Comparative Effectiveness of Aspirin Dosing in Cardiovascular Disease.

BACKGROUND: The appropriate dose of aspirin to lower the risk of death, myocardial infarction, and stroke and to minimize major bleeding in patients with established atherosclerotic cardiovascular disease is a subject of controversy. METHODS: Using an open-label, pragmatic design, we randomly assigned patients with established atherosclerotic cardiovascular disease to a strategy of 81 mg or 325 mg of aspirin per day. The primary effectiveness outcome was a composite of death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke, assessed in a time-to-event analysis. The primary safety outcome was hospitalization for major bleeding, also assessed in a time-to-event analysis. RESULTS: A total of 15,076 patients were followed for a median of 26.2 months (interquartile range [IQR], 19.0 to 34.9). Before randomization, 13,537 (96.0% of those with available information on previous aspirin use) were already taking aspirin, and 85.3% of these patients were previously taking 81 mg of daily aspirin. Death, hospitalization for myocardial infarction, or hospitalization for stroke occurred in 590 patients (estimated percentage, 7.28%) in the 81-mg group and 569 patients (estimated percentage, 7.51%) in the 325-mg group (hazard ratio, 1.02; 95% confidence interval [CI], 0.91 to 1.14). Hospitalization for major bleeding occurred in 53 patients (estimated percentage, 0.63%) in the 81-mg group and 44 patients (estimated percentage, 0.60%) in the 325-mg group (hazard ratio, 1.18; 95% CI, 0.79 to 1.77). Patients assigned to 325 mg had a higher incidence of dose switching than those assigned to 81 mg (41.6% vs. 7.1%) and fewer median days of exposure to the assigned dose (434 days [IQR, 139 to 737] vs. 650 days [IQR, 415 to 922]). CONCLUSIONS: In this pragmatic trial involving patients with established cardiovascular disease, there was substantial dose switching to 81 mg of daily aspirin and no significant differences in cardiovascular events or major bleeding between patients assigned to 81 mg and those assigned to 325 mg of aspirin daily. (Funded by the Patient-Centered Outcomes Research Institute; ADAPTABLE ClinicalTrials.gov number, NCT02697916.).

Comparison of Metoprolol Versus Carvedilol After Acute Myocardial Infarction.

Beta-blockers are typically prescribed following myocardial infarction (MI), but no specific beta-blocker is recommended. Of 7,057 patients enrolled in the OBTAIN multi-center registry of patients with acute MI, 4142 were discharged on metoprolol and 1487 on carvedilol. Beta-blocker dose was indexed to the target daily dose used in randomized clinical trials (metoprolol-200 mg; carvedilol-50 mg), reported as %. Beta-blocker dosage groups were >0% to12.5% (n = 1,428), >12.5% to 25% (n = 2113), >25% to 50% (n = 1,392), and >50% (n = 696). The Kaplan-Meier method was used to calculate 3-year survival. Correction for baseline differences was achieved by multivariable adjustment. Patients treated with carvedilol were older (64.4 vs 63.3 years) and had more comorbidities: hypertension, diabetes, prior MI, congestive heart failure, reduced left ventricular ejection fraction, and a longer length of stay. Mean doses for metoprolol and carvedilol did not significantly differ (37.2 ± 27.8% and 35.8 ± 31.0%, respectively). The 3-year survival estimates were 88.2% and 83.5% for metoprolol and carvedilol, respectively, with an unadjusted HR = 0.72 (p <0.0001), but after multivariable adjustment HR = 1.073 (p = 0.43). Patients in the >12.5% to 25% dose category had improved survival compared with other dose categories. Subgroup analysis of patients with left ventricular ejection fraction ≤40%, showed worse survival with metoprolol versus carvedilol (adjusted HR = 1.281; 95% CI: 1.024 to 1.602, p = 0.03). In patients with left ventricular ejection fraction >40%, there were no differences in survival with carvedilol versus metoprolol. In conclusion, overall survival after acute MI was similar for patients treated with metoprolol or carvedilol, but may be superior for carvedilol in patients with left ventricular ejection fraction ≤40%.

Rationale and Design of the Aspirin Dosing-A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness (ADAPTABLE) Trial.

Importance: Determining the right dosage of aspirin for the secondary prevention treatment of atherosclerotic cardiovascular disease (ASCVD) remains an unanswered and critical question. Objective: To report the rationale and design for a randomized clinical trial to determine the optimal dosage of aspirin to be used for secondary prevention of ASCVD, using an innovative research method. Design, Setting, and Participants: This pragmatic, open-label, patient-centered, randomized clinical trial is being conducted in 15 000 patients within the National Patient-Centered Clinical Research Network (PCORnet), a distributed research network of partners including clinical research networks, health plan research networks, and patient-powered research networks across the United States. Patients with established ASCVD treated in routine clinical practice within the network are eligible. Patient recruitment began in April 2016. Enrollment was completed in June 2019. Final follow-up is expected to be completed by June 2020. Interventions: Participants are randomized on a web platform in a 1:1 fashion to either 81 mg or 325 mg of aspirin daily. Main Outcomes and Measures: The primary efficacy end point is the composite of all-cause mortality, hospitalization for nonfatal myocardial infarction, or hospitalization for a nonfatal stroke. The primary safety end point is hospitalization for major bleeding associated with a blood-product transfusion. End points are captured through regular queries of the health systems' common data model within the structure of PCORnet's distributed data environment. Conclusions and Relevance: As a pragmatic study and the first interventional trial conducted within the PCORnet electronic data infrastructure, this trial is testing several unique and innovative operational approaches that have the potential to disrupt and transform the conduct of future patient-centered randomized clinical trials by evaluating treatments integrated in clinical practice while at the same time determining the optimal dosage of aspirin for secondary prevention of ASCVD. Trial Registration: ClinicalTrials.gov Identifier: NCT02697916.

Utility of the ACE Inhibitor Captopril in Mitigating Radiation-associated Pulmonary Toxicity in Lung Cancer: Results From NRG Oncology RTOG 0123.

OBJECTIVES: The primary objective of NRG Oncology Radiation Therapy Oncology Group 0123 was to test the ability of the angiotensin-converting enzyme inhibitor captopril to alter the incidence of pulmonary damage after radiation therapy for lung cancer; secondary objectives included analyzing pulmonary cytokine expression, quality of life, and the long-term effects of captopril. MATERIALS AND METHODS: Eligible patients included stage II-IIIB non-small cell lung cancer, stage I central non-small cell lung cancer, or limited-stage small cell. Patients who met eligibility for randomization at the end of radiotherapy received either captopril or standard care for 1 year. The captopril was to be escalated to 50 mg three times a day. Primary endpoint was incidence of grade 2+ radiation-induced pulmonary toxicity in the first year. RESULTS: Eighty-one patients were accrued between June 2003 and August 2007. Given the low accrual rate, the study was closed early. No significant safety issues were encountered. Eight patients were ineligible for registration or withdrew consent before randomization and 40 patients were not randomized postradiation. Major reasons for nonrandomization included patients' refusal and physician preference. Of the 33 randomized patients, 20 were analyzable (13 observation, 7 captopril). The incidence of grade 2+ pulmonary toxicity attributable to radiation therapy was 23% (3/13) in the observation arm and 14% (1/7) in the captopril arm. CONCLUSIONS: Despite significant resources and multiple amendments, NRG Oncology Radiation Therapy Oncology Group 0123 was unable to test the hypothesis that captopril mitigates radiation-induced pulmonary toxicity. It did show the safety of such an approach and the use of newer angiotensin-converting enzyme inhibitors started during radiotherapy may solve the accrual problems.

Organization and staffing practices in US cardiac intensive care units: a survey on behalf of the American Heart Association Writing Group on the Evolution of Critical Care Cardiology.

BACKGROUND: The cardiac intensive care unit (CICU) has evolved into a complex patient-care environment with escalating acuity and increasing utilization of advanced technologies. These changing demographics of care may require greater clinical expertise among physician providers. Despite these changes, little is known about present-day staffing practices in US CICUs. METHODS AND RESULTS: We conducted a survey of 178 medical directors of ICUs caring for cardiac patients to assess unit structure and physician staffing practices. Data were obtained from 123 CICUs (69% response rate) that were mostly from academic medical centres. A majority of hospitals utilized a dedicated CICU (68%) and approximately half of those hospitals employed a 'closed' unit model. In 46% of CICUs, an intensivist consult was available, but not routinely involved in care of critically ill cardiovascular patients, while 11% did not have a board-certified intensivist available for consultation. Most CICU directors (87%) surveyed agreed that a closed ICU structure provided better care than an open ICU and 81% of respondents identified an unmet need for cardiologists with critical care training. CONCLUSIONS: We report contemporary structural models and staffing practices in a sample of US ICUs caring for critically ill cardiovascular patients. Although most hospitals surveyed had dedicated CICUs, a minority of CICUs employed a 'closed' CICU model and few had routine intensivist staffing. Most CICU directors agree that there is a need for cardiologists with intensivist training and expertise. These survey data reveal potential areas for continued improvement in US CICU organizational structure and physician staffing.

Comparison of twelve-lead electrocardiogram using a glove-based recording system with standard methodology.

We tested the clinically relevant diagnostic accuracy of a new electrocardiographic (ECG) recording system incorporating all 10 ECG electrodes in a single-size glove worn on the patient's left arm and placed on the chest. The PhysioGlove (PG) was designed to allow fast, reproducible, electrode placement with only minimal training. The American College of Cardiology/American Heart Association ECG recording guidelines and others have repeatedly highlighted the unacceptable progressive deterioration in ECG accuracy mainly resulting from a performer's lack of proficiency and diligence, leading to frequent electrode misplacement. We studied 428 consenting adult patients with a broad spectrum of anthropomorphic characteristics and ECG and cardiovascular pathologic entities. The chest girth was measured to ascertain the single-size PG clinical diagnostic accuracy in ≥90% of this patient population. For each patient, a PG and standard-cable electrocardiogram were consecutively recorded and interpreted by experienced electrocardiographers. The study included 3 phases: phase 1, run-in (n = 120); phase 2, comparative diagnostic accuracy (n = 208); and phase 3, randomized, blinded, diagnostic accuracy (n = 100). Of the entire study population (n = 428), 92% fit the chest girth range of 85 to 118 cm (34 to 47 in.), representing the reference standard clinical diagnostic PG chest girth range. The phase 2 PG diagnostic accuracy was 91.3% for entire chest girth range and 95.7% for the 89.4% of patients with a chest girth within the reference range. The mean PG diagnostic accuracy in phase 3 was 93% (95% confidence interval 89% to 95%). In conclusion, compared with standard-cable electrocardiograms, the PG demonstrated excellent diagnostic accuracy (93% to 95.7%) in ≥90% of a typical western adult patient population. The PG's ease of use and minimal training requirements offer a promising tool to markedly improve ECG clinical diagnostic accuracy in most adult western patients.

Oral antiplatelet therapy for atherothrombotic disease: overview of current and emerging treatment options.

Clinical presentations of atherothrombotic vascular disease, such as acute coronary syndromes, ischemic stroke or transient ischemic attack, and symptomatic peripheral arterial disease, are major causes of morbidity and mortality worldwide. Platelet activation and aggregation play a seminal role in the arterial thrombus formation that precipitates acute manifestations of atherothrombotic disease. As a result, antiplatelet therapy has become the cornerstone of therapy for the prevention and treatment of atherothrombotic disease. Dual antiplatelet therapy with aspirin and a P2Y(12) adenosine diphosphate (ADP) receptor inhibitor, such as clopidogrel or prasugrel, is the current standard-of-care antiplatelet therapy in patients with acute coronary syndromes managed with an early invasive strategy. However, these agents are associated with several important clinical limitations, including significant residual risk for ischemic events, bleeding risk, and variability in the degree of platelet inhibition. The residual risk can be attributed to the fact that aspirin and P2Y(12) inhibitors block only the thromboxane A(2) and ADP platelet activation pathways but do not affect the other pathways that lead to thrombosis, such as the protease-activated receptor-1 pathway stimulated by thrombin, the most potent platelet agonist. Bleeding risk associated with aspirin and P2Y(12) inhibitors can be explained by their inhibitory effects on the thromboxane A(2) and ADP pathways, which are critical for protective hemostasis. Interpatient variability in the degree of platelet inhibition in response to antiplatelet therapy may have a genetic component and contribute to poor clinical outcomes. These considerations underscore the clinical need for therapies with a novel mechanism of action that may reduce ischemic events without increasing the bleeding risk.

Early clopidogrel use in non-ST elevation acute coronary syndrome and subsequent coronary artery bypass grafting.

Clopidogrel use is associated with a significant decrease in major adverse cardiac events when used in patients with non-ST elevation acute coronary syndromes (NSTE-ACS), and guidelines give a class I level of evidence A recommendation for the use of clopidogrel in these patients. The optimal timing of clopidogrel use has not been conclusively determined, but nearly all data available support early use in patients with NSTE-ACS. Despite this, clopidogrel usage is far less than expected based on current guidelines because of concern for bleeding at the time of possible subsequent coronary artery bypass grafting (CABG). Clopidogrel use has been associated with increased perioperative bleeding at the time of CABG, but data are mixed. Numerous studies have conclusively shown that this bleeding risk is confined to those patients receiving clopidogrel within 5 days of CABG. The absolute number of patients exposed to this possible bleeding risk is very small relative to the >1 million patients who present annually with NSTE-ACS and is estimated to be <0.8% of these patients. Recent data have shown that (1) holding clopidogrel for 5 days before CABG is safe in patients with NSTE-ACS and (2) clopidogrel use in patients with NSTE-ACS decreases ischemic events in patients referred for CABG compared to patients who are not given clopidogrel. These data strongly challenge the notion that clopidogrel should be withheld until it is determined if the patient will be referred for CABG.

Overweight and obesity: the pathogenesis of cardiometabolic risk.

Obesity, particularly abdominal adiposity, is increasingly recognized as a cause of elevated cardiometabolic risk--the risk of developing type 2 diabetes mellitus (DM) and cardiovascular disease (CVD). The predominate mechanisms appear to involve the promotion of insulin resistance, driven largely by excess free fatty acids secreted by an expanded adipose tissue mass, and the development of an inflammatory milieu due to increased secretion of inflammatory cytokines and adipokines from adipose tissue. Key proinflammatory cytokines secreted by adipocytes include tumor necrosis factor-alpha, interleukin-6, leptin, resistin, and plasminogen activator inhibitor-1. All have been variously associated with hyperinsulemia, hyperglycemia, insulin resistance, diabetes, and endothelial dysfunction, as well as plaque development, progression, and rupture. Adiponectin, another important adipocyte, has protective cardiometabolic actions; however, adiponectin levels decline with increasing obesity. Understanding the role of obesity in the pathogenesis of cardiometabolic risk is crucial for the development of treatment strategies that will provide maximum benefit for patients with, or at risk for, type 2 DM and CVD.

The role of RAS modification for primary and secondary stroke prevention.

Clinical trial results indicate that the choice of antihypertensive agent can be a determinant of stroke protection, independent of blood pressure (BP) reduction. Angiotensin-converting enzyme inhibitors (ACE-Is) are effective for BP control and stroke protection, but their use may be limited by patient tolerability. Angiotensin receptor blockers appear to provide similar BP control compared with ACE-Is and may also offer the clinician the added benefit of primary and secondary stroke prevention, with the potential for fewer tolerability issues.

Use of and inhospital outcomes after early clopidogrel therapy in patients not undergoing an early invasive strategy for treatment of non-ST-segment elevation myocardial infarction: results from Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association guidelines (CRUSADE).

BACKGROUND: Although current guidelines recommend early initiation of clopidogrel in patients with non-ST-segment elevation myocardial infarction (NSTEMI), the degree to which it has been adopted in clinical practice remains unclear. We sought to determine patterns of early (<24 hours of arrival) clopidogrel use and its association with clinical outcomes in patients with NSTEMI not undergoing early percutaneous intervention (PCI). METHODS: Using data from the CRUSADE initiative, after the exclusion of patients who underwent PCI within 24 hours of arrival, we studied trends in early clopidogrel use among 93,045 patients with NSTEMI. Multivariable logistic regression models were used to determine the association between early clopidogrel treatment and inhospital outcomes. RESULTS: A total of 38.6% of the NSTEMI patients not undergoing PCI within 24 hours of arrival received early clopidogrel. Adjusted inhospital mortality rate was lower in the early clopidogrel group compared to the group that did not receive it on admission (odds ratio 0.68, 95% CI 0.61-0.77). The rate of major bleeding in patients not undergoing coronary artery bypass surgery was similar among the groups treated with and without early clopidogrel (9.5% vs 9.5%, P = .90). CONCLUSIONS: Until recently, up to 50% of NSTEMI patients in contemporary practice in the United States not undergoing PCI within 24 hours of arrival in the United States are not treated according to guideline recommendations. Among a high-risk NSTEMI population not undergoing PCI within 24 hours of arrival, the nonrandomized short-term use of clopidogrel is associated with a lower risk of inhospital mortality without an increased risk of major bleeding.

Insurance coverage and care of patients with non-ST-segment elevation acute coronary syndromes.

BACKGROUND: The impact of insurance coverage on the care of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) is unclear. OBJECTIVE: To compare NSTE ACS care patterns by insurance type. DESIGN: Comparison of Medicaid patients younger than 65 years of age and Medicare patients 65 years of age or older with patients of similar age who have health maintenance organization (HMO) or private insurance coverage. SETTING: 521 U.S. hospitals participating in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC [American College of Cardiology]/AHA [American Heart Association] Guidelines) quality improvement initiative from January 2001 through March 2005. PATIENTS: 37,345 NSTE ACS patients younger than 65 years of age and 59,550 patients 65 years of age or older. MEASUREMENTS: Guideline-recommended treatments, and in-hospital outcomes. RESULTS: Medicaid was the primary payer for 18.7% (6999 of 37,345) of patients younger than age 65 years, whereas Medicare was the primary payer for 67.5% (40,199 of 59,550) of patients age 65 years or older. Medicaid patients were statistically significantly less likely to receive short-term (less than 24 hours) medications and to undergo invasive cardiac procedures than patients covered by HMO and private insurance. They also had higher mortality rates (2.9% vs. 1.2%; adjusted odds ratio, 1.33; 95% CI, 1.08 to 1.63). Medications and invasive procedures were used to a similar extent in patients with Medicare and HMO or private insurance, and respective mortality rates were not significantly different (6.2% vs. 5.6%; adjusted odds ratio, 1.08; 95% CI, 0.99 to 1.18). LIMITATIONS: Self-pay patients and patients without insurance were not assessed. CONCLUSIONS: NSTE ACS patients with Medicaid (but not Medicare) as the primary payer were less likely to receive evidence-based therapies and had worse outcomes than patients with HMO or private insurance as the primary payer. The causes of these treatment differences and solutions for narrowing the gaps in quality require further investigation.

Clopidogrel to treat patients with non-ST-segment elevation acute coronary syndromes after hospital discharge.

BACKGROUND: Clopidogrel added to aspirin improved outcomes after hospitalization in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) in the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, regardless of in-hospital treatment approach. The American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for treating NSTE ACS thus recommend prescribing clopidogrel plus aspirin at discharge for all patients, not just for those undergoing percutaneous coronary intervention (PCI). METHODS: We studied 61 052 patients with high-risk NSTE ACS (defined as the presence of positive cardiac markers and/or ischemic ST-segment changes) from January 2002 through December 2003 at 461 US hospitals participating in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) Quality Improvement Initiative. We evaluated temporal trends of clopidogrel use at discharge since the ACC/AHA 2002 Guidelines update and examined variables associated with clopidogrel use in patients who did not undergo PCI. RESULTS: A total of 34 319 patients (56.2%) received clopidogrel when they were discharged from the hospital. Among patients who did not undergo PCI, variables associated with receiving clopidogrel at discharge included prior PCI, coronary artery bypass grafting (CABG), stroke, or myocardial infarction; hypercholesterolemia; elevated cardiac markers; and cardiology inpatient care. By late 2003, 96.3% of patients who underwent PCI received clopidogrel at discharge, compared with 42.8% of patients who did not undergo cardiac catheterization and 23.5% of the patients who underwent CABG, although clopidogrel prescription at discharge increased in each of these treatment groups from 2002 to 2003. CONCLUSION: Since release of the ACC/AHA Guidelines recommendations for treatment of NSTE ACS, prescription of clopidogrel at hospital discharge in patients with NSTE ACS who are treated with medical therapy alone and in those who undergo CABG has increased, but most of these patients still do not receive clopidogrel at discharge.