Long-Term Exercise Training in Patients With Advanced Chronic Heart Failure / 117 ... Robert Höllriegel , MD ; Ephraim B. Winzer , MD ; Axel Linke , MD ; Volker ...
HEART FAILURE
Long-Term Exercise Training in Patients With Advanced Chronic Heart Failure SUSTAINED BENEFITS ON LEFT VENTRICULAR PERFORMANCE AND EXERCISE CAPACITY
Robert Höllriegel, MD; Ephraim B. Winzer, MD; Axel Linke, MD; Volker Adams, PhD; Norman Mangner, MD; Marcus Sandri, MD; T. Scott Bowen, PhD; Rainer Hambrecht, MD; Gerhard Schuler, MD; Sandra Erbs, MD
■ PURPOSE: In moderately impaired, stable chronic heart failure (CHF) patients, exercise training (ET) enhances exercise capacity. In contrast, the therapeutic benefits of regular ET in patients with advanced CHF, especially in the long-term, are limited or conflicting. Therefore, the aim of the present investigation was to elucidate whether ET performed over 12 months would improve left ventricular performance and exercise capacity in patients with advanced CHF. ■ METHODS: Thirty-seven patients with CHF and New York Heart Association (NYHA) class IIIb were randomized to a sedentary lifestyle or daily ET on a cycle ergometer (in-hospital and home-based at 50%60% of maximal exercise capacity). Cardiopulmonary exercise testing and echocardiography were performed at baseline, 3, 6, and 12 months. ■ RESULTS: Exercise training resulted in continuous decreases in left ventricular end-diastolic diameter at 3, 6, and 12 months versus baseline (all P < .05). This was accompanied by a significant increase in resting left ventricular ejection fraction from 24.1% ± 1.2% at baseline to 38.4% ± 2.0% at 12-month followup (P < .05). Moreover, ET patients increased exercise capacity measured by maximal oxygen uptake . V O2max at 3, 6, and 12 months compared with baseline: 15.3 ± 0.8 mL/min/kg, 17.8 ± 0.8 mL/min/kg, 19.0 ± 0.7 mL/min/kg, and 19.5 ± 0.9 mL/min/kg, respectively (all P < .05 vs baseline). This was associated with a reduced NYHA classification. ■ CONCLUSIONS: Exercise training over 12 months resulted in an improvement in exercise capacity and reversing of left ventricular remodeling in patients with advanced CHF (NYHA IIIb). These beneficial adaptations continued to improve up to 6 months and remained stable thereafter.
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chronic heart failure exercise capacity exercise training left ventricular remodeling Author Affiliations: Department of Internal Medicine/Cardiology (Drs Höllriegel, Winzer, Linke, Adams, Mangner, Sandri, Bowen, Schuler, and Erbs), University of Leipzig–Heart Center, Leipzig, Germany; and Heart Center Bremen (Dr Hambrecht), Klinikum Links der Weser, Bremen, Germany. This study was supported by a grant from the German Heart Foundation (F21/02). All authors have read and approved the manuscript. The authors declare no conflicts of interest. Correspondence: Robert Höllriegel, MD, University of Leipzig, Heart Center, Department of Internal Medicine/ Cardiology, Struempellstrasse 39, 04289 Leipzig, Germany (Robert.Hoellriegel@ med.uni-leipzig.de). DOI:10.1097/HCR.0000000000000165
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Long-Term Exercise Training in Patients With Advanced Chronic Heart Failure / 117
Copyright © 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
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In moderately impaired, stable chronic heart failure (CHF) patients, exercise training (ET) is generally established to improve exercise capacity without serious adverse effects. Indeed, a meta-analysis of 9 randomized controlled trials in CHF revealed clear evidence of an overall reduction in mortality and hospital admission rate as a result of regular ET.1 This was confirmed by the HF-ACTION study, the largest multicenter, randomized controlled study evaluating ET in patients with CHF.2 In the protocolspecified primary analysis, a nonsignificant reduction in the primary combined end point of all-cause mortality or hospitalization was found in the ET group. After adjusting for heart failure etiology and highly prognostic predictors of the primary end point, ET was associated with significant reductions in both all-cause mortality and hospitalization (hazard ratio = 0.89; P = .03), and also cardiovascular mortality or heart failure hospitalization (hazard ratio 0.85; P = .03). Moreover, a recently updated Cochrane review supports the conclusion of reduced risk of hospital admissions, improvements in healthrelated quality of life, and reduced mortality in the longer term.3 Therefore, ET has received a class I (level A) recommendation as an important therapy to “improve functional capacity and symptoms” in patients with CHF.4 However, data regarding the impact of ET on left ventricular (LV) remodeling in patients with CHF are conflicting at least with respect to the training modality.5,6 Furthermore, no robust data evaluating the long-term effects of ET on LV performance and exercise capacity are available for the subgroup of patients with advanced CHF, New York Heart Association (NYHA) functional class IIIb. Specifically, the duration of ET interventions between trials published thus far has been highly variable (ranging from several weeks to several months), with the time course of functional and morphological changes of the LV with respect to ET remaining poorly described.1,4 Therefore, for this trial, we followed up a group of randomized patients previously published by our group.7 Our previous study demonstrated 3 months of regular aerobic ET enhanced endogenous regenerative capacity, restored peripheral vasomotor function, and had anabolic effects in the skeletal muscle, which were also associated with a significant increase in LV function and improvement in exercise capacity.7,8 For this analysis we hypothesized a sustained improvement in LV performance and exercise capacity as a result of continued ET over a period of 12 months in the same cohort of severely impaired CHF patients (NYHA IIIb).
METHODS Patient Selection Patients were randomly assigned to either 3 months of ET (training group, T) or sedentary lifestyle (control group, C) using computer-generated random numbers. After a 3-month followup, the ET group was asked to continue with the ET program to assess LV performance and parameters of exercise capacity in the outpatient setting after further 3 (6-month followup) and 9 months (12-month followup). The initial 3-month trial is registered at http:// www.clinicaltrials.gov (NCT00176384). The protocol of the study was approved by the Ethics Committee of the University of Leipzig, and written informed consent was obtained from all patients. As reported previously in detail, 37 men aged 70 years or younger with CHF were enrolled if they met the following inclusion criteria: (1) documented heart failure as a result of ischemic heart disease or dilated cardiomyopathy (etiology assessed by cardiac catheterization and echocardiography) and clinical signs according to NYHA class IIIb (shortness of breath at minimal work and intermittent shortness of breath at rest); (2) evidence of reduced LV ejection fraction ≤30% and LV end-diastolic diameter ≥60 mm as determined by echocardiography; (3) clinical stability for at least 2 months before enrollment into the study and peak oxygen uptake V· O2max ≤ 20 mL/min/kg of body weight assessed by cardiopulmonary exercise (CPX) testing; (4) optimal individually tailored medication consisting of angiotensin-converting enzyme inhibitors or angiotensin-1 receptor antagonists, beta-blockers, aldosterone antagonists, and diuretics.7,8 Patients with insulin-dependent diabetes mellitus, untreated or uncontrolled arterial hypertension, untreated hyperlipidemia, persistent nicotine dependence, cardiac decompensation within the last 4 weeks, significant valvular heart disease, and unprotected ventricular arrhythmias were excluded from study participation.
Exercise Testing Exercise capacity and workloads for the ET program were both determined by a CPX test performed at baseline, 3, 6, and 12 months. It was performed on a calibrated, electronically braked cycle ergometer in the upright position. Workload increased progressively in increments of 25 W every 3 minutes, from a baseline work rate of 25 W. V· O2max was averaged from the last 30 seconds of the maximal workload. Anaerobic threshold was assessed by the V-slope method of Beaver et al.9 An
118 / Journal of Cardiopulmonary Rehabilitation and Prevention 2016;36:117-124
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JCRP-D-14-00207_LR 118
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experienced cardiologist, who was blinded to patient identity, group assignment, and intervention status, performed all analyses.
Echocardiography All patients underwent a complete resting echocardiography at baseline and again after 3, 6, and 12 months, respectively. Examinations were videotaped and LV diameters, volumes, and ejection fraction were acquired as an average from 5 consecutive beats according to guidelines for 2-dimensional echocardiography.10 An experienced cardiologist, who was blinded to patient identity, group assignment, and intervention status, performed all echocardiographic analyses after completion of 3, 6, and 12 months.
ET Protocol As previously described, the initial phase of the ET program was performed in-hospital to ensure close supervision.7,8 During the first 3 weeks, patients underwent 3 to 6 ET sessions daily, each 5 to 20 minutes individualized to each patient, on a cycle ergometer. Workloads were adjusted so that the heart rate at 50% of the symptom-limited V· O2max as determined at baseline was achieved. The training target heart rate for home-based training (defined as the heart rate reached at 60% of V· O2max) was determined by another CPX test before discharge from hospital. Each patient in the training group was provided with a cycle ergometer for daily home-based ET and asked to exercise close to the target heart rate for 20 to 30 minutes per day for up to 12 months after randomization. Moreover, we performed one supervised group training session for 60 minutes per week consisting of walking, calisthenics, and noncompetitive ball games. Patients assigned to the control group continued their sedentary lifestyle for the 12-month period. Compliance was defined as the percentage of completed ET sessions to those of the planned schedule.
Definition of Serious Adverse Events Serious adverse events were defined as any adverse event that resulted in death, was life-threatening, requiring hospitalization, or resulted in significant disability.
Statistical Analysis Mean value ± standard error was calculated for all variables. Comparisons from baseline characteristics were performed using an analysis of covariance model. All other analyses were performed using a Mann-Whitney U test or t test, where appropriate. Categorical variables were tested applying the χ2 or Fisher exact test. A probability value of less than .05 was considered statistically significant. All investigawww.jcrpjournal.com
tors and staff involved in the data analysis were blinded to patient identity, group assignment, and intervention status. The authors had full access to the data and take responsibility for its integrity.
RESULTS Baseline Demographic and Clinical Variables The demographic and clinical variables of these patients have been reported previously.6,7 Briefly, a total of 37 patients were randomized to either the T group (n = 18) or the C group (n = 19). At baseline, both groups were comparable with respect to age (T: 60 ± 3 years; C: 60 ± 2 years; P = .512), etiology of CHF (T: 56% ischemic heart disease and 44% dilated cardiomyopathy; C: 53% ischemic heart disease and 47% dilated cardiomyopathy; P = .879) and duration of CHF (T: 85 ± 31 months; C: 56 ± 13 months; P = .691), initial left ventricular ejection fraction (LVEF) (T: 24% ± 1%; C: 25% ± 1%; P = .927), V· O2max (T: 15.3 mL/min/kg ± 0.8 mL/min/kg; C: 15.4 mL/ min/kg ± 0.9 mL/min/kg; P = .988), and body mass index (T: 26.5 kg/m2 ± 0.5; C: 25.8 kg/m2 ± 0.7; P = .543). Medical therapy did not differ between the two groups and remained similar during the study.
Dropouts and Clinical Events During the followup period of 12 months, a total of 31 serious adverse events occurred (16 in the T group and 15 in the C group; Table 1). However, only a single hospitalization (because of hypoglycemia) occurred during an exercise session, whereas all other hospitalizations in the T group were not related to ET. For both patient groups, 6 hospitalizations were a consequence of serious adverse events including sustained ventricular tachycardia, implantable cardioverter defibrillator shock after ventricular fibrillation, supraventricular tachycardia with rapid ventricular response >30 seconds, or symptomatic bradycardia (heart rate 30 seconds; supraventricular tachycardia with rapid ventricular response >30 seconds; cardiac arrest; sustained ventricular tachycardia; or symptomatic bradycardia with heart rate
