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PII: S0828-282X(16)30722-X
DOI: 10.1016/j.cjca.2016.07.509
Reference: CJCA 2222
Please cite this article as: Aggarwal S, Moore RD, Arena R, Marra B, McBride A, Martin B-J, Stone
J, Rehabilitation therapy in Peripheral Arterial Disease, Canadian Journal of Cardiology (2016), doi:
10.1016/j.cjca.2016.07.509.
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Nutrition, Integrative Physiology Laboratory, College of Applied Health Sciences, University of Illinois at Chicago,
Chicago, IL
Brenda Marra, BSc., ACSM- CEP®, EIM® Level III, Certified Clinical Exercise Physiologist,
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TotalCardiologyTM Rehabilitation & Risk Reduction, Calgary, Alberta, Canada
Amanda McBride BSc. Kin. ACSM- CEP®, EIM® Level III, CSEP – CEP®, Certified Clinical Exercise
Physiologist, TotalCardiologyTM Rehabilitation & Risk Reduction, Calgary, Alberta, Canada
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Billie-Jean Martin MD PhD FRCSC, Congenital Cardiac Surgery Fellow, University of Alberta, Edmonton,
Alberta, Canada
James Stone MD PhD FRCPC FAACVPR FACC, Clinical Professor, University of Calgary, TotalCardiologyTM
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Rehabilitation & Risk Reduction, Calgary, Alberta, Canada
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Corresponding Author
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Sandeep Aggarwal
TotalCardiologyTM Rehabilitation & Risk Reduction
Talisman Centre, Box 50, 2225 Macleod Trail S.
Calgary, AB T2G 5B6
(P) 403 571 8669
(F) 403 571 6974
(E) saggarwal@totalcardiology.ca
www.tcrehab.ca
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Abstract:
Peripheral Arterial Disease (PAD) is the result of atherosclerosis in the lower limb arteries,
which can give rise to intermittent claudication, limb ulceration, infections and, in some
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circumstances, amputation. As a result of PAD, patients are frequently limited in both walking
duration and speed. These ambulatory deficits impact both functional capacity and quality of
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life. The prevalence of PAD is increasing and patients with this diagnosis have high
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cardiovascular morbidity and mortality. A comprehensive approach is required in order to
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management of metabolic fitness, risk factor modification and exercise training. Supervised
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exercise programs significantly improve functional capacity and quality of life as well as
reducing IC. These programs reduce morbidity and mortality and are cost effective and yet are
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population and has been included in both Canadian and American Guidelines for PAD
management. This review will describe: 1) Key background information related to PAD; 2) The
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modification; and 5) The currently accepted approach to exercise training. Key recommendations
Brief Summary
Peripheral Arterial Disease (PAD), atherosclerosis in the lower limb arteries, frequently limits
walking duration and speed, reducing functional capacity and quality of life. PAD patients have
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improve outcomes in PAD patients. Supervised exercise programs significantly improve
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functional capacity and quality of life, reduce IC, morbidity and mortality and are cost-effective
and yet are uncommonly prescribed. This review provides background information related to
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PAD; approaches to PAD diagnosis; pharmacologic management options; risk-factor
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Background
PAD and reduced functional capacity as well as increased mortality [1, 2]. Intermittent
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claudication, the main symptom of PAD, is a primary factor for the major limitations in mobility,
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physical function and the reduction in quality of life that is typically observed [1, 3, 4]. PAD is
frequently associated with significant cardiovascular disease (CVD) [1] [5] and this remains the
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major cause of the high mortality seen in this population. The natural history of symptomatic
PAD is daunting with more than one fifth having a nonfatal CVD event or death within 5 years
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of diagnosis. Asymptomatic disease, which occurs in half the patients with PAD, is also
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associated with an extremely high rate of CVD events and mortality. Globally, it is estimated
that more than 200 million individuals are living with PAD [6]. Approximately 8.5 million
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people in the United States and 800,000 in Canada have PAD and the prevalence has recently
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been shown to have increased by 13.1 % over the last decade [6] [7] [13]. Females and the
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elderly have a higher prevalence of PAD compared to males and younger individuals [6]. PAD is
estimated to cost 4.37 billion dollars a year in the US, with most of the expenditures associated
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with the high frequency of repeat hospitalizations and revascularization procedures [8].
This review will describe: 1) Key background information related to PAD; 2) The initial
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and 5) The currently accepted approach to exercise training. Key recommendations for
examination and the Ankle-Brachial Index (ABI). Intermittent Claudication is one of four
clinical presentations of PAD [3, 9], which also include pain at rest, digital ulceration and
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gangrene. IC affects roughly 5% of the American population over the age of 55 years and 10-
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40% of individuals with PAD [6, 9]. Intermittent claudication (IC) is defined as pain, cramping
or aching in the calves, thighs, or buttocks that is reproducible with walking and relieved by rest
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[10]. As a result of the decrease in exercise tolerance, it is common for individuals with IC to
develop a walking pattern favouring gait stability over speed velocity [2]. With mild to moderate
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IC, it has been reported that 88% of patients have sensory impairment and 56% have motor
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weakness leading to poor walking biomechanics [3]. Individuals with IC tend to decrease
reductions in daily activity and exercise contribute to a vicious cycle of deconditioning and
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worsening atherosclerosis risk factor management [2], such as blood sugar control in diabetes.
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Current data demonstrates that individuals with IC have an impaired ability to perform activities
of daily living, are limited in both work and leisure time activities and experience a significant
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The ABI is calculated by measuring the ratio of ankle systolic pressure over the brachial
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artery systolic pressure and is the gold standard for assessing PAD and its severity [9]. The ABI
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is a non-invasive measure of the severity of the peripheral disease and is both relatively low in
cost and simple to administer [4]. The ankle pressure may be obtained from highest pressure of
either the dorsalis pedis or the posterior tibial artery [9]. The ABI has been found to be almost
99% specific for PAD [13]. A normal ABI is 1.0-1.3, and 0.91-0.99 borderline for a PAD
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diagnosis. An ABI of 0.41-0.90 defines mild to moderate PAD and severe PAD is defined as an
ABI <0.4. An ABI of >1.3 may indicate severe PAD due to calcified tibial vessels, and
therefore, may require the performance of a Toe-Brachial Index (TBI) [9]. Importantly, the ABI
does not correlate with PAD symptoms [9, 11], nor does it strongly correlate to functional
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capacity in individuals with PAD [14].
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Current Clinical Management Strategies for PAD
Management strategies for PAD include pharmacologic therapy, risk factor control,
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surgical or catheter-based interventions, and exercise training [1, 4]. These approaches will be
symptoms and those that improve CVD outcomes. Pentoxifylline and cilostazol are the two
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methylxanthine derivative and was the first medication approved for IC. It has been shown to
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improve red blood cell deformability, lower fibrinogen levels and inhibit platelet aggregation.
The clinical benefit from pentoxifylline is, however, unpredictable, and may not be significantly
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different compared to placebo [16]. Cilostazol, a phosphodiesterase III inhibitor, is the preferred
medication in the US and the second oral agent developed for mild to moderate IC [16]. Benefits
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are derived from its anti-platelet properties, increased vasodilatation, increased plasma high-
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density lipoprotein and decreased plasma triglyceride level. Cilostazol 100 mg BID has been
shown to increase pain-free walking distance by 40%-70% after 12 weeks and 65%-83% after 24
Medications that are typically utilized to treat individuals with PAD in order to decrease
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their CVD risk include: 1) anti-platelet agents; 2) statins; and 3) angiotensin-converting-enzyme
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inhibitors [2, 3, 9, 15, 17, 18]. Aspirin is commonly recommended for all patients with PAD,
however a meta-analysis of the available data did not show any significant benefit [19]. In the
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CAPRIE PAD subgroup, Clopidogrel was shown to reduce MI, stroke and vascular death by
23.8% compared to aspirin alone [20]. A hazard ratio for the combined endpoint of
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cardiovascular death, MI or stroke was in favour of Dual Antiplatelet (DAPT) with Aspirin and
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Clopidogrel over Aspirin alone in a post hoc analysis of the CHARISMA trial [21]. Patients at
lower risk and without an intervention do not seem to benefit from DAPT with clopidogrel to the
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same extent as those that have had endovascular or surgical intervention [22] [23] [24] [25]. In
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the PEGASUS substudy of 1,143 PAD patients with a history of MI randomized to ticagrelor vs
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placebo there was a reduction in major adverse cardiovascular events with a number needed to
treat of 25. The 60 mg dose also reduced all-cause mortality with a 0.47 hazard ratio(HR). Major
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adverse limb events were also reduced (HR 0.65) [26]. In the 4S trial statin therapy was shown to
reduce CVD events and mortality. In addition there is evidence for a reduction in IC symptoms,
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critical limb ischemia (CLI - limb threatening condition defined as ischemic rest pain, persistent
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ulceration and gangrene) and the need for revascularizations [27]. Ramipril in the HOPE trial
PAD subgroup was shown to have reduced major adverse cardiac events outcomes to the same
degree as the general trial [28]. Treatment and compliance with proven pharmacologic therapies
is suboptimal and poor compliance results in worsened outcomes [18]. The NHANES study for
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example recently demonstrated that only 30.5% of patients with PAD were taking statins [29].
Contemporary treatment has the potential to alter the natural history, but full implementation of
Tobacco reduction
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A primary risk factor target for the management of PAD is the complete cessation of
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cigarette smoking [9, 15, 30, 31]. It has been reported that smoking increases the risk of
developing PAD by seven-fold and the risk of developing CAD by at least two-fold. Notably,
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individuals with PAD who continue to smoke have an increased risk of requiring
revascularization and amputation, and have a higher risk of dying from a MI or stroke compared
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to those who quit [15]. In one case-control study, ABI measured after two cigarettes taken within
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ten minutes of each other found that there was an acute decrease in ABI in chronic smokers [32].
Thus, there are both acute and chronic effects of smoking on the peripheral circulation [1]. In
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addition, several other atherosclerotic risk factors are adversely impacted by smoking including
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Interventional Therapy
The main goals of treatment for individuals affected by PAD are to preserve and improve
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both functional capacity and limb salvage, as well as to decrease overall mortality related to
cardiovascular risk [3, 9]. The main indications for endovascular revascularization (EVR) or
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surgical interventions are CLI as well as IC limiting both occupational and leisure time
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capabilities [9]. However, these procedures are not typically offered to the majority of patients
patients have been shown to increase the ABI and maximal blood flow through the calf by 80-
90%, leading to improved maximal walking distance and quality of life [33].
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Exercise Training
Supervised walking exercise training has been well validated as an effective treatment for
the functional deficits observed in patients with PAD [34, 35]. Data around the mechanism of
action leading to these improvements, the impact of different exercise strategies, and a
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comparison with revascularization have been well studied.
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Pathophysiologic Implications for Exercise: In PAD, the blood flow through a femoral
artery can be 300 mL/min compared to a normal blood flow of 500 mL/min in a healthy
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individual [3]. During exercise, lower extremity blood flow can increase by up to 30-fold in
healthy individuals while an individual with PAD may be limited to a 2-3 fold increase [3]. This
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reduced vascular reserve causes a breakdown in aerobic generation of ATP due to the lack of
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oxygen availability and results in a near obligate dependency on anaerobic metabolism [3].
Anaerobic metabolism leads to depletion of ATP as well as increased creatine phosphate and
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lactic acid leading to muscular pain [3]. The decline in exercise tolerance can lead to weight
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gain, poor lipid management and blood sugar control, all of which may increase the degree of
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disability and atherosclerosis [1, 4]. Exercise therapy has a number of proposed mechanisms to
improve the symptoms of IC. While an increase of blood flow, as evidenced by an improvement
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of rest ABI has not be demonstrated, improved flow with exercise has been identified [36]. Some
density and permeability; 3) increased vascular endothelial growth factors; 4) increased release
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of nitric oxide due to shear stress; 5) reduced blood viscosity; 6) increased mitochondrial
function leading to enhanced oxygen extraction ratios; 7) improved gait proficiency; 8) reversal
Supervised Exercise Program (SEPs): Most SEPs for PAD focus on treadmill and track
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walking [37]. The speed and grade of the initial workload of the treadmill is set to elicit IC
symptoms within 3-5 minutes. Patients walk at this workload until they achieve IC of moderate
severity, which is then followed by a period of sitting or standing until symptoms resolve.
During this procedure, the pain must reach a high level, ~4/5 on the claudication scale (Table 1)
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[33]. When patients are able to walk 8 or more minutes below 4/5 on the claudication scale they
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should progress their intensity by increasing either speed or incline. The exercise-rest-exercise
pattern should be repeated throughout the exercise session. The initial duration includes 35
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minutes of intermittent walking and should be increased by 5 minutes each session until 50
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SEPs have been shown to improve pain-free walking time in individuals with IC by an
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average of 180% and to improve maximal walking time by an average of 120% [9] [38]. SEPs
improve peak walking time (PWT) in PAD patients with IC by 50-200%. When compared to
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EVR or surgery, SEPs demonstrate similar outcomes in patients with IC. In the CLEVER trial, a
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SEP improved PWT and claudication onset time (COT) similar to EVR; both the SEP and EVR
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were better than optimal medical care (OMC) alone. PWT statistically increased by 5.0 ± 5.4
minutes (P <0.001 vs OMC) in the SEP group and 3.2 ± 4.7 minutes (P =0.04 vs OMC) in the
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EVR group vs. only 0.2 ± 2.1 minutes in the OMC group [39]. After EVR, a SEP increased pain
free walking distance (PFWD) by 566 metres vs. 402 metres in the EVR alone group [40]. In a
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randomized controlled trial after lower limb bypass surgery, a SEP produced an 89%
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improvement in the 6 minute walk test (6MWT) vs 47% in the control group [41]. Baseline
functional capacity (FC) correlates with mortality as does a decrease in FC over a 2-year time
span [42] [43]. Completion of a 12 week SEP has been shown to reduce cardiovascular mortality
and morbidity [44]. No prospective trials have been done to assess the effect of a SEP on
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mortality.
interventions and may also improve mortality, although a larger randomized control trial would
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Home Exercise Programs (HEP): Similar to cardiac rehabilitation (CR), HEP services
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are extremely variable and can range from a simple completely unsupervised “go home and
walk” program to a more comprehensive exercise program which includes weekly in-house
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cognitive behaviour therapy (CBT), exercise logs, close phone follow-up and use of exercise
monitoring technologies. This heterogeneity makes it difficult to assess the benefits of HEP or to
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perform meta-analysis of studies comparing HEP to SEPs. When compared to SEPs, a simple
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HEP resulted in a lesser improvement in initial claudication distance (263.4 ± 155.0 metres vs.
483 ± 317.2 metres P < 0.01) [45]. Benefits derived from a more comprehensive HEP especially
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when coupled with group mediated CBT are generally superior to a completely unsupervised
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walking program. Compared to the control group there was a significant improvement in 6MWT
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(355.4 to 381.9 m in the intervention versus 353.1 to 345.6 m in the control group) [46]. The
addition of new technologies for patients to monitor their activities may also improve
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compliance with HEPs. Compared to a non-exercise group, using a step activity monitor in
addition to seven 15 minute meetings with an exercise physiologist over 12 weeks was found to
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equalize the improvement associated with a HEP compared to a SEP [47]. Therefore, although
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SEPs appear to be superior to HEPs, there does appear to be some merits of a HEP in select
populations and with the consideration of CBT and/or a home monitoring infrastructure. A HEP
may still be valuable for those that cannot attend a SEP but should not be the first option offered
to these patients.
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comprehensive review has suggested that the maximum benefit of exercise occurs in the first 2-3
months of supervised exercise; the sessions should be 3 times per week, lasting 30-60 minutes,
with a total training volume of 1500-2000 minutes [48]. Alternative exercise programs have been
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applied with mixed success. Using an individual leg plantar flexion ergometer, Wang was able to
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improve peak oxygen consumption (VO2) and make 11 of 14 patients symptom free at peak VO2
[49]. Lower limb resistance training (RT) with a combination of knee extension, leg press and
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leg curl exercises starting at 50% of 1-repetition maximum has been shown to improve 6MWT
distance walked by 12.4 metres compared to control. In this study, the SEP was superior to RT
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and showed an improvement of 35.9 metres during the 6MWT. This study did not assess the
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effect of combining a standard treadmill/track SEP with RT [50]. These alternative protocols
have been shown to have a lesser effect on IC symptoms; however they may be beneficial for
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those patients unable to walk on a treadmill or track. Upper limb cycle ergometry improves
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symptoms. Consequently, this may be a useful method for initiating exercise in those with severe
functional limitations due to IC or for those who will not exercise into claudication pain
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thresholds [51]. The physiological reasons for this improvement are unclear but may be in part
due to improved lower-limb O2 delivery [52]. Pole striding combines both upper and lower limb
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exercise and in a RCT was show to improve peak VO2 and duration walked compared to placebo
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and vitamin E groups [53]. Pole striding was not compared to a standard SEP but may have
benefits that are greater than lower limb exercise alone due to the additional cross training effect
consideration of the advantages of both aerobic and resistance training (Figure 1). Further
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research combining different modes of exercise to determine the optimal approaches to reduce
Exercise training appears to be highly beneficial in patients with PAD, both in terms of
improving pain-free walking duration and distance, quality of life, as well as potentially
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improving mortality.
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Cost-effectiveness: Dutch insurance data has demonstrated that a stepped care model
with a “SEP first” approach resulted in significantly less costs than an “invasive first” approach
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(€2191 vs. €9851) [54]. A randomized controlled trial comparing EVR to SEP showed the
incremental cost for EVR per Quality adjusted life year (QALY) was €231800 [55]. Using a
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Markow model, which included multiple RCTs, it was demonstrated that SEP had a cost
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effectiveness ratio of £711-1608 compared to a HEP [56]. If a resource intensive comprehensive
HEP model is employed, one could hypothesize that the costs would be similar to or may even
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exceed that of SEPs. Overall these studies suggest that SEPs are more cost effective than EVR as
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an initial strategy and that they are cost effective compared to HEPs.
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Exercise Programs in Canada: Little data exist regarding the number of programs and
volume of patients that are offered SEP for PAD in Canada. In addition, there are no formal
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programs to train cardiologists or internists in PAD management in Canada, as there are in some
other countries. In 2005 a concerted attempt was made by the Canadian Cardiovascular Society
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to improve awareness of PAD and its treatment in Canada [57]. In 2004 a Systematic
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Assessment of Cardiovascular Risk (SAVR) was established in Ontario to improve vascular risk
factors through 8 main guideline mandated therapies (antiplatelets, statins, ACE inhibitors, blood
pressure control, lipid control, glycemic control, smoking cessation and target body mass index -
BMI). They recently published their propensity analysis which showed a reduction in the
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composite risk of death, MI and ischemic stroke by 37% in those enrolled vs not enrolled in their
program [58]. Although this study does not specifically deal with the exercise component of
rehabilitation it shows how a systematic approach to risk factor reduction, which should be
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PAD is observed in up to 40% of hospitalized coronary artery disease patients (average
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age 70) with only 8.7% of patients having typical intermittent claudication [59] [60]. The
average Canadian cardiology practice and CR program may actually be seeing many more PAD
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patients than are actually diagnosed.
Conclusion
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It is clear that PAD is frequent and increasing in prevalence. Exercise training is a cost
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effective strategy with proven efficacy in reducing IC symptoms and CVD morbidity and
mortality. Exercise training programs should not be considered as a stand-alone intervention for
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individuals with PAD, but rather as a central component of a broader treatment approach.
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Specifically, exercise training combined with guideline mandated risk factor modification offers
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the possibility of improving the clinical trajectory of PAD. The goals of comprehensive
prevention strategies, including exercise, are 3 fold: 1) to reduce limb symptoms and improve
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limb salvage; 2) to improve exercise capacity and prevent or lessen physical disability; and 3) to
decrease the occurrence of cardiovascular events [30, 11]. PAD awareness and treatment is
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currently suboptimal and there is a strong need to improve the availability and knowledge of
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outcomes. The incorporation of PAD rehabilitation into existing CR or chronic disease exercise
programs which are equipped to deal with these high risk vascular patients may be a viable
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strategy that would likely be cost effective; 2) Increase awareness and treatment of PAD and its
risk factors. One strategy could be to incorporate PAD training into internal medicine and
cardiology programs with an emphasis on PAD rehabilitation and secondary prevention as has
been done in other countries; 3) Improve access to PAD rehabilitation through government and
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third party payer advocacy initiatives that emphasize cost effectiveness of the “rehabilitation
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first” strategy; 4) A survey of locations offering PAD rehabilitation across Canada should be
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prevention and treatment strategy similar to the SAVR program should be incorporated into all
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With the incorporation of these strategies we should start see a significant improvement
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in outcomes in the Canadian PAD population.
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Claudication Scale
1- No Pain
2- Pain or Discomfort begins
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3- Mild Pain or Discomfort
4- Moderate Pain
5- Severe Pain
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Data from Mays and Regenteiner, 2013 [34].
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- Ask if they were any new presence of symptoms
- Check blood sugar levels if needed
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Once cleared start with 5 minute warm-up
resolve
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