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AIMS: Influenza vaccination is associated with reduced cardiopulmonary morbidity and mortality among patients with heart failure or recent myocardial infarction. The immune response to vaccination frequently results in mild adverse reactions (AR), which leads to vaccine hesitancy. This post hoc analysis explored the association between vaccine-related AR and morbidity and mortality in patients with high-risk cardiovascular disease. METHODS AND RESULTS: The INVESTED trial randomized 5260 patients with recent heart failure hospitalization or acute myocardial infarction to high-dose trivalent or standard-dose quadrivalent inactivated influenza vaccine. We examined the association between vaccine-related AR and adverse clinical outcomes across both treatment groups in propensity-adjusted models. Among 5210 participants with available information on post-vaccination symptoms, 1968 participants (37.8%) experienced a vaccine-related AR. Compared to those without AR, post-vaccination AR, most commonly injection site pain (60.3%), were associated with lower risk for the composite of all-cause death or cardiopulmonary hospitalization (hazard ratio [HR] 0.83 [95% CI, 0.75–0.92], p

Background: Patients evaluated for coronary artery disease have a range of symptoms and underlying risk. The relationships between patient-described symptoms, clinician conclusions, and subsequent clinical management and outcomes remain incompletely described. Methods: In this secondary analysis, we examined the association between 4 types of presenting symptoms (substernal/left-sided chest pain, other chest/neck/arm pain, dyspnea, and other symptoms) and patient risk, noninvasive test results, clinical management, and outcomes for stable outpatients randomized in the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial. Multivariable regression models were used to evaluate differences in noninvasive test result, all-cause death/myocardial infarction/unstable angina hospitalization and cardiovascular death/myocardial infarction by symptom type. Results: Among 9996 patients, most presented with chest pain (47.2% substernal, 29.2% other), followed by dyspnea (14.9%), and other symptoms (8.7%). Patients with dyspnea were older (median age 63 versus 60, P ≤0.02) with higher baseline risk (78.2% with atherosclerotic cardiovascular disease >7.5% versus 67.6%, P ≤0.02). Using patients with substernal chest pain as a reference, there was no difference in noninvasive test positivity across symptom groups (all P >0.05), but test-positive patients with dyspnea (adjusted odds ratio, 0.66 [95% CI, 0.51–0.85]) or other symptoms (adjusted odds ratio, 0.65 [95% CI, 0.47–0.90]) were less likely to be referred for cardiac catheterization. While symptom type alone was not associated with outcomes, symptom presentation with chest pain or dyspnea did modify the association between a positive noninvasive test and clinical outcome (interaction P =0.025 for both all-cause death/myocardial infarction/unstable angina hospitalization and cardiovascular death/MI). Conclusions: Among low-risk outpatients evaluated for coronary artery disease, typicality of symptoms was not closely associated with higher baseline risk but was related to differences in processes of care and the prognostic value of a positive test. Adverse events were not associated with clinician risk estimates or symptoms alone. These unexpected findings highlight the limitation of relying solely on symptom presentation or clinician risk estimation to evaluate patients for suspected coronary artery disease. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01174550.

Atrial fibrillation (AF) is one of the strongest risk factors for ischemic stroke, which is a leading cause of disability and death. Given the aging population, increasing prevalence of AF risk factors, and improved survival in those with cardiovascular disease, the number of individuals affected by AF will continue increasing over time. While multiple proven stroke prevention therapies exist, important questions remain about the optimal approach to stroke prevention at the population and individual patient levels. Our report summarizes the National Heart, Lung, and Blood Institute virtual workshop focused on identifying key research opportunities related to stroke prevention in AF. The workshop reviewed major knowledge gaps and identified targeted research opportunities to advance stroke prevention in AF in the following areas: (1) improving risk stratification tools for stroke and intracranial hemorrhage; (2) addressing challenges with oral anticoagulants; and (3) delineating the optimal roles of percutaneous left atrial appendage occlusion and surgical left atrial appendage closure/excision. This report aims to promote innovative, impactful research that will lead to more personalized, effective use of stroke prevention strategies in people with AF.

ImportanceOnly modest attention has been paid to the contributions of social determinants of health to atrial fibrillation (AF) risk factors, diagnosis, symptoms, management, and outcomes. The diagnosis of AF provides unique challenges exacerbated by the arrhythmia’s often paroxysmal nature and individuals’ disparate access to health care and technologies that facilitate detection. Social determinants of health affect access to care and management decisions for AF, increasing the likelihood of adverse outcomes among individuals who experience systemic disadvantages. Developing effective approaches to address modifiable social determinants of health requires research to eliminate the substantive inequities in health care delivery and outcomes in AF.ObservationsThe National Heart, Lung, and Blood Institute convened an expert panel to identify major knowledge gaps and research opportunities in the field of social determinants of AF. The workshop addressed the following social determinants: (1) socioeconomic status and access to care; (2) health literacy; (3) race, ethnicity, and racism; (4) sex and gender; (5) shared decision-making in systemically disadvantaged populations; and (6) place, including rurality, neighborhood, and community. Many individuals with AF have multiple adverse social determinants, which may cluster in the individual and in systemically disadvantaged places (eg, rural locations, urban neighborhoods). Cumulative disadvantages may accumulate over the life course and contribute to inequities in the diagnosis, management, and outcomes in AF.Conclusions and RelevanceWorkshop participants identified multiple critical research questions and approaches to catalyze social determinants of health research that address the distinctive aspects of AF. The long-term aspiration of this work is to eradicate the substantive inequities in AF diagnosis, management, and outcomes across populations.

The interrelationships between atrial fibrillation (AF) and heart failure (HF) are complex and poorly understood, yet the number of patients with AF and HF continues to increase worldwide. Thus, there is a need for initiatives that prioritize research on the intersection between AF and HF. This article summarizes the proceedings of a virtual workshop convened by the US National Heart, Lung, and Blood Institute to identify important research opportunities in AF and HF. Key knowledge gaps were reviewed and research priorities were proposed for characterizing the pathophysiological overlap and deleterious interactions between AF and HF; preventing HF in people with AF; preventing AF in individuals with HF; and addressing symptom burden and health status outcomes in AF and HF. These research priorities will hopefully help inform, encourage, and stimulate innovative, cost-efficient, and transformative studies to enhance the outcomes of patients with AF and HF.

We previously described the design of six NIH-funded clinical trials designed to increase uptake and reduce disparities in the use of cardiac rehabilitation (CR) and pulmonary rehabilitation (PR) based on age, gender, race/ethnicity, and socioeconomic status. The onset of the COVID-19 global pandemic necessitated signifi cant revisions to the trials to ensure the safety of participants and research staff. This article described necessary modifi cations for assessments, interventions, and data collection to support a no-contact approach centered on the use of virtual/remote techniques that maintain both safety and the original intent and integrity of the trials. The general shift from site-based to home-based interventions and hybrid models of CR and PR will be increasingly important in a post-COVID world.

Catheter ablation has brought major advances in the management of patients with atrial fibrillation (AF). As evidenced by multiple randomized trials, AF catheter ablation can reduce the risk of recurrent AF and improve quality of life. In some studies, AF ablation significantly reduced cardiovascular hospitalizations. Despite the existing data on AF catheter ablation, numerous knowledge gaps remain concerning this intervention. This report is based on a recent virtual workshop convened by the National Heart, Lung, and Blood Institute to identify key research opportunities in AF ablation. We outline knowledge gaps related to emerging technologies, the relationship between cardiac structure and function and the success of AF ablation in patient subgroups in whom clinical benefit from ablation varies, and potential platforms to advance clinical research in this area. This report also considers the potential value and challenges of a sham ablation randomized trial. Prioritized research opportunities are identified and highlighted to empower relevant stakeholders to collaborate in designing and conducting effective, cost-efficient, and transformative research to optimize the use and outcomes of AF ablation.

The GUIDE-IT (GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) trial demonstrated that a strategy to "guide" application of guideline-directed medical therapy (GDMT) by reducing amino-terminal pro-B-type natriuretic peptide (NT-proBNP) was not superior to GDMT alone.The purpose of this study was to examine the prognostic meaning of NT-proBNP changes following heart failure (HF) therapy intensification relative to the goal NT-proBNP value of 1,000 pg/ml explored in the GUIDE-IT trial.A total of 638 study participants were included who were alive and had available NT-proBNP results 90 days after randomization. Rates of subsequent cardiovascular (CV) death/HF hospitalization or all-cause mortality during follow-up and Kansas City Cardiomyopathy Questionnaire (KCCQ) overall scores were analyzed.A total of 198 (31.0%) subjects had an NT-proBNP ≤1,000 pg/ml at 90 days with no difference in achievement of NT-proBNP goal between the biomarker-guided and usual care arms. NT-proBNP ≤1,000 pg/ml by 90 days was associated with longer freedom from CV/HF hospitalization or all-cause mortality (p 0.001 for both) and lower adjusted hazard of subsequent HF hospitalization/CV death (hazard ratio: 0.26; 95% confidence interval: 0.15 to 0.46; p 0.001) and all-cause mortality (hazard ratio: 0.34; 95% confidence interval: 0.15 to 0.77; p = 0.009). Regardless of elevated baseline concentration, an NT-proBNP ≤1,000 pg/ml at 90 days was associated with better outcomes and significantly better KCCQ overall scores (p = 0.02).Patients with heart failure with reduced ejection fraction whose NT-proBNP levels decreased to ≤1,000 pg/ml during GDMT had better outcomes. These findings may help to understand the results of the GUIDE-IT trial. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840).

Thyroid hormones have long been known to have a range of effects on the cardiovascular system. However, significant knowledge gaps exist concerning the precise molecular and biochemical mechanisms governing these effects and the optimal strategies for management of abnormalities in thyroid function in patients with and without preexisting cardiovascular disease. In September 2017, the National Heart, Lung, and Blood Institute convened a Working Group with the goal of developing priorities for future scientific research relating thyroid dysfunction to the progression of cardiovascular disease. The Working Group reviewed and discussed the roles of normal thyroid physiology, the consequences of thyroid dysfunction, and the effects of therapy in 3 cardiovascular areas: cardiac electrophysiology and arrhythmias, the vasculature and atherosclerosis, and the myocardium and heart failure. This report describes the current state of the field, outlines barriers and challenges to progress, and proposes research opportunities to advance the field, including strategies for leveraging novel approaches using omics and big data. The Working Group recommended research in 3 broad areas: (1) investigation into the fundamental biology relating thyroid dysfunction to the development of cardiovascular disease and into the identification of novel biomarkers of thyroid hormone action in cardiovascular tissues; (2) studies that define subgroups of patients with thyroid dysfunction amenable to specific preventive strategies and interventional therapies related to cardiovascular disease; and (3) clinical trials focused on improvement in cardiovascular performance and cardiovascular outcomes through treatment with thyroid hormone or thyromimetic drugs.

There has been sustained focus on the secondary prevention of coronary heart disease and heart failure; yet, apart from stroke prevention, the evidence base for the secondary prevention of atrial fibrillation (AF) recurrence, AF progression, and AF‐related complications is modest. Although there are multiple observational studies, there are few large, robust, randomized trials providing definitive effective approaches for the secondary prevention of AF. Given the increasing incidence and prevalence of AF nationally and internationally, the AF field needs transformative research and a commitment to evidenced‐based secondary prevention strategies. We report on a National Heart, Lung, and Blood Institute virtual workshop directed at identifying knowledge gaps and research opportunities in the secondary prevention of AF. Once AF has been detected, lifestyle changes and novel models of care delivery may contribute to the prevention of AF recurrence, AF progression, and AF‐related complications. Although benefits seen in small subgroups, cohort studies, and selected randomized trials are impressive, the widespread effectiveness of AF secondary prevention strategies remains unknown, calling for development of scalable interventions suitable for diverse populations and for identification of subpopulations who may particularly benefit from intensive management. We identified critical research questions for 6 topics relevant to the secondary prevention of AF: (1) weight loss; (2) alcohol intake, smoking cessation, and diet; (3) cardiac rehabilitation; (4) approaches to sleep disorders; (5) integrated, team‐based care; and (6) nonanticoagulant pharmacotherapy. Our goal is to stimulate innovative research that will accelerate the generation of the evidence to effectively pursue the secondary prevention of AF.

Background NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) is a prognostic biomarker in heart failure (HF) with reduced ejection fraction. However, it is unclear whether there is a sex difference in NT‐proBNP response and whether the therapeutic goal of NT‐proBNP ≤1000 pg/mL has equivalent prognostic value in men and women with HF with reduced ejection fraction. Methods and Results In a secondary analysis of the GUIDE‐IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment) trial we analyzed trends in NT‐proBNP and goal attainment by sex. Differences in clinical characteristics, HF treatment, and time to all‐cause death or HF hospitalization were compared. Landmark analysis at 3 months determined the prognostic value of early NT‐proBNP goal achievement in men and women. Of the 286 (32%) women and 608 (68%) men in the GUIDE‐IT trial, women were more likely to have a nonischemic cause and shorter duration of HF. Guideline‐directed medical therapy was less intense over time in women. The absolute NT‐proBNP values were consistently lower in women; however, the change in NT‐proBNP and clinical outcomes were similar. After adjustment, women achieving the NT‐proBNP goal had an 82% reduction in death or HF hospitalization compared with a 59% reduction in men. Conclusions Men and women with HF with reduced ejection fraction had a similar NT‐proBNP response despite less intensive HF treatment among women. However, compared with men, the early NT‐proBNP goal of ≤1000 pg/mL had greater prognostic value in women. Future efforts should be aimed at intensifying guideline‐directed medical therapy in women, which may result in greater NT‐proBNP reductions and improved outcomes in women with HF with reduced ejection fraction. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01685840.

Clinically recognized atrial fibrillation (AF) is associated with higher risk of complications, including ischemic stroke, cognitive decline, heart failure, myocardial infarction, and death. It is increasingly recognized that AF frequently is undetected until complications such as stroke or heart failure occur. Hence, the public and clinicians have an intense interest in detecting AF earlier. However, the most appropriate strategies to detect undiagnosed AF (sometimes referred to as subclinical AF) and the prognostic and therapeutic implications of AF detected by screening are uncertain. Our report summarizes the National Heart, Lung, and Blood Institute’s virtual workshop focused on identifying key research priorities related to AF screening. Global experts reviewed major knowledge gaps and identified critical research priorities in the following areas: (1) role of opportunistic screening; (2) AF as a risk factor, risk marker, or both; (3) relationship between AF burden detected with long-term monitoring and outcomes/treatments; (4) designs of potential randomized trials of systematic AF screening with clinically relevant outcomes; and (5) role of AF screening after ischemic stroke. Our report aims to inform and catalyze AF screening research that will advance innovative, resource-efficient, and clinically relevant studies in diverse populations to improve the diagnosis, management, and prognosis of patients with undiagnosed AF.

Although both cardiac rehabilitation (CR) and pulmonary rehabilitation (PR) are recommended by clinical practice guidelines and covered by most insurers, they remain severely underutilized. To address this problem, the National Heart, Lung, and Blood Institute (NHLBI), in collaboration with the National Institute on Aging (NIA), developed Funding Opportunity Announcements (FOAs) in late 2017 to support phase II clinical trials to increase the uptake of CR and PR in traditional and community settings. The objectives of these FOAs were to (1) test strategies that will lead to increased use of CR and PR in the US population who are eligible based on clinical guidelines; (2) test strategies to reduce disparities in the use of CR and PR based on age, gender, race/ethnicity, and socioeconomic status; and (3) test whether increased use of CR and PR, whether by traditional center-based or new models, is accompanied by improvements in relevant clinical and patient-centered outcomes, including exercise capacity, cardiovascular and pulmonary risk factors, and quality of life. Five NHLBI grants and a single NIA grant were funded in the summer of 2018 for this CR/PR collaborative initiative. A brief description of the research to be developed in each grant is provided.

This study aims to assess the association between biomarker-guided therapy and left ventricular (LV) remodeling.In patients with heart failure with reduced ejection fraction (HFrEF), it is unclear if lowering natriuretic peptides reflects structural and functional changes in the heart. This study aims to assess the association between biomarker-guided therapy and left ventricular (LV) remodeling.The GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) Echo Substudy was a multicenter study that randomized 268 patients with HFrEF (EF ≤40%) to either pro-B-type natriuretic peptide (NT-proBNP)-guided treatment or usual care. Echocardiograms were performed at baseline and 12 months in 124 patients. Remodeling indices and clinical outcomes were compared between treatment arms and by achievement of the NT-proBNP goal of 1,000 pg/ml at 12 months.At 12 months, the changes in EF and LV volumes were similar between the biomarker-guided and usual care arms with no difference in clinical outcomes; however, lowering NT-proBNP to 1,000 pg/ml, regardless of treatment strategy, was associated with a significantly greater increase in EF compared with those not reaching goal (9.9 ± 8.8% vs. 2.9 ± 7.9%; p 0.001) and lower LV volumes. The extent of reverse remodeling correlated with the change in NT-proBNP: a decrease of 1,000 pg/ml was associated with an increase in EF of 6.7% and a reduction in systolic and diastolic volumes of 17.3 ml/mAmong patients with HFrEF, lowering NT-proBNP to 1,000 pg/ml by 12 months was associated with significant reverse remodeling and improved outcomes. A greater reduction in NT-proBNP was associated with more extensive reverse remodeling. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840).

IMPORTANCE: Despite evidence that guideline-directed medical therapy (GDMT) improves outcomes in patients with heart failure (HF) and reduced ejection fraction, many patients are undertreated. The Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment (GUIDE-IT) trial tested whether a strategy of using target concentrations of N-terminal pro–brain natriuretic peptide (NT-proBNP) to guide optimization of GDMT could improve outcomes. OBJECTIVE: To examine medical therapy for HF in GUIDE-IT and potential reasons why the intervention did not produce improvements in medical therapy. DESIGN, SETTING, AND PARTICIPANTS: GUIDE-IT, a randomized clinical trial performed at 45 sites in the United States and Canada, was conducted from January 16, 2013, to September 20, 2016. A total of 894 patients with HF and reduced ejection fraction (≤40%) were randomized to NT-proBNP−guided treatment with a goal to suppress NT-proBNP concentrations to less than 1000 pg/mL vs usual care. This secondary analysis examined the medical therapy titration and reasons why the intervention did not produce improvements in care and outcomes. Data were analyzed March 27 to June 28, 2019. MAIN OUTCOMES AND MEASURES: For each encounter, medication titrations were captured. A reason was requested if a modification was not made. A Cox proportional hazards regression model was used to assess the independent association of drug class with outcomes. RESULTS: Among the 838 patients available for analysis (566 men [67.5%]; median age, 62.0 years), 6223 visits occurred during 24 months. Adjustments of HF medication were made during 2847 of 5218 qualified visits (54.6%) (all usual care visits and all guided care visits with NT-proBNP level ≥1000 pg/mL) in 862 patients (96.4%). Most adjustments occurred within the first 6 months, primarily within the first 6 weeks. The most common reasons for not adjusting were “clinically stable” and “already at maximally tolerated therapy.” Only 130 patients (15.5%) achieved optimal GDMT (≥50% of the target dose of β-blockers or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or any dose of mineralocorticoid antagonists) at 6 months, an increase from the baseline (79 of 891 [8.9%]) but not different by treatment arm. Higher doses of β-blockers were associated with reduced risk of the composite outcome of HF hospitalization and cardiovascular death (hazard ratio [HR], 0.98; 95% CI, 0.97-1.00; P = .008) and of all-cause death (HR, 0.97; 95% CI, 0.95-0.99; P = .01). Higher doses of angiotensin-converting enzyme inhibitors (HR, 0.84; 95% CI, 0.75-0.93; P

Objectives This study sought to evaluate the influence of baseline physical activity (PA) on responses to aerobic exercise training and clinical events in outpatients with chronic systolic heart failure (HF) from the multicenter HF-ACTION (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure) trial. Background The influence of baseline PA on exercise capacity, responses to exercise training and clinical outcomes in patients with chronic HF is unclear. Methods Of 2,130 participants who provided consent for this analysis, 1,494 patients (64%) had complete baseline PA data, using a modified version of the International Physical Activity Questionnaire–Short Form questionnaire and were included in the analysis; 742 received usual care and 752 were allocated to the exercise training group. Changes in exercise capacity, all-cause mortality and hospitalization, cardiovascular (CV) mortality and hospitalization, and CV mortality and HF hospitalization were evaluated as a function of baseline PA tertile. Results At baseline, the highest PA tertile showed greater peak oxygen uptake, cardiopulmonary exercise test duration, and 6-min walk test distance than the other 2 PA tertiles, as well as lower New York Heart Association functional class, lower Beck depression score, and lower atrial fibrillation prevalence than the lowest PA tertile. Compared to the lowest PA tertile, the middle tertile had 18% lower risk of CV death/CV hospitalizations, and the upper tertile showed 23% lower risk of CV death/HF hospitalizations. Exercise capacity and clinical outcome responses to training were similar and largely nonsignificant across baseline PA tertiles with significant benefit of training on exercise test duration for all tertiles. Conclusions In patients with chronic systolic HF, aerobic exercise training significantly improves exercise test duration to a similar extent across baseline PA tertiles. Although higher baseline PA was associated with lower risk of clinical events, no significant differences in event rates within each PA tertile were seen between subgroups randomized to exercise training versus usual care. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure [HF-ACTION]; NCT00047437 )

The Cardiovascular Disease in Women Committee of the American College of Cardiology, in conjunction with interested parties (from the National Heart, Lung, and Blood Institute, American Heart Association, and European Society of Cardiology), convened a working group to develop a consensus on the syndrome of myocardial ischemia with no obstructive coronary arteries. In general, these patients have elevated risk for a cardiovascular event (including acute coronary syndrome, heart failure hospitalization, stroke, and repeat cardiovascular procedures) compared with reference subjects and appear to be at higher risk for development of heart failure with preserved ejection fraction. A subgroup of these patients also has coronary microvascular dysfunction and evidence of inflammation. This document provides a summary of findings and recommendations for the development of an integrated approach for identifying and managing patients with ischemia with no obstructive coronary arteries and outlines knowledge gaps in the area. Working group members critically reviewed available literature and current practices for risk assessment and state-of-the-science techniques in multiple areas, with a focus on next steps needed to develop evidence-based therapies. This report presents highlights of this working group review and a summary of suggested research directions to advance this field in the next decade.

IMPORTANCE: Although cardiovascular (CV) disease represents the leading cause of morbidity and mortality that increases with age, the best noninvasive test to identify older patients at risk for CV events remains unknown. OBJECTIVE: To determine whether the prognostic utility of anatomic vs functional testing varies based on patient age. DESIGN, SETTING, AND PARTICIPANTS: Prespecified analysis of the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) study, which used a pragmatic comparative effectiveness design. Participants were enrolled from 193 sites across North America and comprised outpatients without known coronary artery disease (CAD) but with symptoms suggestive of CAD. Data were analyzed between October 2018 and April 2019. INTERVENTIONS: Randomization to noninvasive testing with coronary computed tomographic angiography or functional testing. MAIN OUTCOMES AND MEASURES: The composite of CV death/myocardial infarction (MI) over a median follow-up of 25 months. RESULTS: Among 10 003 PROMISE patients, we included the 8966 who received the noninvasive test to which they were randomized and had interpretable results; 6378 (71.1%) were younger than 65 years, 2062 (23.0%) were between ages 65 and 74 years, and 526 (5.9%) were 75 years and older. More than half of participants were women (4720 of 8966 [52.6%]). Only a minority of patients were of nonwhite race/ethnicity, a proportion that was lower among the older age groups (1071 of 6378 [16.8%] for

ObjectivesTo test the relationship between increasing severity of obesity, calculated risk and observed outcomes.MethodsPatients with symptoms suggestive of coronary artery disease (CAD) (n=10 003) were stratified according to body mass index (BMI). We compared risk factors, pooled risk scores and physicians’ perception of risk. Cox regression tested the association between BMI and (1) presence of obstructive CAD and (2) composite clinical endpoints (death, cardiovascular death, unstable angina hospitalisation and myocardial infarction).ResultsBMI was ≥30 kg/m2 in 48% of patients and ≥35 in 20%. Increasingly obese patients were younger, female and non-smoking but with higher prevalence of hypertension, diabetes, black race and sedentary lifestyle. Pooled risk estimates of CAD were highest in those with mid-range BMI. In contrast, physicians’ estimation of the likelihood of significant CAD based on clinical impression increased progressively with BMI. For a 10% increase in the Diamond-Forrester probability of CAD, the adjusted OR for obstructive CAD was 1.5 (95% CI 1.4 to 1.5) in patients with BMI ConclusionsDespite perceptions of higher risk and higher risk scores, increasingly obese patients had obstructive CAD less frequently than predicted and had fewer adverse clinical outcomes. There is a need for risk assessment tools and guidelines that account for obesity.Trial registration numberNCT01174550.

Background Most heart failure (HF) risk scores have been derived from cohorts of stable HF patients and may not incorporate up to date treatment regimens or deep phenotype characterization that change baseline risk over the short- and long-term follow-up period. We undertook the current analysis of participants in the GUIDE-IT (Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment) trial to address these limitations. Methods and results The GUIDE-IT study randomized 894 high-risk patients with HF and reduced ejection fraction (≤ 40%) to biomarker-guided treatment strategy vs. usual care. We performed risk modelling using Cox proportional hazards models and analysed the relationship between 35 baseline clinical factors and the primary composite endpoint of cardiovascular (CV) death or HF hospitalization, the secondary endpoint of all-cause mortality, and the exploratory endpoint of 90-day HF hospitalization or death. Prognostic relationships for continuous variables were examined and key predictors were identified using a backward variable selection process. Predictive models and risk scores were developed. Over a median follow-up of 15 months, the cumulative number of HF hospitalizations and CV deaths was 328 out of 894 patients (Kaplan-Meier event rate 34.5% at 12 months). Frequency of all-cause deaths was 143 out of 894 patients (Kaplan-Meier event rate 12.2% at 12 months). Outcomes for the primary and secondary endpoints between strategy arms of the study were similar. The most important predictor that was present in all three models was the baseline natriuretic peptide level. Hispanic ethnicity, low sodium and high heart rate were present in two of the three models. Other important predictors included the presence or absence of a device, New York Heart Association class, HF duration, black race, co-morbidities (sleep apnoea, elevated creatinine, ischaemic heart disease), low blood pressure, and a high congestion score. Conclusion Risk models using readily available clinical information are able to accurately predict short- and long-term CV events and may be useful in optimizing care and enriching patients for clinical trials. Clinical trial registration ClinicalTrials.gov ID number NCT01685840.

Objectives The aim of this study was to assess for a treatment interaction between statin use and exercise training (ET) response. Background Recent data suggest that statins may attenuate ET response, but limited data exist in patients with heart failure (HF). Methods HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) was a randomized trial of 2,331 patients with chronic HF with ejection fraction ≤35% who were randomized to usual care with or without ET. We evaluated whether there was a treatment interaction between statins and ET response for the change in quality of life and aerobic capacity (peak oxygen consumption and 6-min walk distance) from baseline to 3 months. We also assessed for a treatment interaction among atorvastatin, simvastatin, and pravastatin and change in these endpoints with ET. Multiple linear regression analyses were performed for each endpoint, adjusting for baseline covariates. Results Of 2,331 patients in the HF-ACTION trial, 1,353 (58%) were prescribed statins at baseline. Patients treated with statins were more likely to be older men with ischemic HF etiology but had similar use of renin angiotensin system blockers and beta-blockers. There was no evidence of a treatment interaction between statin use and ET on changes in quality of life or exercise capacity, nor was there evidence of differential association between statin type and ET response for these endpoints (all p values >0.05). Conclusions In a large chronic HF cohort, there was no evidence of a treatment interaction between statin use and short-term change in aerobic capacity and quality of life with ET. These findings contrast with recent reports of an attenuation in ET response with statins in a different population, highlighting the need for future prospective studies. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437)

Background— The Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial found that initial use of ≥64 detector-row computed tomography angiography versus standard functional testing strategies (exercise ECG, stress nuclear methods, or stress echocardiography) did not improve clinical outcomes in 10 003 stable symptomatic patients with suspected coronary artery disease requiring noninvasive testing. Symptom burden and quality of life (QOL) were major secondary outcomes. Methods and Results— We prospectively collected a battery of QOL instruments in 5985 patients at baseline and 6, 12, and 24 months postrandomization. The prespecified primary QOL measures were the Duke Activity Status Index and the Seattle Angina Questionnaire frequency and QOL scales. All comparisons were made as randomized. Baseline variables were well balanced in the 2982 patients randomly assigned to computed tomography angiography testing and the 3003 patients randomly assigned to functional testing. The Duke Activity Status Index improved substantially in both groups over the first 6 months following testing, but we found no evidence for a strategy-related difference (mean difference [anatomic – functional] at 24 months of follow-up, 0.1 [95% confidence interval, –0.9 to 1.1]). Similar results were seen for the Seattle Angina Questionnaire frequency scale (mean difference at 24 months, –0.2; 95% confidence interval, –0.8 to 0.4) and QOL scale (mean difference at 24 months, –0.2; 95% confidence interval, –1.3 to 0.9). None of the secondary QOL measures showed a consistent strategy-related difference. Conclusions— In symptomatic patients with suspected coronary artery disease who required noninvasive testing, symptoms and QOL improved significantly. However, a strategy of initial anatomic testing, in comparison with functional testing, did not provide an incremental benefit for QOL over 2 years of follow-up. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01174550.

Importance Influenza is temporally associated with cardiopulmonary morbidity and mortality among those with cardiovascular disease who may mount a less vigorous immune response to vaccination. Higher influenza vaccine dose has been associated with reduced risk of influenza illness. Objective To evaluate whether high-dose trivalent influenza vaccine compared with standard-dose quadrivalent influenza vaccine would reduce all-cause death or cardiopulmonary hospitalization in high-risk patients with cardiovascular disease. Design, Setting, and Participants Pragmatic multicenter, double-blind, active comparator randomized clinical trial conducted in 5260 participants vaccinated for up to 3 influenza seasons in 157 sites in the US and Canada between September 21, 2016, and January 31, 2019. Patients with a recent acute myocardial infarction or heart failure hospitalization and at least 1 additional risk factor were eligible. Interventions Participants were randomly assigned to receive high-dose trivalent (n = 2630) or standard-dose quadrivalent (n = 2630) inactivated influenza vaccine and could be revaccinated for up to 3 seasons. Main Outcomes and Measures The primary outcome was the time to the composite of all-cause death or cardiopulmonary hospitalization during each enrolling season. The final date of follow-up was July 31, 2019. Vaccine-related adverse events were also assessed. Results Among 5260 randomized participants (mean [SD] age, 65.5 [12.6] years; 3787 [72%] men; 3289 [63%] with heart failure) over 3 influenza seasons, there were 7154 total vaccinations administered and 5226 (99.4%) participants completed the trial. In the high-dose trivalent vaccine group, there were 975 primary outcome events (883 hospitalizations for cardiovascular or pulmonary causes and 92 deaths from any cause) among 884 participants during 3577 participant-seasons (event rate, 45 per 100 patient-years), whereas in the standard-dose quadrivalent vaccine group, there were 924 primary outcome events (846 hospitalizations for cardiovascular or pulmonary causes and 78 deaths from any cause) among 837 participants during 3577 participant-seasons (event rate, 42 per 100 patient-years) (hazard ratio, 1.06 [95% CI, 0.97-1.17];P = .21). In the high-dose vs standard-dose groups, vaccine-related adverse reactions occurred in 1449 (40.5%) vs 1229 (34.4%) participants and severe adverse reactions occurred in 55 (2.1%) vs 44 (1.7%) participants. Conclusions and Relevance In patients with high-risk cardiovascular disease, high-dose trivalent inactivated influenza vaccine, compared with standard-dose quadrivalent inactivated influenza vaccine, did not significantly reduce all-cause mortality or cardiopulmonary hospitalizations. Influenza vaccination remains strongly recommended in this population. Trial Registration ClinicalTrials.gov Identifier:NCT02787044

Background: Patients with type 2 diabetes (T2D) are at high risk of cardiovascular (CV) morbidity/mortality. The ACCORD trial (NCT00000620) tested intensive glycemic, lipid and blood pressure interventions on major CV events in 10,251 T2D patients with baseline HbA1c concentration >7.5%. Despite its landmark findings, a data-driven systematic evaluation of predictors for major cardiovascular events among hundreds of ACCORD variables has not been conducted. Methods: Random Survival Forest (RSF), a machine-learning method for survival analysis, identified important predictors for total mortality (TM), CV death (CVd), hospitalization/death due to heart failure (hdHF), fatal/non-fatal stroke (CVA), non-fatal myocardial infarction (MI) and MACE (composite of CVd, MI and CVA). Among 378 risk factors, including some highly correlated features, the top-ranked predictors (collected at baseline or derived from repeated measures prior to events) were selected, resulting in a hierarchy of predictive variables. Effects of RSF-selected predictors were then evaluated by multivariate Cox Proportional Hazards Models. Results: Table 1 presented the top ten predictors for six major events. Variables associated with changes in renal function predicted TM, CVd, and hdHF with ~90% accuracy. Insulin use was an important predictor along with predefined composite renal microvascular events for MI, CVA and MACE (74-79% accuracy). The Cox regression models based on RSF variable selection yielded similar findings for these important predictors of events. Conclusions: RSF approach revealed that insulin use and overt renal microvascular events were predictors for the occurrence of MI, stroke, and MACE in T2D patients. Moreover, dynamic changes in urinary renal function biomarkers had additional predictive values for fatal events. These results provide important clinical insights for reducing CV events in Type 2 diabetes patients.

Introduction: An objective of the Meta-AnalyTical Interagency Group (MATIG) is to conduct patient-level meta-analyses of cardiovascular outcomes using data from publicly available repositories. We describe challenges with data re-use from a seminal trial, provide a systematic approach to identify and curate data elements for hypothesis generation, and establish stackable trials to support these analyses. Methods: We used data from the ACCORD trial to assess risk factors and their gender specific differences for the event of hospitalization or death due to heart failure (hdHF), in patients with type 2 diabetes*. We identified the data elements needed to answer the research questions, reviewed the trial protocol to verify definitions, extracted patient-level data, performed quality assessment and statistical analysis. The results showed a gender difference in the effect of intensive vs. standard glucose-lowering therapy on hdHF. To validate the findings, we sought additional trials in BioLINCC to develop a compendium for meta-analysis, and repeated these steps for each trial. Results: Challenges for reusing the ACCORD trial included access to complete patient-level data and metadata. The compendium, developed to evaluate the stackability** of data across trials, identified differences in trial designs, patient populations, study interventions, and data elements that may impact the feasibility and interpretation of meta-analysis. An example of compendium components is shown in Table 1. Conclusion: High-quality metadata facilitate re-use of trial repository data. This compendium standardizes common data elements for gender, racial and age-group specific outcome assessment in major clinical trials. It provides the framework to assess the fitness of trials for patient-level meta-analyses. Efforts are underway by MATIG to expand the compendium to include risk factors and major cardiovascular outcomes across multiple large trials for meta-analysis.

This study sought to evaluate the influence of baseline physical activity (PA) on responses to aerobic exercise training and clinical events in outpatients with chronic systolic heart failure (HF) from the multicenter HF-ACTION (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure) trial.The influence of baseline PA on exercise capacity, responses to exercise training and clinical outcomes in patients with chronic HF is unclear.Of 2,130 participants who provided consent for this analysis, 1,494 patients (64%) had complete baseline PA data, using a modified version of the International Physical Activity Questionnaire-Short Form questionnaire and were included in the analysis; 742 received usual care and 752 were allocated to the exercise training group. Changes in exercise capacity, all-cause mortality and hospitalization, cardiovascular (CV) mortality and hospitalization, and CV mortality and HF hospitalization were evaluated as a function of baseline PA tertile.At baseline, the highest PA tertile showed greater peak oxygen uptake, cardiopulmonary exercise test duration, and 6-min walk test distance than the other 2 PA tertiles, as well as lower New York Heart Association functional class, lower Beck depression score, and lower atrial fibrillation prevalence than the lowest PA tertile. Compared to the lowest PA tertile, the middle tertile had 18% lower risk of CV death/CV hospitalizations, and the upper tertile showed 23% lower risk of CV death/HF hospitalizations. Exercise capacity and clinical outcome responses to training were similar and largely nonsignificant across baseline PA tertiles with significant benefit of training on exercise test duration for all tertiles.In patients with chronic systolic HF, aerobic exercise training significantly improves exercise test duration to a similar extent across baseline PA tertiles. Although higher baseline PA was associated with lower risk of clinical events, no significant differences in event rates within each PA tertile were seen between subgroups randomized to exercise training versus usual care. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure [HF-ACTION]; NCT00047437).

The GUIDE-IT (GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) trial prospectively compared the efficacy of an N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided heart failure treatment strategy (target NT-proBNP level 1,000 pg/ml) with optimal medical therapy alone in high-risk patients with heart failure and reduced ejection fraction. When the study was stopped for futility, 894 patients had been enrolled.The purpose of this study was to assess treatment-related quality-of-life (QOL) and economic outcomes in the GUIDE-IT trial.The authors prospectively collected a battery of QOL instruments at baseline and 3, 6, 12, and 24 months post-randomization (collection rates 90% to 99% of those eligible). The principal pre-specified QOL measures were the Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and the Duke Activity Status Index (DASI). Cost data were collected for 735 (97%) U.S.Baseline variables were well balanced in the 446 patients randomized to the NT-proBNP-guided therapy and 448 to usual care. Both the KCCQ and the DASI improved over the first 6 months, but no evidence was found for a strategy-related difference (mean difference [biomarker-guided - usual care] at 24 months of follow-up 2.0 for DASI [95% confidence interval (CI): -1.3 to 5.3] and 1.1 for KCCQ [95% CI: -3.7 to 5.9]). Total winsorized costs averaged $5,919 higher in the biomarker-guided strategy (95% CI: -$1,795, +$13,602) over 15-month median follow-up.A strategy of NT-proBNP-guided HF therapy had higher total costs and was not more effective than usual care in improving QOL outcomes in patients with heart failure and a reduced ejection fraction. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840).

BACKGROUND: Influenza leads to significant cardiopulmonary morbidity and mortality, particularly in patients with cardiovascular disease, that may be prevented with a standard influenza vaccine. However, patients with cardiovascular conditions have a reduced immune response to influenza vaccine, potentially resulting in reduced effectiveness for preventing clinical events. High-dose vaccine augments immune response in cardiac patients, suggesting that a high-dose influenza vaccination strategy may further reduce morbidity and mortality. Alternatively, broader coverage with an influenza vaccine containing an increased number of viral strains is an alternative strategy without direct evaluation. RESEARCH DESIGN AND METHODS: INfluenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated heart failure (INVESTED) is a pragmatic, randomized, double-blind, parallel group, active-controlled trial comparing the effectiveness of an annual vaccination strategy of high-dose trivalent versus standard-dose quadrivalent influenza vaccine in patients with a history of recent heart failure or myocardial infarction hospitalization. The trial will enroll approximately 9300 patients over four influenza seasons. The primary hypothesis is that high dose influenza vaccine will reduce the composite outcome of all-cause mortality and hospitalization from a cardiovascular or pulmonary cause compared with standard dose influenza vaccine within each enrolling season. Approximately 1300 primary outcome events will provide >90% power to detect a 18% relative risk reduction at a two-sided alpha level of 0.05. CONCLUSION: INVESTED is the largest and longest study to assess whether high-dose influenza vaccine is superior to standard-dose influenza vaccine in reducing cardiopulmonary events in a high-risk cardiovascular population patients with heart failure and/or myocardial infarction (ClinicalTrials.gov Identifier: NCT02787044).

Background— Psychosocial factors may influence adherence with exercise training for heart failure (HF) patients. We aimed to describe the association between social support and barriers to participation with exercise adherence and clinical outcomes. Methods and Results— Of patients enrolled in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION), 2279 (97.8%) completed surveys to assess social support and barriers to exercise, resulting in the perceived social support score (PSSS) and barriers to exercise score (BTES). Higher PSSS indicated higher levels of social support, whereas higher BTES indicated more barriers to exercise. Exercise time at 3 and 12 months correlated with PSSS ( r = 0.09 and r = 0.13, respectively) and BTES ( r =−0.11 and r =−0.12, respectively), with higher exercise time associated with higher PSSS and lower BTES (All P P =0.035), which corresponded to a borderline association between increasing BTES and cardiovascular death or HF hospitalization in the exercise group (hazard ratio 1.25, 95% confidence interval 0.99, 1.59), but no association in the usual care group (hazard ratio 0.83, 95% confidence interval 0.66, 1.06). Conclusions— Poor social support and high barriers to exercise were associated with lower exercise time. PSSS did not impact the effect of exercise training on outcomes. However, for cardiovascular death or HF hospitalization, exercise training had a greater impact on patients with lower BTES. Given that exercise training improves outcomes in HF patients, assessment of perceived barriers may facilitate individualized approaches to implement exercise training therapy in clinical practice. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00047437.

BackgroundPatients hospitalized with heart failure are often readmitted. Health literacy may play a substantial role in the high rate of readmissions. The purpose of this study was to examine the association of health literacy with the composite end point of heart failure readmission rates and all-cause mortality in patients with heart failure living in rural areas.Methods and resultsRural adults (n= 575), hospitalized for heart failure within the past 6 months, completed the Short Test of Functional Health Literacy in Adults (STOFHLA) to measure health literacy and were followed for ≥2 years. The percentage of patients with the end point of heart failure readmission or all-cause death was different (P= .001) among the 3 STOFHLA score levels. Unadjusted analysis revealed that patients with inadequate and marginal health literacy were 1.94 (95% confidence interval [CI] 1.43-2.63; P < .001) times, and 1.91 (95% CI 1.36-2.67; P < .001) times, respectively, more likely to experience the outcome. After adjustment for covariates, health literacy remained a predictor of outcomes. Of the other covariates, worse functional class, higher comorbidity burden, and higher depression score predicted worse outcomes.ConclusionsInadequate or marginal health literacy is a risk factor for heart failure rehospitalization or all-cause mortality among rural patients with heart failure.

Despite a variety of pharmacological and device therapies for persons with chronic heart failure (HF), prognosis and quality of life (QOL) remain poor. The need for new effective strategies to improve outcomes for patients with HF is underscored by persistently high mortality, morbidity, healthcare use, and costs associated with HF, with >1 million US HF hospitalizations at an estimated direct and indirect cost in the US of $40 billion in 2012.1 Exercise intolerance is a primary symptom in patients with chronic HF, both those with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF), and is a strong determinant of prognosis and of reduced QOL.2 Exercise training improves exercise intolerance and QOL in patients with chronic stable HFrEF, and has become an accepted adjunct therapy for these patients (Class B level of evidence) based on a fairly extensive evidence base of randomized trials, mostly small.3 The National Heart, Lung, and Blood Institute–funded Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial compared an individualized, supervised, and home-based aerobic exercise program plus guideline-based pharmacological and device therapy with guideline-based therapy alone in persons with HFrEF. The exercise arm showed a modest reduction in cardiovascular hospitalizations and mortality and improved QOL.4,5 However, problems with adherence in the exercise arm probably dampened the potential benefit. This landmark study leaves several unanswered key questions, including the role of exercise dose; the relative benefit of different types of aerobic exercise, including high-intensity interval training (HIIT), and resistance, training relative to aerobic training; combination of exercise training with other therapies; optimization of adherence; benefit for older patients with HF, those with HFpEF or multiple comorbidities, and those with acute decompensated HF. The National Heart, Lung, and Blood Institute convened a working group of experts on June 11, …

Objectives The GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) study is designed to determine the safety, efficacy, and cost-effectiveness of a strategy of adjusting therapy with the goal of achieving and maintaining a target N-terminal pro–B-type natriuretic peptide (NT-proBNP) level of Background Elevations in natriuretic peptide (NP) levels provide key prognostic information in patients with HF. Therapies proven to improve outcomes in patients with HF are generally associated with decreasing levels of NPs, and observational data show that decreases in NP levels over time are associated with favorable outcomes. Results from smaller prospective, randomized studies of this strategy thus far have been mixed, and current guidelines do not recommend serial measurement of NP levels to guide therapy in patients with HF. Methods GUIDE-IT is a prospective, randomized, controlled, unblinded, multicenter clinical trial designed to randomize approximately 1,100 high-risk subjects with systolic HF (left ventricular ejection fraction ≤40%) to either usual care (optimized guideline-recommended therapy) or a strategy of adjusting therapy with the goal of achieving and maintaining a target NT-proBNP level of Conclusions The GUIDE-IT study is designed to definitively assess the effects of an NP-guided strategy in high-risk patients with systolic HF on clinically relevant endpoints of mortality, hospitalization, quality of life, and medical resource use. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure [GUIDE-IT]; NCT01685840 )

Background The use of guideline directed medical therapy (GDMT) improves clinical outcomes in patients with heart failure (HF). Despite this, many patients are under-treated. This led to the hypothesis that serial measurements of natriuretic peptides may be useful to guide titration of medical therapy, and achieve better outcomes (the GUIDE-IT trial). We evaluated the reported reason for not following the protocol and increasing GDMT medications. Methods GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) explored a ‘guided’ therapy with a goal to suppress NT-proBNP ≤1000 pg/mL on clinical outcomes of HF with reduced Ejection Fraction (HFrEF), utilizing a protocol of suggested medication titrations. For each clinical encounter, medication titrations were captured, along with a reason if a modification was not made. 894 patients were randomized to either the biomarker guided or GDMT group. Reasons were provided by the site in categorical and free-text reasons, and mapped to appropriate groupings. There were no differences between groups in rates and % of target doses achieved, but only about half achieved target doses of B-Blockers and ACE-I/ARB, and only half were on an MRA by end of study. Results This analysis included 6223 visits over a maximum of 24 months. In total, medication adjustments were made in 51% of the study visits representing 831(94%) of patients. The majority (74%) of adjustments occurred within the first 6 months, primarily within the first 6 weeks of enrollment (52%). Reasons for not titrating medications are shown in Figure 1. The primary reason for not adjusting medication was clinician decision, with the second top reason listed as already at maximally tolerated therapy. Conclusions Despite a protocol-driven approach to titrating HF medications, many patients did not receive GDMT medication adjustments in GUIDE IT, particularly in the long term. There may be a gap in opportunities to titrate medications for maximal benefit in HF.

The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial was designed to test whether raising HDL levels with niacin reduces cardiovascular risk given that LDL levels are controlled with a statin. We sought to identify

Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) was a randomized, double-blind, placebo-controlled designed to test whether treatment with spironolactone reduces hospitalization due to heart failure (hHF), cardiovascular mortality, or aborted cardiac

Importance The natriuretic peptides are biochemical markers of heart failure (HF) severity and predictors of adverse outcomes. Smaller studies have evaluated adjusting HF therapy based on natriuretic peptide levels (“guided therapy”) with inconsistent results. Objective To determine whether an amino-terminal pro–B-type natriuretic peptide (NT-proBNP)–guided treatment strategy improves clinical outcomes vs usual care in high-risk patients with HF and reduced ejection fraction (HFrEF). Design, Settings, and Participants The Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) study was a randomized multicenter clinical trial conducted between January 16, 2013, and September 20, 2016, at 45 clinical sites in the United States and Canada. This study planned to randomize 1100 patients with HFrEF (ejection fraction ≤40%), elevated natriuretic peptide levels within the prior 30 days, and a history of a prior HF event (HF hospitalization or equivalent) to either an NT-proBNP–guided strategy or usual care. Interventions Patients were randomized to either an NT-proBNP–guided strategy or usual care. Patients randomized to the guided strategy (n = 446) had HF therapy titrated with the goal of achieving a target NT-proBNP of less than 1000 pg/mL. Patients randomized to usual care (n = 448) had HF care in accordance with published guidelines, with emphasis on titration of proven neurohormonal therapies for HF. Serial measurement of NT-proBNP testing was discouraged in the usual care group. Main Outcomes and Measures The primary end point was the composite of time-to-first HF hospitalization or cardiovascular mortality. Prespecified secondary end points included all-cause mortality, total hospitalizations for HF, days alive and not hospitalized for cardiovascular reasons, the individual components on the primary end point, and adverse events. Results The data and safety monitoring board recommended stopping the study for futility when 894 (median age, 63 years; 286 [32%] women) of the planned 1100 patients had been enrolled with follow-up for a median of 15 months. The primary end point occurred in 164 patients (37%) in the biomarker-guided group and 164 patients (37%) in the usual care group (adjusted hazard ratio [HR], 0.98; 95% CI, 0.79-1.22; P = .88). Cardiovascular mortality was 12% (n = 53) in the biomarker-guided group and 13% (n = 57) in the usual care group (HR, 0.94; 95% CI; 0.65-1.37; P = .75). None of the secondary end points nor the decreases in the NT-proBNP levels achieved differed significantly between groups. Conclusions and Relevance In high-risk patients with HFrEF, a strategy of NT-proBNP–guided therapy was not more effective than a usual care strategy in improving outcomes. Trial Registration clinicaltrials.gov Identifier:NCT01685840

Background— We aimed to develop a multivariable statistical model for risk stratification in patients with chronic heart failure with systolic dysfunction, using patient data that are routinely collected and easily obtained at the time of initial presentation. Methods and Results— In a cohort of 2331 patients enrolled in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise TraiNing) study (New York Heart Association class II–IV, left ventricular ejection fraction ≤0.35, randomized to exercise training and usual care versus usual care alone, median follow-up of 2.5 years), we performed risk modeling using Cox proportional hazards models and analyzed the relationship between baseline clinical factors and the primary composite end point of death or all-cause hospitalization and the secondary end point of all-cause death alone. Prognostic relationships for continuous variables were examined using restricted cubic spline functions, and key predictors were identified using a backward variable selection process and bootstrapping methods. For ease of use in clinical practice, point-based risk scores were developed from the risk models. Exercise duration on the baseline cardiopulmonary exercise test was the most important predictor of both the primary end point and all-cause death. Additional important predictors for the primary end point risk model (in descending strength) were Kansas City Cardiomyopathy Questionnaire symptom stability score, higher serum urea nitrogen, and male sex (all P P Conclusions— Risk models using simple, readily obtainable clinical characteristics can provide important prognostic information in ambulatory patients with chronic heart failure with systolic dysfunction. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00047437.

Background— Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) assigned 2331 outpatients with medically stable heart failure to exercise training or usual care. We compared medical resource use and costs incurred by these patients during follow-up. Methods and Results— Extensive data on medical resource use and hospital bills were collected throughout the trial for estimates of direct medical costs. Intervention costs were estimated using patient-level trial data, administrative records, and published unit costs. Mean follow-up was 2.5 years. There were 2297 hospitalizations in the exercise group and 2332 in the usual care group ( P =0.92). The mean number of inpatient days was 13.6 (standard deviation [SD], 27.0) in the exercise group and 15.0 (SD, 31.4) in the usual care group ( P =0.23). Other measures of resource use were similar between groups, except for trends indicating that fewer patients in the exercise group underwent high-cost inpatient procedures. Total direct medical costs per participant were an estimated $50 857 (SD, $81 488) in the exercise group and $56 177 (SD, $92 749) in the usual care group (95% confidence interval for the difference, $−12 755 to $1547; P =0.10). The direct cost of exercise training was an estimated $1006 (SD, $337). Patient time costs were an estimated $5018 (SD, $4600). Conclusions— The cost of exercise training was relatively low for the health care system, but patients incurred significant time costs. In this economic evaluation, there was little systematic benefit in terms of overall medical resource use with this intervention. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00047437.

Coronary artery disease is the leading cause of death in Type 2 diabetes patients (T2D) with lipid abnormalities. Fibrates have emerged as second-line agents to reduce circulating triglycerides and elevate HDL-C. The ACCORD Lipid study, a subset of the ACCORD trial([NCT00000620][1]), investigated

We aimed to develop a multivariable statistical model for risk stratification of high risk heart failure with reduced ejection fraction (HFrEF) patients using patient data routinely collected in clinical practice. The GUIDE-IT (Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment)

Depression is common in patients with heart failure (HF), prognostic for adverse outcomes and purportedly related to disease severity. Psychological and physiologic factors relevant to HF were assessed in HF-ACTION, a large randomized study of aerobic exercise training in patients with systolic HF. The relation of objective and subjective parameters was compared with scores on the Beck Depression Inventory (BDI) to examine the hypothesis that depressive symptoms are better associated with perception of disease severity than with objective markers of HF severity. At baseline, 2,322 of 2,331 subjects entered into HF-ACTION completed questionnaires to assess depression (BDI) and quality of life (Kansas City Cardiomyopathy Questionnaire [KCCQ]). Objective markers of HF severity included ejection fraction, B-type natriuretic peptide, and peak oxygen consumption (using cardiopulmonary exercise testing, with evaluation of duration and respiratory exchange ratio also performed). Measures more likely to be affected by perceived functional status included New York Heart Association (NYHA) classification and the 6-minute walk test. Objective assessments of disease severity were slightly related (peak oxygen consumption) or not related (B-type natriuretic peptide and ejection fraction) to BDI scores. Using multivariate analysis (KCCQ not included), only age, gender, cardiopulmonary exercise testing duration, NYHA class, 6-minute walk distance, and peak respiratory exchange ratio independently correlated with BDI scores. In conclusion, depression was minimally related to objective assessments of severity of disease in patients with HF, but was associated with patient (and clinician) perceptions of disease severity. Addressing depression might improve symptoms in patients with HF.

Abstract Many protocols have been used in clinical and research settings for collecting systolic blood pressure (SBP) measurements to calculate the ankle–brachial index (ABI); however, it is not known how useful it is to replicate measurements and which measures best reflect cardiovascular risk. Standardized measurements of ankle and arm SBP from 5140 overweight or obese individuals with type 2 diabetes were used to estimate sources of variation. Measurement characteristics of leg-specific ABI, as calculated using a standard algorithm based on the highest SBP of the dorsalis pedis or posterior tibial arteries, were projected using simulations. Coefficients of variability ranged from 2% to 3% when single SBP measurements were used and ABI was overestimated by 2–3%. Taking two SBP measurements at each site reduced standard errors and bias each by 30–40%. The sensitivity of detecting low ABI ranges exceeded 90% for ABI within 0.05 of the 0.90 clinical cut-point. The average and the minimum of the two (i.e. right and left) leg-specific ABI values had similar U-shaped relationships with Framingham risk scores; however, the average leg ABI had slightly greater precision. Replicating SBP measurements reduces the error and bias of ABI. Averaging leg-specific values may increase power for characterizing cardiovascular disease risk.

Background The etiology of cognitive impairment in heart failure (HF) is controversial and likely multifactorial. Physicians may hesitate to prescribe evidence-based HF medication because of concerns related to potential negative changes in cognition among a population that is already frequently impaired. We conducted a study to determine if prescription of evidence-based HF medications (specifically, β-blockers, angiotensin-converting enzyme inhibitors, angiotensin-receptor blocking agents, diuretics, and aldosterone inhibitors) was associated with cognition in a large HF sample. Methods A total of 612 patients completed baseline data collection for the Rural Education to Improve Outcomes in Heart Failure clinical trial, including information about medications. Global cognition was evaluated using the Mini-Cog. Results The sample mean (SD) age was 66 (13) years, 58% were men, and 89% were white. Global cognitive impairment was identified in 206 (34%) of the 612 patients. Prescription of evidence-based HF medications was not related to global cognitive impairment in this sample. This relationship was maintained even after adjusting for potential confounders (eg, age, education, and comorbid burden). Conclusion Prescription of evidence-based HF medications is not related to low scores on a measure of global cognitive function in rural patients with HF.

Most studies comparing the effects of fitness and fatness on cardiovascular (CVD) risk have been done with young, healthy participants with low rates of obesity and high levels of fitness. The present study examined the association of cardiorespiratory fitness and obesity with CVD risk factors in an ethnically diverse sample of overweight/obese individuals with type 2 diabetes.Baseline data from Look AHEAD, a study of 5145 overweight or obese individuals with type 2 diabetes, were used to examine the association of BMI categories (overweight, class I, II, or III obesity) and cardiorespiratory fitness (assessed with a maximal graded exercise test and categorized by age- and gender-specific quintiles) on cardiovascular risk factors and on the odds of having hypertension, hyperlipidemia, or HbA1cor = 7%.BMI categories and fitness quintiles were highly associated with each other (P0.0001), with the heaviest participants being the least fit. Only 2-3% of participants had class III obesity and were in the two fittest quintiles or, conversely, were overweight and in the two least-fit quintiles. When fitness and BMI were included in the same model (adjusting for age, smoking, diabetes duration, and race), HbA1c, ankle/brachial index (ABI), and Framingham risk score were most strongly associated with fitness. Systolic blood pressure was most strongly associated with BMI category. Similar results occurred when waist circumference and fitness were considered together.In this large, ethnically diverse sample of overweight/obese individuals with type 2 diabetes, fitness and fatness were highly related to each other but seemed to have different impact on specific CVD risk factors.