Evaluation of the dofetilide risk-management program.
BACKGROUND: Dose-dependent torsades de pointes has been shown to occur with dofetilide (Tikosyn) and sotalol HCl (Betapace AF); thus, detailed dosing and monitoring recommendations to minimize this risk are included in the product labeling for both drugs. Only dofetilide, however, has a mandated risk-management program that restricts distribution of the drug and requires prescriber education on the drug. We investigated whether this program improved adherence to dosing and monitoring recommendations for dofetilide as compared with sotalol. METHODS: Charts for 47 patients taking dofetilide and 117 patients taking sotalol were reviewed. RESULTS: The recommended starting dose was prescribed more frequently in the dofetilide group than in the sotalol group (79% vs 35%, P <.001). A higher number of patients in the dofetilide group compared with the sotalol group received the recommended baseline tests for potassium (100% vs 82%, P <.001), magnesium (89% vs 38%, P <.001), serum creatinine (100% vs 82%, P <.001), and electrocardiography (94% vs 67%, P <.001). A significantly greater proportion of patients in the dofetilide group received recommended electrocardiograms obtained after the first dose (94% for dofetilide vs 43% for sotalol, P <.001) and subsequent doses (80% for dofetilide vs 3.5% for sotalol, P <.001). CONCLUSION: Better adherence to several dosing and monitoring recommendations in the dofetilide group may be caused by the presence of the risk-management program. However, low usage of dofetilide during the study period may signify an unintended, negative consequence of the risk-management program.
Arrhythmias, Cardiac↗
Toward protecting the safety of participants in clinical trials.
It is a widely held belief that the current system of oversight of clinical research, particularly the means of assessing risks and minimizing harms to participants in clinical trials, could be improved. In particular, the system is inefficient with overemphasis on the monitoring ability of some groups such as research ethics review boards and investigators, underemphasis on others such as data monitoring committees (DMCs) and sponsors, confusion about responsibilities for safety and imperfect communication between these different groups. Research ethics review boards are not able to perform safety monitoring by review of individual adverse events and are often burdened by duplicative reviews of large multicenter studies. There are no standards for DMCs to ensure they can reliably identify safety issues. Sponsors may be overreliant on data audits and slow to disseminate safety data in a coherent summary. Investigators, their staffs and clinical sites may not fully appreciate all the nuances of good clinical practice or may be inattentive to the daily conduct of studies. Regulators, particularly those in the United States, have failed to completely harmonize their policies with each other or with international regulatory agencies. We recommend well-designed monitoring plans for all studies that are appropriate to their scope and risk, more centralized review of large multisite studies and closer local scrutiny of single-institution studies. In addition, sponsors should pay greater attention to monitoring adverse events and keeping up-to-date databases or investigator's brochures emphasizing safety issues. A minimal standard of education or expertise in good clinical practice should be established for investigators, their staffs and research ethics review board members. DMC composition and functions should be standardized and regulations should be harmonized nationally and internationally. Finally, there should be a concerted effort to study the efficacy of various components of the system.
Clinical Trials Data Monitoring Committees↗
VALsartan In Acute myocardial iNfarcTion (VALIANT) trial: baseline characteristics in context.
BACKGROUND: The VALsartan In Acute myocardial iNfarcTion (VALIANT) trial compared outcomes with: (1) angiotensin-converting enzyme inhibition (ACEI) with the reference agent captopril; (2) angiotensin-receptor blockade (ARB) with valsartan; or (3) both in patients with heart failure (HF) and/or left ventricular systolic dysfunction (LVSD) after myocardial infarction (MI). AIMS: a goal of this active-control trial was to simulate conditions that would lead current practitioners to use ACEIs. Thus, we compared characteristics of VALIANT patients with those of patients in placebo-controlled trials that established ACEIs as standard treatment. METHODS AND RESULTS: We collected demographic, clinical, medication and imaging information from 14703 patients in 24 countries. This high-risk population was a median 65.8 years old, and 31.1% were female. Most (51.8%) showed imaging evidence of LVSD at enrollment. Most (72%) had Killip class>/=II HF. Patients received evidence-based therapies at rates similar to those of contemporary MI trials and at an improved rate compared with prior placebo-controlled ACEI trials. CONCLUSION: VALIANT represents the largest globally representative cohort enrolled with HF and/or LVSD after MI. Patients were similar to those in placebo-controlled ACEI trials while reflecting improvements in evidence-based care. With enrollment complete, VALIANT is poised to define the optimal strategy for renin-angiotensin system blockade after MI to improve cardiovascular outcomes.
Aged↗
Significance of atrial fibrillation during acute myocardial infarction, and its current management: insights from the GUSTO-3 trial.
The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-3 atrial fibrillation (AF) substudy assessed the prognostic significance of AF during acute myocardial infarction (AMI), the use of antiarrhythmic therapies, and whether different antiarrhythmic therapies were associated with different outcomes. The timing of the onset of AF relative to other post-AMI complications was recorded in the study. Of the 13,858 patients who were in sinus rhythm at the time of enrolment into GUSTO-3, 906 (6.5%) developed AF and 12,952 did not. Worsening heart failure, hypotension, third-degree heart block, and ventricular fibrillation were independent predictors of new-onset AF. The risks of 30-day and 1-year mortality were increased among patients with AF versus patients without AF before (odds ratio [OR] 2.74, 95% confidence interval [CI] 2.56-3.34; and OR 2.93, 95% CI 2.48-3.46, respectively) and after adjustment for baseline factors and pre-AF complications (OR 1.49, 95% CI 1.17-1.89; and OR 1.64, 95% CI 1.35-2.01, respectively). A total of 1,138 patients had data available on the management of their AF, including 117 with a history of paroxysmal AF and 138 with chronic AF prior to AMI. Of these 1,138 patients, 317 (28%) received antiarrhythmic therapies: class I antiarrhythmic drugs in 12%, sotalol in 5% and amiodarone in 15%. Electrical cardioversion was attempted in 116 patients (10%). Sinus rhythm was restored in 72% of patients given class I drugs, 67% of those given sotalol, 79% of those given amiodarone, and 64% of those who underwent electrical cardioversion. After adjustment for baseline characteristics and pre-AF complications, none of the specific antiarrhythmic therapies was associated with a higher chance of having sinus rhythm at discharge or before deterioration to in-hospital death. However, the use of class I antiarrhythmic drugs or sotalol was associated with lower unadjusted 30-day and 1-year mortality rates. After adjustment for baseline factors and pre-AF complications, the ORs for 30-day and 1-year mortality were 0.42 (95% CI 0.19-0.89) and 0.58 (95% CI 0.33-1.04), respectively, with class I agents, and 0.31 (95% CI 0.07-1.32) and 0.31 (95% CI 0.09-1.02), respectively, with sotalol. In contrast, there was no association between the use of amiodarone or electrical cardioversion and 30-day or 1-year mortality. New AF is often secondary to other post-AMI complications, but is in itself an independent predictor of a worse outcome. Clinical management of AF is variable, but in GUSTO-3 there was a strong trend towards lower mortality associated with the use of class I antiarrhythmic agents or sotalol. Randomized trials are needed to investigate this observation further.
Anti-Arrhythmia Agents↗
Aspirin use post-acute coronary syndromes: intolerance, bleeding and discontinuation.
BACKGROUND: While aspirin's secondary prevention benefit is clear, prior reports indicate that 19-83% of eligible patients may not use aspirin chronically. METHODS: We investigated intolerance and bleeding while on aspirin and aspirin discontinuation using 5337 post-acute coronary syndrome patients considered appropriate for chronic antiplatelet therapy who were randomly assigned to aspirin in SYMPHONY and 2nd SYMPHONY and followed for 94 (64,157) days. Multivariable logistic regression models tested associations between baseline characteristics and aspirin discontinuation and bleeding. RESULTS: Nearly 18% of patients discontinued study aspirin; 48% subsequently used open-label aspirin and 5% other antiplatelet or anticoagulant therapy. Black race, recurrent ischemia, hypertension, chronic obstructive pulmonary disease, lighter weight, shorter time to treatment and use of non-steroidal anti-inflammatory agents, diuretics, and digitalis were independently associated with early discontinuation. Early discontinuation was less likely in Eastern Europe, Latin America and Asia. Although major or minor bleeding was common (12.6%), only 1.0% of aspirin-treated patients were reported to discontinue due to bleeding. Gastrointestinal (10.5%) and puncture site (7.6%) were the most common bleeding locations. Bleeding risk was associated with lower estimated creatinine clearance, shorter time to treatment, smoking, Killip class >II, higher systolic blood pressure, and use of aspirin or heparin prior to starting study aspirin. CONCLUSIONS: Despite early initiation and close follow-up, more than 9% of aspirin-treated patients discontinued therapy early and remained off treatment. Addressing the factors associated with both bleeding and discontinuation during chronic therapy is necessary to improve adherence to this inexpensive, life-saving therapy.
Acute Disease↗
Ethics and equipoise: rationale for a placebo-controlled study design of platelet glycoprotein IIb/IIIa inhibition in coronary intervention.
Rarely is it straightforward to specify the design and parameters of a clinical trial investigating an alternative therapy where effective therapies already exist. If existing therapeutic interventions are highly efficacious, safe, inexpensive, and firmly entrenched, an active-control design becomes the logical first choice. Short of this absolute condition, however, the merits and realities of the scientific, clinical, corporate, and regulatory environments need to be weighed before determining the appropriate approach. A state of clinical equipoise with regard to the use of glycoprotein (GP) IIb/IIIa therapy in percutaneous coronary intervention (PCI) provided the unique opportunity to address the complexities in selecting a placebo-controlled design for the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Trial (ESPRIT). ESPRIT investigators assessed whether a high dose of eptifibatide would improve the outcomes of patients undergoing coronary stenting. By using the example of the ESPRIT trial, we examine factors warranting the need for this trial and evaluate the process whereby the United States Food and Drug Administration (FDA) gave approval for a placebo-controlled design. Although the focus of this trial is GP IIb/IIIa inhibition therapy, the issues pertaining to the trial and how they were resolved are general enough to be applied to the design and conduct of clinical trials across a broad spectrum of illnesses and therapeutic modalities.
Angioplasty, Balloon, Coronary↗
Knowledge deficits related to the QT interval could affect patient safety.
BACKGROUND: Recently, some QT-prolonging, noncardiac medications were withdrawn from the U.S. drug market because of continued inappropriate use by health care practitioners despite warnings and label changes from both the drug manufacturers and the U.S. Food and Drug Administration. This led us to assess the health care practitioners' knowledge of the QT interval and medications that may prolong it. METHODS: We surveyed health care practitioners, primarily specialists in cardiology, to identify knowledge deficits related to the QT interval. RESULTS: From a total of 334 survey respondents, 157 (47%) were physicians; 271 (81%) stated that cardiology was their area of specialization. Most of the respondents (86%) said that they would check an ECG before and after starting QT-prolonging medications, but less than half (42%) of all respondents and only 60% of physician respondents were able to accurately measure a sample QT interval on the survey. Less than two-thirds (63%) of respondents were able to accurately identify possible QT-prolonging medications, while only about half (51%) could accurately identify medication combinations that might prolong the QT interval. CONCLUSIONS: We identified significant knowledge deficits regarding the QT interval and QT-prolonging medications. Additional research is needed to determine the extent to which these knowledge deficits may negatively affect patient safety. We must also develop effective strategies to eliminate these deficits.
Cardiology↗
Development and validation of a simple model to predict severe coronary artery disease after myocardial infarction: potential impact on cardiac catheterization use in the United States and Canada.
BACKGROUND: Improved patient selection may optimize the efficiency of cardiac catheterization in both high- and low-rate regions. The purpose of this study was to develop and validate a clinical model for predicting high-risk coronary artery disease (CAD) after myocardial infarction (MI) and to examine the model's potential impact on the use rate of both US and Canadian catheterization practices. METHODS AND RESULTS: By the use of baseline clinical variables from 1122 patients in the angiographic substudy of the Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-1) trial, we developed a model that was predictive of severe CAD (left main or triple-vessel disease). The final model, which included prior MI, age, sex, hyperlipidemia, and decreased left ventricular ejection fraction (C-index = 0.70), was externally validated in 781 patients in the GUSTO IIb trial. Although the probability of severe CAD predicted 5-year survival, the frequency of catheterization in both Canada and the United States bore no relationship to severe CAD risk in the GUSTO-1 trial. By use of the model, we estimated that as much as 15% of US catheterizations from both GUSTO-1 and GUSTO IIb might have been avoided, without significantly compromising the number of patients with severe CAD who were identified (sensitivity = 0.94). By applying the model to Canadian practices, an additional 30 cases of severe CAD might have been identified per every 1000 catheterizations performed, without increasing the catheterization rate. CONCLUSIONS: The likelihood of severe CAD after ST-elevation MI may be predicted from simple baseline clinical variables. The use of a severe CAD predictive model to guide patient selection might enhance the cost-effectiveness of both aggressive and conservative catheterization practices.
Analysis of Variance↗
Anticoagulation in acute cardiac care in patients with chronic kidney disease.
The number of patients with coexisting chronic kidney disease (CKD) and cardiovascular disease is growing rapidly. Treatment of these patients is challenging, primarily because of a lack of pharmacokinetic and clinical trial data associated with these combined disease entities. In this report, we discuss the cardiovascular disease risk associated with CKD and review the use of anticoagulation for acute cardiovascular disease in patients with CKD. We evaluate the potential role of direct thrombin inhibitors in patients with renal disease who have acute coronary syndromes, with particular focus on the clinical efficacy of bivalirudin. We conclude that direct thrombin inhibitors, including bivalirudin and argatroban, may be promising alternatives to heparin in patients who have renal insufficiency and are therefore at an increased risk for bleeding. In the treatment of patients with advanced renal insufficiency and cardiovascular disease, however, these agents should be used with dose modification to account for altered excretion.
Anticoagulants↗
Sustained ventricular arrhythmias and mortality among patients with acute myocardial infarction: results from the GUSTO-III trial.
BACKGROUND: In many patients, ventricular arrhythmias will develop early after acute myocardial infarction. We studied the incidence, timing, and outcomes of such arrhythmias in the international Global Utilization of Streptokinase and TPA (alteplase) for Occluded Coronary Arteries (GUSTO)-III trial. METHODS: We identified independent predictors of inhospital ventricular fibrillation (VF) and ventricular tachycardia (VT) and compared 30-day and 1-year mortality rates of patients who did (n = 1121) and did not (n = 13,921) have these arrhythmias during the index hospitalization. RESULTS: Significant independent predictors of inhospital VF were higher Killip class, lower baseline systolic pressure, intravenous preenrollment lidocaine use, shorter time to thrombolysis, and beta-blocker use <2 weeks before enrollment; independent predictors of inhospital VT were lower baseline systolic pressure, intravenous lidocaine use before enrollment, higher Killip class, faster baseline heart rate, and advanced age. The 30-day mortality rate was 31% in patients with VF, 24% in those with VT, 44% in those with both, and 6% in those with neither (P =.001). The corresponding 1-year mortality rates were 34%, 29%, 49%, and 9% (P =.001). The 30-day and 1-year mortality rates were higher for patients with late (>48 hours after enrollment) versus early arrhythmias (< or =48 hours after enrollment). CONCLUSIONS: Despite thrombolysis, inhospital ventricular arrhythmias are associated with higher 30-day and 1-year mortality rates after acute myocardial infarction, particularly when occurring later during the initial hospitalization. Better therapies are needed to improve outcomes of these arrhythmias.
Acute Disease↗
Chronic kidney disease, mortality, and treatment strategies among patients with clinically significant coronary artery disease.
Cardiovascular disease is an important cause of mortality among patients with chronic kidney disease (CKD). This study describes associations between CKD, cardiac revascularization strategies, and mortality among patients with CKD and cardiovascular disease. All patients undergoing cardiac catheterization at Duke University Medical Center (1995 to 2000) with documented stenosis > or =75% of at least one coronary artery and available creatinine data were included. CKD was staged using creatinine clearance (CrCl) derived from the Cockcroft-Gault formula (normal, > or = 90 ml/min; mild, 60 to 89 ml/min; moderate, 30 to 59 ml/min; severe, 15 to 29 ml/min). Cox proportional-hazard regression estimated the relationship between clinical variables, including CrCl and percutaneous coronary artery intervention (PCI), coronary artery bypass grafting (CABG), medical management, and patient survival. There were 4584 patients included, and 24% had CrCl <60 ml/min. Each 10-ml/min decrement in CrCl was associated with an increase in mortality (hazard ratio, 1.14; P < 0.0001). CABG was associated with a survival benefit among patients with both normal renal function and patients with CKD compared with medical management. In patients with normal renal function, CABG was not associated with survival benefit over PCI. However, in patients with CKD, CABG was associated with improved survival. PCI was associated with a survival benefit compared with medical management among patients with normal, mildly, and moderately impaired renal function. Among patients with severe CKD, PCI was not associated with improved survival. CABG is associated with greater mortality reduction than PCI in severe CKD.
Aged↗
The anticoagulant therapy with bivalirudin to assist in the performance of percutaneous coronary intervention in patients with heparin-induced thrombocytopenia (ATBAT) study: main results.
Up to 5% of patients given heparin develop heparin-induced thrombocytopenia (HIT). These patients may need anticoagulation for acute coronary syndromes (ACS) or percutaneous coronary intervention (PCI), a clinical challenge given the limited alternatives. In a prospective, open-label study, we evaluated the safety and efficacy of bivalirudin in patients with HIT or HIT with thrombotic syndrome (HITTS) undergoing PCI. Patients aged 18 years were enrolled in 24 centers in 2 countries. Bivalirudin was given 5 minutes before PCI (1 mg/kg bolus; 2.5 mg/kg/hour infusion for 4 hours [high-dose group] or 0.75 mg/kg bolus; 1.75 mg/kg/hour infusion [low-dose group]). Clinical and hematological measures were assessed within 24 hours after starting bivalirudin, just before PCI, just before sheath removal, and 48 hours after treatment or at discharge, whichever occurred first. The primary endpoint was major bleeding 48 hours after discontinuation or until discharge, whichever occurred first. From July 1999 to February 2003, 52 patients were recruited. Procedural success (TIMI grade 3 flow and < 50% stenosis) was achieved in 98% of patients, and clinical success (absence of death, emergency bypass surgery, or Q-wave infarction) was achieved in 96%. One high-dose patient who underwent elective bypass surgery had major bleeding (1.9%; 95% CI: 0.05 10.65%), and 7 patients had minor bleeding. No patient had significant thrombocytopenia (platelet count < 50 109/L) after treatment. One patient in the low-dose group died from cardiac arrest ~46 hours after uncomplicated PCI. Bivalirudin appeared safe and provided effective anticoagulation during PCI. These data, and extensive experience with bivalirudin in PCI, support its use in high-risk patients with HIT requiring PCI.
Aged↗
Comparison of outcomes of patients with myocardial infarction when living alone versus those not living alone.
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Aged↗