Comparing the Efficacy of Cardiac Rehabilitation for Patients With Peripheral Artery Disease to Patients With Coronary Artery Disease
Phase: NA
Conditions: Peripheral Arterial Disease, Coronary Artery Disease, Vascular Diseases
Sponsor: University Health Network, Toronto

Comparing the efficacy of cardiac rehabilitation for patients with peripheral artery 
disease to patients with coronary artery disease/Protocol #03 
Version Date: 14 December 2017  
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CLINICAL TRIAL PROTOCOL 
 
 
COMPARING THE EFFICACY OF CARDIAC 
REHABILITATION FOR PATIENTS WITH 
PERIPHERAL ARTERY DISEASE TO PATIENTS 
WITH CORONARY ARTERY DISEASE 
 
 
Dr. Paul Oh 
 
 
Toronto Rehabilitation Institute – Rumsey Centre 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Version # 03  
Date (14/December/2017): 

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Table of Contents  
 
Section 1.0 General Information 
 
 
 
 
 
 
pg. 4  
1.1 Protocol title and date 
 
 
 
 
 
 
pg. 4 
1.2 Name and title of the investigators responsible for conducting the trial pg. 5 
Section 2.0 Background Information 
 
 
 
 
 
pg. 5 
2.1 A summary of previous literature  
 
 
 
 
pg. 5 
2.2. Rationale for the study   
 
 
 
 
 
pg. 8  
2.3 Potential Benefits  
 
 
 
 
 
 
pg. 8  
2.4 Description of the population to be studied. 
 
 
 
pg. 8  
Section 3.0 Study Objectives and Hypothesis 
 
 
 
 
pg. 9 
3.1 A description of the objectives and the purpose of the study. 
 
pg. 9 
3.1.1 Primary objective  
 
 
 
 
 
pg. 9 
3.1.2 Secondary objectives   
 
 
 
 
pg. 9 
3.1.3 Exploratory objectives   
 
 
 
 
pg. 9 
3.2 Study hypothesis  
 
 
 
 
 
 
pg. 9 
Section 4.0 Study Design 
 
 
 
 
 
 
 
pg. 10 
4.1 Primary and secondary endpoints  
 
 
 
 
pg. 10 
4.2 Study Design 
 
 
 
 
 
 
 
pg. 11 
4.3 A description of the measures taken to minimize/avoid bias 
 
pg. 11 
4.4 A description of the trial treatment(s)/ intervention 
 
 
pg. 11 
4.5 The expected duration of subject participation 
 
 
 
pg. 11 
4.6 The expected frequency and duration of study visits (anticipated time   
commitment) for study participants  
 
 
 
 
pg. 12 
4.7 A description of the "stopping rules" or "discontinuation criteria"  
pg. 13 
4.8 The identification of any data to be recorded directly on the CRFs  
pg. 13 
Section 5.0 Selection of Subjects 
 
 
 
 
 
 
pg. 13 
5.1 Subject inclusion criteria.  
 
 
 
 
 
pg. 13 
5.2 Subject exclusion criteria. 
 
 
 
 
 
pg. 13 
5.3 Withdrawal of subjects 
 
 
 
 
 
 
pg. 14 
Section 6.0 Study Intervention 
 
 
 
 
 
 
pg. 14 
Section 7.0 Assessment of Efficacy  
 
 
 
 
 
pg. 14 
Section 8.0 Statistics  
 
 
 
 
 
 
 
pg. 15 
8.1 A description of the statistical methods to be employed  
 
pg. 15 
8.2 The number of subjects planned to be enrolled  
 
 
pg. 16 
8.3 Procedure for accounting for missing, unused, and spurious data 
pg. 16 
Section 9.0 Direct Access to Source Data Documents 
 
 
 
pg. 16 
Section 10.0 Quality Control and Quality Assurance Procedures 
 
pg. 16 
Section 11.0 Ethics  
 
 
 
 
 
 
 
pg. 16 
11.1 Consent process   
 
 
 
 
 
 
pg. 16 
11.1.1 A description of the identification process 
 
 
pg. 17 
11.1.2 A description of who will make initial contact  
 
pg. 17 
11.1.3 A description of who will obtain informed consent   
pg. 17 
11.2 A statement of review and approval of the study by the Research Ethics 
 
Board before any study related procedures commenced. 
 
 
pg. 17 

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11.3. A statement of review and approval of any amendment to the study by the 
 
Research Ethics Board before any changes implemented beside these to eliminate 
 
immediate hazard to the study participants.  
 
 
 
pg. 18 
Section 12.0 Data Handling and Record Keeping  
 
 
 
pg. 18 
12.1.A description of the process for data recording to ensure accuracy,  
 
completeness, legibility, and timeliness of the data.   
 
 
pg. 18 
12.2 A description of where the data will be recorded 
 
 
pg. 18 
Section 13.0 References  
 
 
 
 
 
 
 
pg. 18 
 
List of Abbreviations/ Terminology (in alphabetical order) 
 
6MWT  
6 Minute Walk Test 
CAD   
Coronary Artery Disease 
CLI  
 
Critical Limb Ischemia 
CI  
 
Confidence Interval 
ES  
 
Effect Size 
IC  
 
Intermittent Claudication 
ICC  
 
Intraclass Correlation Coefficient 
PAD   
Peripheral Artery Disease 
SF-36   
Short Form-36 Health Survey 
QOL   
Quality of Life 
TRI  
 
Toronto Rehabilitation Institute 
 
VO2peak  
Peak Oxygen Consumption 
WIQ   
Walking Impairment Questionnaire 
 
Protocol Summary 
 
COMPARING THE EFFICACY OF CARDIAC REHABILITATION FOR 
PATIENTS WITH PERIPHERAL ARTERY DISEASE TO PATIENTS WITH 
CORONRARY ARTERY DISEASE 
 
Short Title: Exercise for PAD 
 
Clinical Phase / Type of Study: Phase IV 
 
Sample Size  
N= 28 x 2 groups (coronary artery disease (CAD) and peripheral artery disease (PAD)) 
 
Study Population  
Patients diagnosed with PAD, CAD or concomitant PAD and CAD. Patients with 
vascular aneurysms, chronic heart failure, cancer, stroke, respiratory disease, chronic 
kidney disease, foot ulcers/skin breakdowns which may impede ability to exercise and 
patients who cannot follow instructions in English will be excluded 
  
Accrual Period 
January 2018 – June 2018 

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Study Design 
This study is a prospective two-arm cohort study with both groups (CAD and PAD) 
undergoing the same intervention (standard 6 month out-patient cardiac rehabilitation 
program offered at the Toronto Rehabilitation Institute Rumsey Centre).  
 
Study Duration 
January 2018- December 2018  
 
Study Agent/ Intervention/ Procedure  
The standard out-patient cardiac rehabilitation program involves weekly 1.5 hour visits at 
the Toronto Rehabilitation Institute Rumsey Centre for 6 months. Each visit will consist 
of an exercise component as well as a risk factor education lecture. Prior to the start of 
the program, participants will attend two assessment sessions with cardiac rehabilitation 
staff members to review medical history as well as complete a cardiopulmonary exercise 
test. During the cardiac rehabilitation program, participants will walk at 60-80% of their 
VO2peak heart rate based on the results of their exercise test, as per standard care 
procedures. Adjustments will be made to the patient’s exercise prescription as their 
fitness improves under the discretion of the cardiac rehabilitation supervisor, as per 
standard care procedures. Patients will also be asked to exercise an additional four times 
during the week on their own time for a total of five times per week, as per standard care 
procedures.  
 
Primary Objective  
The primary objective of this proposed study is to compare the magnitude of the 
responses to a 6-month cardiac rehabilitation program for patients with PAD in contrast 
to patients with CAD. The primary variable of interest will be peak oxygen consumption 
(VO2peak) with a secondary variable of interest being functional capacity, as measured 
by the 6-minute walk test. Tertiary variables of interest will include walking impairment, 
as measured by the Walking Impairment Questionnaire, and quality of life, as measured 
by the Short Form-36 health survey (SF-36). 
 
Secondary Objective The second objective of this proposed study is to determine if the 
magnitude of responses to cardiac rehabilitation for patients with PAD are dependent on 
biological sex or type of PAD (asymptomatic, post-surgical intervention, or intermittent 
claudication). 
 
Exploratory Objectives Exploratory objectives include comparing acute exercise 
responses (prescribed exercise training load, actual training load, exercising heart rate 
and rating of perceived exertion) between PAD and CAD patients. 
 
Endpoints of the study This study will allow for the comparison of the efficacy of 
cardiac rehabilitation for CAD and PAD patients to provide further support of the 
application of exercise rehabilitation for PAD patients. In addition, this study will inform 
future studies investigating optimal exercise prescriptions for PAD patients.  
 

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1.0 General Information 
1.1 Protocol title and date.  
Comparing The Efficacy Of Cardiac Rehabilitation For Patients With Peripheral Artery 
Disease To Patients With Coronary Artery Disease -November 30, 2017 
 
1.2 Name and title of the investigators responsible for conducting the trial 
 
Dr. Paul Oh, Principal Investigator, Medical Director of the Cardiovascular Prevention 
and Rehabilitation Program and a Scientist at the Toronto Rehabilitation Institute (TRI) 
Cindy Nguyen, Co-investigator, M.Sc student at the University of Toronto  
Dr. Scott Thomas, Co-investigator, Professor at the University of Toronto 
 
Study site: 347 Rumsey Road, Toronto, ON, M4G 2V6, 416-597-3422 ext 5200 
 
2.0 Background Information  
2.1 A summary of previous literature 
 
Patients and clinicians have expressed an interest in the use of nonpharmacological 
interventions for health management (Crowe et al., 2015). Exercise is commonly 
recommended as a treatment for patients who present with any type of peripheral artery 
disease (PAD) (Hernando & Conejero, 2007; Ouriel 2001). In fact, participation in 
exercise programs for treatment of intermittent claudication (IC), which is a hallmark 
symptom of PAD consisting of pain with walking, is considered a gold standard 
(Thukkani & Kinlay, 2015). There is strong evidence to support the efficacy of exercise 
training in improving functional capacity and symptoms for patients with asymptomatic 
and symptomatic PAD (Class of recommendation I, level of evidence A) (Gerhard-
Herman et al., 2017).  
 
The AHA/American College of Cardiology recommend supervised exercise at least three 
times a week, 30-45 minutes per session for at least 12 weeks for patients with PAD 
(Gerhard-Herman et al., 2017). All sessions should begin and end with a warm-up and 
cool-down period, respectively. In contrast, the Canadian Guidelines for Cardiac 
Rehabilitation and Cardiovascular Disease Prevention recommend PAD patients with IC 
to exercise for 2 to 5 minutes close to their claudication pain threshold with intermittent 
breaks of 1 to 2 minutes of passive recovery (Canadian Association of Cardiac 
Rehabilitation, 2009). Patients should be encouraged to exercise at least three times a 
week with a goal of gradually decreasing resting time while increasing exercise time 
(Canadian Association of Cardiac Rehabilitation, 2009). Recommendations specifically 
for asymptomatic PAD patients are currently unclear.  
 
Supervised programs, similar to cardiac rehabilitation, have been recommended for 
patients with PAD as first-line therapy prior to consideration for surgical interventions 
(Milani & Lavie, 2007). Previous research has suggested that exercise programs which 
utilize a mix of aerobic and resistance exercise tend to result in greater improvements in 
walking capacity for patients with PAD (Parmenter et al., 2015). In addition, vigorous 
intensity exercise training leads to greater improvements in VO2peak (mean difference 

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1.42 ml/kg/min, 95% CI: 1.04 to 1.80, p<0.00001) compared to moderate intensity 
exercise (mean difference = 0.43/ml/kg/min, 95% CI 0.01 to 0.85, p =0.05) (Parmenter et 
al., 2015). Although optimal exercise prescriptions for patients with PAD remain unclear 
(Parmenter et al., 2015), cardiac rehabilitation programs consisting of progressive 
intensity aerobic and resistance exercises appear to be a good starting point. Patients with 
IC may participate in an interval-style walking program where walking duration and rest 
periods are defined by pain tolerance and the time it takes for the pain to subside 
(Hamburg & Balady, 2011). Conversely, patients without IC are recommended to 
exercise continuously for 30 to 60 minutes per session at a moderate intensity (Hamburg 
& Balady, 2011).  
 
Exercise appears to be an excellent addition to medical therapy and revascularization 
procedures. In a randomized trial of patients with aortoiliac PAD, peak walking time 
improved the greatest among patients who underwent supervised exercise and optimal 
medical therapy for 6 months compared to patients who underwent stent 
revascularization with optimal medical therapy and patients who underwent medical 
therapy alone (Δ5.8±4.6, Δ3.7±4.9, and Δ1.2±2.6 minutes, respectively, P<0.05) 
(Murphy et al., 2012). This suggests that exercise can lead to greater functional 
improvements than endovascular procedures when combined with optimal 
pharmacological interventions. In a trial with femoropopliteal PAD patients randomized 
to angioplasty, supervised exercise or angioplasty and supervised exercise, all 
participants had an improvement in IC distance when assessed at the three month follow-
up (Mazari et al., 2010). Nevertheless, patients randomized to supervised exercise and 
angioplasty had the greatest improvement compared to patients randomized to exercise 
alone and angioplasty alone (Δ108, Δ61.2, Δ59 meters, respectively, P<0.05). A 
clinically relevant improvement in walking distance for patients with PAD is considered 
greater than 100m (Hamburg & Balady, 2011). Exercise and endovascular intervention 
have statistically and clinically significant increases in walking distance. Improvements 
in QOL were also observed in all groups (effect size >0.5) (Mazari et al., 2010). 
Considering the strong evidence, exercise should be automatically recommended in 
combination with endovascular interventions and/or pharmacological therapy.  
 
Exercise rehabilitation has been shown to improve walking ability among PAD patients 
(Haas, Lloyd, Yang & Terjung, 2012; Januszek et al., 2014; McDermott et al., 2013). 
Exercise training can result in two-fold increases in walking time (Bonaca & Creager, 
2015). Clinically significant improvements in walking time have been defined as an 
increase of 5 minutes for patients with PAD (Hamburg & Balady, 2011). Januszek et al. 
(2014) observed a significant change in walking time from 470.8±187.1 seconds at 
baseline to 898.0 ± 358.7 (P<0.001) 12-week treadmill training program 3 times a week 
for patients with IC. Remarkably, improvements in maximal walking time were sustained 
at follow-up (mean 37 weeks) compared to baseline with clinical and statistical 
significance (470.8±187.1 seconds vs. 775.4± 345.4 seconds, P<0.001).  Small but 
statistically significant improvements in relative VO2peak for PAD patients in exercise 
rehabilitation have also been observed compared to control patients who did not 
participate in exercise rehabilitation (Δ=0.62 ml/kg/min (95%CI 0.47 to 0.77, P<0.00001) 
(Parmenter et al., 2015). The training responses across different clinical presentations of 

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PAD (asymptomatic, intermittent claudication (IC), critical ischemia (CLI)) are difficult 
to compare due to various training protocols and limited exercise training data with 
asymptomatic and CLI patients . 
 
Patients with coronary artery disease (CAD) undergoing exercise rehabilitation also have 
significant benefits including a lower risk for cardiovascular mortality (RR=0.74, 95%CI 
0.63 to 0.87), fewer hospitalizations (RR=0.69, 95%CI 0.51 to 0.93) and improvements 
in functional capacity as measured by the  6 minute walk test (6MWT) (Δ=60.43m, 
95%CI 54.57 to 66.30m) (Bellet et al., 2012; Heran et al., 2011). In a prospective cohort 
study with 29 CAD patients undergoing cardiac rehabilitation, there was a significant 
improvement in VO2peak (Δ=2.45 ± 0.5 mL/kg/min, P<0.001) (Lucini et al., 2002). 
Greater improvements in VO2peak were observed in a meta-analysis of CAD patients in 
cardiac rehabilitation compared to CAD patients who did not participate in cardiac 
rehabilitation (mean difference = 3.22ml/kg/min, 95%CI 2.42 to 4.03, P<0.01) (Tang, Fu, 
Zhang, & Zhang, 2014). In spite of the results suggesting that CAD patients have greater 
improvements in VO2peak following cardiac rehabilitation compared to PAD patients, 
there is large variability in exercise prescriptions applied limiting the strength of that 
conclusion.  
 
Although a great deal of research has supported the efficacy of exercise rehabilitation for 
PAD, it is infrequently implemented into clinical practices (Milani & Lavie, 2007). In an 
analysis of the medical treatments accessed by PAD patients, exercise or diet counselling 
were only used in 22% of visits (Berger & Ladapo, 2017). Implementing risk factor 
education and exercise rehabilitation programs for patients with PAD would be consistent 
with the Chronic Care Model to help manage chronic diseases (Lovell, Meyers, Forbes, 
Dresser, & Weiss, 2011). The integration of the Vascular Clinic at the Toronto 
Rehabilitation Institute (TRI) will help to provide opportunities of exercise rehabilitation 
for patients with PAD. 
 
To date, no comparison of cardiac rehabilitation efficacy and acute exercise responses 
has been made between patients with PAD and patients with CAD. Considering some of 
the parallels between the two conditions, as they are both atherosclerotic conditions, and 
the strong recommendations for exercise in both populations, it is worthwhile to compare 
the efficacy of cardiac rehabilitation responses. It is also unclear if the magnitude of 
response for PAD patients is dependent on biological sex and clinical presentation as this 
may influence the development of exercise prescriptions. This proposed study, which is 
in the process of being registered with clinicaltrials.gov, hopes to address these gaps in 
the literature. 
 
 
 
2.2. Rationale for the study  
It is unclear if cardiac rehabilitation will be as effective for patients with PAD as it is for 
improving the function and health outcomes of patients with CAD.  While there are 
common pathological traits of CAD and PAD, there are some distinct features that are 
evident in pathology. Acute responses to exercise have yet to be compared between 

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patient populations.  As well, differences in responses to cardiac rehabilitation based on 
biological sex and clinical presentation of PAD are not well established. With the newly 
implemented cardiac rehabilitation program specifically for patients with PAD at TRI, 
this proposed study is aligned well to address these gaps in the literature. This trial will 
be conducted in compliance with the protocol described below as well as ICH and GCP 
standards.  
 
This research is important as the findings from this study may provide further support for 
the implementation of PAD-specific exercise rehabilitation programs. Determining the 
efficacy of cardiac rehabilitation for patients with PAD can also help contribute to the 
understanding of PAD in relation to exercise. Lastly, determining if the magnitude of 
response is dependent on biological sex and presentation of PAD can help guide future 
research in determining optimal exercise prescriptions 
 
2.3 Potential Benefits 
Patients, the community, and the institution will not benefit directly from this research 
study as the research intervention is standard care procedures which has been provided to 
all patients of the Cardiovascular Prevention and Rehabilitation Program at TRI for 
decades.  
 
The research community will likely benefit from the knowledge gained in this research to 
help better understand exercise for individuals living with PAD. In addition, this research 
may inform future research regarding exercise prescriptions for individuals living with 
PAD. 
 
2.4 Description of the population to be studied. 
Inclusion criteria will include patients over the age of 18 that have been diagnosed with 
lower extremity PAD or CAD. Patients with concomitant CAD and PAD will also be 
included in the study. Group allocation will be based on referring diagnosis. In addition, 
patients must be able to access and participate in the cardiac rehabilitation program at the 
TRI.  
 
Patients diagnosed with PAD from the University Health Network and Sunnybrook 
Hospital will be referred by vascular surgeons to the TRI Rumsey Centre for cardiac 
rehabilitation. Patients with CAD referred to cardiac rehabilitation will be identified 
through consented chart review and invited to participate in the study. 
 
Patients with vascular aneurysms, chronic heart failure, cancer, stroke, respiratory 
disease, or chronic kidney disease will be excluded. Patients with foot ulcers or skin 
breakdowns which may impede ability to exercise will also be excluded. Patients who 
cannot follow instructions in English will be excluded. Patients who attend less than 70% 
of sessions of the weekly sessions at TRI (<10 sessions in total) will be excluded from 
the main analysis and included in an intention-to-treat analysis.  
 
All patients will provide written informed consent prior to study participation.  Patients 
identified with PAD will be referred by their vascular surgeons from Toronto General 

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Hospital to the TRI cardiac rehabilitation program. Upon the initial assessment at TRI, 
PAD patients will be informed about participating in the proposed study by the principal 
investigator. CAD patients who have attended an initial assessment and have consented 
to chart review will have their patient file reviewed to determine if the patient is an 
appropriate match to a PAD patient based on sex, age, presence of diabetes, and assigned 
cardiac rehabilitation supervisor. One of the study investigators will then inform the 
patient during their second assessment at TRI about the study and invite the patient to 
participate in the study. 
 
3.0 Study Objectives and Hypothesis  
3.1 A description of the objectives and the purpose of the study. 
 
The purpose of this study is to compare the efficacy of a 6-month out-patient cardiac 
rehabilitation program for patients with CAD to patients with PAD. 
 
3.1.1 Primary objective  
The primary objective of this proposed study is to compare the magnitude of the 
responses to a 6-month cardiac rehabilitation program for patients with PAD in contrast 
to patients with CAD. The primary variable of interest will be peak oxygen consumption 
(VO2peak) with a secondary variable of interest being functional capacity, as measured 
by the 6-minute walk test. Tertiary variables of interest will include walking impairment, 
as measured by the Walking Impairment Questionnaire, and quality of life, as measured 
by the Short Form-36 health survey (SF-36).  
 
3.1.2 Secondary objectives  
The second objective of this proposed study is to determine if the magnitude of responses 
to cardiac rehabilitation for patients with PAD are dependent on biological sex or type of 
PAD (asymptomatic, post-surgical intervention, or intermittent claudication). 
 
3.1.3 Exploratory objectives  
The exploratory objective is to compare acute exercise responses (prescribed exercise 
training load, actual training load, exercising heart rate and rating of perceived exertion) 
between PAD and CAD patients. 
 
3.2 Study hypothesis 
The primary hypothesis is that patients with CAD will have greater improvements in 
VO2peak and 6-minute walk test compared to patients with PAD (Lucini et al., 2002; 
Parmenter, et al., 2015). However, considering the walking limitations patients with PAD 
often have and the improvements observed with exercise training (Milani & Lavie, 2007; 
Novakovic et al., 2016), it is hypothesized that patients with PAD will have greater 
improvements in the WIQ and QOL compared with patients with CAD. Furthermore, a 
secondary hypothesis that the magnitude of response for patients with PAD will be 
dependent on biological sex and type of PAD. Lastly, it is hypothesized that patients with 
PAD on average will have a greater exercising heart rate, rating of perceived exertion and 
rating of pain severity compare to patients with CAD. 
 

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4.0 Study Design 
 
4.1 Primary and secondary endpoints  
Patients will undergo a baseline assessment with a laboratory technician involving a 
standard battery of measurements and questionnaires for characteristic purposes 
including anthropometrics, resting blood pressure, resting heart rate, smoking status, 
diabetes status, current exercise regimen, and current medications. During this 
assessment, clinicians will review previous and ongoing medical treatment (i.e. surgical 
procedures, next physician visit, ankle-brachial index measurement), presence of angina, 
and conduct resting 12-lead electrocardiograms. This will be followed by a medical 
assessment by a physician to further review medical history and safety precautions for 
exercise. Patients will be sent home with a walking impairment questionnaire (WIQ) 
(McDermott et al., 1998) and a quality of life (QOL) questionnaire (SF-36) (Brazier et 
al., 1992) to be submitted at their next visit. A requisition for blood work will also be 
given to patients to be completed prior to their second visit to determine HbA1c and total 
cholesterol levels.  
 
During the second visit patients will undergo a maximal cardiopulmonary exercise test to 
determine cardiorespiratory fitness as measured by VO2peak and will also have an 
exercising 12-lead electrocardiogram. The cardiopulmonary exercise test will consist of a 
Bruce or modified Bruce treadmill protocol (Noonan and Dean, 2000).  
 
After determining baseline VO2peak, an individualized walking exercise prescription will 
be developed by a cardiac rehabilitation supervisor which corresponds to approximately 
60 to 80% of VO2peak. Patients will be invited to attend weekly 90-minute supervised 
exercise and education sessions at the same time every week for six months, as per 
standard care procedures. Patients will be encouraged to gradually increase their exercise 
time per session as well as frequency of sessions per week.  
 
Clinicians at TRI will record distance walked, rest periods, exercising heart rate (as 
palpated by the radial pulse), ratings of perceived exertion and ratings of pain severity on 
a scale of 0 (no pain) to 10 (worst imaginable pain) (Hawker, Mian, Kendzerska, & 
French, 2011) for each exercise session at TRI. Patients will self-record their other 
exercise sessions on a weekly basis using standard exercise diaries. Frequency, time, 
type, exercising heart rate and rating of perceived exertion will be recorded for each 
exercise session outside of TRI. Patients will wear a non-invasive heart rate monitor 
(Polar) while walking at the 2nd week, 3rd month and 6th month mark of the program to 
help determine acute responses to aerobic exercise. Average exercising heart rate will be 
measured and recorded. VO2peak, 6MWT, QOL (SF-36), and walking impairment (WIQ) 
will be re-assessed at the 3 month and 6 month mark of the program. 
 
Training volume will be quantified for each group for the prescribed and actual exercise 
load. For aerobic exercise, training will be calculated as the product of intensity in heart 
rate reserve, duration, and frequency for both the prescribed and actual exercise. For 
resistance exercise, training will be calculated as the product of weight, numbers of sets, 
and number of repetitions for each exercise for both prescribed and actual exercise. 

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The primary endpoints of interest include change in VO2peak from month 6 to baseline, 
change in 6 minute walk test distance from month 6 to baseline, as well as change in 
walking impairment and quality of life as assessed through questionnaires from month 6 
to baseline.  
 
4.2 Study Design  
This study will be an interventional two-arm prospective cohort study. Both arms (PAD 
and CAD participants) will undergo the same standard 6 month out-patient cardiac 
rehabilitation program. 
 
4.3 A description of the measures taken to minimize/avoid bias 
The University of Health Network policy requires that all patients be aware of any 
medical treatment they are receiving and provide informed consent. As a result, it is not 
possible for patients to be blinded to which treatment they are receiving.  
 
To avoid bias for the ankle brachial index measurement, the order in which blood 
pressure is measured on each limb will be randomized. 
 
4.4 A description of the trial treatment(s)/ intervention  
The standard 6-month out-patient cardiac rehabilitation program consists of weekly 1.5 
hour visits to the TRI Rumsey Centre. After determining baseline VO2peak from the 
exercise stress test, an individualized walking exercise prescription will be developed by 
a cardiac rehabilitation supervisor which corresponds to approximately 60 to 80% of the 
participant’s VO2peak. Participants will be invited to to walk around the track and attend 
education sessions at the same time every week for six months. Patients will be 
encouraged to gradually increase their exercise time walking speed. Patients will be 
encouraged to exercise five times a week with four sessions occurring outside of the 
cardiac rehabilitation program. 
 
4.5 The expected duration of subject participation 
Participants will be part of the program for 6 months, as per standard care procedures.  
 
 
 
 
4.6 The expected frequency and duration of study visits (anticipated time commitment) 
for study participants  
There will be six study visits in total which coincide with standard care visits as well as 
the weekly visits to the cardiac rehabilitation program. Participants will not be required to 
make any additional visits outside of the standard cardiac rehabilitation program. 
 

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The first visit will take approximately 60 minutes and is consistent with standard care at 
the TRI Rumsey Centre cardiac rehabilitation program. A cardiac rehabilitation staff 
member will measure anthropometrics, blood pressure and will review medical history 
(e.g. smoking status, diabetes status, medications, current exercise regimen). The patient 
will also meet with a physician to review any concerns with starting the cardiac 
rehabilitation program. The patient will also be introduced to the study investigator if the 
patient expresses an interest in participating in the research study. All patients are given a 
blood work requisition to be completed at their local medical laboratory and if patients 
choose to consent to participating in the study, they will be given two questionnaires 
(WIQ and SF-36) to be completed for their next visit (approximately 15 minutes to 
complete both questionnaires).  
 
The second visit is also consistent with standard care procedures and involves an exercise 
stress test with cardiac rehabilitation staff members. The exercise test will take 
approximately 60 minutes including preparation time, exercise time and time for 
questions. For the exercise stress test, patients will walk on a treadmill or pedal on a 
bicycle while having their breathing and blood pressure analyzed to measure VO2peak. 
Patients will also be attached to a 12-lead electrocardiogram to non-invasively measure 
activity of the heart. 
 
The third visit will take approximately 30 minutes and will occur before the first cardiac 
rehabilitation class. While lying down in a private examination room, participants will 
have their blood pressure measured with an automated machine twice on the right arm, 
left arm, right ankle and left ankle in a random order. This will allow for calculation of 
the ankle brachial index for characteristic purposes. 
 
The fourth visit will take approximately 60 minutes with 15 minutes occurring before 
class and 45 minutes during the exercise portion of the cardiac rehabilitation class. Prior 
to class, participants will participate in a 6-minute walk test to measure functional 
capacity. This will consist of partiicpants walking as far as they can in 6 minutes at their 
own pace. During the 45 minute exercise component of the cardiac rehabilitation class, 
participants will have a chest strap placed underneath their clothing at the xiphoid-level 
to measure exercising heart rate.  
 
The fifth visit will take approximately 60 minutes and will be structured exactly like the 
fourth study visit. Participants will be asked to participate in a 6-minute walk test 15 
minutes prior to class and will have a heart rate monitor chest strap attached underneath 
their clothing while participating in the exercise portion of the cardiac rehabilitation 
class. Participants will also be given two questionnaires (WIQ and SF-36) to complete for 
their next visit (approximately 15 minutes).  
 
The sixth and final visit at the 6 month mark of the program will take approximately 30 
minutes. Participants will participate in the 6 minute walk test and will be given two 
questionnaires (WIQ and SF-36) to complete. During class, participants will have a heart 
rate monitor chest strap attached underneath their clothing. 
 

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4.7 A description of the "stopping rules" or "discontinuation criteria"  
Participants can choose to withdraw from the study at any time. If the participant 
experiences a musculoskeletal injury during the 6-month cardiac rehabilitation program, 
either alternative exercises will be offered by the cardiac rehabilitation supervisor or they 
will be asked to discontinue the cardiac rehabilitation program until their injury heals. 
 
4.8 The identification of any data to be recorded directly on the CRFs  
All patients are asked during their initial visit to TRI of whether they consent to a chart 
review by research personnel. All participants of the study will have provided consent to 
a chart review and will have study data recorded on a data collection sheet with a unique 
research identification number.  
 
Data to be collected includes age, biological sex, type of PAD or CAD, diabetes status, 
smoking status, risk factors, current exercise regimen, medications, VO2peak, HbA1c 
levels, total cholesterol, blood pressure, and exercise prescription.  
 
5.0 Selection of Subjects 
5.1 Subject inclusion criteria. 
Inclusion criteria will include patients over the age of 18 that have been diagnosed with 
lower extremity PAD or CAD. Patients with concomitant CAD and PAD will also be 
included in the study. Group allocation will be based on referring diagnosis. In addition, 
patients must be able to access and participate in the cardiac rehabilitation program at the 
TRI.  
 
In order to compare patients with PAD to patients with CAD and to control for 
confounding variables, matching will be based on biological sex, age (±5 years), presence 
of diabetes (yes or no), smoking status (current, previous, never), and cardiac 
rehabilitation supervisor. 
 
Patients diagnosed with PAD from the University Health Network and Sunnybrook 
Hospital will be referred by vascular surgeons to the TRI Rumsey Centre for cardiac 
rehabilitation. Patients with CAD referred to cardiac rehabilitation will be identified 
through consented chart review and invited to participate in the study. 
 
5.2 Subject exclusion criteria. 
Patients with vascular aneurysms, chronic heart failure, cancer, stroke, respiratory 
disease, or chronic kidney disease will be excluded. Patients with foot ulcers or skin 
breakdowns which may impede ability to exercise will also be excluded. Patients who 
cannot follow instructions in English will be excluded. Patients who attend less than 70% 
of sessions of the weekly sessions at TRI (<10 sessions in total) will be excluded from 
the main analysis and included in an intention-to-treat analysis.  
 
5.3 Withdrawal of Subjects 
Participants may choose to withdraw from the study at any time. Any data collected will 
be discarded immediately. 
 

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6.0 Study Intervention  
 
The study intervention is consistent with the standard 6-month out-patient cardiac 
rehabilitation program consists of weekly 1.5 hour visits to the TRI Rumsey Centre. After 
determining baseline VO2peak from the exercise stress test, an individualized walking 
exercise prescription will be developed by a cardiac rehabilitation supervisor which 
corresponds to approximately 60 to 80% of the participant’s VO2peak. Participants will 
be invited to walk around the track and attend education sessions at the same time every 
week for 6 months. Patients will be encouraged to gradually increase their exercise time 
walking speed. Patients will be encouraged to exercise five times a week with four 
sessions occurring outside of the cardiac rehabilitation program.  
 
Clinicians at TRI will record distance walked, rest periods, exercising heart rate (as 
palpated by the radial pulse), ratings of perceived exertion (Borg scale) and rating of pain 
severity on the Numeric Rating Scale for Pain (numeric scale from 0 to 10, 0 being no 
pain and 10 being worst pain imaginable) (Hawker, Mian, Kendzerska, & French, 2011) 
for each exercise session at TRI. Patients will self-record their other exercise sessions on 
a weekly basis using exercise diaries. Frequency, time, type, exercising heart rate and 
rating of perceived exertion will be recorded for each exercise session outside of TRI. 
 
7.0 Assessment of Efficacy 
 
Peak oxygen consumption (VO2peak) measured through a treadmill test is a standard 
measure of cardiorespiratory fitness. A meta-regression analysis of various treadmill 
protocols for patients with PAD found that continuous protocols had an intraclass 
correlation coefficient (ICC) of 0.85 (95% CI 0.82 to 0.88) and graded protocols had an 
ICC of 0.83 (95% CI 0.80 to 0.85). Graded protocols were more reliable than continuous 
protocols for absolute claudication distance (ICC=0.95, 95% CI 0.94 to 0.96). 
Continuous protocols had the greatest reliability at a grade of 12 % (ICC=0.91, 95% CI 
0.88 to 0.92) (Nicolai et al., 2009). In addition to being used for characteristic purposes, 
VO2peak can also be an outcome measure to determine the effectiveness of interventions. 
In a systematic review and meta-analysis, the mean difference in relative VO2peak for 
PAD patients who underwent exercise training compared to control patients was 0.62 
ml/kg/min (95%CI 0.47 to 0.77, P<0.00001) (Parmenter et al., 2015). This suggests that 
VO2peak is responsive to changes following exercise interventions. It should be noted 
that although VO2peak is one parameter used to define intensity in exercise prescriptions, 
PAD patients with IC often exercise according to pain tolerance (Hamburg & Balady, 
2011). 
 
The walking impairment questionnaire (WIQ) is a validated method of quickly measuring 
walking ability in men and women with PAD (McDermott et al., 1998). The WIQ 
consists of 14 items related to walking distance, walking speed and stair climbing ability 
using a scale from 0 to 4 to rank degree of difficulty. An overall score below 42.5 
suggests a patient with low walking ability (sensitivity 0.90, specificity of 0.73) whereas 
a score above 75.5 suggests a patient with a high walking ability (sensitivity 0.41, 
specificity 0.90) (Sagar, Brown, Zelt, Pickett & Tranmer, 2012).  In a cross-sectional 

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study validating the WIQ, the WIQ distance score was moderately correlated with 
6MWT times with a Spearman rank correlation coefficient of 0.557 for patients with 
PAD (McDermott et al., 1998). Considering the evidence, the WIQ is a useful clinical 
tool to assess walking ability. 
 
Montgomery and Gardner (1998) determined test-retest reliability using multiple 6MWT 
trials among 64 PAD patients. The distance walked and number of steps taken were 
similar between trials with a reliability coefficient of R=0.94 and R=0.90, respectively. 
QOL can be measured through standardized general questionnaires such as the Short-
Form 36 health survey (SF-36). The SF-36 is the most common instrument used to 
measure health related QOL in physical activity research (Hart & Kang, 2015; Novakovic 
et al., 2016; Stoner et al., 2016). It has high internal consistency (Cronbach’s α>0.8), with 
the exception of social functioning likely due to having only two items in that domain 
(α=0.79), among older adults (Brazier et al., 1992; Walters, Munro & Brazier, 2001). A 
meta-analysis of the reliability of the SF-36 in physical activity research with various 
research designs and patient populations found strong effect sizes (ES) for physical health 
(ES=0.90, 95% CI: 0.88 to 0.92, P<0.001) and mental health (ES=0.90, 95% CI: 0.89 to 
0.91, P<0.001) domains (Hart & Kang, 2015). This suggests that the SF-36 is a 
responsive measure of QOL for physical activity research. The SF-36 is also considered 
to be a suitable general measure of QOL for patients with PAD (Mehta, Subramaniam & 
McCollum, 2003).  
 
8.0 Statistics 
8.1 A description of the statistical methods to be employed 
Primary analysis to determine if patients with CAD or patients with PAD have greater 
improvements in VO2peak, 6MWT, WIQ, and QOL will be tested with a series of two 
factor 2 (time: Baseline, End) by 2 (group: PAD, CAD) analyses of variances with 
Tukey’s Honest Significant Difference (HSD) test for post-hoc corrections. This analysis 
will include patients who attended >70% of on-site cardiac rehabilitation sessions. An 
intention-to-treat analysis will be conducted to include patients who attended less than 
70% of the cardiac rehabilitation program sessions.  
 
The secondary hypothesis that the magnitude of responses for patients with PAD will be 
dependent on biological sex will be tested through conducting a 3 factor 2 (time: 
Baseline, End) by 2 (group: PAD, CAD) by 2 (sex: men, women) analysis of variance. In 
addition to determine if the magnitude of responses are dependent on clinical presentation 
of PAD, a 2 factor 2 (time: Baseline, End) by 2 (type: asymptomatic, post-surgical 
intervention, IC) analysis of variance will be conducted. 
 
To determine if PAD patients have greater exercising heart rate, rating of perceived 
exertion (Borg scale), rating of pain severity (, and training volumes than CAD patients, 
tertiary analysis will involve independent t-tests for these variables. 
 
8.2 The number of subjects planned to be enrolled 
Sample size calculations were conducted using an alpha of 5% and a power of 0.8. 
Calculations were based on the primary and secondary variables of interest (VO2peak 

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and 6MWT distance) for PAD and CAD patients. To be conservative, the largest sample 
size (6MWT) was selected. 
 
Previous literature has found that patients with PAD undergoing exercise training 
compared to PAD patients who did not undergo exercise training had improvements in 
the 6MWT of 34.9m (95 % CI 25.6–44.1 m, P<0.00001) (Parmenter et al., 2015). In 
contrast, patients with CAD had improvements of 29.6±12m following exercise training 
(Jaureguizar et al., 2016). Clinically significant changes have been defined as 20m for the 
6MWT (Perera et al., 2006). A difference of 10 meters between groups is a conservative 
average between what is observed in the literature and the defined clinically significant 
change. The sample size calculation for a power of 0.8 would be 23 participants per 
group. Accounting for a 20% drop out, 28 patients with CAD and 28 patients with PAD 
will be recruited. Statistical significance will be set at a P value of 0.05.  
 
A sample size of 28 participants per group is powered to detect a difference of 1.6 
ml/kg/min between groups for VO2peak. 
 
8.3 Procedure for accounting for missing, unused, and spurious data. 
If data variables are missing, the whole participant data set will be excluded from the 
main statistical analysis. If some data is available, the participant’s data will be included 
in the intension to treat analysis.  
 
9.0 Direct Access to Source Data/Documents 
 
Only study investigators (Dr. Paul Oh, Dr. Scott Thomas, and Cindy Nguyen) will have 
direct access to study related documents.  
 
10.0 Quality Control and Quality Assurance Procedures 
 
Study investigators will review data collection forms as well as the completeness of the 
questionnaires when data is collected to ensure accuracy and completeness. 
 
11.0 Ethics 
11.1 Consent process  
All patients will provide written informed consent prior to study participation.  Patients 
identified with PAD will be referred by their vascular surgeons to the TRI cardiac 
rehabilitation program. Upon the initial assessment at the Rumsey Centre, PAD patients 
will be informed about participating in the proposed study by a cardiac rehabilitation staff 
member. If the patient is interested, the cardiac rehabilitation supervisor will introduce 
the patient to one of the study investigators to provide the potential participant with 
further study details. If the patient wishes to participate in the study, they will provide 
written informed consent.   
 
CAD patients who have attended an initial assessment and have consented to chart 
review will have their patient file reviewed to determine if the patient is an appropriate 
match to a PAD patient based on sex, age (±5 years), presence of diabetes, and assigned 

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cardiac rehabilitation supervisor. A cardiac rehabilitation staff member will inform the 
patient about the research study. If the patient expresses interest, they will be introduced 
to one of the study investigators who will provide further study details during their 
second assessment. 
 
11.1.1 A description of the identification process 
TRI is launching a Vascular Program designed to support patients with PAD seeking 
opportunities to manage their condition. All patients part of the Vascular Program will be 
referred by vascular surgeons. The cardiac rehabilitation staff helping with the Vascular 
Program will be informed about this proposed research study and will introduce all PAD 
patients to the opportunity. If patients express an interest in learning further details, the 
staff member will introduce the patient to one of the study investigators.  
 
CAD patients will be identified through consented chart review. All patients in the 
cardiac rehabilitation program at TRI are asked during the initial assessment whether they 
would like to consent to a chart review by research personnel as part of standard 
procedures. The study investigators will review the patient charts to find a match to a 
participant with PAD. The study investigator will notify the cardiac rehabilitation staff 
members conducting the exercise stress test to inform the patient about the study. If the 
patient expresses interest in learning further details, the staff member will introduce the 
patient to one of the study investigators.  
 
11.1.2 A description of who will make initial contact with research participants  
Potential research participants will be informed about the study through a cardiac 
rehabilitation staff member. If interested, the individual will be introduced to one of the 
study investigators.  
 
11.1.3 A description of who will obtain informed consent from research participants. 
Cindy Nguyen, MSc candidate, will obtain written informed consent from the research 
participants. Ms. Nguyen has over 4 years of research experience as a research assistant 
at the University of Toronto’s Training and Performance Laboratory under supervision 
by Dr. Scott Thomas.  
 
11.2 A statement of review and approval of the study by the Research Ethics Board 
before any study related procedures commenced. 
Participant recruitment and data collection for this study will only begin when approval is 
given by the Research Ethics Board.  
11.3. A statement of review and approval of any amendment to the study by the Research 
Ethics Board before any changes implemented beside these to eliminate immediate 
hazard to the study participants. 
 
If any changes to the study protocol are planned, the Research Ethics Board will be 
contacted and informed through an amendment prior to the change being implemented.   
 
12.0 Data Handling and Record Keeping 
12.1.A description of the process for data recording to ensure accuracy, completeness, 
legibility, and timeliness of the data.  

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Data will be recorded on a data collection sheet and will be reviewed following each 
study visit to ensure accuracy, completeness, and legibility. We hope to begin data 
collection in January 2018 and complete data collection by December 2018. 
 
12.2 A description of where the data will be recorded  
Data will be recorded on a data collection sheet and will be stored in a locked cabinet in 
the TRI Rumsey Centre room 231.  
 
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