- Email: [email protected]
Design of the Training Levels Comparison trial
Design of the Training Levels Comparison Trial Jeannette Y. Lee, PhD, Albert Oberman, MD, Gerald F. Fletcher, MD, James M. Raczynski,
PhD,
Barbara J. Fletcher, RN, MN, Navin C. Nanda, MD, and Betsy E. Jensen, MS
ABSTRACT The Training Levels Comparison (TLC) trial was a grant-supported, multicenter, randomized, controlled clinical trial designed to determine whether cardiac rehabilitation patients would benefit from supervised exercise for a prolonged period (2 years) and whether subjecting patients to a more vigorous exercise program than currently recommended would provide additional cardiac benefit. If high-intensity exercise does not enhance the cardiac benefit, then physical activity should be limited to lowintensity levels that are safer, easier to implement and more adaptable to a greater number of patients. Patients were randomly assigned to either a low-intensity or high-intensity training program. All patients were to attend three l-hour supervised exercise sessions per week for a period of 2 years. Attendance at exercise sessions and adherence to assigned treatments were monitored throughout the study. Patients were evaluated for outcome measures at 3, 6, 12, and 24 months. This paper reports the study design and methodology for the TLC trial, and should be useful in providing methodologies to facilitate comparison of data from other studies with different levels of exercise as an intervention.
INTRODUCTION
Exercise, a key element in cardiac rehabilitation, leads to favorable training adaptations. Regular dynamic exercise increases physical work and functional capacity which provides relief of symptoms in many patients with coronary heart disease [l-4]. Exercise training can produce favorable risk factors and hemodynamic changes: reduction in body weight with constant caloric intake and increased lean body mass, reduced levels of blood triglyceride and increased proportion of cholesterol carried by high density lipoproteins, improved glucose tolerance, and lowered blood pressure during submaximal exercise. There is considerable evidence that long-term physical conditioning
Address reprint requests to: Jeannette Y. Lee, PhD, Biostatistics Unit, Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 Sixth Avenue, South, Birmingham, Alabama 35294-3300. Received janua y 8, 1993; revised September 9, 1993. This work is supported by a grant from the National Heart, Lung, and Blood Institute (ROl HL3759703). Controlled Clinical Trials 15:59-76 (1994) Elsevier Science Inc. 1994 655 Avenue of the Americas, New York, New York 10010
0
59 0197-2456/94/$7.00
60
J.Y. Lee et al. may lower mortality from cardiovascular disease [1,5,6]. Pooling of data from long-term, exercise-based cardiac rehabilitation studies demonstrates a reduced 3-year mortality from reinfarction alone by 25% and from all causes by 20% [7]. There have been few clinical trials with exercise as an intervention, with only one major trial in this country [8]. Previous studies of training programs for cardiac patients have generally been short-term (8-12 weeks) and of mild intensity. Although exercise training produces favorable adaptations, these adaptations are generally attributed to peripheral changes in the muscle rather than to improved cardiac function. Lack of improved cardiac function may be due to inadequate training, and more prolonged training at higher intensity levels may result in desirable cardiac adaptations in coronary heart disease patients [7-121. It is equally possible that the important factor is total dose of exercise, not intensity level, and that benefit may be realized from a lower intensity training program continued over a sufficiently long period of time. This possibility warranted study due to the practical advantages of lower intensity exercise as compared to higher intensity exercise in terms of safety and compliance. There is scant data on which exercise prescriptions are based. Exercise training recommendations were originally based on a short-term study on young men [13]. Prescriptions for exercise programs rarely take into account detailed individual differences in severity of coronary artery disease and left ventricular function. These factors may have significant implications for the training prescription and the likelihood of favorable benefits from exercise. Recent data suggest a differential effect of physical activity on cardiovascular risk factors, hemodynamics, and sympathetic function according to exercise level [ 141. Although resource requirements and adherence issues must be addressed in planning any clinical trial, these concerns are magnified in exercise studies. Implementation of group supervised exercise sessions requires that a suitable room to hold the sessions in and an exercise physiologist to conduct them be available to the study. Inherent in exercise studies are the difficulties in motivating participants to exercise regularly for a long period of time and ensuring adherence to the assigned treatment. Cardiac rehabilitation patients posed a challenge in designing the study due to the variation in the severity of their disease, their medication use, and the effect of their clinical status on their ability to exercise. The response to exercise training may be influenced by severity of disease and medication use. Furthermore, medication use may change over the course of the study. Determination of the primary outcome measure has implications in the Due to the low incidence of cardiac design and sample size requirements. mortality and morbidity, a prohibitively large number of patients would be required to compare treatments with respect to this outcome measure. There was a need to identify an outcome measure that was predictive of cardiac events but could be obtained safely in this target population. Developments in echocardiography as a method for assessing left ventricular function provided an opportunity to evaluate the effects of vigorous exercise on coronary heart disease patients noninvasively. The reproducibility and value of mea-
The Training Levels Comparison Trial
61
surements obtained with two-dimensional echocardiography has recently been demonstrated [ 151. The Training Levels Comparison (TLC) Trial was undertaken to address the question of whether cardiac rehabilitation patients exercised at higher intensity levels than were typically recommended would develop additional cardiac benefit. If high-intensity exercise does not confer additional benefit, then physical activity should be limited to low-intensity levels that are safer, easier to implement, and more adaptable to a greater number of patients. The trial was funded for a 5-year period beginning December 1,1986. Patients enrolled in the study between August 1987 and March 1990. Key events in the TLC trial are listed in Table 1.
OBJECTIVES The primary objective of the trial was to determine if patients with coronary heart disease who exercised at a high intensity over a prolonged time period, would demonstrate improvement in cardiovascular hemodynamics as compared to those who exercised at a lower intensity. The primary outcome measure was the change in left ventricular ejection fraction (LVEF) at peak exercise after 1 year of exercise training. LVEF was chosen as the primary outcome measure due to its prognostic significance with respect to cardiac mortality and morbidity. Secondary objectives of the study were to compare the two training programs with respect to changes in lipid levels, body composition, blood pressure and heart rate measurements, glucose tolerance, and quality of life measures; to assess the effects of time and assigned intensity level on compliance; to compare the two training programs with respect to progression of disease; and to identify patients unlikely to respond to training.
DESIGN
CONSIDERATIONS By using exercise as an intervention and cardiac rehabilitation patients as the target population, several issues had to be addressed in designing the trial: recruiting and identifying patients likely to adhere to an exercise program for two years and maintaining their interest in the trial; meeting the space and personnel requirements for conducting exercise sessions; balancing treatment groups with respect to severity of coronary heart disease; monitoring medication use; and selecting an outcome measure which could be safely evaluated in this patient population and required a sample size which could Table 1
Chronology
Date
Event
December 1, 1986 April 1987 May 1987 August 4, 1987 March 13, 1990 November 30, 1991
Funding initiated for the trial Certification of study personnel at UAB and Emory Recruitment started First patient enrolled Last patient enrolled Funding
ended
for the trial
J.Y. Lee et al.
62
be accrued in a reasonable amount of time. Other issues common to most clinical trials were also addressed: masking, treatments, eligibility criteria, sample size estimation, and length of follow-up. Key features of the design are shown in Table 2.
Masking Masking of patients to their assigned treatment was impractical; however, the primary outcome measure-left ventricular ejection fraction-was determined by the staff at the Echocardiographic Center at a site removed from the clinical centers. Primary outcomes were determined by investigators unaware of the assigned treatment from echocardiograms on videotape. Consequently, the lack of masking did not bias the assessment of the major outcome. The individuals who performed the exercise testing were aware of each patient’s treatment assignment. Although there was the possibility for examiner influence over patients’ efforts on exercise testing, the observers underwent certification and attempted to deliver standard instructions and observe specific indicators for stopping the test. Medical conditions were the overriding reasons for terminating the test. Heart rate, an objective measure, was used to monitor patients during exercise testing. Under these circumTable 2
Design Synopsis Treatment Groups Low-intensity exercise training program High-intensity exercise training program Treatment Long-term exercise training
Type of Trial Therapeutic
Centers Two clinical centers Biostatistical Coordinating Echocardiographic Center Sample Size 200 subjects
Eligibility Criteria Men with CHD Age 30-67 Length of treatment 2 years Data Collection Schedule Initial (El) 3 months (E2) 6 months (E3) 1 year (E4) 2 years (E5)
Center Outcomes of Interest Change in LVEF Lipid levels Glucose tolerance Quality of life measures Compliance Progression of disease Treatment Assignment Random by phone Stratified by history of MI (2 strata) and LVEF (2 strata) Level of Treatment None
Masking
The Training Levels Comparison Trial
63
stances, the investigators felt that the potential for systematic bias was minimal The use of observers unaware of treatment assignment to perform the exercise testing was considered, but deemed infeasible with available resources. Treatments All exercise prescriptions were based on exercise testing of patients maintained on their usual medical regimen including drugs. Patients underwent standardized multistage treadmill exercise testing monitored by two-dimensional, color Doppler echocardiogram at the baseline visit (El) just prior to randomization and at the 3-month visit (E2), 6-month visit (E3), l-year visit (E4), and 2-year visit (E5) after study entry. The results of the exercise testing were used to prescribe exercise for the period following evaluation using the symptom limited test routine. The target heart rate for patients on the low intensity program corresponded to 50% of the VOZ max established on the previous exercise test ? 5 beats/minute. For patients on the high-intensity program, the target heart rate corresponded to 85% of the VO1 max attained on the previous exercise test + 5 beats/minute. The Borg scale of perceived exertion [16] was used in conjunction with heart rate monitoring to ensure that proper intensity levels were maintained. By this method, the patient was taught to relate subjective feelings of exertion such as fatigue or shortness of breath, to heart rate level. There was no control group in this study as the low intensity group represented “usual care” for cardiac rehabilitation patients. Patients participated in structured group exercise sessions directed by an exercise physiologist 3 days per week. Each exercise session was preceded by and concluded with a 5515-minute warm-up and cool-down session, respectively. Each patient was given an exercise prescription that included a 30-minute period of walking or of walking and jogging sequences and 15 minutes of arm-leg bicycle ergometer exercise. In the event that the physical exercise during a session accelerated the heart rate more than expected, the exercise level was lowered so that the target zone was not exceeded. Recreational activities were optional. Patients were discouraged from exercising on their own at intensity levels greater than their assigned levels and were asked to restrict their exercise activities outside of the program to no more than 2 hours per week. Logs of patients’ outside activities were maintained. No attempt was made to modify patients’ risk factors while they were enrolled on the study other than to provide general AHA recommendations during educational sessions. All medical problems were referred to the patient’s private physician. Space and Personnel
Requirements
In order to accrue a sufficient number of patients in a reasonable amount of time, two experienced cardiac rehabilitation centers were used as clinical centers. The research facilities at both centers consisted of a scheduling/reception area, waiting area, blood drawing room, exercise testing rooms, and an exercise room in which the training sessions were held. A motorized
J.Y. Lee et al.
64
treadmill ergometer was required at each clinical center for exercise testing. Both centers were equipped to perform two-dimensional echocardiography. An exercise physiologist was dedicated to this study for 20 hours per week at each center.
Use of Medication A major concern in planning this study was the chronic use of medications in the target population. Although use of some medications such as beta blockers, vasodilators, and calcium channel blockers may influence response to exercise, interruption of medical therapy could have a potentially deleterious effect on a patient’s health, and a negative impact on the patient’s compliance with the trial. Evaluation of the exercise interventions in the context of ongoing medical therapy would be more realistic in terms of prevailing community medical practice. The decision was made to allow patients to continue without any change in their medical regimens. Patients on drug regimens likely to be changed soon after starting on study were not enrolled onto the study until they were on a stable therapeutic regimen. Changes in medication use during the study were documented and were to be taken into account as potential co-founders in the analysis.
Severity of Disease To address the variation in severity of disease between patients, a stratified randomization scheme was used. Patients were characterized with respect to two factors which reflected disease severity: resting LVEF at the initial evaluation (<50%, >50%) and whether or not they had a documented history of a myocardial infarction.
Compliance The TLC Trial required that patients make a long-term commitment to devote a minimum of 3 hours per week to the project. Experience with studies of long duration suggests that compliance can be enhanced by carefully screening for participants who demonstrate an extended interest in the project [17]. To capture participants when they were highly motivated to enroll in an exercise program, an effort was made to recruit participants as soon after their cardiac event as possible. Another compliance issue considered in planning the study was adherence to treatment assignment. The trial had to address the possibility that some patients assigned to the low-intensity program might feel that the intensity level was inadequate to be beneficial and wish to exercise at a more intense level, or that some patients assigned to the high-intensity program might find the program too strenuous and wish to decrease their intensity level. To assess their willingness and commitment to participation, potential participants were asked to attend five l-hour education sessions during the 2week screening period. To be eligible for the trial, attendance at four of the
The Training Levels Comparison Trial
65
five sessions was required. In the first session, they were given an overview of the study protocol that included the rationale and expectations of the study, agenda with time frame for the 2-year study, schedule of the upcoming education sessions, introduction of study staff, and tour of the exercise facility. During the first session, the requirement that patients exercise at their assigned intensity level was emphasized and potential participants were asked to carefully consider this issue before enrolling on the study. Session two covered primary risk factors for CHD: smoking, hypertension, and elevated cholesterol; and related areas: obesity, diabetes, and stress. Although handout material on reducing risk factors for CHD was provided during session 2, no active effort was made to alter risk factors such as smoking or obesity. Potential participants were given a presentation on the benefits of exercise and guidelines for exercise safety in session three. Sessions 4 and 5 were aimed at familiarizing the potential participants with the exercise room, exercise lab, and evaluation procedures. To minimize barriers to participation, exercise sessions were scheduled three times a week on Mondays, Wednesdays, and Fridays, at times chosen to best accommodate patients’ schedules (6 A.M., noon, and 5 Waiting times clinic visits Modest compensation travel expenses center was provided these patients funds have limited their ability After randomization, safety of exercise their assigned intensity level. During heart rate measurements taken and compared target rates. those patients whose heart rate was outside their were counseled about adhere to assigned intensity level. To help patients identify with the project, study was develdence with patients. study name were distributed meetings and to develop ercise sessions.
shirts and
incentives
Group their spouses to maintain interest in the clinic personnel. Positive feedback rates to ex-
A monthly attendance trophy displayed
center with the highest
J.Y. Lee et al.
66
attendance rate. Training records were collected to evaluate compliance. For each patient, a log was kept of each session attended. In addition, all patients were asked to maintain records of outside physical activities. These records were used to determine frequency and duration of outside activities.
Eligibility
Criteria
Because results suggest that response to physical conditioning differ by sex and age, the trial targeted men aged 30 to 67 who had documented evidence of coronary heart disease. Available data indicate that female athletes do not achieve the same absolute levels of VO, max as male athletes, presumably because of lower lean body mass. The exercise ECG response among women differs from men and has different clinical significance. There is little data on cardiac rehabilitation in women to provide the basis for a high-intensity level of exercise that could be used safely. Since relatively little information is available on exercise training responses in women with coronary heart disease, the data on women could not be combined with that for men. Recruitment of women to the trial would be difficult due to the small number of women with coronary heart disease. There is a progressive decline of functional capacity of the cardiovascular system with aging. Recent findings suggest that the heart may be less responsive to training in the elderly than in younger individuals [18]. Table 3 summarizes the selection criteria for the trial. The inclusion criteria were designed to enroll patients whose cardiac event had occurred within 2 years and were willing to make a 2-year commitment to the trial. The exclusion Table 3
Inclusion
and Exclusion
Criteria
Inclusion Male Aged 30 to 67 years At least one of the following within the previous two years Angiographic evidence of ~70% stenosis in own major coronary vessel as defined in the CASS study (19) Myocardial infarction Coronary artery bypass graft Percutaneous transluminal coronary angioplasty Able to perform three METS of exercise Resided within 50 miles of the exercise center Willing to participate in the trial for 2 years Informed consent Exclusion Uncontrolled congestive heart failure Unstable dysrhythmia Unstable angina Uncontrolled diabetes mellitus Uncontrolled systemic hypertension Exercise-limiting concurrent condition Major cardiovascular condition or procedure which is not an inclusion criterion Reported alcohol intake ~21 drinks per week Participation in a regular exercise program at an intensity level greater than walking at a usual pace
67
The Training Levels Comparison Trial criteria were intended to exclude patients with concomitant tions that would limit their participation in the trial.
Sample
medical
condi-
Size Estimation The objective of the trial was to determine which of two levels of exercise training was most likely to be beneficial for patients with coronary artery disease. The primary outcome variable to evaluate efficacy was the change at one year in peak exercise left ventricular ejection fraction (LVEF). Determination of the sample size was based not only on scientific considerations, but on feasibility. Table 4 shows the minimum detectable difference in peak exercise LVEF change for sample sizes of 50, 75, 100, and 150 per group. It was assumed that the change in LVEF in each group was normally distributed with standard deviation of .08, and that all statistical tests would be carried out at the two-sided 0.05 significance level. Based on feasibility, it was decided to accrue a sample size of 100 patients per clinical center for a total of 200 patients. This sample size is sufficient to detect a difference between the two groups of .032 with respect to the oneyear change in peak exercise LVEF with power of .80. As the minimum detectable difference in LVEF represents a small clinical improvement, it was unlikely that a clinically significant change in ejection fraction would be missed in this study.
Length of Follow-Up Although the primary outcome variable was the l-year change in peak exercise LVEF, the duration of the participation in the exercise intervention was 2 years. The purpose of the extended follow up period was to assess if patients further improved their cardiac function with continued exercise. There was also concern that the long-term adherence would deteriorate and that the one-year assessment would be more realistic. A secondary objective was to evaluate cardiac morbidity and mortality trends over a longer period of time. Annual surveillance will be maintained on all patients for an indefinite period to provide data on progression of disease.
ORGANIZATIONAL
STRUCTURE
AND PROCEDURES
The TLC trial was investigator-initiated and funded through a grant from the National Heart, Lung and Blood Institute (NHLBI). The organizational structure consisted of two clinical centers, University of Alabama at Birmingham and Emory University; the Biostatistical Coordinating Center, BirmingTable 4
Minimum
Detectable
Difference
in LVEF
Sample Size per Group Power
50
75
100
150
.80 .90
.045 .052
.037 .042
.032 ,037
,026 ,030
J.Y. Lee et al. ham, Alabama; and the Echocardiographic Center, Birmingham, Alabama. Each clinical center was responsible for recruiting, screening, and enrolling participants; administering the assigned treatment; and following the subjects at 3 months, 6 months, 1 year, and 2 years; and data collection. The Biostatistical Coordinating Center (BCC) and Echocardiographic Center were located at UAB and operated independently from the UAB clinical center. The BCC was responsible for providing data management, computing, and statistical support for the TLC trial. Specific functions of the biostatistical center included working closely with the investigators to develop a manual of operations; assigning study participants to treatment regimens; reviewing all study data for completeness and accuracy; preparing and maintaining the database of study data; implementing computer edit routines to check the data for out-of-range values and inconsistencies; performing statistical analyses on the data; and preparing all statistical reports and analyses for abstracts and manuscripts. The Echocardiographic Center was responsible for reading the echocardiogram tapes from both clinical centers, recording the data, and submitting it to the BCC. Utilization of the Echocardiographic Center was essential for maintaining quality control over this information, and for providing an independent assessment of the primary outcome variable, LVEF. The Steering Committee was the governing body for the TLC trial and consisted of the principal investigator and study coordinator at each clinical center, exercise interventionists, and directors of the Biostatistical Coordinating Center and Echocardiographic Center. The Steering Committee met at least twice a year to review the progress of the study and had overall responsibility for coordinating the activities of the two clinical centers. The meetings of the Steering Committee were the primary forum for discussion of problems with the study, and dissemination of information. The principal investigator at the UAB Clinical Center was chairman of the Steering Committee, and the Emory Clinical Center principal investigator served as cochairman. The geographic proximity of the two clinical centers permitted faceto-face discussion of trial activities that facilitated the operation of the TLC trial.
PATIENT
EVALUATION
Patients were evaluated prior to randomization (El) and at 3 months (E2), 6 months (E3), one year (E4) and two years (E5) after study entry. Table 5 summarizes the patient evaluation schedule.
Eligibility
Criteria
and Demographic
Data
At the initial evaluation, the patient’s eligibility was assessed. As part of the eligibility determination, detailed information was collected regarding the patient’s coronary heart disease: history of and most recent occurrence of a myocardial infarction, coronary artery bypass graft, or percutaneous transluminal coronary angioplasty; and history, date of diagnosis and anatomic description of coronary artery disease with greater than or equal to 70% stenosis. All other eligibility criteria were reviewed. Demographic data collected at the
69
The Training Levels Comparison Trial Table 5
Patient Evaluation
Schedule Evaluation
(1)
Initial Eligibility Demographic data Medical history, physical exam, and physical activity Treadmill exercise test ECG Echocardiogram Blood pressure Heart rate Anthropometric measures Laboratory data Hemoglobin Serum chemistry Lipid levels Glucose and insulin levels Quality-of-life measures General Health Rating Index Profile of Mood States Cook-Medley Hostility Scale SCL90-R Self-Motivation Questionnaire Treatment compliance questionnnaire
3 months
(3) 6 months
(4) 1 year
(5) 2 years
X
X
X
X
X
X
X
(2)
X X X
X
X X X
X
initial evaluation included age, race, marital status, highest educational achieved, and employment status.
X X
level
Medical History and Physical Exam and Physical Activity At the initial evaluation, information was obtained on patients regarding their medical history and that of family members with an emphasis on cardiovascular diseases. Patients were queried about their smoking history, weekly alcohol consumption, and whether they had been placed on any dietary restrictions within the preceding two months. Medication use and physical examination data were recorded. Patients were asked detailed questions regarding their physical activity at the time of the initial evaluation, and prior to their qualifying cardiac event. At all subsequent evaluations, patients were queried regarding changes in their medical history, dietary restrictions, and medication use since the preceding evaluation. Physical examination information and detailed information regarding the patients’ current physical activities outside of the prescribed exercise sessions were recorded at each evaluation.
Treadmill
Exercise Testing
At each evaluation, patients underwent upright exercise testing on a treadmill. Each patient completed resting two-dimensional and color Doppler echocardiographic examination at baseline. Optimal positions for all views, par-
J.Y. Lee et al.
70
titularly the apical window, were marked “X” on the chest to facilitate transducer positioning for rapidly obtaining optimal views immediately after exercise. Patients practiced going from the treadmill to the supine position to minimize the time from immediately postexercise to obtaining recordings. Just prior to upright exercise testing, complete two-dimensional and color Doppler recordings were obtained. Resting control 12-lead ECGs were recorded in the supine and standing positions. Blood pressure and heart rate were measured in the supine and standing positions. Each patient then performed the treadmill exercise according to the Bruce protocol [20]. Leads V2, V5, and AVF were monitored continuously, and a complete 12-lead ECG was recorded automatically at the end of each minute of exercise. Blood pressure and heart rate were measured in the third minute of each exercise stage. Exercise was continued, stage-by-stage, until an indication for termination of exercise occurred. These included subjective maximal exercise as indicated by the patient’s own symptoms of fatigue or breathlessness. Other indications included a drop in systolic blood pressure of > 10 mm Hg, confirmed by a repeat measurement; the occurrence and progression of any symptom to the point of unwillingness of the patient to proceed further; or an electrocardiographic disturbance that indicated that continuation of the test might be detrimental to the patient’s welfare. These ECG abnormalities included evidence of severe ischemia, altered intraventricular conduction, AV block greater than first degree, the development of ventricular arrhythmias more severe than frequent single ventricular premature complexes, or chest discomfort. At the time that exercise was terminated, a t2-lead ECG was recorded, and the patient was transferred immediately to the examining table where the 12lead ECG, blood pressure, and heart rate measurements were repeated. Immediately postexercise (within 30-60 seconds), the primary two-dimensional echocardiographic views and color Doppler recordings were repeated. These post exercise views were completed within 1 to 2 minutes. Two further sets of multiple echocardiographic views were obtained in the postexercise period and completed within the next 4 minutes. In the postexercise period, 12-lead ECGs were recorded every minute, and blood pressure and heart rate were recorded every 2 minutes, until the end of 6 minutes or longer until the patient was stable and asymptomatic. Videotapes of the twodimensional and color echocardiogram during the treadmill exercise test from both clinical centers were sent to the Echocardiographic Center for determination of the LVEF and wall motion scores prior to and immediately following exercise testing.
Anthropometric
Measurements
Height, weight, skinfold thickness, and girths were measured at each evaluation. Skinfold thickness was measured for the following sites: chest, axilla, triceps, subscapula, abdomen, suprailiac, and thigh. All skinfold measurements were made on the right side of the body. Girth measurements were taken of the upper arm, waist, hip and midthigh girths.
The Training Levels Comparison Trial
71
Blood Samples Blood samples were collected at each evaluation. Total cholesterol, HDL cholesterol, LDL cholesterol, and triglyceride levels were determined at each evaluation with a second determination made at the initial evaluation. A central laboratory standardized according to Centers for Disease Control guidelines was used for the lipid levels. Glucose and insulin levels were determined at evaluations 1, 3, and 5 in the fasting state and 1 hour after a 75-g glucose load. Hemoglobin was recorded at the initial evaluation and at evaluation 5.
Quality of Life Measures A battery of quality-of-life measures was chosen to characterize a variety of indexes of psychosocial functioning including state and trait measures of emotional functioning, hostility, and perceptions of health status; self-motivation questionnaire; symptom checklist-90 revised (SCL%R), Profile of Mood States (POMS); Cook-Medley Hostility Scale; and General Health Rating Index. The quality of life measures were collected not only to evaluate and compare the effects of the two training programs with respect to personality traits, but to determine if any of these measures taken at the initial evaluation was predictive for cardiac adaptations and compliance. The self-motivation questionnaire (21) is a 40-item measure of patients’ selfmotivation. It has been demonstrated to have good psychometric properties and has been shown to be associated with exercise adherence in a variety of populations. The SCL-9OR (22) is a self-administered 90-item scale that yields measures on a number of subscales: somatic focus, obsessive compulsiveness, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism. Global indices of positive symptom total, positive symptom distress, and global symptoms are also computed. This scale provides an overall index of emotional disturbance in what may be considered as a trait measure. The Profile of Mood States (23) is a 65-item measure of patients’ mood states and produces scores on six subscales: tension-anxiety, depressiondejection, vigor-activity, fatigue-inertia, anger-hostility, and confusionbewilderment. In contrast to the SCL-90R, the POMS provides more of a measure of mood state. The Cook-Medley Hostility Scale (24) is a 60-item measure of hostility. The measure has been thoroughly investigated psychometrically and been found to have good psychometric properties. The scale was included due to the recent interest in the relationship between hostility and heart disease. The General Health Ratings Index is a 22-item measure of perceptions of health status [25]. The measure provides an overall rating of patients’ perceptions of general health as well as ratings on six subscales: current health, prior health, health outlook, resistance to illness, health worry/concern, and sickness orientation. This measure was included to provide an index of perceived general health.
J.Y. Lee et al.
72 Treatment
Compliance
Questionnaire
Patients were asked to complete a treatment compliance questionnaire at each evaluation. The questionnaire elicited information regarding patients’ perception of the exercise program as beneficial in treating their heart disease and reducing their risk of future heart disease. The questionnaire asks the patient to rate his confidence in his ability to adhere to the exercise protocol and his confidence in recommending his treatment to a friend with heart disease. The treatment compliance questionnaires will be used to identify patients likely to adhere to long-term exercise training and to evaluate whether treatment assignment affected patients’ perceptions of the likelihood of cardiac benefit.
DATA MANAGEMENT A total of 25 data collection forms were developed by the BCC with input from the clinical centers. The forms were tested on a vanguard group of four patients who followed the study protocol. The forms were revised to accommodate problems encountered in the vanguard group. Steering Committee approval was required prior to printing of the forms. All forms were printed with one carbonless copy. Quantities of each form were sent to the clinical centers prior to the start of the study. All data collection forms included identifying information including the name of the study, the name and number of the form and the page number of the form, e.g., page 2 of 8. A small box in the right-hand corner of each page of each form provided a space for the subject’s ID number, clinical center, evaluation number, and date of evaluation. Items requiring completion by TLC certified personnel included space for recording the initials of the staff member who performed the procedure. At the BCC, forms were reviewed for completeness and consistency prior to data entry. The study coordinators from the clinical centers were contacted to provide missing data and to resolve any inconsistencies. Screen displays for data entry were designed to emulate the forms. Numerical range checks were built into the entry process to flag out-of-range or inconsistent values. Forms were entered centrally at the BCC by trained data entry technicians. All forms were keyed in twice by different technicians and discrepancies had to be resolved before the record could be added to the database. The BCC performed edit checks on the database with each database update. Consistency checks across screens included identifying missing or delinquent forms for each evaluation and determining any major deviations from the schedule of evaluations. Queries were directed to the clinical centers and resolved prior to finalizing the database.
TRAINING
AND QUALITY
CONTROL
The approach to quality control between clinical centers was based on standardization of measurements and intervention through certification and recertification of study personnel; development of a manual of operations
The Training Levels Comparison Trial
73
which detailed procedures for recording measurements, conducting exercise sessions, and equipment maintenance; and periodic meetings and progress reports to resolve any problems at the clinical centers. Specific quality control measures for certification procedures, equipment maintenance and monitoring of data collection were instituted at each center. Each clinical center was responsible for the following: certification of personnel responsible for exercise testing, anthropometry and pulmonary function testing; certification maintenance of blood pressure devices, treadmills, scales, and skinfold calipers; inspection and certification of the physical environment of the clinic; validation of data collection and coding procedures; and review of laboratory specimen handling, shipping, and storage. Recruitment
and Randomization
Study patients were recruited through media releases and local area physicians. The initial evaluation included screening phone calls to potential participants to exclude those who were ineligible due to age, medical history, or current level of exercise activity, and a review of their medical records. Those deemed eligible underwent a two-week screening period during which additional clinical information was obtained. During screening, documentation of potential participants’ CHD event was obtained, and they underwent exercise testing to assess their ability to perform at least 3 METS of exercise. Eligible patients were scheduled for an individual counseling and randomization visit within two weeks after their eligibility was established. During the visit, the study plan was reviewed with the candidate. At that point, patients were asked to sign the informed consent form. Patients were classified into one of four strata based on their documented history of myocardial infarction and resting LVEF (G 50%, > 50%) to eliminate two anticipated sources of variation. Within each stratum, patients were assigned in equal numbers to the two intensity levels of exercise intervention. To randomize a patient, the study coordinator telephoned the BCC. After providing the BCC with information on the patient’s documented history of myocardial infarction and resting LVEF, an intensity level was assigned by the BCC and communicated to the study coordinator. To confirm the assigned level, the study coordinator completed a randomization form including the intensity level assignment and submitted it to the BCC. Statistical
Analyses
Statistical analyses of the TLC Trial’s results are in progress. Analysis of variance methods will be used to compare the two exercise training programs with respect to the change in peak LVEF at 1 year, the primary endpoint of the study. To assess the effects of the treatments after adjusting for factors that might influence the peak exercise LVEF including compliance, analysis of covariance methods will be used. Between center variation will be assessed for all outcomes. Repeated measures analyses will be used to evaluate time trends in LVEF. Analyses of variance will be used to evaluate the effects of treatment assignment and timepoint (E2, E3, E4, E5) on the changes in lipid levels, body
J.Y. Lee et al.
74
composition, heart rate and blood pressure measurements. Insulin and glucose levels, and all subscales and global indices of the quality of life measures will be evaluated in a similar manner, but the timepoints will be limited to E3 and E5. In all analyses, a test for interaction between treatment assignment and timepoint will be performed. If a significant interaction is detected, the variation attributed to the differences between the two treatments will be compared to the interaction effects to determine statistical significance. Analyses of covariance will be used to assess the effects of treatment after adjusting for baseline characteristics which may be correlated with these outcome measures. Analyses of covariance will be used to evaluate the effects of treatment and time on compliance. Regression analyses methods will be used to evaluate the effects of time on compliance within each treatment group. One of the secondary objectives of the study was to compare the treatments with respect to the incidence of and time to new clinical manifestation of coronary heart disease as an assessment of safety. The two treatments will be compared with respect to the incidence of new cardiac events using the normal approximation to the Poisson distribution. The product limit method will be used to describe the distribution of times to new cardiac events. For patients who did not experience a new cardiac event, their time will be censored at the date of the last follow up. The log-rank test will be used to compare the two training levels with respect to the time to new cardiac events. If there are a sufficient number of new cardiac events, a proportional hazards model will be used to evaluate the influence of other prognostic factors on the time to a new cardiac event.
CONCLUSIONS This study extends the findings of previous studies of exercise training in coronary heart disease patients by using a longer study participation period and a more vigorous level of exercise in the high intensity group to evaluate the effect of dose of exercise on cardiac adaptations. The study addresses the important clinical question of whether prolonged exercise training at a highintensity level offers advantages over training at a low-intensity level. If highintensity exercise training does not produce superior results as compared to low-intensity exercise training, then exercise programs should be limited to low-intensity levels that are safer and can be used in a larger proportion of cardiac rehabilitation patients.
REFERENCES 1. Oberman A: Rehabilitation of patients with coronary artery disease. In Heart Disease: A Textbook of Cardiovascular Medicine, 2nd Ed, Braunwald E, Ed., Philadelphia, Saunders Publishing Co., 1983, 1384-1398. 2. Fletcher GF, ed: Exercise in the Practice of Medicine. Mount Kisco, NY, Futura Publishing Company, Inc., 1982. 3. Blomquist CC: Role of exercise training in secondary prevention of ischemic heart disease. Prev Med 12~228232, 1983. 4. Haskell WL: Mechanisms by which physical activity may enhance the clinical status
The Training Levels Comparison
75
Trial
of cardiac patients. In Heart Disease and Rehabilitation, Second Edition, Pollock ML and Schmidt DH, Eds., New York, J Wiley, 1986, 303-324. 5. May GS, Eberlein KA, Furberg CD, Passamani ER, DeMets DL: Secondary prevention after myocardial infarction: A review of long-term trials. Frog Cardiovasc Dis XXIV(4):331-352, 1982. 6. Yusuf S, Peto R: Exercise after myocardial infarction reduces mortality: Evidence from randomized controlled trials (RCTs). J Am Co11 Cardiol3:622, 1984 (Abstract). 7. Oberman A: Does cardiac rehabilitation increase long-term cardial infarction? Circulation 80(2):416418, 1989.
survival after myo-
8. Oberman A, Naughton J: The National Exercise and Heart Disease Project. In Heart Disease and Rehabilitation, 2nd Ed, Pollock ML, Schmidt DH, Eds, New York, Wiley, 1986, 369-385. 9. Ehsani AA, Martin WH, Heath GW, Coyle EF: Cardiac effects of prolonged and intense exercise training in patients with coronary artery disease. Am J Cardiol 50:246-253, 1982. 10. Williams RS, McKinnis RA, Cobb FR, Higginbotham MB, Wallace AC, Coleman RE, Califf RM: Effects of physical conditioning on left ventricular ejection fraction in patients with coronary artery disease. Circulation 70(1):69-75, 1984. 11. Paterson DH, Shephard RJ, Cunningham D, Jones NL, Andrew G: Effects of physical training on cardiovascular function following myocardial infarction. J Appl Physiol 47(3):482-489, 1979. 12. Hagberg JM, Ehsani AA, Holloszy JO: Effect of 12 months of intense exercise training on stroke volume in patients with coronary artery disease. Circulation 67(6):1194-1199, 1983. 13. Haskell WL, Montoye HJ, Orenstein D: Physical activity and exercise to achieve health related physical fitness components. Public Health Rep 100:202-212, 1985. 14. Jennings G, Nelson L, Nestel P, Esler M, Korner P, Burton D, Bazelmas J: The effects of changes in physical activity on major cardiovascular risk factors, hemodynamics, sympathetic function, and glucose utilization in man: A controlled study of four levels of activity. Circulation 73(1):30-40, 1986. 15. Oberman A, Fan P-H, Nanda NC, Lee JY, Huster WJ, Sulentic JA, Storey OF: Reproducibility of two-dimensional exercise echocardiography. J Am Co11 Cardiol 14:923-S, 1989. 16. Borg GA: Psychophysical 381, 1982.
bases of perceived exertion. Med Sci Sports Exert 14:377-
17. Sulentic J, Dunnam L, Thiel J, Fletcher B, Oberman A, Fletcher G, Sheffield T, Lee J: Training levels comparison study: factors influencing exercise compliance. Presented at the meeting of the American College of Cardiology, Anaheim, California, March 1989. 18. Shocken DD, Blumenthal JA, Port S, et al: Physical conditioning and left ventricular performance in the elderly. Assessment by radionuclide angiography. Am J Cardiol 41:155-660, 1978. 19. Principal investigators of CASS and their associates: National Heart, Lung, and Blood Institute Coronary Artery Surgery Study (CASS). Circulation 63(6):1-80 (monograph 79), 1981. 20. American College of Sports Medicine. Guidelines for Exercise Testing and Prescription, 4th ed. Philadelphia, Lea & Febiger, 1991. 21. Dishman RK, Ickes W: Self-motivation Behav Med 4:421-438, 1981.
and adherence
to therepeutic
exercise.
J
22. Derogatis LR: SCL-90 Revised Version Manual-l. Clinical Psychometrics Research Unit, Johns Hopkins University School of Medicine, Baltimore, MD, 1983. 23. McNair JR, Lorr M, Droppleman LF: ETlS Manual for the Profile of Mood States. San Diego, CA, Educational Testing Service, 1971.
J.Y. Lee et al. 24. Cook W, Medley D: Proposed hostility and pharisaic-virtue J Appl Psycho1 238:414-418, 1954.
scales for the MMPI.
25. Davies AR, Sherbourne CD, Peterson JR, Ware JE: Scoring Manual: Adult Health Status and Patient Satisfaction Measures Used in RAND’s insurance Experiment. Santa Monica, CA, the RAND Corporation, 1988.
PhD,
Barbara J. Fletcher, RN, MN, Navin C. Nanda, MD, and Betsy E. Jensen, MS
ABSTRACT The Training Levels Comparison (TLC) trial was a grant-supported, multicenter, randomized, controlled clinical trial designed to determine whether cardiac rehabilitation patients would benefit from supervised exercise for a prolonged period (2 years) and whether subjecting patients to a more vigorous exercise program than currently recommended would provide additional cardiac benefit. If high-intensity exercise does not enhance the cardiac benefit, then physical activity should be limited to lowintensity levels that are safer, easier to implement and more adaptable to a greater number of patients. Patients were randomly assigned to either a low-intensity or high-intensity training program. All patients were to attend three l-hour supervised exercise sessions per week for a period of 2 years. Attendance at exercise sessions and adherence to assigned treatments were monitored throughout the study. Patients were evaluated for outcome measures at 3, 6, 12, and 24 months. This paper reports the study design and methodology for the TLC trial, and should be useful in providing methodologies to facilitate comparison of data from other studies with different levels of exercise as an intervention.
INTRODUCTION
Exercise, a key element in cardiac rehabilitation, leads to favorable training adaptations. Regular dynamic exercise increases physical work and functional capacity which provides relief of symptoms in many patients with coronary heart disease [l-4]. Exercise training can produce favorable risk factors and hemodynamic changes: reduction in body weight with constant caloric intake and increased lean body mass, reduced levels of blood triglyceride and increased proportion of cholesterol carried by high density lipoproteins, improved glucose tolerance, and lowered blood pressure during submaximal exercise. There is considerable evidence that long-term physical conditioning
Address reprint requests to: Jeannette Y. Lee, PhD, Biostatistics Unit, Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 Sixth Avenue, South, Birmingham, Alabama 35294-3300. Received janua y 8, 1993; revised September 9, 1993. This work is supported by a grant from the National Heart, Lung, and Blood Institute (ROl HL3759703). Controlled Clinical Trials 15:59-76 (1994) Elsevier Science Inc. 1994 655 Avenue of the Americas, New York, New York 10010
0
59 0197-2456/94/$7.00
60
J.Y. Lee et al. may lower mortality from cardiovascular disease [1,5,6]. Pooling of data from long-term, exercise-based cardiac rehabilitation studies demonstrates a reduced 3-year mortality from reinfarction alone by 25% and from all causes by 20% [7]. There have been few clinical trials with exercise as an intervention, with only one major trial in this country [8]. Previous studies of training programs for cardiac patients have generally been short-term (8-12 weeks) and of mild intensity. Although exercise training produces favorable adaptations, these adaptations are generally attributed to peripheral changes in the muscle rather than to improved cardiac function. Lack of improved cardiac function may be due to inadequate training, and more prolonged training at higher intensity levels may result in desirable cardiac adaptations in coronary heart disease patients [7-121. It is equally possible that the important factor is total dose of exercise, not intensity level, and that benefit may be realized from a lower intensity training program continued over a sufficiently long period of time. This possibility warranted study due to the practical advantages of lower intensity exercise as compared to higher intensity exercise in terms of safety and compliance. There is scant data on which exercise prescriptions are based. Exercise training recommendations were originally based on a short-term study on young men [13]. Prescriptions for exercise programs rarely take into account detailed individual differences in severity of coronary artery disease and left ventricular function. These factors may have significant implications for the training prescription and the likelihood of favorable benefits from exercise. Recent data suggest a differential effect of physical activity on cardiovascular risk factors, hemodynamics, and sympathetic function according to exercise level [ 141. Although resource requirements and adherence issues must be addressed in planning any clinical trial, these concerns are magnified in exercise studies. Implementation of group supervised exercise sessions requires that a suitable room to hold the sessions in and an exercise physiologist to conduct them be available to the study. Inherent in exercise studies are the difficulties in motivating participants to exercise regularly for a long period of time and ensuring adherence to the assigned treatment. Cardiac rehabilitation patients posed a challenge in designing the study due to the variation in the severity of their disease, their medication use, and the effect of their clinical status on their ability to exercise. The response to exercise training may be influenced by severity of disease and medication use. Furthermore, medication use may change over the course of the study. Determination of the primary outcome measure has implications in the Due to the low incidence of cardiac design and sample size requirements. mortality and morbidity, a prohibitively large number of patients would be required to compare treatments with respect to this outcome measure. There was a need to identify an outcome measure that was predictive of cardiac events but could be obtained safely in this target population. Developments in echocardiography as a method for assessing left ventricular function provided an opportunity to evaluate the effects of vigorous exercise on coronary heart disease patients noninvasively. The reproducibility and value of mea-
The Training Levels Comparison Trial
61
surements obtained with two-dimensional echocardiography has recently been demonstrated [ 151. The Training Levels Comparison (TLC) Trial was undertaken to address the question of whether cardiac rehabilitation patients exercised at higher intensity levels than were typically recommended would develop additional cardiac benefit. If high-intensity exercise does not confer additional benefit, then physical activity should be limited to low-intensity levels that are safer, easier to implement, and more adaptable to a greater number of patients. The trial was funded for a 5-year period beginning December 1,1986. Patients enrolled in the study between August 1987 and March 1990. Key events in the TLC trial are listed in Table 1.
OBJECTIVES The primary objective of the trial was to determine if patients with coronary heart disease who exercised at a high intensity over a prolonged time period, would demonstrate improvement in cardiovascular hemodynamics as compared to those who exercised at a lower intensity. The primary outcome measure was the change in left ventricular ejection fraction (LVEF) at peak exercise after 1 year of exercise training. LVEF was chosen as the primary outcome measure due to its prognostic significance with respect to cardiac mortality and morbidity. Secondary objectives of the study were to compare the two training programs with respect to changes in lipid levels, body composition, blood pressure and heart rate measurements, glucose tolerance, and quality of life measures; to assess the effects of time and assigned intensity level on compliance; to compare the two training programs with respect to progression of disease; and to identify patients unlikely to respond to training.
DESIGN
CONSIDERATIONS By using exercise as an intervention and cardiac rehabilitation patients as the target population, several issues had to be addressed in designing the trial: recruiting and identifying patients likely to adhere to an exercise program for two years and maintaining their interest in the trial; meeting the space and personnel requirements for conducting exercise sessions; balancing treatment groups with respect to severity of coronary heart disease; monitoring medication use; and selecting an outcome measure which could be safely evaluated in this patient population and required a sample size which could Table 1
Chronology
Date
Event
December 1, 1986 April 1987 May 1987 August 4, 1987 March 13, 1990 November 30, 1991
Funding initiated for the trial Certification of study personnel at UAB and Emory Recruitment started First patient enrolled Last patient enrolled Funding
ended
for the trial
J.Y. Lee et al.
62
be accrued in a reasonable amount of time. Other issues common to most clinical trials were also addressed: masking, treatments, eligibility criteria, sample size estimation, and length of follow-up. Key features of the design are shown in Table 2.
Masking Masking of patients to their assigned treatment was impractical; however, the primary outcome measure-left ventricular ejection fraction-was determined by the staff at the Echocardiographic Center at a site removed from the clinical centers. Primary outcomes were determined by investigators unaware of the assigned treatment from echocardiograms on videotape. Consequently, the lack of masking did not bias the assessment of the major outcome. The individuals who performed the exercise testing were aware of each patient’s treatment assignment. Although there was the possibility for examiner influence over patients’ efforts on exercise testing, the observers underwent certification and attempted to deliver standard instructions and observe specific indicators for stopping the test. Medical conditions were the overriding reasons for terminating the test. Heart rate, an objective measure, was used to monitor patients during exercise testing. Under these circumTable 2
Design Synopsis Treatment Groups Low-intensity exercise training program High-intensity exercise training program Treatment Long-term exercise training
Type of Trial Therapeutic
Centers Two clinical centers Biostatistical Coordinating Echocardiographic Center Sample Size 200 subjects
Eligibility Criteria Men with CHD Age 30-67 Length of treatment 2 years Data Collection Schedule Initial (El) 3 months (E2) 6 months (E3) 1 year (E4) 2 years (E5)
Center Outcomes of Interest Change in LVEF Lipid levels Glucose tolerance Quality of life measures Compliance Progression of disease Treatment Assignment Random by phone Stratified by history of MI (2 strata) and LVEF (2 strata) Level of Treatment None
Masking
The Training Levels Comparison Trial
63
stances, the investigators felt that the potential for systematic bias was minimal The use of observers unaware of treatment assignment to perform the exercise testing was considered, but deemed infeasible with available resources. Treatments All exercise prescriptions were based on exercise testing of patients maintained on their usual medical regimen including drugs. Patients underwent standardized multistage treadmill exercise testing monitored by two-dimensional, color Doppler echocardiogram at the baseline visit (El) just prior to randomization and at the 3-month visit (E2), 6-month visit (E3), l-year visit (E4), and 2-year visit (E5) after study entry. The results of the exercise testing were used to prescribe exercise for the period following evaluation using the symptom limited test routine. The target heart rate for patients on the low intensity program corresponded to 50% of the VOZ max established on the previous exercise test ? 5 beats/minute. For patients on the high-intensity program, the target heart rate corresponded to 85% of the VO1 max attained on the previous exercise test + 5 beats/minute. The Borg scale of perceived exertion [16] was used in conjunction with heart rate monitoring to ensure that proper intensity levels were maintained. By this method, the patient was taught to relate subjective feelings of exertion such as fatigue or shortness of breath, to heart rate level. There was no control group in this study as the low intensity group represented “usual care” for cardiac rehabilitation patients. Patients participated in structured group exercise sessions directed by an exercise physiologist 3 days per week. Each exercise session was preceded by and concluded with a 5515-minute warm-up and cool-down session, respectively. Each patient was given an exercise prescription that included a 30-minute period of walking or of walking and jogging sequences and 15 minutes of arm-leg bicycle ergometer exercise. In the event that the physical exercise during a session accelerated the heart rate more than expected, the exercise level was lowered so that the target zone was not exceeded. Recreational activities were optional. Patients were discouraged from exercising on their own at intensity levels greater than their assigned levels and were asked to restrict their exercise activities outside of the program to no more than 2 hours per week. Logs of patients’ outside activities were maintained. No attempt was made to modify patients’ risk factors while they were enrolled on the study other than to provide general AHA recommendations during educational sessions. All medical problems were referred to the patient’s private physician. Space and Personnel
Requirements
In order to accrue a sufficient number of patients in a reasonable amount of time, two experienced cardiac rehabilitation centers were used as clinical centers. The research facilities at both centers consisted of a scheduling/reception area, waiting area, blood drawing room, exercise testing rooms, and an exercise room in which the training sessions were held. A motorized
J.Y. Lee et al.
64
treadmill ergometer was required at each clinical center for exercise testing. Both centers were equipped to perform two-dimensional echocardiography. An exercise physiologist was dedicated to this study for 20 hours per week at each center.
Use of Medication A major concern in planning this study was the chronic use of medications in the target population. Although use of some medications such as beta blockers, vasodilators, and calcium channel blockers may influence response to exercise, interruption of medical therapy could have a potentially deleterious effect on a patient’s health, and a negative impact on the patient’s compliance with the trial. Evaluation of the exercise interventions in the context of ongoing medical therapy would be more realistic in terms of prevailing community medical practice. The decision was made to allow patients to continue without any change in their medical regimens. Patients on drug regimens likely to be changed soon after starting on study were not enrolled onto the study until they were on a stable therapeutic regimen. Changes in medication use during the study were documented and were to be taken into account as potential co-founders in the analysis.
Severity of Disease To address the variation in severity of disease between patients, a stratified randomization scheme was used. Patients were characterized with respect to two factors which reflected disease severity: resting LVEF at the initial evaluation (<50%, >50%) and whether or not they had a documented history of a myocardial infarction.
Compliance The TLC Trial required that patients make a long-term commitment to devote a minimum of 3 hours per week to the project. Experience with studies of long duration suggests that compliance can be enhanced by carefully screening for participants who demonstrate an extended interest in the project [17]. To capture participants when they were highly motivated to enroll in an exercise program, an effort was made to recruit participants as soon after their cardiac event as possible. Another compliance issue considered in planning the study was adherence to treatment assignment. The trial had to address the possibility that some patients assigned to the low-intensity program might feel that the intensity level was inadequate to be beneficial and wish to exercise at a more intense level, or that some patients assigned to the high-intensity program might find the program too strenuous and wish to decrease their intensity level. To assess their willingness and commitment to participation, potential participants were asked to attend five l-hour education sessions during the 2week screening period. To be eligible for the trial, attendance at four of the
The Training Levels Comparison Trial
65
five sessions was required. In the first session, they were given an overview of the study protocol that included the rationale and expectations of the study, agenda with time frame for the 2-year study, schedule of the upcoming education sessions, introduction of study staff, and tour of the exercise facility. During the first session, the requirement that patients exercise at their assigned intensity level was emphasized and potential participants were asked to carefully consider this issue before enrolling on the study. Session two covered primary risk factors for CHD: smoking, hypertension, and elevated cholesterol; and related areas: obesity, diabetes, and stress. Although handout material on reducing risk factors for CHD was provided during session 2, no active effort was made to alter risk factors such as smoking or obesity. Potential participants were given a presentation on the benefits of exercise and guidelines for exercise safety in session three. Sessions 4 and 5 were aimed at familiarizing the potential participants with the exercise room, exercise lab, and evaluation procedures. To minimize barriers to participation, exercise sessions were scheduled three times a week on Mondays, Wednesdays, and Fridays, at times chosen to best accommodate patients’ schedules (6 A.M., noon, and 5 Waiting times clinic visits Modest compensation travel expenses center was provided these patients funds have limited their ability After randomization, safety of exercise their assigned intensity level. During heart rate measurements taken and compared target rates. those patients whose heart rate was outside their were counseled about adhere to assigned intensity level. To help patients identify with the project, study was develdence with patients. study name were distributed meetings and to develop ercise sessions.
shirts and
incentives
Group their spouses to maintain interest in the clinic personnel. Positive feedback rates to ex-
A monthly attendance trophy displayed
center with the highest
J.Y. Lee et al.
66
attendance rate. Training records were collected to evaluate compliance. For each patient, a log was kept of each session attended. In addition, all patients were asked to maintain records of outside physical activities. These records were used to determine frequency and duration of outside activities.
Eligibility
Criteria
Because results suggest that response to physical conditioning differ by sex and age, the trial targeted men aged 30 to 67 who had documented evidence of coronary heart disease. Available data indicate that female athletes do not achieve the same absolute levels of VO, max as male athletes, presumably because of lower lean body mass. The exercise ECG response among women differs from men and has different clinical significance. There is little data on cardiac rehabilitation in women to provide the basis for a high-intensity level of exercise that could be used safely. Since relatively little information is available on exercise training responses in women with coronary heart disease, the data on women could not be combined with that for men. Recruitment of women to the trial would be difficult due to the small number of women with coronary heart disease. There is a progressive decline of functional capacity of the cardiovascular system with aging. Recent findings suggest that the heart may be less responsive to training in the elderly than in younger individuals [18]. Table 3 summarizes the selection criteria for the trial. The inclusion criteria were designed to enroll patients whose cardiac event had occurred within 2 years and were willing to make a 2-year commitment to the trial. The exclusion Table 3
Inclusion
and Exclusion
Criteria
Inclusion Male Aged 30 to 67 years At least one of the following within the previous two years Angiographic evidence of ~70% stenosis in own major coronary vessel as defined in the CASS study (19) Myocardial infarction Coronary artery bypass graft Percutaneous transluminal coronary angioplasty Able to perform three METS of exercise Resided within 50 miles of the exercise center Willing to participate in the trial for 2 years Informed consent Exclusion Uncontrolled congestive heart failure Unstable dysrhythmia Unstable angina Uncontrolled diabetes mellitus Uncontrolled systemic hypertension Exercise-limiting concurrent condition Major cardiovascular condition or procedure which is not an inclusion criterion Reported alcohol intake ~21 drinks per week Participation in a regular exercise program at an intensity level greater than walking at a usual pace
67
The Training Levels Comparison Trial criteria were intended to exclude patients with concomitant tions that would limit their participation in the trial.
Sample
medical
condi-
Size Estimation The objective of the trial was to determine which of two levels of exercise training was most likely to be beneficial for patients with coronary artery disease. The primary outcome variable to evaluate efficacy was the change at one year in peak exercise left ventricular ejection fraction (LVEF). Determination of the sample size was based not only on scientific considerations, but on feasibility. Table 4 shows the minimum detectable difference in peak exercise LVEF change for sample sizes of 50, 75, 100, and 150 per group. It was assumed that the change in LVEF in each group was normally distributed with standard deviation of .08, and that all statistical tests would be carried out at the two-sided 0.05 significance level. Based on feasibility, it was decided to accrue a sample size of 100 patients per clinical center for a total of 200 patients. This sample size is sufficient to detect a difference between the two groups of .032 with respect to the oneyear change in peak exercise LVEF with power of .80. As the minimum detectable difference in LVEF represents a small clinical improvement, it was unlikely that a clinically significant change in ejection fraction would be missed in this study.
Length of Follow-Up Although the primary outcome variable was the l-year change in peak exercise LVEF, the duration of the participation in the exercise intervention was 2 years. The purpose of the extended follow up period was to assess if patients further improved their cardiac function with continued exercise. There was also concern that the long-term adherence would deteriorate and that the one-year assessment would be more realistic. A secondary objective was to evaluate cardiac morbidity and mortality trends over a longer period of time. Annual surveillance will be maintained on all patients for an indefinite period to provide data on progression of disease.
ORGANIZATIONAL
STRUCTURE
AND PROCEDURES
The TLC trial was investigator-initiated and funded through a grant from the National Heart, Lung and Blood Institute (NHLBI). The organizational structure consisted of two clinical centers, University of Alabama at Birmingham and Emory University; the Biostatistical Coordinating Center, BirmingTable 4
Minimum
Detectable
Difference
in LVEF
Sample Size per Group Power
50
75
100
150
.80 .90
.045 .052
.037 .042
.032 ,037
,026 ,030
J.Y. Lee et al. ham, Alabama; and the Echocardiographic Center, Birmingham, Alabama. Each clinical center was responsible for recruiting, screening, and enrolling participants; administering the assigned treatment; and following the subjects at 3 months, 6 months, 1 year, and 2 years; and data collection. The Biostatistical Coordinating Center (BCC) and Echocardiographic Center were located at UAB and operated independently from the UAB clinical center. The BCC was responsible for providing data management, computing, and statistical support for the TLC trial. Specific functions of the biostatistical center included working closely with the investigators to develop a manual of operations; assigning study participants to treatment regimens; reviewing all study data for completeness and accuracy; preparing and maintaining the database of study data; implementing computer edit routines to check the data for out-of-range values and inconsistencies; performing statistical analyses on the data; and preparing all statistical reports and analyses for abstracts and manuscripts. The Echocardiographic Center was responsible for reading the echocardiogram tapes from both clinical centers, recording the data, and submitting it to the BCC. Utilization of the Echocardiographic Center was essential for maintaining quality control over this information, and for providing an independent assessment of the primary outcome variable, LVEF. The Steering Committee was the governing body for the TLC trial and consisted of the principal investigator and study coordinator at each clinical center, exercise interventionists, and directors of the Biostatistical Coordinating Center and Echocardiographic Center. The Steering Committee met at least twice a year to review the progress of the study and had overall responsibility for coordinating the activities of the two clinical centers. The meetings of the Steering Committee were the primary forum for discussion of problems with the study, and dissemination of information. The principal investigator at the UAB Clinical Center was chairman of the Steering Committee, and the Emory Clinical Center principal investigator served as cochairman. The geographic proximity of the two clinical centers permitted faceto-face discussion of trial activities that facilitated the operation of the TLC trial.
PATIENT
EVALUATION
Patients were evaluated prior to randomization (El) and at 3 months (E2), 6 months (E3), one year (E4) and two years (E5) after study entry. Table 5 summarizes the patient evaluation schedule.
Eligibility
Criteria
and Demographic
Data
At the initial evaluation, the patient’s eligibility was assessed. As part of the eligibility determination, detailed information was collected regarding the patient’s coronary heart disease: history of and most recent occurrence of a myocardial infarction, coronary artery bypass graft, or percutaneous transluminal coronary angioplasty; and history, date of diagnosis and anatomic description of coronary artery disease with greater than or equal to 70% stenosis. All other eligibility criteria were reviewed. Demographic data collected at the
69
The Training Levels Comparison Trial Table 5
Patient Evaluation
Schedule Evaluation
(1)
Initial Eligibility Demographic data Medical history, physical exam, and physical activity Treadmill exercise test ECG Echocardiogram Blood pressure Heart rate Anthropometric measures Laboratory data Hemoglobin Serum chemistry Lipid levels Glucose and insulin levels Quality-of-life measures General Health Rating Index Profile of Mood States Cook-Medley Hostility Scale SCL90-R Self-Motivation Questionnaire Treatment compliance questionnnaire
3 months
(3) 6 months
(4) 1 year
(5) 2 years
X
X
X
X
X
X
X
(2)
X X X
X
X X X
X
initial evaluation included age, race, marital status, highest educational achieved, and employment status.
X X
level
Medical History and Physical Exam and Physical Activity At the initial evaluation, information was obtained on patients regarding their medical history and that of family members with an emphasis on cardiovascular diseases. Patients were queried about their smoking history, weekly alcohol consumption, and whether they had been placed on any dietary restrictions within the preceding two months. Medication use and physical examination data were recorded. Patients were asked detailed questions regarding their physical activity at the time of the initial evaluation, and prior to their qualifying cardiac event. At all subsequent evaluations, patients were queried regarding changes in their medical history, dietary restrictions, and medication use since the preceding evaluation. Physical examination information and detailed information regarding the patients’ current physical activities outside of the prescribed exercise sessions were recorded at each evaluation.
Treadmill
Exercise Testing
At each evaluation, patients underwent upright exercise testing on a treadmill. Each patient completed resting two-dimensional and color Doppler echocardiographic examination at baseline. Optimal positions for all views, par-
J.Y. Lee et al.
70
titularly the apical window, were marked “X” on the chest to facilitate transducer positioning for rapidly obtaining optimal views immediately after exercise. Patients practiced going from the treadmill to the supine position to minimize the time from immediately postexercise to obtaining recordings. Just prior to upright exercise testing, complete two-dimensional and color Doppler recordings were obtained. Resting control 12-lead ECGs were recorded in the supine and standing positions. Blood pressure and heart rate were measured in the supine and standing positions. Each patient then performed the treadmill exercise according to the Bruce protocol [20]. Leads V2, V5, and AVF were monitored continuously, and a complete 12-lead ECG was recorded automatically at the end of each minute of exercise. Blood pressure and heart rate were measured in the third minute of each exercise stage. Exercise was continued, stage-by-stage, until an indication for termination of exercise occurred. These included subjective maximal exercise as indicated by the patient’s own symptoms of fatigue or breathlessness. Other indications included a drop in systolic blood pressure of > 10 mm Hg, confirmed by a repeat measurement; the occurrence and progression of any symptom to the point of unwillingness of the patient to proceed further; or an electrocardiographic disturbance that indicated that continuation of the test might be detrimental to the patient’s welfare. These ECG abnormalities included evidence of severe ischemia, altered intraventricular conduction, AV block greater than first degree, the development of ventricular arrhythmias more severe than frequent single ventricular premature complexes, or chest discomfort. At the time that exercise was terminated, a t2-lead ECG was recorded, and the patient was transferred immediately to the examining table where the 12lead ECG, blood pressure, and heart rate measurements were repeated. Immediately postexercise (within 30-60 seconds), the primary two-dimensional echocardiographic views and color Doppler recordings were repeated. These post exercise views were completed within 1 to 2 minutes. Two further sets of multiple echocardiographic views were obtained in the postexercise period and completed within the next 4 minutes. In the postexercise period, 12-lead ECGs were recorded every minute, and blood pressure and heart rate were recorded every 2 minutes, until the end of 6 minutes or longer until the patient was stable and asymptomatic. Videotapes of the twodimensional and color echocardiogram during the treadmill exercise test from both clinical centers were sent to the Echocardiographic Center for determination of the LVEF and wall motion scores prior to and immediately following exercise testing.
Anthropometric
Measurements
Height, weight, skinfold thickness, and girths were measured at each evaluation. Skinfold thickness was measured for the following sites: chest, axilla, triceps, subscapula, abdomen, suprailiac, and thigh. All skinfold measurements were made on the right side of the body. Girth measurements were taken of the upper arm, waist, hip and midthigh girths.
The Training Levels Comparison Trial
71
Blood Samples Blood samples were collected at each evaluation. Total cholesterol, HDL cholesterol, LDL cholesterol, and triglyceride levels were determined at each evaluation with a second determination made at the initial evaluation. A central laboratory standardized according to Centers for Disease Control guidelines was used for the lipid levels. Glucose and insulin levels were determined at evaluations 1, 3, and 5 in the fasting state and 1 hour after a 75-g glucose load. Hemoglobin was recorded at the initial evaluation and at evaluation 5.
Quality of Life Measures A battery of quality-of-life measures was chosen to characterize a variety of indexes of psychosocial functioning including state and trait measures of emotional functioning, hostility, and perceptions of health status; self-motivation questionnaire; symptom checklist-90 revised (SCL%R), Profile of Mood States (POMS); Cook-Medley Hostility Scale; and General Health Rating Index. The quality of life measures were collected not only to evaluate and compare the effects of the two training programs with respect to personality traits, but to determine if any of these measures taken at the initial evaluation was predictive for cardiac adaptations and compliance. The self-motivation questionnaire (21) is a 40-item measure of patients’ selfmotivation. It has been demonstrated to have good psychometric properties and has been shown to be associated with exercise adherence in a variety of populations. The SCL-9OR (22) is a self-administered 90-item scale that yields measures on a number of subscales: somatic focus, obsessive compulsiveness, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism. Global indices of positive symptom total, positive symptom distress, and global symptoms are also computed. This scale provides an overall index of emotional disturbance in what may be considered as a trait measure. The Profile of Mood States (23) is a 65-item measure of patients’ mood states and produces scores on six subscales: tension-anxiety, depressiondejection, vigor-activity, fatigue-inertia, anger-hostility, and confusionbewilderment. In contrast to the SCL-90R, the POMS provides more of a measure of mood state. The Cook-Medley Hostility Scale (24) is a 60-item measure of hostility. The measure has been thoroughly investigated psychometrically and been found to have good psychometric properties. The scale was included due to the recent interest in the relationship between hostility and heart disease. The General Health Ratings Index is a 22-item measure of perceptions of health status [25]. The measure provides an overall rating of patients’ perceptions of general health as well as ratings on six subscales: current health, prior health, health outlook, resistance to illness, health worry/concern, and sickness orientation. This measure was included to provide an index of perceived general health.
J.Y. Lee et al.
72 Treatment
Compliance
Questionnaire
Patients were asked to complete a treatment compliance questionnaire at each evaluation. The questionnaire elicited information regarding patients’ perception of the exercise program as beneficial in treating their heart disease and reducing their risk of future heart disease. The questionnaire asks the patient to rate his confidence in his ability to adhere to the exercise protocol and his confidence in recommending his treatment to a friend with heart disease. The treatment compliance questionnaires will be used to identify patients likely to adhere to long-term exercise training and to evaluate whether treatment assignment affected patients’ perceptions of the likelihood of cardiac benefit.
DATA MANAGEMENT A total of 25 data collection forms were developed by the BCC with input from the clinical centers. The forms were tested on a vanguard group of four patients who followed the study protocol. The forms were revised to accommodate problems encountered in the vanguard group. Steering Committee approval was required prior to printing of the forms. All forms were printed with one carbonless copy. Quantities of each form were sent to the clinical centers prior to the start of the study. All data collection forms included identifying information including the name of the study, the name and number of the form and the page number of the form, e.g., page 2 of 8. A small box in the right-hand corner of each page of each form provided a space for the subject’s ID number, clinical center, evaluation number, and date of evaluation. Items requiring completion by TLC certified personnel included space for recording the initials of the staff member who performed the procedure. At the BCC, forms were reviewed for completeness and consistency prior to data entry. The study coordinators from the clinical centers were contacted to provide missing data and to resolve any inconsistencies. Screen displays for data entry were designed to emulate the forms. Numerical range checks were built into the entry process to flag out-of-range or inconsistent values. Forms were entered centrally at the BCC by trained data entry technicians. All forms were keyed in twice by different technicians and discrepancies had to be resolved before the record could be added to the database. The BCC performed edit checks on the database with each database update. Consistency checks across screens included identifying missing or delinquent forms for each evaluation and determining any major deviations from the schedule of evaluations. Queries were directed to the clinical centers and resolved prior to finalizing the database.
TRAINING
AND QUALITY
CONTROL
The approach to quality control between clinical centers was based on standardization of measurements and intervention through certification and recertification of study personnel; development of a manual of operations
The Training Levels Comparison Trial
73
which detailed procedures for recording measurements, conducting exercise sessions, and equipment maintenance; and periodic meetings and progress reports to resolve any problems at the clinical centers. Specific quality control measures for certification procedures, equipment maintenance and monitoring of data collection were instituted at each center. Each clinical center was responsible for the following: certification of personnel responsible for exercise testing, anthropometry and pulmonary function testing; certification maintenance of blood pressure devices, treadmills, scales, and skinfold calipers; inspection and certification of the physical environment of the clinic; validation of data collection and coding procedures; and review of laboratory specimen handling, shipping, and storage. Recruitment
and Randomization
Study patients were recruited through media releases and local area physicians. The initial evaluation included screening phone calls to potential participants to exclude those who were ineligible due to age, medical history, or current level of exercise activity, and a review of their medical records. Those deemed eligible underwent a two-week screening period during which additional clinical information was obtained. During screening, documentation of potential participants’ CHD event was obtained, and they underwent exercise testing to assess their ability to perform at least 3 METS of exercise. Eligible patients were scheduled for an individual counseling and randomization visit within two weeks after their eligibility was established. During the visit, the study plan was reviewed with the candidate. At that point, patients were asked to sign the informed consent form. Patients were classified into one of four strata based on their documented history of myocardial infarction and resting LVEF (G 50%, > 50%) to eliminate two anticipated sources of variation. Within each stratum, patients were assigned in equal numbers to the two intensity levels of exercise intervention. To randomize a patient, the study coordinator telephoned the BCC. After providing the BCC with information on the patient’s documented history of myocardial infarction and resting LVEF, an intensity level was assigned by the BCC and communicated to the study coordinator. To confirm the assigned level, the study coordinator completed a randomization form including the intensity level assignment and submitted it to the BCC. Statistical
Analyses
Statistical analyses of the TLC Trial’s results are in progress. Analysis of variance methods will be used to compare the two exercise training programs with respect to the change in peak LVEF at 1 year, the primary endpoint of the study. To assess the effects of the treatments after adjusting for factors that might influence the peak exercise LVEF including compliance, analysis of covariance methods will be used. Between center variation will be assessed for all outcomes. Repeated measures analyses will be used to evaluate time trends in LVEF. Analyses of variance will be used to evaluate the effects of treatment assignment and timepoint (E2, E3, E4, E5) on the changes in lipid levels, body
J.Y. Lee et al.
74
composition, heart rate and blood pressure measurements. Insulin and glucose levels, and all subscales and global indices of the quality of life measures will be evaluated in a similar manner, but the timepoints will be limited to E3 and E5. In all analyses, a test for interaction between treatment assignment and timepoint will be performed. If a significant interaction is detected, the variation attributed to the differences between the two treatments will be compared to the interaction effects to determine statistical significance. Analyses of covariance will be used to assess the effects of treatment after adjusting for baseline characteristics which may be correlated with these outcome measures. Analyses of covariance will be used to evaluate the effects of treatment and time on compliance. Regression analyses methods will be used to evaluate the effects of time on compliance within each treatment group. One of the secondary objectives of the study was to compare the treatments with respect to the incidence of and time to new clinical manifestation of coronary heart disease as an assessment of safety. The two treatments will be compared with respect to the incidence of new cardiac events using the normal approximation to the Poisson distribution. The product limit method will be used to describe the distribution of times to new cardiac events. For patients who did not experience a new cardiac event, their time will be censored at the date of the last follow up. The log-rank test will be used to compare the two training levels with respect to the time to new cardiac events. If there are a sufficient number of new cardiac events, a proportional hazards model will be used to evaluate the influence of other prognostic factors on the time to a new cardiac event.
CONCLUSIONS This study extends the findings of previous studies of exercise training in coronary heart disease patients by using a longer study participation period and a more vigorous level of exercise in the high intensity group to evaluate the effect of dose of exercise on cardiac adaptations. The study addresses the important clinical question of whether prolonged exercise training at a highintensity level offers advantages over training at a low-intensity level. If highintensity exercise training does not produce superior results as compared to low-intensity exercise training, then exercise programs should be limited to low-intensity levels that are safer and can be used in a larger proportion of cardiac rehabilitation patients.
REFERENCES 1. Oberman A: Rehabilitation of patients with coronary artery disease. In Heart Disease: A Textbook of Cardiovascular Medicine, 2nd Ed, Braunwald E, Ed., Philadelphia, Saunders Publishing Co., 1983, 1384-1398. 2. Fletcher GF, ed: Exercise in the Practice of Medicine. Mount Kisco, NY, Futura Publishing Company, Inc., 1982. 3. Blomquist CC: Role of exercise training in secondary prevention of ischemic heart disease. Prev Med 12~228232, 1983. 4. Haskell WL: Mechanisms by which physical activity may enhance the clinical status
The Training Levels Comparison
75
Trial
of cardiac patients. In Heart Disease and Rehabilitation, Second Edition, Pollock ML and Schmidt DH, Eds., New York, J Wiley, 1986, 303-324. 5. May GS, Eberlein KA, Furberg CD, Passamani ER, DeMets DL: Secondary prevention after myocardial infarction: A review of long-term trials. Frog Cardiovasc Dis XXIV(4):331-352, 1982. 6. Yusuf S, Peto R: Exercise after myocardial infarction reduces mortality: Evidence from randomized controlled trials (RCTs). J Am Co11 Cardiol3:622, 1984 (Abstract). 7. Oberman A: Does cardiac rehabilitation increase long-term cardial infarction? Circulation 80(2):416418, 1989.
survival after myo-
8. Oberman A, Naughton J: The National Exercise and Heart Disease Project. In Heart Disease and Rehabilitation, 2nd Ed, Pollock ML, Schmidt DH, Eds, New York, Wiley, 1986, 369-385. 9. Ehsani AA, Martin WH, Heath GW, Coyle EF: Cardiac effects of prolonged and intense exercise training in patients with coronary artery disease. Am J Cardiol 50:246-253, 1982. 10. Williams RS, McKinnis RA, Cobb FR, Higginbotham MB, Wallace AC, Coleman RE, Califf RM: Effects of physical conditioning on left ventricular ejection fraction in patients with coronary artery disease. Circulation 70(1):69-75, 1984. 11. Paterson DH, Shephard RJ, Cunningham D, Jones NL, Andrew G: Effects of physical training on cardiovascular function following myocardial infarction. J Appl Physiol 47(3):482-489, 1979. 12. Hagberg JM, Ehsani AA, Holloszy JO: Effect of 12 months of intense exercise training on stroke volume in patients with coronary artery disease. Circulation 67(6):1194-1199, 1983. 13. Haskell WL, Montoye HJ, Orenstein D: Physical activity and exercise to achieve health related physical fitness components. Public Health Rep 100:202-212, 1985. 14. Jennings G, Nelson L, Nestel P, Esler M, Korner P, Burton D, Bazelmas J: The effects of changes in physical activity on major cardiovascular risk factors, hemodynamics, sympathetic function, and glucose utilization in man: A controlled study of four levels of activity. Circulation 73(1):30-40, 1986. 15. Oberman A, Fan P-H, Nanda NC, Lee JY, Huster WJ, Sulentic JA, Storey OF: Reproducibility of two-dimensional exercise echocardiography. J Am Co11 Cardiol 14:923-S, 1989. 16. Borg GA: Psychophysical 381, 1982.
bases of perceived exertion. Med Sci Sports Exert 14:377-
17. Sulentic J, Dunnam L, Thiel J, Fletcher B, Oberman A, Fletcher G, Sheffield T, Lee J: Training levels comparison study: factors influencing exercise compliance. Presented at the meeting of the American College of Cardiology, Anaheim, California, March 1989. 18. Shocken DD, Blumenthal JA, Port S, et al: Physical conditioning and left ventricular performance in the elderly. Assessment by radionuclide angiography. Am J Cardiol 41:155-660, 1978. 19. Principal investigators of CASS and their associates: National Heart, Lung, and Blood Institute Coronary Artery Surgery Study (CASS). Circulation 63(6):1-80 (monograph 79), 1981. 20. American College of Sports Medicine. Guidelines for Exercise Testing and Prescription, 4th ed. Philadelphia, Lea & Febiger, 1991. 21. Dishman RK, Ickes W: Self-motivation Behav Med 4:421-438, 1981.
and adherence
to therepeutic
exercise.
J
22. Derogatis LR: SCL-90 Revised Version Manual-l. Clinical Psychometrics Research Unit, Johns Hopkins University School of Medicine, Baltimore, MD, 1983. 23. McNair JR, Lorr M, Droppleman LF: ETlS Manual for the Profile of Mood States. San Diego, CA, Educational Testing Service, 1971.
J.Y. Lee et al. 24. Cook W, Medley D: Proposed hostility and pharisaic-virtue J Appl Psycho1 238:414-418, 1954.
scales for the MMPI.
25. Davies AR, Sherbourne CD, Peterson JR, Ware JE: Scoring Manual: Adult Health Status and Patient Satisfaction Measures Used in RAND’s insurance Experiment. Santa Monica, CA, the RAND Corporation, 1988.