Stephen J. Ellis

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.

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.

6-min walk test provides prognostic utility comparable to cardiopulmonary exercise testing in ambulatory outpatients with systolic heart failure.

OBJECTIVES The goal of this study was to compare the prognostic efficacy of the 6-min walk (6MW) and cardiopulmonary exercise (CPX) tests in stable outpatients with chronic heart failure (HF). BACKGROUND CPX and 6MW tests are commonly applied as prognostic gauges for systolic HF patients, but few direct comparisons have been conducted. METHODS Stable New York Heart Association (NYHA) functional class II and III systolic HF patients (ejection fraction ≤ 35%) from the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial were studied. 6MW distance (6MWD) and CPX indices (peak oxygen consumption [VO(2)] and ventilatory equivalents for exhaled carbon dioxide [VE/VCO(2)] slope) were compared as predictors of all-cause mortality/hospitalization and all-cause mortality over 2.5 years of mean follow-up. RESULTS A total of 2,054 HF-ACTION participants underwent both CPX and 6MW tests at baseline (median age 59 years; 71% male; 64% NYHA functional class II and 36% NYHA functional class III/IV). In unadjusted models and in models that included key clinical and demographic covariates, C-indices of 6MWD were 0.58 and 0.65 (unadjusted) and 0.62 and 0.72 (adjusted) in predicting all-cause mortality/hospitalization and all-cause mortality, respectively. C-indices for peak VO(2) were 0.61 and 0.68 (unadjusted) and 0.63 and 0.73 (adjusted). C-indices for VE/VCO(2) slope were 0.56 and 0.65 (unadjusted) and 0.61 and 0.71 (adjusted); combining peak VO(2) and VE/VCO(2) slope did not improve the C-indices. Overlapping 95% confidence intervals and modest integrated discrimination improvement values confirmed similar prognostic discrimination by 6MWD and CPX indices within adjusted models. CONCLUSIONS In systolic HF outpatients, 6MWD and CPX indices demonstrated similar utility as univariate predictors for all-cause hospitalization/mortality and all-cause mortality. However, 6MWD or CPX indices added only modest prognostic discrimination to models that included important demographic and clinical covariates.

Relation of Depression to Severity of Illness in Heart Failure (from Heart Failure And a Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION))

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.

Factors Related to Morbidity and Mortality in Patients With Chronic Heart Failure With Systolic DysfunctionClinical Perspective

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.

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.

Outcomes, health policy, and managed care: relationships between patient-reported outcome measures and clinical measures in outpatients with heart failure.

BACKGROUND Patient-reported outcomes are increasingly used to assess the efficacy of new treatments. Understanding relationships between these and clinical measures can facilitate their interpretation. We examined associations between patient-reported measures of health-related quality of life and clinical indicators of disease severity in a large, heterogeneous sample of patients with heart failure. METHODS Patient-reported measures, including the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the EuroQol Visual Analog Scale (VAS), and clinical measures, including peak VO(2), 6-minute walk distance, and New York Heart Association (NYHA) class, were assessed at baseline in 2331 patients with heart failure. We used general linear models to regress patient-reported measures on each clinical measure. Final models included for significant sociodemographic variables and 2-way interactions. RESULTS The KCCQ was correlated with peak VO(2) (r = .21) and 6-minute walk distance (r = .27). The VAS was correlated with peak VO(2) (r = .09) and 6-minute walk distance (r = .11). Using the KCCQ as the response variable, a 1-SD difference in peak Vo(2) (4.7 mL/kg/min) was associated with a 2.86-point difference in the VAS (95% CI, 1.98-3.74) and a 4.75-point difference in the KCCQ (95% CI, 3.78-5.72). A 1-SD difference in 6-minute walk distance (105 m) was associated with a 2.78-point difference in the VAS (95% CI, 1.92-3.64) and a 5.92-point difference in the KCCQ (95% CI, 4.98-6.87); NYHA class III was associated with an 8.26-point lower VAS (95% CI, 6.59-9.93) and a 12.73-point lower KCCQ (95% CI, 10.92-14.53) than NYHA class II. CONCLUSIONS These data may inform deliberations about how to best measure benefits of heart failure interventions, and they generally support the practice of considering a 5-point difference on the KCCQ and a 3-point difference on the VAS to be clinically meaningful.

Efficacy and safety of pyridoxal 5'-phosphate (MC-1) in high-risk patients undergoing coronary artery bypass graft surgery: the MEND-CABG II randomized clinical trial.

CONTEXT Coronary artery bypass graft (CABG) surgery is frequently performed and effective; however, perioperative complications related to ischemia-reperfusion injury, including myocardial infarction (MI), remain common and result in significant morbidity and mortality. MC-1, a naturally occurring pyridoxine metabolite and purinergic receptor antagonist, prevents cellular calcium overload and may reduce ischemia-reperfusion injury. Phase 2 trial data suggest that MC-1 may reduce death or MI in high-risk patients undergoing CABG surgery. OBJECTIVE To assess the efficacy and safety of MC-1 administered immediately before and for 30 days after surgery in patients undergoing CABG surgery. DESIGN, SETTING, AND PARTICIPANTS The MC-1 to Eliminate Necrosis and Damage in Coronary Artery Bypass Graft Surgery II Trial, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial, with 3023 intermediate- to high-risk patients undergoing CABG surgery with cardiopulmonary bypass enrolled between October 2006 and September 2007 at 130 sites in Canada, the United States, and Germany. INTERVENTIONS Patients received either MC-1, 250 mg/d (n = 1519), or matching placebo (n = 1504) immediately before and for 30 days after CABG surgery. MAIN OUTCOME MEASURES The primary efficacy outcome was cardiovascular death or nonfatal MI, defined as a creatine kinase (CK) MB fraction of at least 100 ng/mL or new Q waves through postoperative day 30. RESULTS The primary efficacy outcome occurred in 140 of 1510 patients (9.3%) in the MC-1 group and 133 of 1486 patients (9.0%) in the placebo group (risk ratio, 1.04; 95% confidence interval, 0.83-1.30; P = .76). All-cause mortality was higher among patients assigned to MC-1 than placebo at 4 days (1.0% vs 0.3%; P = .03) but was similar at 30 days (1.9% vs 1.5%; P = .44). There was no difference in the 8- to 24-hour CK-MB area under the curve between the MC-1 and placebo groups (median, 270 [interquartile range, 175-492] vs 268 [interquartile range, 170-456] hours x ng/mL; P = .11). CONCLUSION In this population of intermediate- to high-risk patients undergoing CABG surgery, MC-1 did not reduce the composite of cardiovascular death or nonfatal MI. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00402506