Effect of an exercise-based cardiac rehabilitation program on quality of life of patients with chronic Chagas cardiomyopathy: results from the PEACH randomized clinical trial

Study design

The complete description and the main results for clinical and functional variables of the PEACH study (“Exercise Program in Chagas Heart Disease” in Portuguese) have been previously published19,20. In short, PEACH study was a single-center, superiority randomized parallel-group clinical trial of exercise training versus no exercise training (control), conducted from March 2015 to January 2017 at the Evandro Chagas National Institute of Infectious Diseases (INI) of the Oswaldo Cruz Foundation (Fiocruz). Individuals followed at INI were sequentially recruited to participate in the study. The sample comprised CD patients (confirmed by two distinct serological tests) of both sexes, older than 18 years, diagnosed with CCC, left ventricular ejection fraction (LVEF) < 45%, without or with HF symptoms (CCC stages B2 or C, respectively), New York Heart Association (NYHA) functional class I or II during three months before study enrollment, clinically stable and under optimal medical therapy according to HF guidelines over the prior six weeks before study enrollment. Exclusion criteria were the presence of major comorbidities or limitations that could preclude exercise training, pregnancy, unavailability to attend exercise sessions 3 times a week, practice of regular exercise training at baseline (> 1 week) in the three months prior to the study, smoking, or evidence of associated non-CCC.

Sealed envelopes filled with a computer-generated sequence were used to randomly allocate the eligible patients between the two groups in a 1:1 ratio using WinPepi software. The sequence was generated in blocks and stratified according to CCC stages (B2 and C) by a single researcher who was not involved in the recruitment.

Sample size calculation for the present study considered a significant mean difference between groups of 42.98 in the SF-36 role limitations due to physical problems scale, with a standard deviation of 39.43 points for the control and 34.32 points for the intervention group21. Assuming α = 0.05 and β = 0.20, 26 participants were required (13 in the intervention group and 13 in the control group).

Measurements

Sociodemographic (age, sex, schooling, and self-reported race), anthropometric, clinical, cardiac function, and maximal progressive cardiopulmonary exercise test (CPET) variables of the eligible patients were obtained during the initial assessment.

Schooling included the years of formal study, stratified into two categories (< 9 years and ≥ 9 years). Self-reported race was recategorized as white and non-white (including black, mulatto, indigenous, and yellow). Anthropometric evaluation consisted of measurements of height and weight, according to Lohman et al.22. Body mass index (BMI) was calculated as the ratio of weight (kg) to height squared (m2) and classified according to the World Health Organization definition23. Clinical variables, such as stage of CCC, NYHA functional class, presence of electrocardiogram abnormalities (ventricular premature beats, sustained and non-sustained ventricular tachycardia, right branch block, left anterior hemiblock, non-specific ventricular repolarization changes, atrial fibrillation, first-degree atrioventricular block, and second-degree atrioventricular block), and medications, were obtained from medical records. Systolic cardiac function was determined by means of left ventricular ejection fraction (LVEF) using the modified Simpson’s rule24. Maximal symptom-limited CPET was performed on a treadmill (Inbramed, Porto Alegre, RS, Brazil) with a ramp protocol and active recovery, using a VO2000 gas analyzer (MedGraphics, St. Paul, MN, USA) connected to a computerized Ergo PC Elite system (Micromed, Brasília, DF, Brazil).

QoL was assessed at baseline, after three months and at the end of follow-up (six months) using the Portuguese version of the Medical Outcomes Study 36-Item Short-form of Health Survey (SF-36) questionnaire25,26,27. This instrument has good internal consistency, test–retest reliability, and construct validity in Brazilian populations across different age groups and health conditions, including individuals with CCC11,27,28,29,30,31,32. SF-36 is a generic multidimensional instrument consisting of 36 questions, referring to the four weeks prior to the interview and divided into eight different scales: physical functioning, role limitations due to physical problems, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems and mental health. These scales define two summary scores: physical component summary (PCS) and mental component summary (MCS). Both PCS and MCS have contributions from all eight scales, but with higher weights for the first four scales in the PCS and for the last four scales in the MCS. The final score ranges from zero (worse QoL) to 100 (best QoL)25,26.

Intervention

Patients randomized for the exercise group performed physical exercise sessions for 60 min, three times a week, for six months. Each session consisted of 30 min of aerobic exercise on a treadmill or cycle ergometer, 20 min of strength training comprising two sets of 12 repetitions for the major muscle groups (sit-ups, push-ups, and pull-ups), and 10 min of stretching exercises. Aerobic exercise intensity was set according to the heart rate at anaerobic threshold obtained during the CPET (90–100% of heart rate at anaerobic threshold in the first month of exercise training and 100–110% of heart rate at anaerobic threshold thereafter)33. The anaerobic threshold values used to determine the target heart rate were derived from the baseline cardiopulmonary exercise tests for training sessions conducted between baseline and the 3rd month, and from the 3-month cardiopulmonary exercise test for training sessions between the 3rd and 6th months. For those patients in which anaerobic threshold was not identified during the CPET (n = 13; 43%), training intensity was prescribed according to the Hellerstein formula [HR = (102 + maximum metabolic equivalents achieved)/1.41)]34, in which the target heart rate ranged from 70% of maximum heart rate obtained in the CPET to the Hellerstein’s formula percentage in the first month, and from the Hellerstein’s formula percentage to 85% of maximum heart rate in the following months. Borg scale was used as an adjuvant of exercise intensity prescription (targeting 2–4 in CR10 Borg scale). The intensity of exercise was controlled by an exercise physiologist that supervised all exercise sessions. All exercise sessions were center-based and carried out in the morning, in an indoor environment with controlled temperature and under a multidisciplinary supervision (including an exercise physiologist and physician). No guidance was given to participants for home-based exercises (outside of the center-based program). Patients in the control group were not provided with a formal exercise prescription.

During the study, patients from both groups underwent monthly appointments with their cardiologist, based on the recommendations of the Brazilian Consensus on CD35. In addition, both groups received identical nutritional and pharmaceutical counseling during the study. Nutritional counseling consisted of general orientation about healthy eating habits, such as reducing the consumption of saturated fatty acids and increasing the intake of poly- and monounsaturated fatty acids, vitamins, and high-fiber carbohydrates. Reductions in sodium consumption and water intake were also stimulated for those patients with HF. Pharmaceutical care consisted of guiding about medication usage, drug dosage, and compliance, added to the monthly distribution of personalized packages, with the pills organized by the time and days that should be taken, according to medical prescription19.

Data analysis

Descriptive analysis consisted of mean and standard deviation for continuous variables and number of observations and percentage for categorical variables. The longitudinal analysis of the effects of exercise-based CR on QoL was performed using mixed linear models. This approach enable us to assess the interaction term (group x time) to estimate the rate of changes between groups in the outcomes. Models were fitted adjusting for each respective baseline QoL value. All participants were considered in the statistical analysis, regardless of compliance or loss to follow-up, characterizing an intention-to-treat analysis. Line graphs were constructed to visually illustrate the crude trajectories of QoL scales during the follow-up in each group.

The Research Electronic Data Capture (REDCap) web application was used for data management and the data analysis was conducted using Stata 13.0. Statistical significance was set at p ≤ 0.05 for all analyses.

Ethical considerations

All participants received information about the goals and procedures of the study and voluntarily agreed to participate by means of signing a written informed consent. The study was performed in accordance to the resolution 466/2012 of the Brazilian National Council of Health and was approved by the Institutional Research Ethics Committee (CAAE: 38038914.6.0000.5262) in February, 2015. The clinical trial was registered at ClinicalTrials.gov (NCT02517632).

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