Supervised Exercise Training for Chronic Heart Failure With Preserved Ejection Fraction: A Scientific Statement From the American Heart Association and American College of Cardiology.

Heart failure with preserved ejection fraction (HFpEF) is one of the most common forms of heart failure; its prevalence is increasing, and outcomes are worsening. Affected patients often experience severe exertional dyspnea and debilitating fatigue, as well as poor quality of life, frequent hospitalizations, and a high mortality rate. Until recently, most pharmacological intervention trials for HFpEF yielded neutral primary outcomes. In contrast, trials of exercise-based interventions have consistently demonstrated large, significant, clinically meaningful improvements in symptoms, objectively determined exercise capacity, and usually quality of life. This success may be attributed, at least in part, to the pleiotropic effects of exercise, which may favorably affect the full range of abnormalities-peripheral vascular, skeletal muscle, and cardiovascular-that contribute to exercise intolerance in HFpEF. Accordingly, this scientific statement critically examines the currently available literature on the effects of exercise-based therapies for chronic stable HFpEF, potential mechanisms for improvement of exercise capacity and symptoms, and how these data compare with exercise therapy for other cardiovascular conditions. Specifically, data reviewed herein demonstrate a comparable or larger magnitude of improvement in exercise capacity from supervised exercise training in patients with chronic HFpEF compared with those with heart failure with reduced ejection fraction, although Medicare reimbursement is available only for the latter group. Finally, critical gaps in implementation of exercise-based therapies for patients with HFpEF, including exercise setting, training modalities, combinations with other strategies such as diet and medications, long-term adherence, incorporation of innovative and more accessible delivery methods, and management of recently hospitalized patients are highlighted to provide guidance for future research.

The Longitudinal Decline in Peak VO2 with Aging in Healthy Individuals is Associated with a Reduction in Peripheral Oxygen Utilization but not in Cardiac Output.

Aging is associated with a significant decline in exercise fitness assessed by maximal exercise oxygen consumption (VO2-max). The specific VO2-max components driving this decline, namely cardiac output (CO) and arteriovenous oxygen difference (A-V) O2, remain unclear. We examined this issue by analyzing data from 99 community-dwelling participants (baseline age 21-96 years; average follow-up 12.6 years) from the Baltimore Longitudinal Study of Aging, free of clinical cardiovascular disease. VO2-peak, a surrogate of VO2-max, was used to assess aerobic capacity during upright cycle exercise. Peak exercise left ventricular (LV) volumes, heart rate, and cardiac output were estimated using repeated gated cardiac blood pool scans. The Fick equation was used to calculate (A-V) O2-peak from CO-peak and VO2-peak. In unadjusted models, VO2-peak, (A-V) O2-peak, and CO-peakdeclined longitudinally over time at steady rates with advancing age. In multiple linear regression models adjusting for baseline values and peak workload, however, steeper declines in VO2-peak and (A-V) O2 peak were observed with advanced entry age but not in CO-peak. The association between the declines in VO2-peak and (A-V) O2-peakwas stronger among those >=50 years compared to their younger counterparts but the difference between the two age groups did not reach statistical significance. These findings suggest that age-associated impairment of peripheral oxygen utilization during maximal exercise poses a stronger limitation on peak VO2 than that of CO. Future studies examining interventions targeting the structure and function of peripheral muscles and their vasculature to mitigate age-associated declines in (A-V) O2 are warranted.

Implementing the National Heart, Lung, and Blood Institute's Strategic Vision in the Division of Cardiovascular Sciences-2022 Update.

Spurred by the 2016 release of the National Heart, Lung, and Blood Institute's Strategic Vision, the Division of Cardiovascular Sciences developed its Strategic Vision Implementation Plan-a blueprint for reigniting the decline in cardiovascular disease (CVD) mortality rates, improving health equity, and accelerating translation of scientific discoveries into better cardiovascular health (CVH). The 6 scientific focus areas of the Strategic Vision Implementation Plan reflect the multifactorial nature of CVD and include (1) addressing social determinants of CVH and health inequities, (2) enhancing resilience, (3) promoting CVH and preventing CVD across the lifespan, (4) eliminating hypertension-related CVD, (5) reducing the burden of heart failure, and (6) preventing vascular dementia. This article presents an update of strategic vision implementation activities within Division of Cardiovascular Sciences. Overarching and cross-cutting themes include training the scientific workforce and engaging the extramural scientific community to stimulate transformative research in cardiovascular sciences. In partnership with other NIH Institutes, Federal agencies, industry, and the extramural research community, Division of Cardiovascular Sciences strategic vision implementation has stimulated development of numerous workshops and research funding opportunities. Strategic Vision Implementation Plan activities highlight innovative intervention modalities, interdisciplinary systems approaches to CVD reduction, a life course framework for CVH promotion and CVD prevention, and multi-pronged research strategies for combatting COVID-19. As new knowledge, technologies, and areas of scientific research emerge, Division of Cardiovascular Sciences will continue its thoughtful approach to strategic vision implementation, remaining poised to seize emerging opportunities and catalyze breakthroughs in cardiovascular sciences.

Health Status after Invasive or Conservative Care in Coronary and Advanced Kidney Disease.

BACKGROUND: In the ISCHEMIA-CKD trial, the primary analysis showed no significant difference in the risk of death or myocardial infarction with initial angiography and revascularization plus guideline-based medical therapy (invasive strategy) as compared with guideline-based medical therapy alone (conservative strategy) in participants with stable ischemic heart disease, moderate or severe ischemia, and advanced chronic kidney disease (an estimated glomerular filtration rate of <30 ml per minute per 1.73 m2 or receipt of dialysis). A secondary objective of the trial was to assess angina-related health status. METHODS: We assessed health status with the Seattle Angina Questionnaire (SAQ) before randomization and at 1.5, 3, and 6 months and every 6 months thereafter. The primary outcome of this analysis was the SAQ Summary score (ranging from 0 to 100, with higher scores indicating less frequent angina and better function and quality of life). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate the treatment effect with the invasive strategy. RESULTS: Health status was assessed in 705 of 777 participants. Nearly half the participants (49%) had had no angina during the month before randomization. At 3 months, the estimated mean difference between the invasive-strategy group and the conservative-strategy group in the SAQ Summary score was 2.1 points (95% credible interval, -0.4 to 4.6), a result that favored the invasive strategy. The mean difference in score at 3 months was largest among participants with daily or weekly angina at baseline (10.1 points; 95% credible interval, 0.0 to 19.9), smaller among those with monthly angina at baseline (2.2 points; 95% credible interval, -2.0 to 6.2), and nearly absent among those without angina at baseline (0.6 points; 95% credible interval, -1.9 to 3.3). By 6 months, the between-group difference in the overall trial population was attenuated (0.5 points; 95% credible interval, -2.2 to 3.4). CONCLUSIONS: Participants with stable ischemic heart disease, moderate or severe ischemia, and advanced chronic kidney disease did not have substantial or sustained benefits with regard to angina-related health status with an initially invasive strategy as compared with a conservative strategy. (Funded by the National Heart, Lung, and Blood Institute; ISCHEMIA-CKD ClinicalTrials.gov number, NCT01985360.).

Management of Coronary Disease in Patients with Advanced Kidney Disease.

BACKGROUND: Clinical trials that have assessed the effect of revascularization in patients with stable coronary disease have routinely excluded those with advanced chronic kidney disease. METHODS: We randomly assigned 777 patients with advanced kidney disease and moderate or severe ischemia on stress testing to be treated with an initial invasive strategy consisting of coronary angiography and revascularization (if appropriate) added to medical therapy or an initial conservative strategy consisting of medical therapy alone and angiography reserved for those in whom medical therapy had failed. The primary outcome was a composite of death or nonfatal myocardial infarction. A key secondary outcome was a composite of death, nonfatal myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. RESULTS: At a median follow-up of 2.2 years, a primary outcome event had occurred in 123 patients in the invasive-strategy group and in 129 patients in the conservative-strategy group (estimated 3-year event rate, 36.4% vs. 36.7%; adjusted hazard ratio, 1.01; 95% confidence interval [CI], 0.79 to 1.29; P = 0.95). Results for the key secondary outcome were similar (38.5% vs. 39.7%; hazard ratio, 1.01; 95% CI, 0.79 to 1.29). The invasive strategy was associated with a higher incidence of stroke than the conservative strategy (hazard ratio, 3.76; 95% CI, 1.52 to 9.32; P = 0.004) and with a higher incidence of death or initiation of dialysis (hazard ratio, 1.48; 95% CI, 1.04 to 2.11; P = 0.03). CONCLUSIONS: Among patients with stable coronary disease, advanced chronic kidney disease, and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of death or nonfatal myocardial infarction. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA-CKD ClinicalTrials.gov number, NCT01985360.).

Natural History of Patients With Ischemia and No Obstructive Coronary Artery Disease: The CIAO-ISCHEMIA Study.

BACKGROUND: Ischemia with no obstructive coronary artery disease (INOCA) is common and has an adverse prognosis. We set out to describe the natural history of symptoms and ischemia in INOCA. METHODS: CIAO-ISCHEMIA (Changes in Ischemia and Angina over One Year in ISCHEMIA Trial Screen Failures With INOCA) was an international cohort study conducted from 2014 to 2019 involving angina assessments (Seattle Angina Questionnaire) and stress echocardiograms 1 year apart. This was an ancillary study that included patients with a history of angina who were not randomly assigned in the ISCHEMIA trial. Stress-induced wall motion abnormalities were determined by an echocardiographic core laboratory blinded to symptoms, coronary artery disease status, and test timing. Medical therapy was at the discretion of treating physicians. The primary outcome was the correlation between the changes in the Seattle Angina Questionnaire angina frequency score and changes in echocardiographic ischemia. We also analyzed predictors of 1-year changes in both angina and ischemia, and we compared CIAO participants with ISCHEMIA participants with obstructive coronary artery disease who had stress echocardiography before enrollment, as CIAO participants did. RESULTS: INOCA participants in CIAO were more often female (66% of 208 versus 26% of 865 ISCHEMIA participants with obstructive coronary artery disease, P<0.001), but the magnitude of ischemia was similar (median 4 ischemic segments [interquartile range, 3-5] both groups). Ischemia and angina were not significantly correlated at enrollment in CIAO (P=0.46) or ISCHEMIA stress echocardiography participants (P=0.35). At 1 year, the stress echocardiogram was normal in half of CIAO participants, and 23% had moderate or severe ischemia (≥3 ischemic segments). Angina improved in 43% and worsened in 14%. Change in ischemia over 1 year was not significantly correlated with change in angina (ρ=0.029). CONCLUSIONS: Improvement in ischemia and angina were common in INOCA but not correlated. Our INOCA cohort had a degree of inducible wall motion abnormalities similar to concurrently enrolled ISCHEMIA participants with obstructive coronary artery disease. Our results highlight the complex nature of INOCA pathophysiology and the multifactorial nature of angina. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02347215.

Outcomes of Participants With Diabetes in the ISCHEMIA Trials.

BACKGROUND: Among patients with diabetes and chronic coronary disease, it is unclear if invasive management improves outcomes when added to medical therapy. METHODS: The ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trials (ie, ISCHEMIA and ISCHEMIA-Chronic Kidney Disease) randomized chronic coronary disease patients to an invasive (medical therapy + angiography and revascularization if feasible) or a conservative approach (medical therapy alone with revascularization if medical therapy failed). Cohorts were combined after no trial-specific effects were observed. Diabetes was defined by history, hemoglobin A1c ≥6.5%, or use of glucose-lowering medication. The primary outcome was all-cause death or myocardial infarction (MI). Heterogeneity of effect of invasive management on death or MI was evaluated using a Bayesian approach to protect against random high or low estimates of treatment effect for patients with versus without diabetes and for diabetes subgroups of clinical (female sex and insulin use) and anatomic features (coronary artery disease severity or left ventricular function). RESULTS: Of 5900 participants with complete baseline data, the median age was 64 years (interquartile range, 57-70), 24% were female, and the median estimated glomerular filtration was 80 mL·min-1·1.73-2 (interquartile range, 64-95). Among the 2553 (43%) of participants with diabetes, the median percent hemoglobin A1c was 7% (interquartile range, 7-8), and 30% were insulin-treated. Participants with diabetes had a 49% increased hazard of death or MI (hazard ratio, 1.49 [95% CI, 1.31-1.70]; P<0.001). At median 3.1-year follow-up the adjusted event-free survival was 0.54 (95% bootstrapped CI, 0.48-0.60) and 0.66 (95% bootstrapped CI, 0.61-0.71) for patients with diabetes versus without diabetes, respectively, with a 12% (95% bootstrapped CI, 4%-20%) absolute decrease in event-free survival among participants with diabetes. Female and male patients with insulin-treated diabetes had an adjusted event-free survival of 0.52 (95% bootstrapped CI, 0.42-0.56) and 0.49 (95% bootstrapped CI, 0.42-0.56), respectively. There was no difference in death or MI between strategies for patients with diabetes versus without diabetes, or for clinical (female sex or insulin use) or anatomic features (coronary artery disease severity or left ventricular function) of patients with diabetes. CONCLUSIONS: Despite higher risk for death or MI, chronic coronary disease patients with diabetes did not derive incremental benefit from routine invasive management compared with initial medical therapy alone. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

Predictors of outcome in the ISCHEMIA-CKD trial: Anatomy versus ischemia.

BACKGROUND: The ISCHEMIA-CKD (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches-Chronic Kidney Disease) trial found no advantage to an invasive strategy compared to conservative management in reducing all-cause death or myocardial infarction (D/MI). However, the prognostic influence of angiographic coronary artery disease (CAD) burden and ischemia severity remains unknown in this population. We compared the relative impact of CAD extent and severity of myocardial ischemia on D/MI in patients with advanced chronic kidney disease (CKD). METHODS: Participants randomized to invasive management with available data on coronary angiography and stress testing were included. Extent of CAD was defined by the number of major epicardial vessels with ≥50% diameter stenosis by quantitative coronary angiography. Ischemia severity was assessed by site investigators as moderate or severe using trial definitions. The primary endpoint was D/MI. RESULTS: Of the 388 participants, 307 (79.1%) had complete coronary angiography and stress testing data. D/MI occurred in 104/307 participants (33.9%). Extent of CAD was associated with an increased risk of D/MI (P < .001), while ischemia severity was not (P = .249). These relationships persisted following multivariable adjustment. Using 0-vessel disease (VD) as reference, the adjusted hazard ratio (HR) for 1VD was 1.86, 95% confidence interval (CI) 0.94 to 3.68, P = .073; 2VD: HR 2.13, 95% CI 1.10 to 4.12, P = .025; 3VD: HR 4.00, 95% CI 2.06 to 7.76, P < .001. Using moderate ischemia as the reference, the HR for severe ischemia was 0.84, 95% CI 0.54 to 1.30, P = .427. CONCLUSION: Among ISCHEMIA-CKD participants randomized to the invasive strategy, extent of CAD predicted D/MI whereas severity of ischemia did not.

Prognostic Impact of Cardiovascular Versus Noncardiovascular Hospitalizations in Heart Failure With Preserved Ejection Fraction: Insights From TOPCAT.

BACKGROUND: Patients with heart failure (HF) with preserved ejection fraction are commonly admitted to the hospital for both cardiovascular (CV) and noncardiovascular (non-CV) reasons. The prognostic implications of non-CV hospitalizations in this population are not well understood. In this study, we aimed to examine the prognostic implications of hospitalizations owing to CV and non-CV reasons in a HF with preserved ejection fraction population. METHODS AND RESULTS: The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT) randomized 3445 stable outpatients with chronic HF with a left ventricular ejection fraction of 45% or greater and either prior hospitalization for HF or elevated natriuretic peptides to treatment with spironolactone or placebo. Hospitalizations for any cause were reported by investigators during study follow-up and characterized according to prespecified category causes. This analysis focused on the subset of TOPCAT participants enrolled in the Americas (n = 1767), in which 2973 hospitalizations were observed in 1062 subjects (60%) over a mean follow-up of 3.3 years of study follow-up, of which 1474 (49%) were ascribed to CV causes. Among 1056 first hospitalizations, 478 (45%) were for CV reasons and 578 (55%) for non-CV reasons. Mortality rates were lowest for participants not hospitalized during the trial (3.2 per 100 patient-years [PY]), but similarly elevated after first hospitalization for CV and non-CV reasons (11.0 per 100 PY vs 12.6 per 100 PY, respectively; P = .24). Among those hospitalized for CV reasons, mortality rates were similar after hospitalization for HF and non-CV related reasons (15.2 per 100 PY vs 12.6 per 100 PY; P = .23). Recurrent hospitalization, whether owing to CV or non-CV causes, was associated with a heightened risk for subsequent mortality, with similar death rates after hospitalization twice for CV reasons (18.5 per 100 PY), twice for non-CV reasons (21.6 per 100 PY), or once each for CV and non-CV reasons (18.4 per 100 PY). CONCLUSIONS: Among patients with HF with preserved ejection fraction, hospitalization for any cause is associated with a heightened risk for postdischarge mortality, with an even higher risk associated with recurrent hospitalization. Given the high burden of non-CV hospitalizations in this population, the targeted management of comorbid medical illness may be critical to decreasing morbidity and mortality.

Association of Physical Activity With Maximal and Submaximal Tests of Exercise Capacity in Middle- and Older-Aged Adults.

Although physical activity (PA) is an important determinant of exercise capacity, the association between these constructs is modest. The authors investigated the associations of self-reported and objectively measured PA with maximal and submaximal tests of exercise capacity. Participants aged ≥40 years (N = 413; 49.6% female) completed a PA questionnaire, wore a uniaxial accelerometer (5.2 ± 1.1 days), and performed maximal (cardiopulmonary exercise test [CPET]) and submaximal (long-distance corridor walk) tests with indirect calorimetry (oxygen consumption, V˙O2). Linear regression models were fitted to assess the variation in exercise capacity explained (partial eta squared, η2) by PA variables. Accelerometer-measured vigorous (η2 = 22% female; η2 = 16% male) and total PA (η2 = 17% female; η2 = 13% male) explained the most variance in CPET V˙O2 (p < .001). All η2 values were lower for long-distance corridor walk V˙O2 (η2 ≤ 11%). Age contributed more to CPET V˙O2 than any PA variable in males (η2 = 32%), but not in females (η2 = 19%). Vigorous and total PA play important roles in CPET V˙O2 in mid to late life.

Testosterone concentrations and risk of cardiovascular events in androgen-deficient men with atherosclerotic cardiovascular disease.

BACKGROUND: Whether androgen deficiency among men increases the risk of cardiovascular (CV) events or is merely a disease marker remains a subject of intense scientific interest. OBJECTIVES: Among male subjects in the AIM-HIGH Trial with metabolic syndrome and low baseline levels of high-density lipoprotein (HDL)-cholesterol who were randomized to niacin or placebo plus simvastatin, we examined the relationship between low baseline testosterone (T) concentrations and subsequent CV outcomes during a mean 3-year follow-up. METHODS: In this post hoc analysis of men with available baseline plasma T concentrations, we examined the relationship between clinical/demographic characteristics and T concentrations both as a continuous and dichotomous variable (<300 ng/dL ["low T"] vs. ≥300 ng/dL ["normal T"]) on rates of pre-specified CV outcomes, using Cox proportional hazards models. RESULTS: Among 2118 male participants in whom T concentrations were measured, 643 (30%) had low T and 1475 had normal T concentrations at baseline. The low T group had higher rates of diabetes mellitus, hypertension, elevated body mass index, metabolic syndrome, higher blood glucose, hemoglobin A1c, and triglyceride levels, but lower levels of both low-density lipoprotein and HDL-cholesterol, and a lower rate of prior myocardial infarction (MI). Men with low T had a higher risk of the primary composite outcome of coronary heart disease (CHD) death, MI, stroke, hospitalization for acute coronary syndrome, or coronary or cerebral revascularization (20.1%) compared with the normal T group (15.2%); final adjusted HR 1.23, P = .07, and a higher risk of the CHD death, MI, and stroke composite endpoint (11.8% vs. 8.2%; final adjusted HR 1.37, P = .04), respectively. CONCLUSIONS: In this post hoc analysis, there was an association between low baseline testosterone concentrations and increased risk of subsequent CV events in androgen-deficient men with established CV disease and metabolic syndrome, particularly for the composite secondary endpoint of CHD death, MI, and stroke. CONDENSED ABSTRACT: In this AIM-HIGH Trial post hoc analysis of 2118 men with metabolic syndrome and low HDL-cholesterol with available baseline plasma testosterone (T) samples, 643 males (30%) had low T (mean: 229 ng/dL) and 1475 (70%) had normal T (mean: 444 ng/dL) concentrations. The "low T" group had a 24% higher risk of the primary 5-component endpoint (20.1%) compared with the normal T group (15.2%); final adjusted HR 1.23, P = .07). There was also a 31% higher risk of the secondary composite endpoint: coronary heart disease death, myocardial infarction, and stroke (11.8% vs. 8.2%, final adjusted HR 1.37, P = .04) in the low vs. normal T group, respectively.

Ischemia and No Obstructive Coronary Artery Disease (INOCA): Developing Evidence-Based Therapies and Research Agenda for the Next Decade.

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.

Prioritizing Functional Capacity as a Principal End Point for Therapies Oriented to Older Adults With Cardiovascular Disease: A Scientific Statement for Healthcare Professionals From the American Heart Association.

Adults are living longer, and cardiovascular disease is endemic in the growing population of older adults who are surviving into old age. Functional capacity is a key metric in this population, both for the perspective it provides on aggregate health and as a vital goal of care. Whereas cardiorespiratory function has long been applied by cardiologists as a measure of function that depended primarily on cardiac physiology, multiple other factors also contribute, usually with increasing bearing as age advances. Comorbidity, inflammation, mitochondrial metabolism, cognition, balance, and sleep are among the constellation of factors that bear on cardiorespiratory function and that become intricately entwined with cardiovascular health in old age. This statement reviews the essential physiology underlying functional capacity on systemic, organ, and cellular levels, as well as critical clinical skills to measure multiple realms of function (eg, aerobic, strength, balance, and even cognition) that are particularly relevant for older patients. Clinical therapeutic perspectives and patient perspectives are enumerated to clarify challenges and opportunities across the caregiving spectrum, including patients who are hospitalized, those managed in routine office settings, and those in skilled nursing facilities. Overall, this scientific statement provides practical recommendations and vital conceptual insights.

International Study of Comparative Health Effectiveness with Medical and Invasive Approaches-Chronic Kidney Disease (ISCHEMIA-CKD): Rationale and design.

BACKGROUND: Patients with chronic kidney disease (CKD) and stable ischemic heart disease are at markedly increased risk of cardiovascular events. Prior trials comparing a strategy of optimal medical therapy (OMT) with or without revascularization have largely excluded patients with advanced CKD. Whether a routine invasive approach when compared with a conservative strategy is beneficial in such patients is unknown. METHODS: ISCHEMIA-CKD is a National Heart, Lung, and Blood Institute-funded randomized trial designed to determine the comparative effectiveness of an initial invasive strategy (cardiac catheterization and optimal revascularization [percutaneous coronary intervention or coronary artery bypass graft surgery, if suitable] plus OMT) versus a conservative strategy (OMT alone, with cardiac catheterization and revascularization [percutaneous coronary intervention or coronary artery bypass graft surgery, if suitable] reserved for failure of OMT) on long-term clinical outcomes in 777 patients with advanced CKD (defined as those with estimated glomerular filtration rate <30 mL/min/1.73m2 or on dialysis) and moderate or severe ischemia on stress testing. Participants were randomized in a 1:1 fashion to the invasive or a conservative strategy. The primary end point is a composite of death or nonfatal myocardial infarction. Major secondary endpoints are a composite of death, nonfatal myocardial infarction, hospitalization for unstable angina, hospitalization for heart failure, or resuscitated cardiac arrest; angina control; and disease-specific quality of life. Safety outcomes such as initiation of maintenance dialysis and a composite of initiation of maintenance dialysis or death will be reported. The trial is projected to have 80% power to detect a 22% to 24% reduction in the primary composite end point with the invasive strategy when compared with the conservative strategy. CONCLUSIONS: ISCHEMIA-CKD will determine whether an initial invasive management strategy improves clinical outcomes when added to OMT in patients with advanced CKD and stable ischemic heart disease.

Incident Hyperkalemia, Hypokalemia, and Clinical Outcomes During Spironolactone Treatment of Heart Failure With Preserved Ejection Fraction: Analysis of the TOPCAT Trial.

BACKGROUND: In patients with heart failure and preserved ejection fraction (HF-PEF) randomized in the Americas as part of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, treatment with spironolactone enhanced the risk of hyperkalemia but reduced the risk of hypokalemia. We examined the clinical correlates and prognostic implications of incident hypo- and hyperkalemia during study follow-up. METHODS: We defined the region-specific incidence of hypokalemia (potassium [K+] <3.5 mmol/l) and hyperkalemia (K+ ≥5.5 mmol/l) among both placebo- and spironolactone-assigned patients in TOPCAT. Factors associated with incident hypokalemia and hyperkalemia and the relationship between incident K+ abnormalities and the risk of subsequent mortality were analyzed in multivariable regression models restricted to the Americas. RESULTS: In the Americas, assignment to spironolactone increased risk for hyperkalemia (hazard ratio 3.21, 95% confidence interval 2.46-4.20, P < .001) and reduced risk of hypokalemia (hazard ratio 0.43, 95% confidence interval 0.34-0.55, P < .001). Assignment to spironolactone, lower estimated glomerular filtration rate, higher baseline K+, diabetes, and lower hemoglobin were associated with incident hyperkalemia, whereas assignment to placebo, lower K+, younger age, lower estimated glomerular filtration rate, and use of diuretics at baseline were associated with hypokalemia. The combination of spironolactone and an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker was associated with incremental risk for hyperkalemia and protection from hypokalemia. Independent of region, both hypokalemia and hyperkalemia, were associated with higher risk for cardiovascular and all-cause mortality in multivariable-adjusted Cox regression models. CONCLUSIONS: Both hyperkalemia and hypokalemia are associated with heightened risk for mortality in HF-PEF. Use of spironolactone in this population requires careful laboratory surveillance of K+ and creatinine, particularly in high-risk groups.

Spironolactone for heart failure with preserved ejection fraction.

BACKGROUND: Mineralocorticoid-receptor antagonists improve the prognosis for patients with heart failure and a reduced left ventricular ejection fraction. We evaluated the effects of spironolactone in patients with heart failure and a preserved left ventricular ejection fraction. METHODS: In this randomized, double-blind trial, we assigned 3445 patients with symptomatic heart failure and a left ventricular ejection fraction of 45% or more to receive either spironolactone (15 to 45 mg daily) or placebo. The primary outcome was a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. RESULTS: With a mean follow-up of 3.3 years, the primary outcome occurred in 320 of 1722 patients in the spironolactone group (18.6%) and 351 of 1723 patients in the placebo group (20.4%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.77 to 1.04; P=0.14). Of the components of the primary outcome, only hospitalization for heart failure had a significantly lower incidence in the spironolactone group than in the placebo group (206 patients [12.0%] vs. 245 patients [14.2%]; hazard ratio, 0.83; 95% CI, 0.69 to 0.99, P=0.04). Neither total deaths nor hospitalizations for any reason were significantly reduced by spironolactone. Treatment with spironolactone was associated with increased serum creatinine levels and a doubling of the rate of hyperkalemia (18.7%, vs. 9.1% in the placebo group) but reduced hypokalemia. With frequent monitoring, there were no significant differences in the incidence of serious adverse events, a serum creatinine level of 3.0 mg per deciliter (265 µmol per liter) or higher, or dialysis. CONCLUSIONS: In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. (Funded by the National Heart, Lung, and Blood Institute; TOPCAT ClinicalTrials.gov number, NCT00094302.).

Socioeconomic and partner status in chronic heart failure: Relationship to exercise capacity, quality of life, and clinical outcomes.

BACKGROUND: Prognosis in patients with heart failure (HF) is commonly assessed based on clinical characteristics. The association between partner status and socioeconomic status (SES) and outcomes in chronic HF requires further study. METHODS: We performed a post hoc analysis of HF-ACTION, which randomized 2,331 HF patients with ejection fraction ≤35% to usual care ± aerobic exercise training. We examined baseline quality of life and functional capacity and outcomes (all-cause mortality/hospitalization) by partner status and SES using adjusted Cox models and explored an interaction with exercise training. Outcomes were examined based on partner status, education level, annual income, and employment. RESULTS: Having a partner, education beyond high school, an income >$25,000, and being employed were associated with better baseline functional capacity and quality of life. Over a median follow-up of 2.5 years, higher education, higher income, being employed, and having a partner were associated with lower all-cause mortality/hospitalization. After multivariable adjustment, lower mortality was seen associated with having a partner (hazard ratio 0.91, 95% CI 0.81-1.03, P=.15) and more than a high school education (hazard ratio 0.91, CI 0.80-1.02, P=.12), although these associations were not statistically significant. There was no interaction between any of these variables and exercise training on outcomes (all P>.5). CONCLUSIONS: Having a partner and higher SES were associated with greater functional capacity and quality of life at baseline but were not independent predictors of long-term clinical outcomes in patients with chronic HF. These findings provide information that may be considered as potential variables impacting outcomes.

High-Sensitivity Cardiac Troponin I as a Gatekeeper for Coronary Computed Tomography Angiography and Stress Testing in Patients with Acute Chest Pain.

BACKGROUND: Most patients presenting to the emergency department (ED) with suspected acute coronary syndrome (ACS) undergo noninvasive cardiac testing with a low diagnostic yield. We determined whether a combination of high-sensitivity cardiac troponin I (hs-cTnI) and cardiovascular risk factors might improve selection of patients for cardiac testing. METHODS: We included patients from the Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography (ROMICAT) I and II trials who presented to the ED with acute chest pain and were referred for cardiac testing. Based on serial hs-cTnI measurements and cardiovascular risk factors, we derived and validated the criterion for no need of cardiac testing. We predicted the effect of this criterion on the effectiveness of patient management. RESULTS: A combination of baseline hs-cTnI (<4 ng/L) and cardiovascular risk factors (<2) ruled out ACS with a negative predictive value of 100% in ROMICAT I. We validated this criterion in ROMICAT II, identifying 29% patients as not needing cardiac testing. An additional 5% of patients were identified by adding no change or a decrease between baseline and 2 h hs-cTnI as a criterion. Assuming those patients would be discharged from the ED without cardiac testing, implementation of hs-cTnI would increase ED discharge rate (24.3% to 50.2%, P < 0.001) and decrease the length of hospital stay (21.4 to 8.2 h, P < 0.001), radiation dose (10.2 to 7.7 mSv, P < 0.001), and costs of care (4066 to 3342 US$, P < 0.001). CONCLUSIONS: We derived and validated a criterion for combined hs-cTnI and cardiovascular risk factors that identified acute chest pain patients with no need for cardiac testing and could improve effectiveness of patient management. ClinicalTrials.gov Identifiers: NCT00990262 and NCT01084239.

Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction.

AIMS: While mineralocorticoid receptor antagonists (MRAs) have been shown to benefit patients with reduced left ventricular ejection fraction (LVEF), spironolactone did not reduce the primary endpoint of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest in patients with heart failure with preserved ejection fraction (HFpEF) in the TOPCAT trial, which enrolled patients with LVEF of 45% or greater. We utilized data from TOPCAT to assess the relationship between LVEF as well as outcomes and efficacy of spironolactone. METHODS AND RESULTS: We assessed differences in baseline characteristics and outcomes across LVEF categories in 3444 patients with HFpEF, and determined whether LVEF modified the treatment effect of spironolactone. Ejection fraction ranged from 44 to 85%. Patients with higher ejection fraction were older, more likely to be female, less likely to have a history of myocardial infarction, and more likely to have a history of hypertension and diabetes. The incidence of the primary endpoint and cardiovascular death was highest in patients at the lower end of the ejection fraction spectrum. Ejection fraction modified the spironolactone treatment effect, particularly in the patients enrolled in the Americas, for the primary outcome (P = 0.046) and for heart failure hospitalization (P = 0.039), with stronger estimated benefits of spironolactone at the lower end of the ejection fraction spectrum with respect to the primary endpoint (LVEF <50%: HR 0.72, 95% CI 0.50, 1.05; LVEF ≥60%: HR 0.97, 95% CI 0.76, 1.23) and heart failure hospitalization (LVEF <50%: HR 0.76, 95% CI 0.46, 1.27; LVEF ≥60%: HR 0.98, 95% CI 0.74, 1.30). CONCLUSION: In patients with HFpEF enrolled in TOPCAT, patient characteristics and outcomes varied substantially by LVEF. The potential efficacy of spironolactone was greatest at the lower end of the LVEF spectrum. CLINICALTRIALSGOV NUMBER: NCT00094302.