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.

Authorship in a multicenter clinical trial: The Heart Failure-A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) Authorship and Publication (HAP) scoring system results.

BACKGROUND: Few guidelines exist regarding authorship on manuscripts resulting from large multicenter trials. The HF-ACTION investigators devised a system to address assignment of authorship on trial publications and tested the outcomes in the course of conducting the large, multicenter, National Heart, Lung, and Blood Institute-funded trial (n = 2,331; 82 clinical sites; 3 countries). The HF-ACTION Authorship and Publication (HAP) scoring system was designed to enhance rate of dissemination, recognize investigator contributions to the successful conduct of the trial, and harness individual expertise in manuscript generation. METHODS: The HAP score was generated by assigning points based on investigators' participation in trial enrollment, follow-up, and adherence, as well as participation in committees and other trial activity. Overall publication rates, publication rates by author, publication rates by site, and correlation between site publication and HAP score using a Poisson regression model were examined. RESULTS: Fifty peer-reviewed, original manuscripts were published within 6.5 years after conclusion of study enrollment. In total, 137 different authors were named in at least 1 publication. Forty-five (55%) of the 82 sites had an author named to at least 1 article. A Poisson regression model examining incident rate ratios revealed that a higher HAP score resulted in a higher incidence of a manuscript, with a 100-point increase in site score corresponding to an approximately 32% increase in the incidence of a published article. CONCLUSIONS: Given the success in publishing a large number of manuscripts and widely distributing authorship, regular use of a transparent, objective authorship assignment system for publishing results from multicenter trials may be recommended to optimize fairness and dissemination of trial results.

Exercise training and pacing status in patients with heart failure: results from HF-ACTION.

BACKGROUND: We sought to determine if outcomes with exercise training in heart failure (HF) vary according to ventricular pacing type. METHODS AND RESULTS: Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) randomized 2,331 outpatients with HF and left ventricular ejection fraction ≤35% to usual care plus exercise training or usual care alone. We examined the relationship between outcomes and randomized treatment according to ventricular pacing status with the use of Cox proportional hazards modeling. In HF-ACTION 1,118 patients (48%) had an implanted cardiac rhythm device: 683 with right ventricular (RV) and 435 with biventricular (BiV) pacemakers. Patients with pacing devices were older, more frequently white, and had lower peak VO2 (P < .001 for all). Peak VO2 improved similarly with training in groups with and without pacing devices. The primary composite end point-all-cause death or hospitalization-was reduced only in patients randomized to exercise training without a device (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.67-0.93 [P = .004]; RV lead: HR 1.04, 95% CI 0.84-1.28 [P = .74]; BiV pacing: HR 1.05, 95% CI 0.82-1.34 [P = .72]; interaction P = .058). CONCLUSIONS: Exercise training may improve exercise capacity in patients with implanted cardiac devices. However, the apparent beneficial effects of exercise on hospitalization or death may be attenuated in patients with implanted cardiac devices and requires further study.

Associations between seattle heart failure model scores and medical resource use and costs: findings from HF-ACTION.

BACKGROUND: Prognostic models, such as the Seattle Heart Failure Model (SHFM), have been developed to predict patient survival. The extent to which they predict medical resource use and costs has not been explored. In this study, we evaluated relationships between baseline SHFM scores and 1-year resource use and costs using data from a clinical trial. METHODS AND RESULTS: We applied generalized linear models to examine the relative impact of a 1-unit increase in SHFM scores on counts of medical resource use and direct medical costs at 1 year of follow-up. Of 2331 randomized patients, 2288 (98%) had a rounded integer SHFM score between -1 and 2, consistent with predicted 1-year survival of 98% and 74%, respectively. At baseline, median age was 59 years, 28% of patients were women, and nearly two-thirds of the cohort had New York Heart Association class II heart failure and one-third had class III heart failure. Higher SHFM scores were associated with more hospitalizations (rate ratio per 1-unit increase, 1.86; P < .001), more inpatient days (2.30; P < .001), and higher inpatient costs (2.28; P < .001), outpatient costs (1.54; P < .001), and total medical costs (2.13; P < .001). CONCLUSION: Although developed to predict all-cause mortality, SHFM scores also predict medical resource use and costs.

Association between resting heart rate, chronotropic index, and long-term outcomes in patients with heart failure receiving ß-blocker therapy: data from the HF-ACTION trial.

AIMS: The aim of this study was to assess the association between resting heart rate (HR), chronotropic index (CI), and clinical outcomes in optimally treated chronic heart failure (HF) patients on ß-blocker therapy. METHODS AND RESULTS: We performed a sub-study in 1118 patients with HF and reduced ejection fraction (EF < 35%) included in the HF-ACTION trial. Patients in sinus rhythm who received a ß-blocker and who performed with maximal effort on the exercise test were included. Chronotropic index was calculated as an index of HR reserve achieved, by using the equation (220-age) for estimating maximum HR. A sensitivity analysis using an equation developed for HF patients on ß-blockers was also performed. Cox proportional hazards models were fit to assess the association between CI and clinical outcomes. Median (25th, 75th percentiles) follow-up was 32 (21, 44) months. In a multivariable model including resting HR and CI as continuous variables, neither was associated with the primary outcome of all-cause mortality or hospitalization. However, each 0.1 unit decrease in CI <0.6 was associated with 17% increased risk of all-cause mortality (hazard ratio 1.17, 95% confidence interval 1.01-1.36; P = 0.036), and 13% increased risk of cardiovascular mortality or HF hospitalization (hazard ratio 1.13, 1.02-1.26; P = 0.025). Overall, 666 of 1118 (60%) patients had a CI <0.6. Chronotropic index did not retain statistical significance when dichotomized at a value of ≤ 0.62. CONCLUSION: In HF patients receiving optimal medical therapy, a decrease in CI <0.6 was associated with adverse clinical outcomes. Obtaining an optimal HR response to exercise, even in patients receiving optimal ß-blocker therapy, may be a therapeutic target in the HF population.

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, ß-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 ß-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 ß-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 ß-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. ß-Blocker selectivity was not associated with differences in outcome for patients with vs without COPD.

Race, exercise training, and outcomes in chronic heart failure: findings from Heart Failure - a Controlled Trial Investigating Outcomes in Exercise TraiNing (HF-ACTION).

BACKGROUND: The strength of race as an independent predictor of long-term outcomes in a contemporary chronic heart failure (HF) population and its association with exercise training response have not been well established. We aimed to investigate the association between race and outcomes and to explore interactions with exercise training in patients with ambulatory HF. METHODS: We performed an analysis of HF-ACTION, which randomized 2331 patients with HF having an ejection fraction ≤35% to usual care with or without exercise training. We examined characteristics and outcomes (mortality/hospitalization, mortality, and cardiovascular mortality/HF hospitalization) by race using adjusted Cox models and explored an interaction with exercise training. RESULTS: There were 749 self-identified black patients (33%). Blacks were younger with significantly more hypertension and diabetes, less ischemic etiology, and lower socioeconomic status versus whites. Blacks had shorter 6-minute walk distance and lower peak VO2 at baseline. Over a median follow-up of 2.5 years, black race was associated with increased risk for all outcomes except mortality. After multivariable adjustment, black race was associated with increased mortality/hospitalization (hazard ratio [HR] 1.16, 95% CI 1.01-1.33) and cardiovascular mortality/HF hospitalization (HR 1.46, 95% CI 1.20-1.77). The hazard associated with black race was largely caused by increased HF hospitalization (HR 1.58, 95% CI 1.27-1.96), given similar cardiovascular mortality. There was no interaction between race and exercise training on outcomes (P > .5). CONCLUSIONS: Black race in patients with chronic HF was associated with increased prevalence of modifiable risk factors, lower exercise performance, and increased HF hospitalization, but not increased mortality or a differential response to exercise training.

Associations between hemoglobin level, resource use, and medical costs in patients with heart failure: findings from HF-ACTION.

BACKGROUND: Reports that patients with heart failure and anemia incur greater costs and medical resource use have relied largely on data with limited clinical detail. METHODS: HF-ACTION, a large trial of exercise training in heart failure, recorded hemoglobin at baseline. Medical resource use and hospital bills for inpatient and emergency department visits were collected throughout the study. We analyzed hemoglobin as a continuous variable to evaluate relationships with medical resource use and costs over 1 year. RESULTS: Among 1,763 patients with baseline hemoglobin levels, those with lower hemoglobin levels tended to be older, African American, and women and to have more severe heart failure. Lower hemoglobin was significantly associated with more hospital admissions, inpatient days, outpatient visits, and urgent care or emergency department visits (all P < .005, unadjusted). Although cost outliers influenced estimates, these observations were distributed across hemoglobin levels. Mean 1-year costs across hemoglobin levels defined as ≤ 11, >11-12, >12-13, >13-14, >14-15, and >15 g/dL were $21,106, $20,189, $16,249, $17,989, $13,216, and $12,492, respectively (P < .001, unadjusted). Significant associations remained after multivariable adjustment. CONCLUSIONS: Patients with lower baseline hemoglobin levels experienced progressively greater resource use and higher costs.

Benefit of exercise therapy for systolic heart failure in relation to disease severity and etiology-findings from the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise Training study.

BACKGROUND: This post hoc analysis of the HF-ACTION cohort explores the primary and secondary results of the HF-ACTION study by etiology and severity of illness. METHODS: HF-ACTION randomized stable outpatients with reduced left ventricular (LV) function and heart failure (HF) symptoms to either supervised exercise training plus usual care or to usual care alone. The primary outcome was all-cause mortality or all-cause hospitalization; secondary outcomes included all-cause mortality, cardiovascular mortality or cardiovascular hospitalization, and cardiovascular mortality or HF hospitalization. The interaction between treatment and risk variable, etiology or severity as determined by risk score, New York Heart Association class, and duration of cardiopulmonary exercise test was examined in a Cox proportional hazards model for all clinical end points. RESULTS: There was no interaction between etiology and treatment for the primary outcome (P = .73), cardiovascular (CV) mortality or CV hospitalization (P = .59), or CV mortality or HF hospitalization (P = .07). There was a significant interaction between etiology and treatment for the outcome of mortality (P = .03), but the interaction was no longer significant when adjusted for HF-ACTION adjustment model predictors (P = .08). There was no significant interaction between treatment effect and severity, except a significant interaction between cardiopulmonary exercise duration and training was identified for the primary outcome of all-cause mortality or all-cause hospitalization. CONCLUSION: Consideration of symptomatic (New York Heart Association classes II to IV) patients with HF with reduced LV function for participation in an exercise training program should be made independent of the cause of HF or the severity of the symptoms.

Relationship of technetium-99m tetrofosmin-gated rest single-photon emission computed tomography myocardial perfusion imaging to death and hospitalization in heart failure patients: results from the nuclear ancillary study of the HF-ACTION trial.

BACKGROUND: We hypothesized that the severity of resting perfusion abnormalities assessed by the summed rest score (SRS) would be associated with a higher rate of adverse outcomes in patients with heart failure (HF) and reduced left ventricular (LV) ejection fraction (EF). METHODS: A subset of 240 subjects from HF-ACTION underwent resting technetium-99m tetrofosmin-gated single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). Images were evaluated using a 17-segment model to derive the SRS and additional nuclear variables. RESULTS: After adjusting for prespecified covariates, SRS was significantly associated with the primary end point (hazard ratio 0.98, 95% confidence interval [CI] 0.97-1.00, P = .04), with a higher SRS corresponding to lower risk of an event. This association was not present in the unadjusted analysis. The relationship between SRS and the primary outcome was likely due to a higher event ratein patients with ischemic HF and a low SRS. The LV phase SD was not predictive of the primary outcome (hazard ratio 1.00, 95% confidence interval 0.99-1.01, P = .49). In a post hoc analysis, nuclear variables provided incremental prognostic information when added to clinical information (P = .006). CONCLUSIONS: Gated SPECT MPI provides important information in patients with HF and reduced LVEF. In the adjusted analysis, SRS has an unexpected relationship with the primary end point. Phase SD was not associated with the primary end point. Rest-gated SPECT MPI provides incrementally greater prognostic information than clinical information alone.

Method for establishing authorship in a multicenter clinical trial.

With the emergence of large multicenter trials over the past 20 years, the numbers of investigators involved and publications resulting from each study have grown exponentially. An efficient, fair, and effective way to establish authorship on study-related manuscripts could diminish conflict among the investigators and help ensure robust and timely dissemination of study results. This article describes a process developed by the investigators in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial (ClinicalTrials.gov registration number: NCT00047437) to establish authorship of the manuscripts describing the baseline characteristics, study design, and trial outcomes in an equitable and transparent manner based on objective, quantifiable contributions to the study as a whole. The HF-ACTION investigators developed a scoring system that assigned points to investigators by using the criteria established for enrollment, adherence to the exercise program, data completion, committee service, and other trial efforts. The scoring system has been successfully implemented for baseline manuscripts and has allowed many investigators to participate in the HF-ACTION publication process.

Relationship of age and exercise performance in patients with heart failure: the HF-ACTION study.

BACKGROUND: More than three fourths of patients with heart failure (HF) are 65 years and older, and older age is associated with worse symptoms and prognoses than is younger age. Reduced exercise capacity is a chief HF complaint and indicates poorer prognosis, especially among elderly persons, but the mechanisms underlying functional decline in older patients with HF are largely unknown. METHODS: Baseline cardiopulmonary exercise testing data from the HF-ACTION trial were assessed to clarify age effects on peak oxygen consumption (VO(2)) and ventilation-carbon dioxide production (VE/VCO(2)) slope. RESULTS: Among 2,331 New York Heart Association class II-IV patients with HF, increased age corresponded to decreased peak VO(2) (-0.14 mL kg(-1) min(-1) per year >40 years; P < .0001) and increased VE/VCO(2) slope (0.30 U/y >70 years; P < .0001). In a multivariable model with 34 other potential determinants, age was the strongest independent predictor of peak VO(2) (partial R(2) 0.130, total R(2) 0.392; P < .001) and a significant but relatively weaker predictor of VE/VCO(2) slope (partial R(2) 0.037, total R(2) 0.199; P < .001). Blunted peak heart rate was also a strong predictor of peak VO(2). Although peak heart rate and age were strongly correlated, both were significant independent predictors of peak VO(2) when analyzed simultaneously in a model. Aggregate comorbidity increased significantly with age but did not account for age effects on peak VO(2). CONCLUSIONS: Age is the strongest predictor of peak VO(2) and a significant predictor of VE/VCO(2) slope in the HF-ACTION population. Age-dependent comorbidities do not explain changes in peak VO(2). Age-related changes in cardiovascular physiology, potentially magnified by the HF disease state, should be considered a contributor to the pathophysiology and a target for more effective therapy in older patients with HF.

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.

Baseline differences in the HF-ACTION trial by sex.

BACKGROUND: In patients with heart failure (HF), assessment of functional capacity plays an important prognostic role. Both 6-minute walk and cardiopulmonary exercise testing have been used to determine physical function and to determine prognosis and even listing for transplantation. However, as in HF trials, the number of women reported has been small, and the cutoffs for transplantation have been representative of male populations and extrapolated to women. It is also well known that peak VO(2) as a determinant of fitness is inherently lower in women than in men and potentially much lower in the presence of HF. Values for a female population from which to draw for this important determination are lacking. METHODS: The HF-ACTION trial randomized 2,331 patients (28% women) with New York Heart Association class II-IV HF due to systolic dysfunction to either a formal exercise program in addition to optimal medical therapy or to optimal medical therapy alone without any formal exercise training. To characterize differences between men and women in the interpretation of final cardiopulmonary exercise testing models, the interaction of individual covariates with sex was investigated in the models of (1) VE/VCO(2), (2) VO(2) at ventilatory threshold (VT), (3) distance on the 6-minute walk, and (4) peak VO(2). RESULTS: The women were younger than the men and more likely to have a nonischemic etiology and a higher ejection fraction. Dose of angiotensin converting enzyme inhibitor (ACEI) was lower in the women, on average. The lower ACEI dose may reflect the higher use of angiotensin II receptor blocker (ARB) in women. Both the peak VO(2) and the 6-minute walk distance were significantly lower in the women than in the men. Perhaps the most significant finding in this dataset of baseline characteristics is that the peak VO(2) for women was significantly lower than that for men with similar ventricular function and health status. CONCLUSION: Therefore, in a well-medicated, stable, class II-IV HF cohort of patients who are able to exercise, women have statistically significantly lower peak VO(2) and 6-minute walk distance than men with similar health status and ventricular function. These data should prompt careful thought when considering prognostic markers for women and listing for cardiac transplant.

Myocardial perfusion, function, and dyssynchrony in patients with heart failure: baseline results from the single-photon emission computed tomography imaging ancillary study of the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION) Trial.

BACKGROUND: There are currently limited data on the relationships between resting perfusion abnormalities, left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) functional class, and exercise capacity as defined by peak VO(2) and 6-minute walk test in patients with heart failure (HF) and reduced LVEF. Furthermore, the association between resting perfusion abnormalities and left ventricular dyssynchrony is currently unknown. This article addresses the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION) gated SPECT imaging (gSPECT) substudy baseline results. METHODS: HF-ACTION was a multicenter, randomized controlled trial of aerobic exercise training versus usual care in 2,331 stable patients with LVEF of < or = 35% and NYHA class II to IV HF symptoms treated with optimal medical therapy. Subjects enrolled in the HF-ACTION substudy underwent resting Tc-99m tetrofosmin gSPECT at baseline (n = 240). Images were evaluated for extent and severity of perfusion abnormalities using a 17-segment and a 5-degree gradation severity score (summed rest score [SRS]). Left ventricular function and dyssynchrony were assessed using validated available commercial software. RESULTS: The average age of patients enrolled was 59, 69% were male, 63% were white, and 33% were African American. Of the 240 participants, 129 (54%) were ischemic and 111 (46%) were nonischemic in etiology. The median LVEF by gSPECT for the entire cohort was 26%. Among the nuclear variables, there was a modest correlation between LVEF and SRS (r = -0.31, P < .0001) and there were stronger correlations between phase SD and SRS (r = 0.66, P < .0001) as well as phase SD and LVEF (r = -0.50, P < .0001). Patients with NYHA class III symptoms had more severe and significant degrees of dyssynchrony (median phase SD 54 degrees ) than those with NYHA class II symptoms (median phase SD 39 degrees, P = .001). Patients with an ischemic etiology had a higher SRS (P < .0001) and significantly more dyssynchrony (P < .0001) than those who were nonischemic. However, there was no difference in LVEF or objective measures of exercise capacity between these groups. With respect to peak VO(2), there was a weak correlation with LVEF (r = 0.18, P = .006) and no correlation with SRS (r = -0.04, P = 0.59) or with dyssynchrony (r = -0.13, P = .09). A weak but statistically significant correlation between SRS and 6-minute walk was observed (r = -0.15, P = .047). CONCLUSIONS: Gated SPECT imaging can provide important information in patients with HF due to severe LV dysfunction including quantitative measures of global systolic function, perfusion, and dyssynchrony. These measurements are modestly but significantly related to symptom severity and objective measures of exercise capacity.

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.

A randomized, double-blind, placebo-controlled, multicenter study to evaluate the cardioprotective effects of MC-1 in patients undergoing high-risk coronary artery bypass graft surgery: MC-1 to Eliminate Necrosis and Damage in Coronary Artery Bypass Graft Surgery Trial (MEND-CABG) II--study design and rationale.

BACKGROUND: Coronary artery bypass graft (CABG) surgery is effective in relieving angina and improving survival and quality of life in patients with obstructive coronary artery disease; however, recurrent angina, myocardial infarction, neurological injury, and death can occur in the perioperative and postoperative period. MC-1 (pyridoxal 5'-phosphate) is a novel agent that has shown promise in reducing myocardial necrosis by reducing cellular calcium overload after percutaneous coronary intervention and CABG surgery in high-risk patients undergoing these procedures. METHODS: MEND-CABG II is a phase III study evaluating the efficacy and safety of MC-1 in reducing cardiovascular morbidity and mortality after CABG. High-risk patients undergoing CABG surgery will be randomly assigned to receive either MC-1 (250 mg/d) or matching placebo immediately before and continuing for 30 days after the procedure. The primary end point is the occurrence of cardiovascular death or nonfatal myocardial infarction through postoperative day 30. A total of 3023 patients were enrolled at 130 sites in Canada, the United States, and Germany between October 2006 and September 2007, with results anticipated shortly after completion of 90-day follow-up in March 2008. CONCLUSIONS: The data from the MEND-CABG II trial will establish whether peri- and postoperative treatment with MC-1 can decrease the short- and intermediate-term morbidity and mortality of high-risk patients undergoing CABG surgery.

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.

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