Heart Failure: A Controlled Trial Investigating Outcomes Of Exercise Training Research Articles

Development a nomogram prognostic model for survival in heart failure patients based on the HF-ACTION data

BackgroundThe risk assessment for survival in heart failure (HF) remains one of the key focuses of research. This study aims to develop a simple and feasible nomogram model for survival in HF based on the Heart Failure-A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION) to support clinical decision-making.MethodsThe HF patients were extracted from the HF-ACTION database and randomly divided into a training cohort and a validation cohort at a ratio of 7:3. Multivariate Cox regression was used to identify and integrate significant prognostic factors to form a nomogram, which was displayed in the form of a static nomogram. Bootstrap resampling (resampling = 1000) and cross-validation was used to internally validate the model. The prognostic performance of the model was measured by the concordance index (C-index), calibration curve, and the decision curve analysis.ResultsThere were 1394 patients with HF in the overall analysis. Seven prognostic factors, which included age, body mass index (BMI), sex, diastolic blood pressure (DBP), exercise duration, peak exercise oxygen consumption (peak VO2), and loop diuretic, were identified and applied to the nomogram construction based on the training cohort. The C-index of this model in the training cohort was 0.715 (95% confidence interval (CI): 0.700, 0.766) and 0.662 (95% CI: 0.646, 0.752) in the validation cohort. The area under the ROC curve (AUC) value of 365- and 730-day survival is (0.731, 0.734) and (0.640, 0.693) respectively in the training cohort and validation cohort. The calibration curve showed good consistency between nomogram-predicted survival and actual observed survival. The decision curve analysis (DCA) revealed net benefit is higher than the reference line in a narrow range of cutoff probabilities and the result of cross-validation indicates that the model performance is relatively robust.ConclusionsThis study created a nomogram prognostic model for survival in HF based on a large American population, which can provide additional decision information for the risk prediction of HF.

Prognostic Value of Depressive Symptoms for Cardiovascular Events in Female Patients With Heart Failure With Reduced Ejection Fraction and Heart Failure With Preserved Ejection Fraction.

Among those with heart failure (HF), women are more likely to develop depression than men. Few studies have focused on the outcomes of female patients with HF with depressive symptoms. A total of 506 female patients with HF with preserved ejection fraction were included in this secondary analysis from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) cohort, and 439 female patients with HF with reduced ejection fraction were included from the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) cohort. Depressive symptoms were measured using the Patient Health Questionnaire-9 and Beck Depression Inventory-II. The depression class was categorized by severity, and the change in clinical depression class was defined as aggravated (1-grade increase) or improved (1-grade decrease). The prognostic value of depressive symptoms was determined by using multivariable Cox proportional hazards models. Female patients with improved depressive symptoms had worse depressive status at baseline and lower baseline Kansas City Cardiomyopathy Questionnaire scores. Depression class at the 12-month visit and depression class change were the dominant prognostic factors for cardiovascular death in female patients with HF with preserved ejection fraction (hazard ratio [HR], 1.43 [95% CI, 1.02-2.01], P=0.036; HR, 1.71 [95% CI, 1.14-2.55], P=0.009). Among the patients with HF with reduced ejection fraction, both the depression class at baseline and depression class change had significant prognostic effects on cardiovascular death (HR, 3.30 [95% CI, 1.70-6.39], P<0.001; HR, 2.21 [95% CI, 1.28-3.80], P=0.004). However, the prognostic value of depressive assessments for hospitalization in patients with HF is unclear. In female patients with HF with reduced ejection fraction, the depression class at baseline was most strongly associated with cardiovascular death, whereas in female patients with HF with preserved ejection fraction, the change in depression class exhibited a more significant prognostic trend.

Oxygen Uptake Efficiency Slope and Prognosis in Heart Failure With Reduced Ejection Fraction

The prognostic utility of the oxygen uptake efficiency slope (OUES) in heart failure with reduced ejection fraction is uncertain. In this post hoc analysis of the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial (n=2,074), we tested for associations of OUES and peak oxygen uptake (VO2) with heart failure hospitalization or cardiovascular death in multivariable Cox regression models, adjusting for minute ventilation/carbon dioxide production (VE/VCO2) slope and other important confounders. Harrell's C-statistics assessed the discriminatory performance of OUES and peak VO2. Lower OUES was associated with increased risk of the outcome (quartile 1 vs 4: hazard ratio 2.1 [1.5 to 2.9, p<0.001]). Peak VO2 had greater discrimination than OUES in comparable models (e.g., C-statistic=0.73 vs 0.70, p<0.001, respectively). In the subgroup with respiratory exchange ratio <1 (n=358), peak VO2 was associated with the outcome (p<0.001) but OUES was not (p=0.96). In conclusion, whereas OUES was associated with clinical outcomes independently of VE/VCO2 slope, its prognostic utility was inferior to that of peak VO2, even when measured at submaximal effort.

Distinct Impact of Noncardiac Comorbidities on Exercise Capacity and Functional Status in Chronic Heart Failure

BackgroundNoncardiac comorbidities (NCCs) are common in patients with heart failure (HF), but how they jointly affect exercise capacity and functional status is relatively unexplored. ObjectivesThis study sought to investigate the cumulative effects of NCC on exercise capacity and functional status in chronic HF. MethodsBaseline NCC-status was assessed in HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training), IRONOUT-HF (Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure), NEAT-HFpEF (Nitrate’s Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction), INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF), and RELAX-HFpEF (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) trials, and relations with peak Vo2 and 6-minute walk test (6MWT), Kansas City Cardiomyopathy Questionnaire (KCCQ), and all-cause death were determined according to HF type (with reduced vs preserved ejection fraction). Cluster analysis of the different NCCs was performed. ResultsA total of 2,777 patients were evaluated (mean age: 60 ± 13 years; median NCC burden in HF with preserved vs reduced ejection fraction: 3 [IQR: 2-4] vs 2 [IQR: 1-3]; P < 0.001). Obesity played a more important role in HF with preserved ejection fraction in limiting peak Vo2 and 6MWT. There was a progressive decline in peak Vo2, 6MWT, and KCCQ with increasing NCC burden. Cluster analysis revealed 3 NCC clusters: cluster 1: predominance of stroke and cancer; cluster 2: predominance of chronic kidney disease and peripheral vascular disease; and cluster 3: predominance of obesity and diabetes. Patients in cluster 3 had the worst peak Vo2, 6MWT, and KCCQ despite having the lowest N-terminal pro–B-type natriuretic peptide and exhibited diminished response to aerobic exercise training (peak Vo2Pinteraction = 0.045); however, it had similar risk for all-cause death as cluster 1, whereas cluster 2 had higher risk of death than cluster 1 (HR: 1.60 [95% CI: 1.25-2.04]; P < 0.001). ConclusionsNCC type and burden have a significant and cumulative effect on exercise capacity, occur in clusters, and are associated with clinical outcomes in patients with chronic HF.

A Computable Algorithm for Medication Optimization in Heart Failure With Reduced Ejection Fraction

BackgroundGuideline-directed medical therapy (GDMT) optimization can improve outcomes in heart failure with reduced ejection fraction. ObjectivesThe objective of this study was to determine if a novel computable algorithm appropriately recommended GDMT. MethodsClinical trial data from the GUIDE-IT (Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment in Heart Failure) and HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trials were evaluated with a computable medication optimization algorithm that outputs GDMT recommendations and a medication optimization score (MOS). Algorithm-based recommendations were compared to medication changes. A Cox proportional-hazards model was used to estimate the associations between MOS and the composite primary end point for both trials. ResultsThe algorithm recommended initiation of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, beta-blockers, and mineralocorticoid receptor antagonists in 52.8%, 34.9%, and 68.1% of GUIDE-IT visits, respectively, when not prescribed the drug. Initiation only occurred in 20.8%, 56.9%, and 15.8% of subsequent visits. The algorithm also identified dose titration in 48.8% of visits for angiotensin-converting enzyme inhibitor/angiotensin receptor blockers and 39.4% of visits for beta-blockers. Those increases only occurred in 24.3% and 36.8% of subsequent visits. A higher baseline MOS was associated with a lower risk of cardiovascular death or heart failure hospitalization (HR: 0.41; 95% CI: 0.21-0.80; P = 0.009) in GUIDE-IT and all-cause death and hospitalization (HR: 0.61; 95% CI: 0.44-0.84; P = 0.003) in HF-ACTION. ConclusionsThe algorithm accurately identified patients for GDMT optimization. Even in a clinical trial with robust protocols, GDMT could have been further optimized in a meaningful number of visits. The algorithm-generated MOS was associated with a lower risk of clinical outcomes. Implementation into clinical care may identify and address suboptimal GDMT in patients with heart failure with reduced ejection fraction.

Abstract 15226: Association of Estimated Pulse Wave Velocity to Mortality in Heart Failure With Reduced Ejection Fraction. Insights From the HF-Action Trial

Introduction: Ventriculo-arterial coupling dynamics influence outcomes in heart failure (HF). Arterial stiffness (AS) is a key determinant of vascular load on the heart. We hypothesized that estimated pulse wave velocity (ePWV) would be associated with mortality. Methods: We analyzed the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) database for the association of ePWV with survival. ePWV was calculated using mean blood pressure (MBP) and Age using the equation: 9.587 – 0.402 х age + 4.560 х 10 –3 х age 2 – 2.621 х 10 –5 х age 2 х MBP + 3.176 х 10 –3 х age х MBP – 1.832 х 10 –2 х MBP. MBP was calculated as diastolic BP (DBP) + 0.4(SBP – DBP). Kaplan-Meier survival curves and Cox proportional hazards regression were used for analysis. Results: Among 768 patients (age 58.0 +/- 12.8 years, 31.8 % female), the median ePWV was 8.5 (IQR 7.2 to 10.2). There was a moderate correlation between ePWV and peak VO2 (r=-0.20, p&lt;0.0001) and between ePWV and the six-minute walk duration (r=-0.20, p&lt;0.0001). The unadjusted HR for ePWV and all-cause mortality was 1.15 per unit increase (95% CI 1.05-125). The unadjusted HRs for ePWV component covariates of age and MBP with all-cause mortality were 1.03 per year (95% CI 1.02-1.05, p &lt; 0.0001) and 0.985 per mm Hg (95% CI 0.971-1.000, p=0.053), respectively. With adjustment by peak VO2 above or below the median in a multivariable model, increasing ePWV was still associated with a greater probability of all-cause mortality (HR 1.11 per unit increase, 95% CI 1.01-1.21, p=0.02). In the model with adjustment by the six-minute walk duration, risk associated with ePWV was similar (HR 1.09, 95% CI 0.998-1.120, p=0.056). Kaplan-Meier curves also demonstrated an increased risk for ePWV greater than the median value of 8.5 (Figure). Conclusion: ePWV is associated with all-cause mortality in stable HF patients. More studies are needed to assess the utility of ePWV as a therapeutic target in HF.

Frailty Status Modifies the Efficacy of Exercise Training Among Patients With Chronic Heart Failure and Reduced Ejection Fraction: An Analysis From the HF-ACTION Trial.

Supervised aerobic exercise training (ET) is recommended for stable outpatients with heart failure (HF) with reduced ejection fraction (HFrEF). Frailty, a syndrome characterized by increased vulnerability and decreased physiologic reserve, is common in patients with HFrEF and associated with a higher risk of adverse outcomes. The effect modification of baseline frailty on the efficacy of aerobic ET in HFrEF is not known. Stable outpatients with HFrEF randomized to aerobic ET versus usual care in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial were included. Baseline frailty was estimated using the Rockwood frailty index (FI), a deficit accumulation-based model of frailty assessment; participants with FI scores >0.21 were identified as frail. Multivariable Cox proportional hazard models with multiplicative interaction terms (frailty × treatment arm) were constructed to evaluate whether frailty modified the treatment effect of aerobic ET on the primary composite end point (all-cause hospitalization or mortality), secondary end points (composite of cardiovascular death or cardiovascular hospitalization, and cardiovascular death or HF hospitalization), and Kansas City Cardiomyopathy Questionnaire score. Separate models were constructed for continuous (FI) and categorical (frail versus not frail) measures of frailty. Among 2130 study participants (age, 59±13 years; 28% women), 1266 (59%) were characterized as frail (FI>0.21). Baseline frailty burden significantly modified the treatment effect of aerobic ET (P interaction: FI × treatment arm=0.02; frail status [frail versus nonfrail] × treatment arm=0.04) with a lower risk of primary end point in frail (hazard ratio [HR], 0.83 [95% CI, 0.72-0.95]) but not nonfrail (HR, 1.04 [95% CI, 0.87-1.25]) participants. The favorable effect of aerobic ET among frail participants was driven by a significant reduction in the risk of all-cause hospitalization (HR, 0.84 [95% CI, 0.72-0.99]). The treatment effect of aerobic ET on all-cause mortality and other secondary endpoints was not different between frail and nonfrail patients (P interaction>0.1 for each). Aerobic ET was associated with a nominally greater improvement in Kansas City Cardiomyopathy Questionnaire scores at 3 months among frail versus nonfrail participants without a significant treatment interaction by frailty status (P interaction>0.2). Among patients with chronic stable HFrEF, baseline frailty modified the treatment effect of aerobic ET with a greater reduction in the risk of all-cause hospitalization but not mortality.

Abstract 64: Cardiac Rehabilitation: A Missed Opportunity For Heart Failure Medication Optimization?

Background: Guideline-directed medical therapy (GDMT) reduces hospitalization and death in heart failure with reduced ejection fraction (HFrEF), but GDMT is often not fully optimized. Cardiac rehabilitation, with frequent in-person assessment, may provide an unrealized opportunity to optimize GDMT. Methods: We analyzed the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study, which showed cardiac rehabilitation in stable HFrEF was safe and improved functional status. We applied a previously validated GDMT optimization algorithm to the baseline HF-ACTION data. It uses medications/doses, vitals, and labs to calculate a medication optimization score (MOS: range 0-100%; 100% is fully optimized for clinical status). We hypothesized the MOS would identify GDMT titration opportunities and predict clinical outcomes. Results: Of 2130 patients, 27% (n=578) had MOS 100%; GDMT barriers (e.g. low blood pressure, renal dysfunction) were more common in this group. Among 1552 non-optimized patients (age 58±13, 28% female, 39% non-White, ejection fraction 25±7%) the median MOS was 50% (IQR 38-60%) (Figure 1). After adjustment using the HF-ACTION risk model, higher MOS was associated with a decrease in death or all-cause hospitalization (HR 0.66, 95% CI 0.48-0.90, p=0.009); for each 10% MOS increase (example: metoprolol increase from 100 to 200 mg daily) the composite endpoint decreased 4.1%. Figure 2 shows survival curves for an MOS of 25%, 50% and 75%. Conclusion: Among patients with HFrEF undergoing cardiac rehabilitation, the MOS outlines ample opportunity for GDMT titration and predicts clinical outcomes in non-optimized patients

Circulating long chain acylcarnitines and outcomes in diabetic heart failure: an HF-ACTION clinical trial substudy

BackgroundWhether differences in circulating long chain acylcarnitines (LCAC) are seen in heart failure (HF) patients with and without diabetes mellitus (DM), and whether these biomarkers report on exercise capacity and clinical outcomes, remains unknown. The objective of the current study was to use metabolomic profiling to identify biomarkers that report on exercise capacity, clinical outcomes, and differential response to exercise in HF patients with and without DM.MethodsTargeted mass spectrometry was used to quantify metabolites in plasma from participants in the heart failure: a controlled trial investigating outcomes of exercise training (HF-ACTION) trial. Principal components analysis was used to identify 12 uncorrelated factors. The association between metabolite factors, diabetes status, exercise capacity, and time to the primary clinical outcome of all-cause mortality or all-cause hospitalization was assessed.ResultsA total of 664 participants were included: 359 (54%) with DM. LCAC factor levels were associated with baseline exercise capacity as measured by peak oxygen consumption (beta 0.86, p = 2 × 10−7, and were differentially associated in participants with and without DM (beta 1.58, p = 8 × 10−8 vs. 0.67, p = 9 × 10−4, respectively; p value for interaction = 0.012). LCAC levels changed to a lesser extent in participants with DM after exercise (mean ∆ 0.09, p = 0.24) than in those without DM (mean ∆ 0.16, p = 0.08). In univariate and multivariate modeling, LCAC factor levels were associated with time to the primary outcome (multivariate HR 0.80, p = 2.74 × 10−8), and were more strongly linked to outcomes in diabetic participants (HR 0.64, p = 3.21 × 10−9 v. HR 0.90, p = 0.104, p value for interaction = 0.001). When analysis was performed at the level of individual metabolites, C16, C16:1, C18, and C18:1 had the greatest associations with both exercise capacity and outcomes, with higher levels associated with worse outcomes. Similar associations with time to the primary clinical outcome were not found in a control group of patients without HF from the CATHeterization GENetics (CATHGEN) study.ConclusionsLCAC biomarkers are associated with exercise status and clinical outcomes differentially in HF patients with and without DM. Impaired fatty acid substrate utilization and mitochondrial dysfunction both at the level of the skeletal muscle and the myocardium may explain the decreased exercise capacity, attenuated response to exercise training, and poor clinical outcomes seen in patients with HF and DM.Trial Registration clinicaltrials.gov Identifier: NCT00047437.

Abstract 16003: Genetic Variation Associated With Favorable Exercise Response in Patients With Systolic Heart Failure: A Hf-action Trial Substudy

Background: Exercise has shown benefit in patients with systolic heart failure, including in the clinical trial Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION). There is heterogeneity in who derives benefit from exercise, and the biologic mechanisms of favorable response to exercise in systolic heart failure are not well understood. Hypothesis: Genetic variation is an underlying factor influencing heterogeneity in response to exercise in patients with systolic heart failure. Methods: The HF-ACTION trial randomized individuals with systolic heart failure (left ventricular ejection fraction &lt;35%) to supervised exercise versus usual care. In this study, we performed a genome wide association study (GWAS) in the HF-ACTION biorepository using the Axiom Biobank1 genotyping array (13,403,591 single nucleotide polymorphisms [SNPs] after quality control on directly genotyped and 1000 genomes imputed data), in N=377 study subjects who completed the supervised exercise arm. Using change in peak VO2 as our outcome, we ran within-ancestry GWASes, modeling SNP effects as both additive and dominant, and conducted across-ancestry meta-analysis within each genetic model. Results: Five loci met genome-wide significance in the European ancestry analyses, 5 loci in the African ancestry, and 8 in the meta-analyses. The two most significantly associated loci across both additive and dominant meta-analysis models were rs111577308 located in the histone acetylation for transcription elongator complex 3 gene ( ELP3, p=1.212x10 -9 ) and rs75444785 located in the phosphodiesterase 4D gene ( PDE4D , p=1.565x10 -9 ). ELP3 is responsible for histone modifications related to DNA transcription factor complexes, and PDE4D is involved in cyclic AMP cell signaling. In silico analysis of these loci showed that they are in linkage with regions associated with skeletal muscle and peripheral vascular disease phenotypes. Conclusions: Using a genome-wide association study in a well-phenotyped clinical trial of exercise in systolic heart failure, we found common genetic variants in genes involved in DNA transcription histone modification and cyclic AMP cell signaling that are associated with a more favorable response to exercise.

Impact of Age on Comorbidities and Outcomes in Heart Failure With Reduced Ejection Fraction

ObjectivesThis study sought to determine whether age modifies the impact of key comorbidities on clinical outcomes for patients with heart failure with reduced ejection fraction (HFrEF). BackgroundComorbidities impact outcomes in HFrEF. However, the effect of age on the impact of comorbidities on prognosis is not clearly understood. MethodsCox proportional hazards models were used assessed interactions between age and comorbidities on the primary composite endpoint (all-cause mortality or hospitalization) and secondary endpoints in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) multicenter trial of 2,331 patients with HFrEF. ResultsAge did not significantly modify the effect of any comorbidity on the primary endpoint. However, age significantly modified the effect of body mass index (BMI) on all-cause mortality (interaction p = 0.02). Among patients ≥70 years of age, there was a U-shaped relationship between BMI and 1-year mortality, where BMI of 20 kg/m2 corresponded to 17.6%; a BMI of 30 kg/m2 corresponded to 7.0%; and a BMI of 40 kg/m2 corresponded to 11%. For patients <60 years of age, mortality increased nonsignificantly from 3.2% to 3.7% with increasing BMI. Age also modified the effect of depressive symptoms on all-cause mortality (interaction p = 0.03). Among patients ≥70 years of age, a 1-year mortality rate significantly increased from 7.8% for a Beck Depression Inventory (BDI) score of 5% to 15.6% for BDI of 20. For patients <60 years of age, mortality was nonsignificantly related to BDI. Cumulative comorbidity scores were stronger predictors than age for mortality/hospitalization. ConclusionsIn chronic HFrEF, age markedly altered the impact of BMI and depressive symptoms on all-cause mortality, with much higher risk in older patients, but was not as strong a predictor of mortality/hospitalizations as cumulative comorbidity score. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437)

Dose Response of β-Blockers in Adrenergic Receptor Polymorphism Genotypes.

Background In heart failure (HF) with reduced ejection fraction, 2 clinical trials, the BEST (β-Blocker Evaluation of Survival Trial) and HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training), have reported an effectiveness interaction between the ADRB1 (β-1 adrenergic receptor) Arg389Gly polymorphism and β-blockers (BBs). HF-ACTION additionally reported a dose-related interaction of unclear origin. If confirmed and pharmacogenetically resolved, these findings may have important implications for HF with reduced ejection fraction precision therapy. We used uniform methodology to investigate BB dose-ADRB1 Arg389Gly polymorphism interaction with major clinical end points in BEST/bucindolol and HF-ACTION/other BB databases. Methods This was a retrospective analysis of prospectively designed DNA substudies from BEST (N=1040) and HF-ACTION (N=957). Subjects were genotyped for ADRB1 Arg389Gly and ADRA2C (α2C adrenergic receptor) Ins322-325Del. BB dose was defined as either no/low dose or high dose, according to total daily dose of either bucindolol (BEST subjects) or other BB (HF-ACTION subjects) standardized to carvedilol equivalents. The main outcome of interest was all-cause mortality, and CV mortality/HF hospitalization was a secondary outcome. Results Subjects in each trial had less all-cause mortality with high- versus no/low-dose BB if they had ADRB1 Arg389Arg (BEST: hazard ratio [HR]=0.40, P=0.002; HF-ACTION: HR=0.45, P=0.005) but not Arg389Gly genotype (both P>0.2). Among gene-dose groups, there was a differential favorable treatment effect of 46% for high-dose bucindolol with ADRB1 Arg389Arg versus Gly carrier genotype (HR, 0.54; P=0.018), but not for no/low-dose bucindolol. In contrast, HF-ACTION Arg389Arg genotype subjects taking no/low-dose BB had greater all-cause mortality compared with 389Gly carriers (HR, 1.83; P=0.015), whereas all-cause mortality did not vary by genotype among subjects taking high-dose BB (HR, 0.84; P=0.55). Conclusions The enhanced HF with reduced ejection fraction efficacy of bucindolol in the ADRB1 Arg389Arg versus 389Gly carrier genotypes occurs at high dose. Other BBs taken at low dose have reduced efficacy for Arg389Arg genotype subjects compared with 389Gly carriers, suggesting a greater relative treatment effect at high dose. These data support guideline recommendations to use high, clinical trial target doses of all BBs to treat HF with reduced ejection fraction.

Causes of Death Among Patients with and without DIabetes and Chronic Heart Failure: Insights from the HF-ACTION and ASIAN-HF Registry

Introduction Causes of death among patients with heart failure with reduced ejection fraction (HFrEF) with and without diabetes (DM) have not been well described. We used data from a multinational HFrEF cohort to evaluate the specific causes (COD) of death in patients with and without DM. Methods Combined patient level data from the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial and the Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) registry were used in this analysis. Overall, 6182 patients with LVEF ≤ 35% were used. All COD were independently adjudicated. Sub distribution models were used to evaluate the risk of each COD between patients with and without DM. Results There were 2,445 (40%) patients with DM and 3,737 (60%) patients without DM. Among patients with DM there were 527 deaths: 322 CV (61% of deaths); 80 non CV (15% of deaths); 125 unknown (24% of deaths). Among patients without DM there were 607 deaths: 380 CV (63% of deaths); 73 non-CV (12% of deaths); 154 unknown (25% of deaths). Sudden death was the most common COD, occurring in 22% and 30% of deaths in patients with/without DM, respectively. There were modest differences in COD among patients with/without diabetes (figure). After adjusting for baseline variables, DM was not associated with an increased risk of CV death (subdistribution HR [sHR] 1.13; 95% CI 0.90-1.43); sudden death (sHR 0.87; 95% CI 0.60-1.27); HF death (sHR 1.08; 95% CI 0.73-1.59). DM was associated with an increased risk of MI/stroke death (sHR 2.22 95% CI 1.23 - 3.99). Results were consistent across the individual HF-ACTION and ASIAN-HF cohorts. Conclusion Among a well characterized multinational HFrEF cohort, the most common adjudicated COD in patients with and without DM was sudden death. Patients with DM, compared to without DM, did not have an increased risk of CV death, sudden death or HF death. While the presence of DM was associated with an increased risk of MI/stroke death, this accounted for only a small portion. Therapies to reduce the risk of sudden death and HF death should be evaluated in all HFrEF patients, regardless of DM status.

Prevalent digoxin use and subsequent risk of death or hospitalization in ambulatory heart failure patients with a reduced ejection fraction—Findings from the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) randomized controlled trial

BackgroundDespite more than 200 years of clinical experience and a pivotal trial, recently published research has called into question the safety and efficacy of digoxin therapy in heart failure (HF). MethodsHF-ACTION (ClinicalTrials.gov Number: NCT00047437) enrolled 2331 outpatients with HF and an EF ≤35% between April 2003 and February 2007 and randomized them to aerobic exercise training versus usual care. Patients were grouped according to prevalent digoxin status at baseline. The association between digoxin therapy and outcomes was assessed using Cox proportional hazard and inverse-probability weighted (IPW) regression models adjusted for demographics, medical history, medications, laboratory values, quality of life, and exercise parameters. ResultsThe prevalence of digoxin therapy decreased from 52% during the first 6 months of enrollment to 35% at the end of the HF-ACTION trial (P <0.0001). Study participants were 59± 13 years of age, 72% were male, and approximately half had an ischemic etiology of HF. Patients receiving digoxin at baseline tended to be younger and were more likely to report New York Heart Association functional class III/IV symptoms (rather than class II) compared to those not receiving digoxin. Patients taking digoxin had worse baseline exercise capacity as measured by peak VO2 and 6-min walk test and greater impairments in health status as reflected by the Kansas City Cardiomyopathy Questionnaire. The association between digoxin and the risk of death or hospitalization differed depending on whether Cox proportional hazard (Hazard Ratio 1.03, 95% Confidence Interval 0.92–1.16; P = .62) or IPW regression models (HR 1.08, 95% CI 1.00–1.17; P = .057) were used to adjust for potential confounders. ConclusionAlthough digoxin use was associated with high-risk clinical features, the association between digoxin therapy and outcomes was dependent on the statistical methods used for multivariable adjustment. Clinical equipoise exists and additional prospective research is required to clarify the role of digoxin in contemporary clinical practice including its effects on functional capacity, quality of life, and long-term outcomes.

Utility of Growth Differentiation Factor-15, A Marker of Oxidative Stress and Inflammation, in Chronic Heart Failure: Insights From the HF-ACTION Study

ObjectivesThis study sought to determine the relationship between growth differentiation factor (GDF)-15 and clinical outcomes in ambulatory patients with heart failure and reduced ejection fraction (HFrEF). BackgroundThe prognostic utility of GDF-15, a member of the transforming growth factor-β cytokine family, among patients with HF is unclear. MethodsWe assessed GDF-15 levels in 910 patients enrolled in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial, a randomized clinical trial of exercise training in patients with HFrEF. Median follow-up was 30 months. Cox proportional hazard models assessed the relationships between GDF-15 and clinical outcomes. ResultsThe median GDF-15 concentration was 1,596 pg/ml. Patients in the highest tertile of GDF-15 were older and had measurements of more severe HF (higher N-terminal pro–B-type natriuretic peptide [NT-proBNP] concentrations and lower peak oxygen uptake on cardiopulmonary exercise testing [CPX]). GDF-15 therapy was a significant predictor of all-cause death (unadjusted hazard ratio [HR]: 2.03 when GDF-15 was doubled; p < 0.0001). This association persisted after adjustment for demographic and clinical and biomarkers including high sensitivity troponin T (hs-TnT) and NT-proBNP (HR: 1.30 per doubling of GDF-15; p = 0.029). GDF-15 did not improve discrimination (as measured by changes in c-statistics and the integrated discrimination improvement) in addition to baseline variables, including hs-TnT and NT-proBNP or variables found in CPX testing. ConclusionsIn demographically diverse, well-managed patients with HFrEF, GDF-15 therapy provided independent prognostic information in addition to established predictors of outcomes. These data support a possible role for GDF-15 in the risk stratification of patients with chronic HFrEF. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437)

Increased Left Atrial Size in Chronic Systolic Heart Failure is Associated with Adverse Events: Insights From the HF-ACTION Trial

Introduction: Left atrial (LA) size is associated with adverse outcomes in multiple cardiovascular conditions. The implications of LA size on clinical outcomes in ambulatory systolic heart failure (HF) patients on optimal medical therapy is less studied. Hypothesis: We hypothesized that increasing LA dimensions by echocardiography would be associated with exercise impairments and unfavorable clinical outcomes in patients with HF. Methods: The Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) dataset was analyzed with respect to baseline patient findings (age, gender, New York Heart Association [NYHA] class, and history of atrial fibrillation or flutter [AF/AFl], echocardiographic findings (left ventricular ejection fraction [LVEF], left atrial dimension [LA-dim], and mitral regurgitation (MR) grade), baseline exercise findings (cardiopulmonary exercise test (CPET) exercise duration, CPET peak oxygen consumption [peak VO2], and 6-minute walk distance), and clinical outcomes during 4 years of follow-up (all-cause mortality and the primary endpoint of survival free of death or hospitalization). Kaplan-Meier survival curves, multivariable Cox proportional hazards regression, and multivariable linear regression were used. Results: Among the N = 2125 patients in the dataset, the median age was 51 years (IQR 59–68 years), 28.1% were female, and the median LA-dim was 4.5 cm (IQR 4.0–5.0 cm). Patients with LA-dim in the highest quartile (severe LA enlargement) had greater risks of both the primary endpoint and all-cause mortality (Figure; P < .0001 for both). After adjustment for age, gender, NYHA class, AF/AFl, LVEF, and MR grade, the LA-dim was independently associated with both all-cause mortality (HR 1.32 per 1 cm increase, 95% CI 1.08–1.60, P = .006) and the primary endpoint (HR 1.25 per 1 cm increase, 95% CI 1.13–1.37, P < .0001). LA-dim was also linearly associated with exercise parameters after covariate adjustment, including peak VO2 (adjusted standardized coefficient = -0.17, P < .0001), CPET exercise duration (adjusted standardized coefficient = -0.15, P < .0001), and 6-minute walk distance (adjusted standardized coefficient = -0.08, P = .006). Conclusions: Increasing LA dimensions is associated with reduced exercise capacity, increased hospitalization and mortality among systolic HF patients. More studies are needed to understand the prognostic implications of LA size in HF.

Relation of Angina Pectoris to Outcomes, Quality of Life, and Response to Exercise Training in Patients With Chronic Heart Failure (from HF-ACTION)

Angina pectoris (AP) is associated with worse outcomes in heart failure (HF). We investigated the association of AP with health-related quality of life (HRQoL), exercise capacity, and clinical outcomes and its interaction with exercise training in an HF population. Wegrouped 2,331 patients with HF with reduced ejection fraction in the Heart Failure: AControlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial of usual care±exercise training according to whether they had self-reported AP byCanadian classification score. HRQoL and clinical outcomes were assessed by AP status.In HF-ACTION, 406 patients (17%) had AP at baseline (44% with Canadian classification score ≥II) with HF severity similar to those without AP. Patients with AP had similar baseline exercise capacity but worse depressive symptoms and HRQoL. AP was associated with 22% greater adjusted risk for all-cause mortality/hospitalizations, driven by hospitalizations. There was significant interaction between baseline AP and exercise training peak VO2 change (p= 0.019) but not other end points. Exercise training was associated with greater peak VO2 improvement after 3months in patients with AP (treatment effect= 1.25ml/kg/min, 95% CI 0.6 to 1.9). In conclusion, AP was associated with worse HRQoL and depressive symptoms. Despite greater peak VO2 improvement with exercise training, patients with AP experienced more adverse outcomes.

Response to Exercise Training and Outcomes in Patients With Heart Failure and Diabetes Mellitus: Insights From the HF-ACTION Trial

BackgroundIn HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training), exercise training improved functional capacity in heart failure with reduced ejection fraction (HFrEF). Previous studies have suggested that diabetes mellitus (DM) may be associated with an attenuated response to exercise. We explored whether DM attenuated the improvement in functional capacity with exercise. Methods and ResultsHF-ACTION randomized 2331 patients with HFrEF to medical therapy with or without exercise training over a median follow-up of 2.5 years. We examined the interaction between DM and exercise response measured by change in 6-minute walk distance (6MWD) and peak VO2. We also examined outcomes by DM status. In HF-ACTION, 748 (32%) patients had DM. DM patients had lower functional capacity at baseline and had lower exercise volumes at 3 months. There was a significant interaction between DM status and exercise training for change in peak VO2 (interaction P = .02), but not 6MWD. In the exercise arm, DM patients had a smaller mean increase in peak VO2 than non-DM patients (P = .03). There was no interaction between DM and exercise on clinical outcomes. After risk adjustment, DM was associated with increased all-cause mortality/hospitalization (P = .03). ConclusionsIn HF-ACTION, DM was associated with lower baseline functional capacity, an attenuated improvement in peak VO2, and increased hospitalizations.

Psychosocial Factors, Exercise Adherence, and Outcomes in Heart Failure Patients: Insights From Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION).

Psychosocial factors may influence adherence with exercise training for heart failure (HF) patients. We aimed to describe the association between social support and barriers to participation with exercise adherence and clinical outcomes. Of patients enrolled in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION), 2279 (97.8%) completed surveys to assess social support and barriers to exercise, resulting in the perceived social support score (PSSS) and barriers to exercise score (BTES). Higher PSSS indicated higher levels of social support, whereas higher BTES indicated more barriers to exercise. Exercise time at 3 and 12 months correlated with PSSS (r= 0.09 and r= 0.13, respectively) and BTES (r=-0.11 and r=-0.12, respectively), with higher exercise time associated with higher PSSS and lower BTES (All P<0.005). For cardiovascular death or HF hospitalization, there was a significant interaction between the randomization group and BTES (P=0.035), which corresponded to a borderline association between increasing BTES and cardiovascular death or HF hospitalization in the exercise group (hazard ratio 1.25, 95% confidence interval 0.99, 1.59), but no association in the usual care group (hazard ratio 0.83, 95% confidence interval 0.66, 1.06). Poor social support and high barriers to exercise were associated with lower exercise time. PSSS did not impact the effect of exercise training on outcomes. However, for cardiovascular death or HF hospitalization, exercise training had a greater impact on patients with lower BTES. Given that exercise training improves outcomes in HF patients, assessment of perceived barriers may facilitate individualized approaches to implement exercise training therapy in clinical practice. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437.

Heart Rate or Beta-Blocker Dose? Association With Outcomes in Ambulatory Heart Failure Patients With Systolic Dysfunction: Results From the HF-ACTION Trial

ObjectivesThis study aimed to compare whether reduced heart rate (HR) or higher beta-blocker (BB) dose affected outcomes to a greater extent in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial population. BackgroundRecent data have shown that HR is an important modifiable factor in reducing mortality in heart failure (HF) patients. It has also been shown that titration of doses of BBs improves outcomes of morbidity and mortality in chronic HF patients with reduced ejection fraction. We aimed to compare whether reduced HR or higher BB dose affected outcomes to a greater extent in the HF-ACTION trial population. MethodsHF-ACTION 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. BB dose at baseline was standardized by use of carvedilol equivalents. BB dose and HR were analyzed by discrete groups (higher/lower dose; higher/lower HR). The relationship of BB dose, HR, and the primary endpoint of all-cause mortality or all-cause hospitalization and other cardiovascular secondary endpoints were determined before and after adjustment for variables found to be significantly associated with outcome in the HF-ACTION cohort. ResultsThere was a significant inverse relationship between either BB dose (higher was better) or HR (lower was better) and all-cause death or hospitalization in unadjusted analysis; however, only BB dose was significant for improved mortality outcomes. After adjustment for other predictors of outcome, only BB dose remained significant for improving all-cause death or hospitalization. BB dose, but not HR, was associated with improved outcomes of other cardiovascular endpoints in unadjusted analysis but did not remain significant when adjusted for other predictors of outcome in this cohort. ConclusionsThere were more associated improvements in outcomes with higher BB dose than with reduced HR in this well-treated HF cohort with systolic dysfunction, which suggests that titration of BB doses may confer a greater benefit than reduction of HR in such patients. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437)