Steven J. Keteyian

Efficacy and Safety of Exercise Training in Patients With Chronic Heart Failure: HF-ACTION Randomized Controlled Trial

CONTEXT Guidelines recommend that exercise training be considered for medically stable outpatients with heart failure. Previous studies have not had adequate statistical power to measure the effects of exercise training on clinical outcomes. OBJECTIVE To test the efficacy and safety of exercise training among patients with heart failure. DESIGN, SETTING, AND PATIENTS Multicenter, randomized controlled trial of 2331 medically stable outpatients with heart failure and reduced ejection fraction. Participants in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) were randomized from April 2003 through February 2007 at 82 centers within the United States, Canada, and France; median follow-up was 30 months. INTERVENTIONS Usual care plus aerobic exercise training, consisting of 36 supervised sessions followed by home-based training, or usual care alone. MAIN OUTCOME MEASURES Composite primary end point of all-cause mortality or hospitalization and prespecified secondary end points of all-cause mortality, cardiovascular mortality or cardiovascular hospitalization, and cardiovascular mortality or heart failure hospitalization. RESULTS The median age was 59 years, 28% were women, and 37% had New York Heart Association class III or IV symptoms. Heart failure etiology was ischemic in 51%, and median left ventricular ejection fraction was 25%. Exercise adherence decreased from a median of 95 minutes per week during months 4 through 6 of follow-up to 74 minutes per week during months 10 through 12. A total of 759 patients (65%) in the exercise training group died or were hospitalized compared with 796 patients (68%) in the usual care group (hazard ratio [HR], 0.93 [95% confidence interval {CI}, 0.84-1.02]; P = .13). There were nonsignificant reductions in the exercise training group for mortality (189 patients [16%] in the exercise training group vs 198 patients [17%] in the usual care group; HR, 0.96 [95% CI, 0.79-1.17]; P = .70), cardiovascular mortality or cardiovascular hospitalization (632 [55%] in the exercise training group vs 677 [58%] in the usual care group; HR, 0.92 [95% CI, 0.83-1.03]; P = .14), and cardiovascular mortality or heart failure hospitalization (344 [30%] in the exercise training group vs 393 [34%] in the usual care group; HR, 0.87 [95% CI, 0.75-1.00]; P = .06). In prespecified supplementary analyses adjusting for highly prognostic baseline characteristics, the HRs were 0.89 (95% CI, 0.81-0.99; P = .03) for all-cause mortality or hospitalization, 0.91 (95% CI, 0.82-1.01; P = .09) for cardiovascular mortality or cardiovascular hospitalization, and 0.85 (95% CI, 0.74-0.99; P = .03) for cardiovascular mortality or heart failure hospitalization. Other adverse events were similar between the groups. CONCLUSIONS In the protocol-specified primary analysis, exercise training resulted in nonsignificant reductions in the primary end point of all-cause mortality or hospitalization and in key secondary clinical end points. After adjustment for highly prognostic predictors of the primary end point, exercise training was associated with modest significant reductions for both all-cause mortality or hospitalization and cardiovascular mortality or heart failure hospitalization. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00047437.

Effects of exercise training on health status in patients with chronic heart failure: HF-ACTION randomized controlled trial.

CONTEXT Findings from previous studies of the effects of exercise training on patient-reported health status have been inconsistent. OBJECTIVE To test the effects of exercise training on health status among patients with heart failure. DESIGN, SETTING, AND PATIENTS Multicenter, randomized controlled trial among 2331 medically stable outpatients with heart failure with left ventricular ejection fraction of 35% or less. Patients were randomized from April 2003 through February 2007. INTERVENTIONS Usual care plus aerobic exercise training (n = 1172), consisting of 36 supervised sessions followed by home-based training, vs usual care alone (n = 1159). Randomization was stratified by heart failure etiology, which was a covariate in all models. MAIN OUTCOME MEASURES Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary scale and key subscales at baseline, every 3 months for 12 months, and annually thereafter for up to 4 years. The KCCQ is scored from 0 to 100 with higher scores corresponding to better health status. Treatment group effects were estimated using linear mixed models according to the intention-to-treat principle. RESULTS Median follow-up was 2.5 years. At 3 months, usual care plus exercise training led to greater improvement in the KCCQ overall summary score (mean, 5.21; 95% confidence interval, 4.42 to 6.00) compared with usual care alone (3.28; 95% confidence interval, 2.48 to 4.09). The additional 1.93-point increase (95% confidence interval, 0.84 to 3.01) in the exercise training group was statistically significant (P < .001). After 3 months, there were no further significant changes in KCCQ score for either group (P = .85 for the difference between slopes), resulting in a sustained, greater improvement overall for the exercise group (P < .001). Results were similar on the KCCQ subscales, and no subgroup interactions were detected. CONCLUSIONS Exercise training conferred modest but statistically significant improvements in self-reported health status compared with usual care without training. Improvements occurred early and persisted over time. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00047437.

Capillary density of skeletal muscle: A contributing mechanism for exercise intolerance in class II-III chronic heart failure independent of other peripheral alterations

OBJECTIVES The study was conducted to determine if the capillary density of skeletal muscle is a potential contributor to exercise intolerance in class II-III chronic heart failure (CHF). BACKGROUND Previous studies suggest that abnormalities in skeletal muscle histology, contractile protein content and enzymology contribute to exercise intolerance in CHF. METHODS The present study examined skeletal muscle biopsies from 22 male patients with CHF compared with 10 age-matched normal male control patients. Aerobic capacities, myosin heavy chain (MHC) isoforms, enzymes, and capillary density were measured. RESULTS The patients with CHF demonstrated a reduced peak oxygen consumption when compared to controls (15.0+/-2.5 vs. 19.8+/-5.0 ml x kg(-1) x min(-1), p <0.05). Using cell-specific antibodies to directly assess vascular density, there was a reduction in capillary density in CHF measured as the number of endothelial cells/fiber (1.42+/-0.28 vs. 1.74+/-0.35, p = 0.02). In CHF, capillary density was inversely related to maximal oxygen consumption (r = 0.479, p = 0.02). The MHC IIx isoform was found to be higher in patients with CHF versus normal subjects (28.5+/-13.6 vs. 19.5+/-9.4, p <0.05). CONCLUSIONS There was a significant reduction in microvascular density in patients with CHF compared with the control group, without major differences in other usual histologic and biochemical aerobic markers. The inverse relationship with peak oxygen consumption seen in the CHF group suggests that a reduction in microvascular density of skeletal muscle may precede other skeletal muscle alterations and play a critical role in the exercise intolerance characteristic of patients with CHF.

Factors Related to Morbidity and Mortality in Patients with Chronic Heart Failure with Systolic Dysfunction: The HF-ACTION Predictive Risk Score Model

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<0.0001). Important additional predictors for the mortality risk model were higher serum urea nitrogen, male sex, and lower body mass index (all P<0.0001). 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.

Reproducibility of Peak Oxygen Uptake and Other Cardiopulmonary Exercise Testing Parameters in Patients With Heart Failure (from the Heart Failure and A Controlled Trial Investigating Outcomes of exercise traiNing)

Peak oxygen uptake (pVo2) is an important parameter in assessing the functional capacity and prognosis of patients with heart failure. In heart failure trials, change in pVo2 was often used to assess the effectiveness of an intervention. However, the within-subject variability of pVo2 on serial testing may limit its usefulness. This study was designed to evaluate the within-subject variability of pVo2 over 2 baseline cardiopulmonary exercise tests. As a substudy of the HF-ACTION trial, 398 subjects (73% men, 27% women; mean age 59 years) with heart failure and left ventricular ejection fraction < or =35% underwent 2 baseline cardiopulmonary exercise tests within 14 days. Mean pVo2 was unchanged from test 1 to test 2 (15.16 +/- 4.97 vs 15.18 +/- 4.97 ml/kg/min; p = 0.78). However, mean within-subject absolute change was 1.3 ml/kg/min (10th, 90th percentiles 0.1, 3.0), with 46% of subjects increasing and 48% decreasing on the second test. Other parameters, including the ventilation-to-carbon-dioxide production slope and Vo2 at ventilatory threshold, also showed significant within-subject variation with minimal mean differences between tests. In conclusion, pVo2 showed substantial within-subject variability in patients with heart failure and should be taken into account in clinical applications. However, on repeated baseline cardiopulmonary exercise tests, there appears to be no familiarization effect for Vo2 in patients with HF. Therefore, in multicenter trials, there is no need to perform >1 baseline cardiopulmonary exercise test.

Cardiorespiratory Fitness and Risk of Incident Atrial Fibrillation Results From the Henry Ford Exercise Testing (FIT) Project

Background— Poor cardiorespiratory fitness (CRF) is an independent risk factor for cardiovascular morbidity and mortality. However, the relationship between CRF and atrial fibrillation (AF) is less clear. The aim of this analysis was to investigate the association between CRF and incident AF in a large, multiracial cohort that underwent graded exercise treadmill testing. Methods and Results— From 1991 to 2009, a total of 64 561 adults (mean age, 54.5±12.7 years; 46% female; 64% white) without AF underwent exercise treadmill testing at a tertiary care center. Baseline demographic and clinical variables were collected. Incident AF was ascertained by use of International Classification of Diseases, Ninth Revision code 427.31 and confirmed by linkage to medical claim files. Nested, multivariable Cox proportional hazards models were used to estimate the independent association of CRF with incident AF. During a median follow-up of 5.4 years (interquartile range, 3–9 years), 4616 new cases of AF were diagnosed. After adjustment for potential confounders, 1 higher metabolic equivalent achieved during treadmill testing was associated with a 7% lower risk of incident AF (hazard ratio, 0.93; 95% confidence interval, 0.92–0.94; P<0.001). This relationship remained significant after adjustment for incident coronary artery disease (hazard ratio, 0.92; 95% confidence interval, 0.91–0.93; P<0.001). The magnitude of the inverse association between CRF and incident AF was greater among obese compared with nonobese individuals (P for interaction=0.02). Conclusions— There is a graded, inverse relationship between cardiorespiratory fitness and incident AF, especially among obese patients. Future studies should examine whether changes in fitness increase or decrease risk of atrial fibrillation. This association was stronger for obese compared with nonobese, especially among obese patients.

Clinical characteristics, response to exercise training, and outcomes in patients with heart failure and chronic obstructive pulmonary disease: Findings from Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION)

BACKGROUND The aim of this study was to investigate the clinical characteristics, exercise training response, β-blocker selectivity, and outcomes in patients with heart failure (HF) and chronic obstructive pulmonary disease (COPD). METHODS We performed an analysis of HF-ACTION, which randomized 2,331 patients with HF having an ejection fraction of ≤35% to usual care with or without aerobic exercise training. We examined clinical characteristics and outcomes (mortality/hospitalization, mortality, cardiovascular [CV] mortality/CV hospitalization, and CV mortality/HF hospitalization) by physician-reported COPD status using adjusted Cox models and explored an interaction with exercise training. The interaction between β-blocker cardioselectivity and outcomes was investigated. RESULTS Of patients with COPD status documented (n = 2311), 11% (n = 249) had COPD. Patients with COPD were older, had more comorbidities, and had lower use of β-blockers compared with those without COPD. At baseline, patients with COPD had lower peak oxygen consumption and higher V(E)/V(CO)(2) slope. During a median follow-up of 2.5 years, COPD was associated with increased mortality/hospitalization, mortality, and CV mortality/HF hospitalization. After multivariable adjustment, the risk of CV mortality/HF hospitalization remained increased (hazard ratio [HR] 1.46, 95% CI 1.14-1.87), whereas mortality/hospitalization (HR 1.15, 95% CI 0.96-1.37) and mortality (HR 1.33, 95% CI 0.99-1.76) were not significantly increased. There was no interaction between COPD and exercise training on outcomes or between COPD and β-blocker selectivity on mortality/hospitalization (all P > .1). CONCLUSIONS Chronic obstructive pulmonary disease in patients with HF was associated with older age, more comorbidities, reduced exercise capacity, and increased CV mortality/HF hospitalization, but not a differential response to exercise training. β-Blocker selectivity was not associated with differences in outcome for patients with vs without COPD.

Relationship of beta-blocker dose with outcomes in ambulatory heart failure patients with systolic dysfunction: results from the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial.

Objectives To examine the association between baseline beta-blocker (BB) dose and outcomes in the HF-ACTION trial.OBJECTIVES This study sought to examine the association between baseline beta-blocker (BB) dose and outcomes in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial. BACKGROUND Beta-blockers reduce morbidity and mortality in chronic heart failure (HF) patients with reduced ejection fraction, but it is unclear whether titrating to higher BB doses improves outcomes in this setting. METHODS The HF-ACTION trial was a randomized, multicenter trial enrolling 2,331 ambulatory HF patients with systolic dysfunction (New York Heart Association functional class II to IV, left ventricular ejection fraction <0.35) randomized to exercise training versus usual care, with median follow-up of 2.5 years. The BB dose at baseline was standardized with carvedilol equivalents and analyzed as a continuous variable and by discrete dose groups. The relationship between BB dose and the primary endpoint of all-cause mortality or all-cause hospitalization and other cardiovascular secondary endpoints was determined before and after adjustment for variables significantly associated with outcomes in the HF-ACTION cohort. RESULTS Ninety-five percent of patients were receiving a BB. There was a significant inverse relationship between BB dose and all-cause death or hospitalization but not other cardiovascular endpoints after adjustment for other predictors of outcome, with a linear benefit up to the 50-mg daily dose. There was a significant association between BB dose and change in peak VO(2) at 3 months. There was no increase in bradycardia with higher doses of BB. CONCLUSIONS There was a significant inverse relationship between BB dose and the endpoint of all-cause death or all-cause hospitalization in this well-treated HF cohort with systolic dysfunction, supporting recommendations that titrating doses up to 50 mg/day might confer a benefit in such patients. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437).

Clinical role of exercise training in the management of patients with chronic heart failure

Prior exercise research and the recently completed HF-ACTION (Heart Failure and A Controlled Trial Investigating Outcomes of Exercise Training) trial indicate that regular exercise represents an effective therapy in the management of patients with stable chronic heart failure (HF) due to left ventricular systolic dysfunction. This review summarizes the results from these studies and provides a guide for prescribing exercise. Regular aerobic-type exercise training improves exercise capacity; does not worsen and may, in fact, mildly improve cardiac function; and partially improves other physiological abnormalities that develop because of chronic HF (eg, autonomic and skeletal muscle function). Regular exercise is safe, improves health status, and modestly reduces ( approximately 15%) combined risk for cardiovascular death or HF-related hospitalization. Even greater physiological and clinical benefits appear likely in patients with HF who adhere to a higher volume of exercise (eg, 6 MET-hr per week). The exercise regimen should include an aerobic-type activity performed at least 30 minutes, 5 or more days per week, and at an intensity approximating 55% to 80% of heart rate reserve. Resistance training should be considered for patients who first demonstrate they are able to tolerate aerobic exercise training. Common to other interventions that also rely on human behavior, long-term adherence to exercise in patients with HF remains a challenge and requires additional research to determine strategies aimed at improving compliance. Areas of needed research include identifying which patient subgroup(s) benefits the most and determination of the optimal intensity, duration, and frequency of exercise needed to maximize clinical benefits and attenuate fatigue.

Exercise training in heart failure

Patients with heart failure challenge the clinician with a constellation of difficult clinical, pathophysiologic, and psychologic issues. As a result, until recently, exercise training was not considered a safe and effective treatment strategy to be used in these patients. However, in the past 10 years, data from both randomized and nonrandomized trials showed that regular exercise training in patients with stable Class II and III heart failure can safely improve exercise tolerance, attenuate an overactivated sympathetic nervous system, partially reverse skeletal muscle abnormalities, and enhance health-related quality of life. These outcomes are achievable with a relatively moderate dose of physical activity, such as 30 to 60 minutes of walking or cycling 3 to 5 days per week at an intensity equivalent to 60% to 70% of peak oxygen consumption. Sufficiently powered trials are needed to assess morbidity, mortality, and cost-effectiveness endpoints relative to exercise training in patients with heart failure.