Canadian Journal of Cardiology 38 (2022) 634e644

Review
Building Your Peripheral Artery Disease Toolkit: Medical
Management of Peripheral Artery Disease in 2022
Vinai C. Bhagirath, MD, MSc,a,b David Nash, BHSc,c Darryl Wan, MD,a and
Sonia S. Anand, MD, PhDa,b
a
Department of Medicine, McMaster University, Hamilton, Ontario, Canada
b
Population Health Research Institute, Hamilton, Ontario, Canada
c
Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada

ABSTRACT 
RESUM 
E
Peripheral artery disease (PAD) is associated with substantial La maladie arte rielle peripherique (MAP) est associe e à une morbidite

morbidity, including a high risk of cardiovascular and limb events and substantielle, avec notamment un risque e leve
 d’eve
nements car-
death. A growing body of evidence has demonstrated the benefits of diovasculaires et d’e venements touchant les membres, ainsi que de
antithrombotic therapy, lipid lowering, blood pressure control, diabetes decès. De plus en plus d’e vidences ont de montre  les avantages d’un
management, smoking cessation, and exercise programs on improving traitement antithrombotique, d’une re duction des taux lipidiques, du
symptoms and reducing these complications. Guidelines make specific contrôle de la pression arte rielle, d’une prise en charge du diabète, de
recommendations on how to use these strategies to prevent adverse l’arrêt du tabac et des programmes d’exercice physique pour atte nuer
cardiovascular and limb outcomes in patients with PAD. Unfortunately, les symptômes et en re duire les complications. Les lignes directrices
antithrombotic therapies, statins, optimal antihypertensives, smoking font des recommandations spe cifiques sur la façon d’utiliser ces
cessation counselling and therapies, and exercise programs have all strategies pour pre
venir les effets inde sirables au niveau des membres
been consistently shown to be underutilised in PAD patients both in et du système cardiovasculaire chez les patients atteints de MAP.
Canada and globally. A variety of barriers to optimal utilisation of Malheureusement, il a e  te
 demontre  que les traitements anti-
evidence-based medical therapies have been described at the patient, thrombotiques, les statines, les meilleurs antihypertenseurs, les con-
health care provider, and system levels. These include lack of seils et les the rapies de de saccoutumance au tabac et les

Peripheral artery disease (PAD) is defined by the narrowing amputation or die.6 Even in the absence of symptoms, the
and obstruction of the noncoronary and nonintracranial ar- development of PAD indicates the presence of more wide-
teries, and it is estimated to affect more than 200 million spread atherosclerosis.7 For this reason, in addition to major
people worldwide.1 In Canada, it has been estimated that 1 in adverse limb events (MALE), PAD patients are also at risk for
20 people over the age of 50 years have PAD,2 with prevalence major adverse cardiovascular (CV) events (MACE) and
likely to be rising with increasing age and rates of diabetes.3 increased mortality.8 The cumulative incidence risk of MACE
Manifestations of PAD in the lower extremities include among patients with PAD alone is similar to those with
intermittent claudication, which causes significant functional established coronary artery disease (CAD), and this risk is
impairment and a reduction in health-related quality of life.4 increased 2-fold in patients with both PAD and CAD.9 Ca-
Patients may also develop critical limb ischemia (CLI), which nadian data reveal that age-adjusted mortality is higher for
is characterised by resting leg pain and tissue loss (ulcers, patients with PAD than for patients with CAD or ischemic
gangrene) and often requires surgical intervention (ie, revas- stroke in this country.3
cularisation or amputation).5 One year after revascularisation The morbidity and mortality associated with PAD can be
for CLI in Canada, more than 25% of patients undergo combatted with the effective use of secondary preventative
therapies including lifestyle modification and medications
such as antithrombotic, lipid-lowering, and antihypertensive
Received for publication October 29, 2021. Accepted February 5, 2022.
drugs (Table 1). However, these therapies are underutilised,
Corresponding author: Dr Vinai Chander Bhagirath, C2-239 DBCVSRI, both in Canada and globally.6,10 Barriers to implementation
237 Barton St E, Hamilton, Ontario L8L 2X2, Canada. Tel.: þ1-905-521-
2100 x40727; fax: þ1-905-538-8946.
of therapies can be classified as occurring at the level of the
E-mail: [email protected] patient, health care provider, or health system (Fig. 1). Pa-
See page 641 for disclosure information. tients and health care providers may face capability barriers

https://doi.org/10.1016/j.cjca.2022.02.004
0828-282X/Ó 2022 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
Bhagirath et al. 635
Building Your PAD Toolkit

knowledge among patients and health care providers, and lack of programmes d’activite  physique sont autant d’outils sous-utilise
s chez
access to secondary prevention programs. We review the evidence for les patients atteints de MAP, tant au Canada que dans le monde.
preventive therapies in PAD, evidence for underutilisation of these Divers obstacles à l’utilisation optimale des the rapies me dicales,
therapies, and barriers to their use. Core elements of PAD secondary fondees sur des donne es probantes, ont ete
 detaille
s au niveau des
prevention clinics are proposed, and a summary of optimal medical patients, des fournisseurs de soins de sante  et du système. Cela inclut
therapies and relevant tools is provided. This review may help clini- le manque de connaissances des patients et des fournisseurs de soins
cians who treat patients with PAD to develop a toolkit to overcome de sante , et du manque d’accès aux programmes de pre vention sec-
these barriers in order to improve utilisation of medical therapies, with ondaire. Nous re alisons la synthèse des e vidences concernant les
the ultimate goal of improving outcomes for PAD patients. therapies preventives dans la MAP, les preuves de la sous-utilisation
de ces the rapies et les obstacles à leur utilisation. Les e le
ments fon-
damentaux des cliniques de pre vention secondaire pour la prise en
charge de la MAP sont propose s, et un re sume  des the rapies
me dicales optimales et des outils pertinents est propose . Cet examen
peut aider les cliniciens qui traitent les patients atteints de MAP à
developper une boîte à outils pour surmonter ces obstacles afin
d’ame liorer l’utilisation des the
rapies me dicales, dans le but ultime
d’ame liorer le pronostic des patients atteints de MAP.

related to knowledge or capacity to act, and intention barriers lack of knowledge regarding smoking as a causative factor,20 a
related to attitudes or motivations.11 This narrative review higher level of addiction in this population, and environ-
outlines the current evidence supporting the use of medical mental factors such as higher smoking rates among other
therapies for prevention of adverse CV and limb events in members of the household and social circle.17 Innovative in-
patients with PAD, and barriers to their implementation. terventions, such as SMS- or app-based counseling strategies,
Strategies are then suggested to build a PAD toolkit to deliver have been shown to be beneficial,21 but their effectiveness
better preventive care to this population. may vary in different populations.22 Although these potential
patient-level barriers should motivate increased attempts by
health care systems to encourage smoking cessation, we find
Lifestyle Modification that the opposite is true, with PAD patients receiving less
counselling on smoking cessation than patients with CAD.19
Smoking cessation The high site-by-site variability in implementation of smoking
All PAD patients who smoke should be encouraged to cessation counselling suggests that health system factors, such
quit.12,13 Continued smoking is associated with increased as access to smoking cessation programs, play a role.18 A re-
mortality and decreased amputation-free survival14 and can view of smoking cessation interventions found that published
have negative impacts on postsurgical outcomes.15 The use of interventions were less successful in women than in men,
nicotine replacement therapy or other medications (eg, suggesting a need to consider gender when designing and
bupropion, varenicline) is safe and effective, and can be implementing smoking cessation interventions.23
offered in conjunction with intensive counselling and/or a
referral to a smoking cessation program.12,13 A recent sys- Structured exercise therapy
tematic review of smoking cessation trials in PAD found that
methods previously tested in other populations may not Exercise therapy in the form of a supervised exercise
necessarily be effective for patients with PAD,16 although program is an additional lifestyle modification that should be
more intensive counselling and use of varenicline may encouraged in PAD patients experiencing claudication.12,13
improve chances of success.17 Guidelines recommend that These programs are typically more effective than home-
PAD patients who smoke should be advised to quit, and based programs,24 perhaps because of differences in in-
assisted with a smoking cessation plan that includes tensity or opportunity for encouragement/motivation.
pharmacotherapy.12,13 However, logistical obstacles (eg, transportation to the fa-
cility) exist for some patients, and unsupervised programs
should still be considered if those are more practical for a
Barriers to smoking cessation
given patient.25 The benefits of exercise are numerous; reg-
Implementation of smoking cessation counselling is sub- ular physical activity is associated with reduced all-cause
optimal. Even in specialised vascular specialty clinics, only mortality,26 and exercise programs result in significant im-
75.2% of newly referred PAD patients who were current provements in functional capacity.27 In the Claudication:
smokers were counselled on smoking cessation.18 Rates of Exercise Versus Endoluminal Revascularization (CLEVER)
counselling are worse for patients without comorbid CAD. trial, the difference in peak walking time between patients
Berger and Ladapo found that PAD patients with comorbid receiving supervised exercise vs stent revascularisation was
CAD were more likely to receive smoking cessation coun- nonsignificant (P ¼ 0.16) at 18-month follow-up.28 This
seling (odds ratio 4.4) at a given visit, compared with patients highlights that noninvasive approaches can be considered
with PAD alone.19 even in the treatment of function-limiting claudication.
Possible patient-level explanations for reduced effectiveness Guidelines recommend structured exercise programs to
of smoking cessation interventions in PAD patients include improve symptoms and function.12,13
636 Canadian Journal of Cardiology
Volume 38 2022

Barriers to structured exercise therapy PAD-specific outcomes have not been reported. Further
randomised controlled trials are required to clarify the role of
Studies have found that patients with PAD are less likely to
the Mediterranean diet in the development and progression of
start and complete exercise therapy programs,29 and patients
PAD.
with PAD experience less improvement in cardiorespiratory
The limited evidence for dietary interventions in PAD
fitness than those with CAD alone.30 A few studies have
patients is reflected in the absence of recommendations for
qualitatively examined barriers to PAD patients’ use of pre-
dietary counselling in PAD guidelines.12,13
ventive therapies. At the patient level, claudication pain itself
is a barrier. The pain that is associated with walking for people
with claudication discourages participation in exercise pro-
grams.31,32 A systematic review suggests that alternative ex- Medications
ercise regimens that do not involve development of maximal Antiplatelet agents
claudication pain improve adherence and completion rates.33
Transportation to supervised exercise program sites may be The rationale for the use of antiplatelet therapy in PAD is
more difficult for people with PAD, which may be alleviated derived from the role of platelets in atherothrombosis, and the
by use of home-based exercise programs that use pedome- proven efficacy of these drugs in other atherosclerotic disease
ters.34 Women are less likely to complete the therapy than states (ischemic stroke, CAD).7 Current European and
men owing to unaddressed patient-level barriers including American guidelines for the treatment of PAD recommend
difficulty with transportation and family responsibilities.35 At the use of single antiplatelet therapy (SAPT; 75-325 mg/day
the provider level, surveys have found that health care prac- aspirin or 75 mg/day clopidogrel) in symptomatic PAD pa-
titioners lack knowledge regarding PAD-specific exercise tients.12,13 This guidance is supported by a meta-analysis of
protocols.36 Health care providers appear to refer women with 18 prospective randomised trials (5269 PAD patients)
cardiac disease less frequently than men to exercise assessing the effectiveness of aspirin (alone or with dipyr-
programs.35 idamole) vs placebo in which a reduction in odds for cardiac
The biggest barrier is systemic lack of access to exercise events (pooled relative risk [RR] 0.88, 95% confidence in-
programs. Surveys and systematic reviews demonstrate that terval [CI] 0.76-1.04) was observed.44 Previous data from the
most PAD patients do not have access to supervised exercise Antithrombotic Trialists’ Collaboration demonstrated that the
programs.36-38 Where they do have access, the programs often use of antiplatelet therapy in general (aspirin or other drugs) is
do not have PAD-specific protocols, education among staff is associated with a 23% relative risk reduction (8% absolute) of
often limited, and funding is poor.36 Referral for supervised serious vascular events in PAD patients (P ¼ 0.004).45 The
exercise therapy was found to be especially sensitive to site-by- Clopidogrel vs Aspirin in Patients at Risk of Ischaemic Events
site availability of exercise programs for these patients, even in (CAPRIE) trial forms the basis for inclusion of clopidogrel
specialised vascular clinics.18 into guidelines, in which a PAD subgroup on clopidogrel
rather than aspirin experienced a 23.8% relative risk reduction
Diet (95% CI 8.9-36.2; P ¼ 0.0028) in stroke, MI, or vascular
death with a similar safety profile.46 The Examining Use of
The body of literature investigating the role of diet in the Ticagrelor in PAD (EUCLID) trial did not find a benefit of
generation and propagation of PAD is heterogeneous. Most of ticagrelor over clopidogrel for either MACE or MALE.47 The
these studies lack impact owing to their small sizes or obser- efficacy of SAPT in asymptomatic PAD patients is not well
vational designs. Previous studies, such as the Northern established.48 Studies investigating the use of dual antiplatelet
Manhattan Study (NOMAS)39 and the Coronary Diet therapy (DAPT) in stable PAD, with the addition of either
Intervention With Olive Oil and Cardiovascular Prevention clopidogrel, ticagrelor, or vorapaxar to aspirin, suggest that
(CORDIOPREV) study,40 among others, have suggested that while there are some benefits in terms of reducing CV and
the Mediterranean diet may reduce the progression of carotid limb events, these are counterbalanced by an excess major
atherosclerosis as measured by carotid intimal medial thick- bleeding risk.48-50
ness (CIMT). However, this remains a surrogate marker, and
the role of serial CIMT assessments has not been established
Anticoagulants
in clinical practice, nor has it been shown to affect clinical
outcomes. The effect of dietary intake on plaque development Oral anticoagulants have proven benefit in reducing CV
and progression has not been well studied in the PAD cohort. events in CAD51 and have since been studied in patients with
The only randomised controlled trial which has reported PAD in combination with antiplatelet therapy. In the
on the role of diet and the presence of PAD is a subgroup Warfarin Antiplatelet Vascular Evaluation (WAVE) trial,
analysis of the Prevención con Dieta Mediterránea (PRE- which assessed the combination of warfarin (target interna-
DIMED) study.41 In this primary prevention study, ran- tional normalized ratio 2-3) and antiplatelet therapy vs
domisation to a Mediterranean diet was associated with a antiplatelet alone, no significant difference in MI, stoke, or
significantly lower risk of PAD development. However, the death from CV causes was observed (RR 0.92, 95% CI 0.73-
trial suffered from inconsistencies in methodology leading to 1.16; P ¼ 0.48).52 Furthermore, a significant increase in life-
the subsequent retraction and republication of the overall threatening bleeding was noted in the combination group (RR
study.42 The Lyon Diet Heart Study was a randomised trial of 3.41, 95% CI 1.84-6.35), limiting the utility of adding
secondary prevention in patients with prior myocardial warfarin. These findings were consistent with the Dutch
infarction (MI).43 Although the Mediterranean diet was Bypass, Oral Anticoagulants or Aspirin (Dutch BOA) trial of
shown to improve the rate of CV death and nonfatal MI, moderate- to high-intensity warfarin compared with aspirin
Bhagirath et al. 637
Building Your PAD Toolkit

Table 1. Summary of optimal evidence-based medical therapy for reduction of vascular events in stable symptomatic PAD, with selected published
guidelines* and tools
Smoking cessation  Review of smoking status at each visit
 Counselling to quit at each visit
 Offer smoking cessation pharmacotherapy to those interested
B Centers for Disease Control and Prevention clinical cessation tools: https://www.cdc.gov/tobacco/basic_information/for-
health-care-providers/clinical-tools/index.html
B Ottawa Model for Smoking Cessation: https://ottawamodel.ottawaheart.ca/about-omsc
B Canadian Cancer Society Smokers’ Helpline: þ1-866-366-3667, https://smokershelpline.ca/
Structured exercise therapy  Interested patients should be referred to an evidence-based exercise therapy program
B Vascular Disease Foundation/American Association of Cardiovascular and Pulmonary Rehabilitation PAD exercise training
toolkit: a guide for health care professionals: http://www.nccraonline.org/wp-content/uploads/2017/03/pad-exercise-
training-toolkit-AACVPR.pdf
Antithrombotics  Single antiplatelet therapy (eg, 75 mg clopidogrel daily) or combination low-dose aspirin daily and 2.5 mg rivaroxaban twice
daily in patients with symptomatic PAD, with preference for combination therapy in those at higher risk of ischemic events
without high risk of bleeding
Lipid-lowering therapy  Statin therapy (eg, 40 mg rosuvastatin daily)
 Consider adding PCSK9 inhibitor in patients at high risk of ischemic events with LDL-C > 1.8 mmol/L despite maximal
tolerated statin
Antihypertensives  Hypertension should be controlled according to current guidelines
 Consider ACEi or ARB first line
70
B Hypertension Canada’s 2020 comprehensive hypertension guidelines
Diabetes management  Comprehensive coordinated care plan for diabetes control
 Guideline-based pharmacotherapy including SGLT2 inhibitor or GLP-1 receptor agonist
B 2019 European Society of Cardiology (ESC)/European Association for the Study of Diabetes (EASD) guideline on dia-
betes, prediabetes, and cardiovascular diseases110
 Regular foot screening
B International Working Group on the Diabetic Foot 2019 prevention guideline: https://iwgdfguidelines.org/prevention-
guideline/
ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; LDL-C, low-density lipoprotein cholesterol; PAD, peripheral artery disease;
SGLT2, sodium-glucose cotransporter 2.
* The following guidelines provide recommendations on all of the categories in this table: 2017 European Society of Cardiology guidelines on the diagnosis and
treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery13; and 2016 American Heart Association/American College
of Cardiology guideline on the management of patients with lower extremity peripheral artery disease.12

alone in patients after infrainguinal open surgical revascular- COMPASS trial.58 The predominant reasons for exclusion
isation, which found no clear evidence of efficacy and an included high bleeding risk (contraindication to rivaroxaban),
excess of life-threatening bleeding.53 need for full-dose anticoagulant use, and requirement for
A strategy of adding a low dose of direct oral anticoagulants DAPT (after acute coronary syndrome [ACS], or percuta-
to antiplatelet therapy was proven to reduce MACE in pa- neous coronary intervention with stent).58
tients with recent coronary events.54 In the subsequent Car- Kaplovitch et al. summarises best antithrombotic therapy
diovascular Outcomes for People Using Anticoagulation for stable symptomatic PAD considering the newest clinical
Strategies (COMPASS) trial, patients with stable atheroscle- evidence (ie, COMPASS).48 SAPT in the form of aspirin or
rotic disease (PAD or CAD) were randomly assigned to clopidogrel remains standard in mild disease, with the evi-
receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg dence for clopidogrel being slightly superior. The use of
once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg rivaroxaban (2.5 mg twice daily) in combination with aspirin
once daily) alone (1:1:1).9 Among the subgroup of 7470 should now be considered in patients who are at high risk for
patients with PAD the combination of low-dose rivaroxaban MACE and MALE and at low risk for bleeding.48 Patients
and aspirin was associated with a reduction in MACE (hazard with PAD who endure an ACS or an acute cerebrovascular
ratio [HR] 0.72, 95% CI 0.57-0.90) and MALE (HR 0.54, event should be managed according to those corresponding
95% CI 0.35-0.84) compared with aspirin alone.55 An guidelines.59 For example, in patients with PAD and CAD,
increased risk of major bleeding was observed in patients DAPT (aspirin and ticagrelor) is often used in the 6-12
receiving the combination therapy, but no excess in severe months following ACS. There is evidence to support the
bleeding, including fatal bleeding, symptomatic bleeding into continuation of long-term DAPT in those patients,60 but
a critical organ, or surgical site bleeding requiring reoperation, given the benefit of low-dose rivaroxaban and aspirin in
was observed. Even when MALE did occur, combination reducing MACE and MALE, returning to the COMPASS
therapy reduced recurrent MALE by 43% (P ¼ 0.01) and, regimen after 6 or 12 months is reasonable.61
total vascular amputations by 58% (P ¼ 0.01).56 Patients at The use of antithrombotic therapy after vascular surgery for
high risk of MACE and MALE, such as those with PAD patients is less well defined, but a course of DAPT after
concomitant heart failure, diabetes, renal insufficiency, and peripheral revascularisation is reasonable, according to the 2017
polyvascular disease, experienced the greatest risk reduction American Heart Association guidelines.12 However, after those
from rivaroxaban plus aspirin therapy.57 These findings are guidelines were published, strong evidence from the Vascular
applicable to many real-world PAD patients; in the Reduction Outcomes Study of ASA Along With Rivaroxaban in Endo-
of Atherothrombosis for Continued Health (REACH) regis- vascular or Surgical Limb Revascularization for PAD
try, 68.4% of real-world PAD patients met eligibility for the (VOYAGER PAD) trial revealed similar benefits and risks for
638 Canadian Journal of Cardiology
Volume 38 2022

PCSK9 Inhibition in Subjects With Elevated Risk (FOUR-

IER) trial, patients in the treatment arm experienced a
reduction in the risk of CV death, MI, stroke, hospitalisation
for unstable angina, or coronary revascularisation (HR 0.85,
95% CI 0.79-0.92; P < 0.001).66 The reduction in the pri-
mary end point was consistent across different baseline LDL-
C levels, even in the quartile of participants with a low
baseline median LDL-C of 1.9 mmol/L. A subanalysis of the
3642 patients with PAD revealed a 27% composite relative
risk reduction in MACE and MALE among PAD patients
(HR 0.73, 95% CI 0.60-0.88; 10.9% vs 15.0%, absolute risk
reduction 4.1%; no. needed to treat: 25).67 Strikingly, there
appeared to be an approximately linear relationship between
LDL-C levels and reduction of MACE/MALE, all the way
down to an LDL-C of 10 mg/dL (0.6 mmol/L). PCSK-9
inhibition with alirocumab also reduced limb events in pa-
tients after acute coronary syndrome (HR 0.69, 95% CI 0.54-
0.89; P ¼ 0.004), and the benefit was associated with baseline
lipoprotein(a) but not LDL-C levels.68
Figure 1. Barriers to optimal utilisation of evidence-based secondary
preventive therapies for patients with peripheral artery disease (PAD). Blood pressure control
SET, structured exercise therapy.
Elevated blood pressure (BP) is one of the main risk factors
PAD patients after lower-extremity infrainguinal peripheral for the development of PAD, and PAD patients who are
revascularisation (endovascular or surgical) as found for stable hypertensive have poorer outcomes.69 Current guidelines
patients in the COMPASS trial. Acute limb ischemia, major endorse the use of blood pressureelowering medications in
amputation, MI, ischemic stroke, or death from CV events PAD patients with hypertension to reduce the risk of MI,
occurred less frequently in the rivaroxaban plus aspirin group at stroke, heart failure, and CV death.12,13,70 Angiotensin-
3 years (17.3% vs 19.9%, HR 0.85, 95% CI 0.76-0.96; P ¼ converting enzyme inhibitors (ACEis) or angiotensin recep-
0.009).62 Meta-analysis of the 2 trials revealed consistent tor blockers (ARBs) are typically used as first-line therapies
beneficial effects with the use of that combination.63 owing to their beneficial effects in this population. In the
Heart Outcomes Prevention Evaluation (HOPE) trial, pa-
Statins tients with vascular disease or diabetes who were randomised
to receive ramipril (10 mg daily) rather than placebo experi-
The initiation of statin therapy in all patients with PAD is enced a 22% relative reduction in MACE (RR 0.78, 95% CI
supported by current guidelines.12,13 In the Heart Protection 0.70-0.86; P < 0.001).71 A subgroup analysis revealed that
Study, 20,536 adults with vascular disease (6748 PAD pa- ramipril was beneficial in both clinical and subclinical (ankle-
tients) were randomly assigned to receive either 40 mg sim- brachial index [ABI] < 0.9, no symptoms) PAD, and the
vastatin daily or placebo.64 In those patients with PAD absolute benefit of ramipril was twice as large in those with a
receiving simvastatin, a 22% relative reduction (95% CI 15%- low ABI (50 vs 24 per 1000 events prevented).72 ARBs are a
29%) in the rate of first major vascular event (MI, coronary safe and effective alternative, and a trial that investigated the
death, stroke, or revascularisation) was observed, and this ef- use of telmisartan vs ramipril in patients with vascular disease
fect was significant across different PAD subgroups.64 found no significant difference in CV outcomes.73 High-
Observational data from the REACH registry demonstrates quality evidence to inform the optimal BP target specifically
that statin users have a significantly lower risk of adverse limb in PAD patients is lacking. A subgroup analysis of Systolic
outcomes (worsening claudication/new episode of CLI, new Blood Pressure Intervention Trial (SPRINT) trial found a
percutaneous/surgical revascularisation, or amputation) at 4 reduction in the composite of MACE and heart failure, but an
years compared with nonestatin users (HR 0.82, 95% CI increase in serious adverse events, with intensive BP control
0.72-0.92; P ¼ 0.0013).65 The impact of unmeasured con- (systolic BP target < 120 vs 135-139 mm Hg) in the PAD
founding, such as the “healthy user” effect, cannot be over- subpopulation.74 A post hoc analysis of the International
looked. However, this was thought to play a minor role, Verapamil SR/Trandolapril Study (INVEST) trial, which was
because the patients receiving statins had more comorbidities designed to compare hypertension treatment strategies in
and a greater severity of disease. CAD, included 2699 patients with PAD. A J-shape rela-
tionship was observed between systolic BP achieved and the
PCSK-9 inhibitors primary outcome of all-cause mortality, MI, or stroke, with
the lowest frequency of the outcome observed in patients with
Newly developed PCSK-9 inhibitors have emerged as an
a BP of 135-145/60-90 mm Hg.75
additional tool that can be used to lower low-density lipo-
protein cholesterol (LDL-C). Forty-eight weeks after ran-
Glycemic control
domisation to either evolocumab (either 140 mg every 2
weeks or 420 mg monthly, subcutaneous injection) or placebo Diabetes is a strong risk factor for PAD, and increasing
in the Further Cardiovascular Outcomes Research With rates of diabetes may be driving an increasing share of
Bhagirath et al. 639
Building Your PAD Toolkit

hospitalisations for PAD.76 A subanalysis of the EUCLID trial Barriers to implementation of recommended
revealed that each 1% elevation of HbA1c was associated with medications
a 14.2% increased risk of MACE.77 In diabetic patients un-
dergoing infrapopliteal balloon angioplasty, lower rates of Despite evidence-based guidelines espousing the use of
primary patency (16% vs 46%; P ¼ 0.005) and higher rates of preventive medications for PAD patients,12,13 studies have
MALE (35% vs 23%; P ¼ 0.05) were observed among pa- revealed persistently low adherence to these guidelines over
tients with a fasting blood glucose above the median.78 decades. Of 647 patients with PAD included in an analysis of
In terms of choice of medication, sodium-glucose the U.S. National Health and Nutrition Examination Survey
cotransporter 2 (SGLT2) inhibitors have beneficial effects in database from 1999 to 2004, only 30.5% were using a statin,
diabetics with high CV risk. In the Canagliflozin Cardiovas- 35.8% were using aspirin, and 24.9% were using an ACEi or
cular Assessment Study (CANVAS) trial, which assessed the ARB.90 Similarly, in an analysis of 1982 visits of patients with
efficacy of canagliflozin vs placebo in participants with type 2 PAD in national outpatient databases in the U.S. from 2005
diabetes and high CV risk, a reduction in MI, stroke, or CV to 2012, a statin was used in 33.1%, any antiplatelet therapy
mortality (HR 0.86, 95% CI 0.75-0.97; P < 0.001 for was used in 35.7%, and an ACEi or ARB in 28.4%.19 Data
noninferiority; P ¼ 0.02 for superiority) but increase in from Denmark reveal better adherence to guidelines, although
amputation rate (HR 1.97, 95% CI 1.41-2.75) was utilisation was still suboptimal, with 53% of patients on an-
observed.79 The mechanistic explanation for this particular tiplatelet agents, 40% on a statin, and 20% on an ACEi or
finding is unknown.80 However, no difference in amputation ARB.91 Adherence rates may be higher in specialised vascular
rate was observed in the Canagliflozin and Renal Events in clinics, with prospective data from the Patient-Centered
Diabetes With Established Nephropathy Clinical Evaluation Outcomes Related to Treatment Practices in Peripheral
(CREDENCE) trial among patients with type 2 diabetes and Arterial Disease: Investigating Trajectories (PORTRAIT)
chronic kidney disease taking canagliflozin vs placebo (HR study of PAD patients treated at vascular care sites in the U.S.,
1.11, 95% CI 0.79-1.56).81 One observational study suggests The Netherlands, and Australia revealing that 89% patients
that in adults over 65 years of age with baseline CVD who were on antiplatelets and 83% on statins.18
start taking canagliflozin vs a glucagon-like peptide 1 (GLP-1) Data also reveal that patients with PAD are less likely than
receptor agonist, the number needed to treat for an additional similar patients with CAD to use these therapies, despite equal
harmful outcome is high (556 patients at 6 months).82 The or greater benefit with their use. For example, Berger et al.
magnitude of this risk may be outweighed by the immense found that PAD patients with comorbid CAD were more
cardioprotective effects of these medications. The concern likely to receive antiplatelets, statin, and ACEi/ARB (odds
regarding amputation and SGLT2 inhibitors appears to be ratio 2.6 for each) at a given visit compared with patients with
specific to canagliflozin,83 and a recent analysis of dapagli- PAD alone.19
flozin revealed that it has clinical benefits in CV outcomes At the patient level, although there is little data specific to
regardless of PAD status, without an incremental risk of PAD, one study found that more than 30% of patients with
amputation.84 In the subgroup of PAD patients from the PAD older than 65 years were no longer taking antiplatelet
Empagliflozin Cardiovascular Outcome Event Trial in Type therapy 5 years after initial prescription,92 and among those
2 Diabetes Mellitus PatientseRemoving Excess Glucose who did persist with therapy, 15% had less than 80% of days
(EMPA-REG OUTCOME) trial, treatment with empagli- covered.93 Several factors may contribute to poor adherence to
flozin vs placebo resulted in statistically significant reductions prescribed therapy. Awareness of PAD as a diagnosis and
in all-cause mortality (HR 0.62, 95% CI 0.44-0.88) and CV understanding of the disease has been found to be poor even
death (HR 0.57, 95% CI 0.37-0.88).85 GLP-1 receptor ag- among patients attending clinics for PAD.94,95 Descriptive
onists are other glucose-lowering medications that also reduce studies show that many patients with PAD, even in the
adverse cardiac outcomes in high-risk diabetic patients.86 context of recent hospitalisation for limb ischemia, express
Guidelines recommend comprehensive care plans coordi- weak belief in the necessity of medication.20 Patient education
nated among team members for patients with PAD and co- can improve utilisation of guideline-based therapies, and a
morbid diabetes.12 network meta-analysis found that patient education as a
component of cardiac rehabilitation reduced the hazards of
MI and hospitalisation. However, there is a lack of stand-
Therapies to improve walking distance
ardisation of patient education interventions, likely related to
There is some evidence to support the use of cilostazol, a the heterogeneous preferences and needs of patients, leading
vasodilator, to improve walking distance in patients with to difficulty in delivering evidence-based patient education in
stable intermittent claudication, but no benefit in reducing PAD.94 Cost may also affect the use of medications, as pa-
CV events has been found for it, and it is contraindicated in tients with PAD have lower socioeconomic status than pa-
patients with left ventricular dysfunction and heart failure.87 tients with CAD.96 In a Canadian survey, 70% of vascular
Cilostazol’s clinical utility is limited by side-effects (head- surgeons cited cost as their principal concern regarding pre-
ache), contraindications (heart failure), and marginal benefit scription of combination low-dose rivaroxaban and aspirin.97
compared with distance gained through supervised exer- Providing medications at no cost improved adherence among
cise.88 Pentoxifylline is a medication that increases red cell patients who cited cost as a barrier in a randomised controlled
deformability, and theoretically may improve peripheral trial.98
blood flow, but current guidelines do not endorse its use in Research into health care providerelevel barriers to
improving walking distance, owing to limited conclusive medication prescription in PAD is limited, but may include
evidence.89 capability barriers (such as lack of knowledge and skills) and
640 Canadian Journal of Cardiology
Volume 38 2022

Table 2. Proposed core elements for PAD secondary prevention clinics of the reasons for these sex differences are poorly understood,
1) Access to a secondary prevention program underrepresentation of women in clinical trials may result in
A clinic with an explicit mandate to optimise preventive therapy for PAD therapies that are optimised and marketed for men more than
patients should be identified and made accessible for PAD patients. for women.35
2) Referral system
A system to prompt and accept referrals from inpatient and outpatient
environments should be established. Clear criteria for referrals should be
communicated.
3) Intake assessment
How can barriers to optimal use of secondary prevention
Screening for smoking status, hypertension, diabetes, current activity levels therapies in PAD be overcome?
and limitations, lipid profile, and diet should occur at intake.
4) Patient education Strategies to optimise secondary prevention therapies in
Patients should be educated about PAD manifestations, risk factors, and PAD should address barriers at patient, health care provider,
therapies, with consideration of their individual learning needs and and system levels. An approach similar to that of the Ontario
preferences. Core Elements for Stroke Prevention Clinics,103 and consis-
5) Medication optimisation
Procedures for medication reconciliation, recognition of suboptimal
tent with the Cardiac Care Network of Ontario Standards for
prescribing, and optimisation should be followed. the Provision of Cardiovascular Rehabilitation,104 can be
6) Smoking cessation taken. The following core elements for PAD secondary pre-
Smoking status should be reviewed, smokers should be counselled to quit at vention clinics are proposed: 1) access to a secondary pre-
every visit, and those who are interested should be offered vention program; 2) an established system for referral to the
pharmacotherapy.
7) Diabetes care program; 3) intake assessment that includes risk factor
Patients with diabetes should receive comprehensive coordinated care, screening; 4) patient education on manifestations, risk factors,
including guideline-based foot screening. and therapies for PAD; 5) medication optimisation; 6) a
8) Exercise smoking cessation plan; 7) access to comprehensive diabetes
Patients should be referred to a PAD-specific structured exercise program,
which may take place in collaboration with a cardiac rehabilitation
care; 8) access to an evidence-based exercise program; 9)
program. communication and coordination with other health care team
9) Communication with health team members members; and 10) quality assurance (Table 2).
The intake assessment and any recommended changes to the medical plan The first step is to identify a clinic that can see patients
should be documented and communicated to other members of the specifically to optimise preventive therapy for PAD patients.
patient’s health team. At discharge from the clinic, clear follow-up
instructions should be communicated. This may be a vascular surgery clinic, vascular medicine clinic,
10) Quality assurance or part of a cardiac rehabilitation program. Accessibility for
Data on the proportion of patients offered and utilising each component of PAD patients, including transportation options and distance
evidence-based secondary prevention should be collected and regularly from parking to the site, should be considered.31,32
reviewed.
A system to prompt and accept referrals from vascular
PAD, peripheral artery disease. surgery wards, vascular surgery clinics, and primary care clinics
should be established and clearly communicated. Patients who
have undergone revascularisation or amputation are at highest
risk of CV events and may be targeted for more intensive
intention barriers (lack of motivation owing to previous failed secondary prevention efforts. We are currently studying the
attempts, doubts about the efficacy or importance of pre- use of a discharge checklist to be used after revascularisation
ventive therapies, and habits).99 “Diffusion of responsibility,” that includes assessment of major risk factors, ensures
in which there is lack of clarity regarding who will be ensuring consideration of antithrombotic therapy, statins, and coun-
optimisation of secondary prevention of vascular outcomes, selling on smoking cessation, and referral to a comprehensive
may act as another barrier for primary care physicians and secondary prevention program (Medical Care GAPs in Pe-
vascular surgeons,100 as has been shown in other disease ripheral Arterial Disease e Checklist implementation Pilot
states.101 In a Canadian study, hospitalisation for PAD Trial) GAP-PAD Check Pilot Trial.
resulted in high rates of antithrombotics use at discharge, but Once patients are seen in the prevention clinic, their intake
no improvement was seen in prescription of statins (60.8% vs assessment should include screening for smoking status, hy-
56.3%; P ¼ 0.23) or ACEis/ARBs (48.7% vs 50.6%; P ¼ pertension, diabetes, current activity levels and limitations,
0.58) when comparing preadmission and postdischarge pre- lipid profile, and diet.104
scriptions.10 This suggests that inpatient providers may focus Patients should receive educational materials in print or
on certain medications, assuming others will be managed by electronically about PAD manifestations, risk factors, and
outpatient providers. Lack of access to comprehensive sec- therapies.
ondary prevention programs, such as exists for cardiac reha- The clinic should use a medication reconciliation proced-
bilitation, limits opportunities to provide comprehensive ure to accurately capture current medications. Tools for
secondary prevention for PAD patients. medication reconciliation are available from the Institute for
Of particular concern is the low rate of prescription of Safe Medication Practices Canada.105 Patients who are not
evidence-based therapies for women with PAD. Although prescribed or on suboptimal doses of statin, ACEi or ARB,
these data are limited, there are parallels with women with and antithrombotics, should receive evidence-based therapy as
CAD, who also are less likely to receive prescriptions for outlined above. Prescription of lower-cost brands of approved
guideline-recommended antiplatelet or statin therapy, and are medications may improve adherence.106 Adherence to, and
less likely to have their hypertension controlled, despite tolerance of, guideline-recommended therapies should be
similar observed benefits in trials as for men.102 Although all routinely assessed.
Bhagirath et al. 641
Building Your PAD Toolkit

Smoking status should be reviewed with every PAD pa- 2010: a systematic review and analysis. Lancet 2013;382(9901):
tient, and those who are currently smoking and interested in 1329-40.
quitting should be offered nicotine replacement therapy, 2. Makowsky M, McMurtry MS, Elton T, et al. Prevalence and treat-
bupropion, or varenicline. The Centers for Disease Control ment patterns of lower extremity peripheral arterial disease among
and Prevention website hosts tools for clinicians to help pa- patients at risk in ambulatory health settings. Can J Cardiol 2011;27:
tients with smoking cessation,107 and in Canada, the Ottawa 389.e11-8.
Model for Smoking Cessation108 can help to improve provi-
3. Blais C, Rochette L, Ouellet S, Huynh T. Complex evolution of
sion of smoking cessation services. A free smokers’ helpline is
epidemiology of vascular diseases, including increased disease burden:
available in Canada at þ1-866-366-3667 and from 2000 to 2015. Can J Cardiol 2020;36:740-6.
SmokersHelpline.ca.109
Patients with diabetes should receive coordinated and 4. Meru AV, Mittra S, Thyagarajan B, Chugh A. Intermittent claudica-
comprehensive management, especially those with CLI, in tion: an overview. Atherosclerosis 2006;187:221-37.
whom improved glycemic control reduces the risk of ampu- 5. Kinlay S. Management of critical limb ischemia. Circ Cardiovasc Interv
tation and failure of revascularisation.13,110 Guideline-based 2016;9:e001946.
regular foot screening should be ensured.111
Interested patients should be referred to an evidence-based 6. Li B, Rizkallah P, Eisenberg N, Forbes TL, Roche-Nagle G. Rates of
exercise program. The Vascular Disease Foundation (VDF) intervention for claudication versus chronic limb-threatening ischemia
in Canada and United States [e-pub ahead of print]. Ann Vasc Surg
and the American Association of Cardiovascular and Pulmo-
2021. https://doi.org/https://doi.org/10.1016/j.avsg.2021.10.068.
nary Rehabilitation (AACVPR) have produced a toolkit that
outlines protocols and considerations to set up supervised 7. Abramson BL, Huckell V, Anand S, et al. Canadian Cardiovascular
exercise programs tailored to PAD patients.112 Society Consensus Conference: peripheral arterial diseasedexecutive
Other providers involved in care of the patient should be summary. Can J Cardiol 2005;21:997-1006.
routinely identified. Notes from the secondary prevention 8. Criqui MH, Aboyans V. Epidemiology of peripheral artery disease. Circ
clinic should be communicated to these team members, and a Res 2015;116:1509-26.
mechanism should be created to ensure handover of ongoing
secondary prevention efforts once the patient is discharged 9. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or
from the clinic.12 without aspirin in stable cardiovascular disease. N Engl J Med
2017;377:1319-30.
Finally, performance should be regularly reviewed for
adherence to guidelines; ideally, data on the proportion of 10. Kaplovitch E, Collins A, McClure G, et al. Medical therapy following
patients who are offered each component of evidence-based urgent/emergent revascularization in Peripheral artery disease patients
secondary prevention should be collected. Patient satisfac- (Canadian Limb Ischemia Registry (CANALISE I). CJC Open 2021;3:
tion surveys can provide data on how to improve adherence. 1325-32.

11. Michie S, Johnston M, Abraham C, et al. Making psychological theory

useful for implementing evidence based practice: a consensus approach.
Conclusion Qual Saf Health Care 2005;14:26-33.
Although evidence-based guidelines identify life-saving
therapies to prevent adverse CV events in PAD patients, 12. Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC
guideline on the management of patients with lower extremity periph-
these therapies are underutilised. A variety of patient-, pro-
eral artery disease: a report of the American College of Cardiology/
vider-, and system-level barriers contribute to this under-
American Heart Association Task Force on Clinical Practice Guidelines.
utilisation. By building a PAD toolkit, some of these barriers Circulation 2017;135:e726-79.
can be overcome, and morbidity and mortality can be reduced
for patients with PAD. 13. Aboyans V, Ricco JB, Bartelink MLEL, et al. 2017 ESC guidelines on
the diagnosis and treatment of peripheral arterial diseases, in collabo-
ration with the European Society for Vascular Surgery (ESVS): docu-
ment covering atherosclerotic disease of extracranial carotid and
Funding Sources
vertebral, mesenteric, renal, upper and lower extremity arteries.
Dr Anand holds a Tier 1 Canada Research Chair in Ethnic Endorsed by: the European Stroke Organization (ESO), the Task Force
Diversity and Cardiovascular Disease, and a Heart & Stroke for the Diagnosis and Treatment of Peripheral Arterial Diseases of the
Foundation/Michael G. DeGroote Chair in Population European Society of Cardiology (ESC) and of the European Society for
Health Research McMaster University. Vascular Surgery (ESVS). Eur Heart J 2018;39:763-816.

14. Armstrong EJ, Wu J, Singh GD, et al. Smoking cessation is associated

with decreased mortality and improved amputation-free survival among
Disclosures
patients with symptomatic peripheral artery disease. J Vasc Surg
Dr Bhagirath discloses grants from Pfizer Canada and 2014;60:1565-71.
honoraria from Bayer. Dr Anand receives honoraria for
speaking and consultancy from Bayer and Janssen. The other 15. Willigendael EM, Teijink JAW, Bartelink ML, et al. Smoking and the
authors have no conflicts of interest to disclose. patency of lower extremity bypass grafts: a meta-analysis. J Vasc Surg
2005;42:67-74.

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