This is an evaluator-blinded, randomized controlled clinical trial with parallel groups, 2 arms, superiority trial with 1:1 allocation ratio.
Study setting
The evaluations will be performed at the Pneumocardiovascular laboratory, and the intervention program will be performed at the Physical Therapy Office, both located in the University Hospital of Natal/RN, Brazil.
Participants
Potential participants with stable CVI that meet the eligibility criteria have been recruited from the vascular surgery outpatient clinic. They have been invited to participate in an initial evaluation by a blinded evaluator through a questionnaire that will include socio-demographic data, co-morbidities, time of CVI diagnosis, and detailed clinical and functional information. The disease classification will be based on the CEAP criteria including: clinical manifestations (C), etiologic factors (E), anatomic distribution of disease (A), and underlying pathophysiologic findings (P) [4]. Ulcer morphological characteristics (if present), range of motion (ROM), exercise capacity, muscle endurance and parameters related to QOL will also be assessed.
This study will include male and female patients aged between 35-69 years, with chronic venous insufficiency diagnosed by venous vascular echo-Doppler (VED), CEAP between 2 to 6, and without Peripheral Arterial Disease (PAD) (ankle-brachial index ≤ 0.9) [19]. This study will exclude subjects who do not agree to participate, have ulcers > 4 cm diameter, or clinical signs and/or confirmed diagnosis of infection will be excluded. The patients who already perform any type of supervised exercise, are unable to attend physiotherapy sessions twice a week, and/or have co-morbidities incompatible with moderate to intense exercises [20] such as: acute or uncontrolled congestive heart failure, uncontrolled or unstable angina, uncontrolled cardiac dysrhythmia causing hemodynamic symptoms, severe symptomatic aortic stenosis, recent deep venous thrombosis, recent pulmonary embolism, acute pericarditis or myocarditis, dissecting aneurysms (known or suspected), unstable or uncontrolled blood pressure (systolic pressure > 160 mmHg, diastolic pressure > 100 mmHg), acute systemic infection, or uncontrolled diabetes, limiting musculoskeletal diseases, or difficulty to understand the activities will also be excluded.
All participants will sign the informed consent form that will be explained before the evaluation. During the functional tests, hemodynamic cardiac parameters (cardiac output, ejection fraction, and systolic volume) and bilateral electrical activity of the triceps surae and tibialis anterior muscles will be assessed.
Design
The evaluations will start in January 2020, and the exercise programme will be performed over the next 2 months. After evaluation, the subjects will be randomly allocated to 2 evaluator-blinded groups: treatment group (TG) and control group (CG). Patients in the TG will perform the exercise program as described in this protocol and will start 1 week after the initial evaluation. The patients in the CG group will continue their usual treatments (medication use, compression stockings and medical guidance). After 8 weeks of intervention, the patients will be reevaluated (using the same initial evaluation questionnaire) by the same blinded evaluator for each group. The main outcome measures will be: endurance of calf muscle, issues related to QOL, exercise capacity and ROM. A final reassessment will be performed 8-weeks after the reevaluation, as shown in Figures 1 and 2.
All participants will receive educational information regarding the disease, as well as the usual care and treatments to improve symptoms and quality of life (QOL).
Sample size
The sample size is based on a study [6] which used the difference between 2 independent means and the standard deviation of the heel rise test. The calculated effect size was 1.28; the α error was 0.05 and the power was 95%. After analysis the final sample size was 26 subjects. A G*Power version 3.1 program was used for statistical analysis.
Recruitment
Subjects will be recruited at the medical clinic of the University Department of Clinical Medicine in the city of Natal/RN - Brazil. This outpatient facility has 5 physicians specialized in vascular surgery. The inclusion and exclusion criteria will be presented to the physicians personally. The physicians will be asked to refer all subjects who meet the inclusion criteria for the study. All the participants will sign the informed consent form which will be explained by the evaluator before the evaluation.
Randomization and group allocation
The randomization.com program will be used to randomize the participants into two groups (control or treatment) and stratification will be performed to ensure balance between the groups within 2 strata (CEAP 2 and 3 and CEAP 4 to 6). A separate researcher will contact the participants by telephone to initiate treatment to guarantee a blinded evaluation on screening phase.
Blinding
The researcher who will perform the initial and final evaluations will be blinded to the subjects’ allocation groups. The participants will be instructed not to make any comments regarding group allocation. The evaluator will not have access to the treatment site where the protocol will be performed to reduce the possibility of interfering with the blinding.
INTERVENTIONS
Exercise prescription
The exercise program will consist of aerobic training, strengthening, cardiovascular and flexibility exercises. The aerobic exercises will be performed using a cycle ergometer and the muscle strengthening will be performed using resistive loads for the triceps surae muscles. The subjects will receive a written and illustrated guide for performing active stretching exercises of the triceps surae and tibialis anterior muscles at home 24 hours after supervision [21]. The exercise program will last ~40 minutes and will be performed twice a week, for a total of 16 sessions. The heart rate and blood pressure will be checked at the beginning and end of the training, as well as at the end of each series.
Aerobic training
The perceived fatigue of the participants will be measured using the modified 0-10 BORG scale [22], every five minutes. The subjects will warm up for 5 minutes on the cycle ergometer without load at the beginning of the protocol. Next, the subjects will perform the aerobic exercises using the cycle ergometer for 15 minutes. The load will be adjusted at a setting up to moderate intensity (between 4 -6 of the modified BORG scale 0-10).
Resistance training
To strengthen the triceps surae muscles, the patients will perform full range mild intensity calf raise exercises. The submaximal load of 10 RM (repetition maximum) estimated percentage 80% of RM [23] will be individually calculated based on momentary muscle failure (inability to perform 10 concentric contraction without significant posture change and repetition velocity during changes against a certain resistance) [24]. To calculate the submaximal load of 10 RM, weight will be added until momentary muscle failure of the individual is achieved during calf raise exercises. The last load successfully lifted before momentary muscle failure will be used. The calculated load will be used to customize the training level and will be changed according to the patient´s weekly performance. The exercise will consist of 3 sets of 10 repetitions with a 1-minute rest interval. Successive load progression will be made during the programme, maintaining the same volume according to the patient’s performance. The exercises during the initial sessions will be performed without any load. The loads will be applied using an adjustable weight vest according to each patient.
Cardiovascular training
The bench step-up exercise will be performed on a rubber step at a height of 20 cm. The subjects will be instructed to walk up and down on steps with one foot at a time using free cadence. They will be instructed to perform the movement as fast as possible for 12 repetitions and exercise progression will be according to individual tolerance.
The load during the program execution may be decreased, the rest time increased or the session interrupted if the subject reports very intense perceived fatigue (7 or above, BORG scale), complains of limiting pain, or develops symptoms incompatible with physical activity. The participants will perform only the exercises under supervision of the physiotherapist responsible for the study protocol. The patients showing exercise limitation due to pain, change in medication, undergo any alternative treatment, or miss 3 consecutive intervention sessions will be excluded. The data will be included in records for further analysis even after exclusion. Medical assistance will be provided to any participant who has an injury caused by the study in accordance with the resolution 466/12 of the National Health Council.
Health education speeches
All the subjects will be invited to attend an educational speech about the disease, risk factors, lifestyle changes, and lower limb care (hygiene, exercises, dressings), as well as the benefits of using compressive techniques. The speeches will be performed by the blind evaluator who will perform the evaluations and reassessments.
Counseling for compression stocking
Compression stocking will be prescribed for subjects not using compressive techniques based on the clinical severity with 20-30 mmHg, 30 to 40 mmHg, and 40 to 50 mmHg for patients with CEAP C2-C3, CEAP C4 to C6, and recurring ulcers respectively [2]. Compliance will be recorded daily in a notebook.
Strategies to improve adherence to intervention protocols
The subjects will receive a follow-up guide containing questions regarding compressive therapy, stretching and lower limb positioning during rest.
Relevant concomitant care and interventions that are permitted or prohibited during the trial:
The controls will be instructed to maintain their usual activities and treatments and not perform any type of supervised exercises during the 2 months after their first evaluation. During this period, the patients (independent of the allocation group) who need to perform some type of elective surgery or other treatment modality for venous disease other than the usually prescribed treatment (such as medication use, compression stockings and medical guidance), will be withdrawn from the study.