Clinical trial NCT03335319: The Effect Of An Expanded Long Term Periodization Exercise Training In Patients With Cardiovascular Disease
Official title: The Effect Of An Expanded Long Term Periodization Exercise Training In Patients With Cardiovascular Disease: Central And Peripheral Adaptations
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Cardiovascular Diseases
Coronary Artery Disease
Keywords: Cardiovascular Disease
Coronary Artery Disease
Cardiopulmonary Exercise Testing
Oxygen Uptake Kinetics
Skeletal Muscle Oxygenation
Exercise Training
Periodized Exercise
Lead sponsor: University of Lisbon
Sponsor class: OTHER
First posted: 2017-11-07
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomized and stratified (by gender and age) into either one of the two groups exercise training groups: 1) periodization or 2) non periodization. The randomization code will be developed with a computer random-number generator to select random permuted blocks.
Primary purpose: PREVENTION

Brief summary: Benefits from cardiac rehabilitation (CR) programs are evidence based and widely recognized. Less than 50% of people who participate in hospital-based CR programs maintain an exercise regimen for as long as six months after completion. Despite the benefits associated with regular exercise training (ET), adherence with supervised exercise-based CR remains low.

Current exercise guidelines for CR focus on moderate intensity steady state exercises, with walking and cycling being the most recommended types of ET. The repetitive nature of this type of activity can become monotonous for the patient, affecting exercise adherence, compliance and training outcomes. Exercise periodization is a method typically used in sports training, but the impact of periodized exercise to yield optimal beneficial effects in cardiac patients is still unclear.

In healthy or trained populations, periodization aims to optimize ET adaptations as compared with non periodized training, to prevent overtraining and to avoid plateauing of training adaptations. Periodized methods are considered to be superior to non periodized methods in trained populations and appears to be superior in inactive adults. In most of the CR programs there are no periodization or exercise progression during medium to long term interventions. Further randomized controlled trials (RCT) are necessary to evaluate long-term periodization outcomes.

The purpose of this research project is twofold:

1. To conduct a 12-month randomized control trial to evaluate the effects of a periodized ET regime versus a non periodized ET regime (guidelines) on VO2 peak, maximal strength, body composition, functionality and quality of life in cardiovascular disease patients.
2. to differentiate the effects of a 12-month periodized ET regime versus a non periodized ET regime on the different components of the oxygen kinetics response and oxidative adaptations in cardiovascular disease patients.

These patients will be randomized in 2 ET groups: 1) periodization; 2) non periodization. This experimental design will occur during 48 weeks 3 times per week with 4 assessment time points: M0) before starting the ET program (baseline); M1) 3 months after starting the ET; M2) 6 months after starting the ET program and M3) 12 months at the end of the community-based ET program.

Detailed description: Cardiac Rehabilitation (CR) of patients with Cardiovascular Disease (CVD) has been practiced in Europe to varying degrees since the early 1970s. CR is a comprehensive, long-term program involving medical evaluation, prescribed Exercise Training (ET), cardiac risk factor modification, education and counselling. These programs are designed to limit the physiologic and psychological effects of cardiac illness, reduce the risk for sudden death or re-infarction, control cardiac symptoms, stabilize or reverse the atherosclerotic process, and enhance the psychosocial and vocational status of selected patients. Furthermore, it is a safe, useful and an effective treatment for patients with coronary artery disease (CAD), particularly after myocardial infarction, but also for patients with cardiac interventions and chronic stable heart failure.

Exercise adherence after a hospital-based CR program is reported to be poor with only 30% to 60% of those who complete a phase II CR program are still exercising 6 months later and after 12 months, up to 50 to 80% of participants failing to adhere to exercise. Despite the benefits associated with regular ET, adherence with supervised exercise-based CR remains low.

A brief review of meta-analysis studies that assess the impact of different types of exercise in short term outcomes for participants of CR will now be presented. The findings of a meta-analysis in 2015 indicated that high intensity interval training (HIIT) is more effective than moderate continuous training (MCT) for the improvement of both VO2 peak and the anaerobic threshold in patients with stable CAD. The greater improvement in VO2 peak following HIIT compared to MCT (4.6 ± 3.1 versus 2.8 ± 2.4 ml/kg/min) is important in the context of a 10-25% survival advantage with every 3.5 ml/kg/min improvement in VO2 peak.

Another meta-analysis in 2016, compared HIIT and MCT in their ability to improve patients aerobic exercise capacity and various cardiovascular risk factors. Ten studies with 472 patients were included for analyses (218 HIIT, 254 MCT) and the main conclusions were that HIIT improves the mean VO2 peak in patients with CAD more than MCT, although MCT was associated with a more pronounced numerical decline in patients resting heart rate and body weight.

Current CR guidelines recommend the inclusion of a standardized resistance training (RT) program. A recent meta-analysis of ET programs in patients with CAD revealed that the addition of RT training to MCT led to superior improvements in body composition, muscle strength, peak work capacity, and a trend for greater increases in VO2 peak. Similar to HIIT, RT has not been shown to compromise patient safety or program adherence.

Less is known about central and peripheral adaptations during long term effects on HIIT, MCT or even aerobic combined training with RT. In 2016, a systematic review and meta-analysis with a total of 63 studies with 14,486 participants with CAD median follow-up of 12 months were included. It was concluded that exercise-based CR reduces cardiovascular mortality and provides important data showing reductions in hospital admissions and improvements in quality of life. Madssen et al, showed that a 12-month maintenance exercise program consisting of infrequent supervised exercise sessions did not result in improved adherence to exercise or increased VO2 peak in CAD patients compared to usual care. One monthly session during a year of HIIT was not enough to improve or maintain exercise capacity. In the literature there is a lack of evidence on the effects in exercise capacity, muscle strength and body composition in long term weekly supervised exercise sessions on a maintenance exercise program in CVD patients.

Current exercise guidelines for CR focus on moderate intensity steady state exercises, with walking and cycling being the most recommended types of ET. Multiple training variables can be manipulated during exercise prescription, including repetitions, interval length, rest period length and intensity of resistance. In this regard, much insight could be gained from approaches used in sport conditioning, where exercise prescription is designed to be physiologically and psychologically sustainable using periodization.

Periodization is defined as an organized cyclic program that uses planned variations in intensity, volume, and specificity to minimize fatigue and maximize performance outcomes. In healthy or trained populations, periodization aims to optimize ET adaptations as compared with non periodized training, to prevent overtraining and to avoid plateauing of training adaptations. Periodized methods are considered to be superior to non periodized methods in trained populations and appears to be superior in inactive adults. Interestingly, a recent study investigated the effect of 22 weeks of 2 different types of periodization and non periodization resistance training protocols on a comprehensive range of physical function and health outcomes in apparently healthy untrained older adults. Contrary of what was hypothesised, all three training models were equally effective for promoting significant improvements in various physical function and physiological health outcomes through resistance training in this population.

In most of the CR programs there are no periodization or exercise progression during medium to long term interventions. Evaluate long-term periodization outcomes and assess the length of change observed in supervised CR programs might be of interest and necessary.

This study will hopefully contribute to generate evidence-based exercise prescription approaches to prolong the ET after the end of hospital-based CR programs.

The purpose of this research project is twofold:

1. To conduct a 12-month randomized control trial to evaluate the effects of a periodized ET regime versus a non periodized ET regime (guidelines) on VO2 peak, maximal strength, body composition, functionality and quality of life in CVD.
2. to differentiate the effects of a 12-month periodized ET regime versus a non periodized ET regime on the different components of the oxygen kinetics response and oxidative adaptations in CVD patients.

The hypothesis for this study are: 1) considering that this type of periodization exerts higher stress on the cardiovascular and neuromuscular systems, so that there could be greater adaptations leading to higher increases in VO2max, muscle strength, body composition and functionality compared to non periodized ET regime; 2) there will be a better improvement microvascular O2 delivery in the exercise transient in response to periodized ET regime that will be associated with a faster adjustment of pulmonary VO2 kinetics than in non periodized group. Improvements in microvascular O2 delivery will be indicated by a better matching between the rate of adjustment of muscle deoxygenation relative to phase II pulmonary VO2, which represents a decreased reliance on O2 extraction for a given pulmonary VO2.

STUDY DESIGN:

A longitudinal RCT research design performed in the Cardiovascular Rehabilitation Center of the University of Lisbon (CRECUL) at the Lisbon University Stadium (EUL) using two distinct ET prescriptions (periodization vs non periodization) will be applied in cardiovascular disease patients. Briefly, following the informed consent process, patients will be randomized and stratified (by gender and age) to periodization or non periodization groups. The randomization code will be developed with a computer random-number generator to select random permuted blocks. Participants will exercise for a period of 12 months. All the same assessments, except the echocardiogram that will be done in M0 and M3 (for risk stratification), are going to be taken in 4 different time points during a year: M0 - baseline, M1 - 3 months after starting the ET, M2 - 6 months after starting the ET and M3 - 12 months after starting the ET. The patients will be randomized into either one of the two ET group.

Sample size was calculated (G-Power, Version 3.1.3) assuming a difference in peak oxygen uptake (VO2 peak) between groups of 3 ml/kg/min to be a clinical important difference with a standard deviation of 3.5 ml/kg/min, α=0.05, 1-β=0.80 and an expected dropout rate of 50%. The calculations yielded a total minimum sample size of 56 participants (28 in each group).

The following assessments on the 4 time points will be performed at the Pulido Valente Hospital, Faculty of Human Kinetics - University of Lisbon (FMH-UL) and Academia de Fitness at EUL: Echocardiogram (Echo) (MyLab Alpha, ESAOTE); cardiopulmonary exercise test (CPET) (Ergostik, Geratherm Respiratory GmbH, Bad Kissingen); skeletal muscle deoxygenation dynamics (NIMO, Nirox srl); body composition - dual energy radiographic absorptiometry (DXA, Hologic Explorer-W); objective measured physical activity - accelerometer (ActiGraph GT3X+); functional physical fitness - Fullerton Functional Fitness Test; isometric strength - portable hand dynamometer JAMAR plus digital (Sammons Preston); maximal strength - 1RM and Quality of Life questionnaire (Short Form-36 Health Survey).

All assessment moments will be done in 1 to 2 weeks:

Day 1 - Echo and CPET will be performed at the Hospital; Day 2 and 3 - during the day and time of the ET session at the EUL, the patient will perform: functional physical fitness tests; maximal strength; isometric strength and Quality of Life questionnaire; Day 4 - In FMH-UL, the dual energy radiographic absorptiometry (DXA) exam and the activation of the accelerometer to measure the objective measured physical activity will be done.

Day 5 - Submaximal CPET with the skeletal muscle deoxygenation dynamics at the Hospital.

In order to assure the confidentiality of the participants an ID code will be attributed to each participant in the database and all the equipment's and sheets used. A single researcher will perform the database management.

DATA ANALYSIS:

Data will be analyzed in M0, M1, M2 and M3. It will be tested the data for normality and homogeneity of variance with the Shapiro Wilk and Levene's tests, respectively. Data analysis will be described according to the established purposes for this project (descriptive values: mean, standard deviation, range, % change) and comparisons of means will be used for all purposed outcomes intra and inter groups. Baseline characteristics between groups will be evaluated with oneway ANOVA. Mixed between within subjects ANOVA will be conducted in a 2 (pre vs post ET) design to assess efficiency of the program. When a significant interaction is observed, t tests, or Wilcoxon signed-rank tests will be used to determine where the interaction occurred.

M0 versus M1, M0 versus M2, M0 versus M3, M1 versus M2, M2 versus M3 and M1 versus M3 will be compared to evaluate the changes in patients and trace the necessary timespan for such changes using General Linear Mixed Model Analysis for repeated measures with Tukey's post hoc procedure for the mean comparisons. Pearson product moment correlation coefficient or Spearman's rank correlation coefficient will be used to study the relationship between different variables by group and correlation coefficients will be compared between groups. Statistical significance will be set at an alpha level of 0.05. Other statistical procedures can be done.

Statistical analyses will be conducted using Statistical Package for the Social Sciences (SPSS) 22.0 (IBM SPSS Statistics, Chicago, IL, USA).

Eligibility criteria: Inclusion Criteria:

* angiographically documented coronary artery disease in at least one major epicardial vessel
* myocardial infarction,
* coronary revascularization (coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, or coronary artery stent),

Exclusion Criteria:

* heart failure
* unstable angina pectoris
* heart transplants with either cardiac resynchronization therapy or implantable defibrillators
* inability to comply with guidelines for participation in exercise testing and training
* significant limiting and/or unstable comorbidities that would prevent full participation

Primary outcomes:
measure: Change of peak oxygen consumption during cardiopulmonary exercise testing
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
measure: Change of oxygen kinetics during submaximal test
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
Secondary outcomes:
measure: Change of Anaerobic Threshold VO2 during cardiopulmonary exercise testing
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
measure: Change of Anaerobic Threshold Heart Rate during cardiopulmonary exercise testing
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
measure: Change of Anaerobic Threshold Watts during cardiopulmonary exercise testing
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
measure: Change of Respiratory Compensation Point VO2 during cardiopulmonary exercise testing
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
measure: Change of Respiratory Compensation Point Heart Rate during cardiopulmonary exercise testing
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
measure: Change of Respiratory Compensation Point Watts during cardiopulmonary exercise testing
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
measure: Change of Peak Heart Rate reached during cardiopulmonary exercise testing
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
measure: Change of Maximal Watts reached during cardiopulmonary exercise testing
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
measure: Change of Deoxyhaemoglobin of the vastus lateralis muscle at the submaximal test
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
measure: Change of Oxyhaemoglobin of the vastus lateralis muscle at the submaximal test
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
measure: Change of Total Haemoglobin of the vastus lateralis muscle at the submaximal test
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
measure: Change of Maximal Strength
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
measure: Change of Lean Soft-Tissue
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
measure: Change of Fat Mass
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
measure: Change of Bone Mineral Content
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
measure: Change of Quality of Life
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
Other outcomes:
measure: Change of six minute walking test distance
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
measure: Change of 30-second chair stand repetitions
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
measure: Change of 8-foot up and go test duration
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
measure: Change of chair sit-and-reach distance reached
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
measure: Change of back scratch test distance reached
timeFrame: At baseline, 3 months after starting the ET, 6 months after starting the ET and 12 months after starting the ET
Locations:
city: Lisbon
country: Portugal
facility: Faculty of Human Kinetics - University of Lisbon
state: Cruz Quebrada
Study officials:
affiliation: Faculty of Human Kinetics, University of Lisbon
name: Helena Santa-Clara, PhD
role: PRINCIPAL_INVESTIGATOR
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