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Canadian Journal of Cardiology

Canadian Cardiovascular Society 2022 Guidelines for Peripheral Arterial Disease

      Abstract

      Patients with widespread atherosclerosis such as peripheral artery disease (PAD) have a high risk of cardiovascular and limb symptoms and complications, which affects their quality of life and longevity. Over the past 2 decades there have been substantial advances in diagnostics, pharmacotherapy, and interventions including endovascular and open surgical to aid in the management of PAD patients. To summarize the evidence regarding approaches to diagnosis, risk stratification, medical and intervention treatments for patients with PAD, guided by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework, evidence was synthesized, and assessed for quality, and recommendations provided—categorized as weak or strong for each prespecified research question. Fifty-six recommendations were made, with 27% (15/56) graded as strong recommendations with high-quality evidence, 14% (8/56) were designated as strong recommendations with moderate-quality evidence, and 20% (11/56) were strong recommendations with low quality of evidence. Conversely 39% (22/56) were classified as weak recommendations. For PAD patients, strong recommendations on the basis of high-quality evidence, include smoking cessation interventions, structured exercise programs for claudication, lipid-modifying therapy, antithrombotic therapy with a single antiplatelet agent or dual pathway inhibition with low-dose rivaroxaban and aspirin; treatment of hypertension with an angiotensin converting enzyme or angiotensin receptor blocker; and for those with diabetes, a sodium-glucose cotransporter 2 inhibitor should be considered. Furthermore, autogenous grafts are more effective than prosthetic grafts for surgical bypasses for claudication or chronic limb-threatening ischemia involving the popliteal or distal arteries. Other recommendations indicated that new endovascular techniques and hybrid procedures be considered in patients with favourable anatomy and patient factors, and finally, the evidence for perioperative risk stratification for PAD patients who undergo surgery remains weak.

      Résumé

      Les patients atteints d'athérosclérose généralisée telle que la maladie artérielle périphérique (MAP) présentent un risque élevé de symptômes et de complications cardiovasculaires et au niveau des membres, ce qui affecte leur qualité de vie et leur longévité. Au cours des 20 dernières années, des progrès considérables ont été réalisés en matière de diagnostic, de pharmacothérapie et d'interventions, notamment endovasculaires et chirurgicales à ciel ouvert, pour faciliter la prise en charge des patients atteints de MAP. Pour récapituler les données probantes relatives aux approches de diagnostic, à la stratification du risque, aux traitements médicaux et interventionnels pour les patients atteints de MAP, éclairé selon le cadre Grading of Recommendations, Assessment, Development, and Evaluation (GRADE), ces évidences ont été synthétisées et évaluées en fonction de critères de qualité, puis des recommandations ont été exposées - classées comme faibles ou fortes pour chacune des questions de recherche préspécifiées. Cinquante-six recommandations ont été formulées, dont 27 % (15/56) ont été classées en tant que fortes recommandations avec des donnnées probantes de haute qualité, 14 % (8/56) ont été désignées en tant que fortes recommandations avec des donnnées probantes de qualité modérée, et 20 % (11/56) étaient des recommandations fortes avec des donnnées probantes de faible qualité. Inversement, 39 % (22/56) ont été classées comme faibles recommandations. Pour les patients atteints de MAP, les fortes recommandations, basées sur des donnnées probantes de haute qualité, comprennent des interventions de sevrage tabagique, des programmes d'exercices structurés pour la claudication, un traitement modulant les taux lipidiques, un traitement antithrombotique avec un seul agent antiplaquettaire ou une inhibition duale avec de faibles doses de rivaroxaban et d'aspirine; un traitement contre l'hypertension par une enzyme de conversion de l'angiotensine ou un bloqueur des récepteurs de l'angiotensine; et pour les diabétiques, un inhibiteur du cotransporteur sodium-glucose de type 2 devrait être envisagé. En outre, les greffes de matériel autogène sont plus efficaces que les greffons prothétiques pour les pontages chirurgicaux dans le cas de claudication ou d'ischémie chronique menaçant un membre et impliquant les artères poplitées ou distales. D'autres recommandations attestent que les nouvelles techniques endovasculaires et les procédures hybrides doivent être envisagées chez les patients présentant une anatomie et des facteurs favorables. Enfin, les évidences restent fragiles dans le cas d'une stratification du risque péri-opératoire pour les patients atteints de MAP et subissant une intervention chirurgicale.
      Peripheral arterial disease (PAD) is often asymptomatic, and is underdiagnosed, under-recognized, and undertreated. It is associated with significant cardiovascular (CV) and cerebrovascular morbidity and mortality. Since the 2005 Canadian Cardiovascular Congress Consensus Conference on PAD, newer data are available to inform clinicians on best practices to manage patients with PAD.
      Section 1 of this guideline provides evidence-based recommendations on the diagnosis and screening of patients with PAD, with a focus primarily on lower-extremity PAD. We discuss the most accurate signs, symptoms, and tests for detecting PAD in symptomatic and asymptomatic individuals. We review whether routine screening of patients at high risk for, or with established atherosclerosis, benefit from routine screening for PAD to reduce limb ischemia and global CV outcomes. We also review the evidence for screening patients with PAD for coronary artery disease (CAD) or cerebrovascular disease, to determine if this improves prognosis.
      Section 2 provides evidence-based recommendations and highlights the recent substantial advancements in the medical management of patients with PAD. We provide recommendations for clinicians who care for PAD patients regarding smoking cessation and exercise therapy. We also review the key evidence that supports risk factor modification and drug therapy including: (1) blood pressure (BP) diagnosis, lowering, and targets, and selection of BP medications; (2) the use of glucose-lowering medications; (3) the effectiveness of lipid-lowering agents including statins, proprotein convertase subtilisin/Kexin-9 (PCSK-9) inhibitors, and the role of icosapent ethyl. A substantial body of literature regarding the efficacy and safety of antithrombotic therapy in patients with PAD is reviewed, integrating recent evidence for low-dose rivaroxaban and aspirin to reduce major adverse CV and major adverse limb events (MALE). Use of antithrombotics in a broad range of PAD patients is discussed, from outpatients to those with lower extremity revascularization, including endovascular and open surgical approaches.
      Section 3 provides guidance on revascularization procedures for patients with PAD. Preoperative assessment and risk stratification, and indications for revascularization are also reviewed. Significant advancements in technology and techniques of revascularization, particularly for endovascular procedures, are discussed to inform the nonsurgeon clinician caring for the patient with PAD. For surgeons and interventionalists, evidence for choosing between open surgical and endovascular procedures are reviewed.
      Please refer to the Supplementary Material for expanded information on the topics that follow.

      Methodology

      The topics and scope were chosen by the 3 co-chairs. Aortic diseases were explicitly excluded. The primary and secondary panelists were assigned to each of the topic areas on the basis of consideration of their research and clinical expertise, with consideration for geography and gender. Primary panelists were asked to develop the health care questions and outline Population, Intervention, Comparison, Outcome (PICO) questions, if applicable. Evidence reviews were led by the primary panelists and supported by a targeted scan for on-topic systematic reviews and meta-analyses from 2016 to 2021 for the topics, identified by the McMaster Evidence Review Synthesis Team (MERST). The search was conducted in PubMed using keywords: “peripheral artery disease” and “diagnosis,” and “meta-analysis.” This search resulted in 369 citations, which were reviewed for each of the guideline topics. This initial search was augmented for each PICO question, the results of which can be found on ccs.ca. For sections on lipid-lowering, glucose-lowering, and antithrombotic therapy, which were dominated by multiple recent randomized controlled trials (RCTs), MERST completed a more detailed literature review (see ccs.ca). The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) scale for rating the strength of recommendations and the quality of evidence was applied.
      Canadian Cardiovascular Society
      Framework for Application of GRADE in CCS Guideline Development.
      When each section was complete, the primary panelists voted on the recommendations and if more than two-thirds of the members agreed, it was confirmed. Secondary panelists were then asked to read the entire document and provide comments. The recommendation discussions are prefaced by the PICO points we considered in their development.

      1. Diagnosis and Screening

      1.1 Diagnosis of PAD

      PICO 1.1a: What are the most accurate signs, symptoms, and tests for detecting asymptomatic PAD in adults at risk of PAD?
      PICO 1.1b: What are the most accurate signs, symptoms, and tests (Ankle-Brachial Index [ABI], Toe-Brachial Index [TBI], transcutanous oxygen pressure [TcP02], plethysmographic waveforms, magnetic resonance angiography [MRA], computed tomography angiography [CTA], etc) for detecting PAD in adult men and women who present with lower limb symptoms?
      PICO 1.1c: What are the most accurate signs, symptoms, and tests (ABI, TBI, TcPO2, plethysmographic waveforms, MRA, CTA, etc) for detecting PAD in adult men and women with diabetes or chronic kidney disease who present with lower limb symptoms?
      Lower extremity PAD is prevalent among people aged 50 years and older. Among those with lower limb symptoms suggestive of claudication, it is important for clinicians to distinguish PAD from other causes of leg pain (Table 1), starting with a thorough clinical history and physical examination focused on relevant signs and symptoms. A validated diagnostic questionnaire for PAD used in epidemiological studies is the Edinburgh Claudication Questionnaire (Table 2), which has a 91.3% (95% confidence interval [CI], 88.1%-94.5%) sensitivity and 99.3% (95% CI, 98.9%-100%) specificity.
      • Lend G.C.
      • Fowkes F.G.R.
      The Edinburgh Claudication Questionnaire: an improved version of the WHO/Rose questionnaire for use in epidemiological surveys.
      Table 1Differential diagnosis for leg pain or claudication
      • Hennion D.R.
      • Siano K.A.
      Diagnosis and treatment of peripheral arterial disease.
      Neurogenic
      • Spinal stenosis
      • Peripheral neuropathy
      • Peripheral nerve pain (eg, radiculopathy)
      • Spondylolisthesis
      Musculoskeletal
      • Arthritis of the hip or knee
      • Symptomatic Baker cyst
      • Chronic exertional compartment syndrome
      • Stress fracture
      • Muscle spasms or cramps
      Vascular
      • Peripheral arterial disease
      • Chronic limb-threatening ischemia
      • Venous insufficiency
      • Deep venous thrombosis
      • Nonatherosclerotic arterial disease (eg, popliteal entrapment syndrome)
      Other
      • Restless leg syndrome
      • Malignancy
      Table 2Edinburgh Claudication Questionnaire
      • 1.
        Do you get a pain or discomfort in your leg(s) when you walk?
      • 2.
        Does this pain ever begin when you are standing still or sitting?
      • 3.
        Do you get it if you walk uphill or hurry?
      • 4.
        Do you get it when you walk at an ordinary pace on the level?
      • 5.
        What happens to it if you stand still?
      •  Usually continues more than 10 minutes
      •  Usually disappears in 10 minutes or less
      • 6.
        Where do you get this pain or discomfort?
      Only 5%-10% of patients with PAD present with classical symptoms of intermittent claudication.
      • Bauersachs R.
      • Debus S.
      • Nehler M.
      • et al.
      A targeted literature review of the disease burden in patients with symptomatic peripheral artery disease.
      Other patients present with nonspecific back, buttocks, or leg discomfort, whereas some are asymptomatic. Classic features of claudication include: (1) muscle pain, typically involving calf muscles or the muscle group distal to an arterial tenosis or occlusion and often described as cramping in nature; (2) pain that develops only when the muscle is exercised; and (3) pain that resolves usually within 10 minutes of discontinuation of exercise or resting. Typically, patients with vasculogenic claudication experience cramping muscle pain after walking a similar distance. Intermittent claudication differs from chronic limb-threatening ischemia, which includes ischemic rest pain, gangrene, or ulceration on the lower extremity.
      After a thorough clinical history, clinicians should conduct a focused peripheral vascular examination. Confirmation of the diagnosis of PAD then requires specific tests, considering the broad differential for leg pain (see section 1.1 of the Supplementary Material for more information).
      There are a number of confirmatory diagnostic tests that help establish the diagnosis of PAD. Some of these tests are more invasive and others are specialized and/or centre-specific. The most widely used test is the ABI.
      The ABI is an inexpensive, noninvasive test that involves measuring the systolic BP at the arm (or over the brachial artery) and ankle (or over the dorsal pedis or posterior tibial artery) while the patient is supine, using a continuous-wave Doppler device (Fig. 1). The higher value of systolic pressure at the ankle is divided by the higher of the arm pressures (right or left) to obtain the ABI.
      • Aboyans V.
      • Criqui M.H.
      • Abraham P.
      • et al.
      Measurement and interpretation of the Ankle-Brachial Index: a scientific statement from the American Heart Association.
      ,
      • Khan N.A.
      • Rahim S.A.
      • Anand S.S.
      • Simel D.L.
      • Panju A.
      Does the clinical examination predict lower extremity peripheral arterial disease?.
      The most widely used and accepted ABI calculation is shown in Figure 1. An ABI < 0.9 suggests PAD.
      • Aboyans V.
      • Criqui M.H.
      • Abraham P.
      • et al.
      Measurement and interpretation of the Ankle-Brachial Index: a scientific statement from the American Heart Association.
      Figure thumbnail gr1
      Figure 1Calculating Ankle-Brachial Index (ABI). Image from the video “How to Detect Peripheral Arterial Disease (PAD).” Reproduced with permission from the Quebec Society of Vascular Sciences (QSVS) / Société des sciences vasculaires du Québec (SSVQ). See the video in English “How to Detect Peripheral Arterial Disease (PAD)” (https://youtu.be/5ux13-XjzgQ) and in French “Comment détecter la maladie artérielle périphérique (MAP)” (https://www.youtube.com/watch?v=MX4fAqL_15g).
      The incidence of PAD varies according to the prevalence of risk factors for the disease such as smoking, hypertension, hypercholesterolemia, and diabetes mellitus.
      • Bauersachs R.
      • Debus S.
      • Nehler M.
      • et al.
      A targeted literature review of the disease burden in patients with symptomatic peripheral artery disease.
      Medial arterial calcinosis, which is more prevalent in patients with diabetes, chronic kidney disease, and advanced age, results in poorly compressible arteries.
      • Tehan P.E.
      • Santos D.
      • Chuter V.H.
      A systematic review of the sensitivity and specificity of the toe-brachial index for detecting peripheral artery disease.
      This might falsely normalize or artificially elevate ABI to a value exceeding 1.4, rendering this test less reliable.
      Many studies have investigated the accuracy of ABI, oscillometric ABI, TBI, near-infrared technology, pulse oximetry, pulse wave velocity, transcutaneous oxygenation, computed tomography, magnetic resonance imaging, and conventional angiography for diagnosing PAD. The TBI can be calculated with arm and great toe arterial BP measurements. The great toe systolic pressures are divided by the highest arm pressure to establish a TBI measurement for each leg. ABI and TBI are the most studied, but there is a paucity of data for most other tests for the diagnosis of PAD. From these accuracy studies, test characteristics have a very wide range depending on symptoms and risk factors of the population (eg, sensitivity of 45%-100% and specificity of 16%-100% for TBI).
      • Tehan P.E.
      • Santos D.
      • Chuter V.H.
      A systematic review of the sensitivity and specificity of the toe-brachial index for detecting peripheral artery disease.
      There is also a lack of consistency with respect to how to perform an ABI or TBI. With TBI, the diagnostic cutoff for PAD is variable among studies, although < 0.60 is commonly used.
      Data suggest that ABI is a reliable way to diagnose PAD. Table 3 shows a comparison of general sensitivity and specificity ranges for these test modalities.
      Table 3Pooled estimates of sensitivity and specificity for diagnosis of PAD reported in systematic reviews
      • Herraiz-Adillo Á.
      • Cavero-Redondo I.
      • Álvarez-Bueno C.
      • Pozuelo-Carrascosa D.P.
      • Solera-Martínez M.
      The accuracy of toe brachial index and ankle brachial index in the diagnosis of lower limb peripheral arterial disease: a systematic review and meta-analysis.
      • Chuter V.H.
      • Searle A.
      • Barwick A.
      • et al.
      Estimating the diagnostic accuracy of the ankle–brachial pressure index for detecting peripheral arterial disease in people with diabetes: a systematic review and meta-analysis.
      • Normahani P.
      • Mustafa C.
      • Shalhoub J.
      • et al.
      A systematic review and meta-analysis of the diagnostic accuracy of point-of-care tests used to establish the presence of peripheral arterial disease in people with diabetes.
      Study populationTest modalitySensitivity (95% CI), %Specificity (95% CI), %
      PADABI < 0.961 (55-69)92 (89-95)
      TBI < 0.681 (70-94)77 (66-90)
      PAD and diabetesABI < 0.960-65 (48-71)87 (78-92)
      TBI < 0.683 (59-94)66 (41-84)
      Tibial waveform83 (73-89)87 (76-93)
      ABI, Ankle-Brachial Index; CI, confidence interval; PAD, peripheral arterial disease; TBI, Toe-Brachial Index.
      An ABI might be insufficient to be used alone for the detection of PAD in people with diabetes and chronic kidney disease because of the higher probability of medial calcification. The literature is limited on diagnosis in patients with chronic kidney disease. Other tests such as the TBI, tibial waveform, and/or transcutaneous oxygenation should be considered for diagnosing PAD in the case that ABI > 1.4, suggestive of calcified arteries.

      1.1.1 Sex/gender differences

      Although population-based studies suggest higher prevalence of asymptomatic disease and more complex or multilevel and severe disease at the time of diagnosis for women, there is a paucity of studies that specifically examined sex differences in diagnosis of PAD.
      • Higgins P.
      • Higgins A.
      Epidemiology of peripheral arterial disease in women.
      • Ortmann J.
      • Nüesch E.
      • Traupe T.
      • Diehm N.
      • Baumgartner I.
      Gender is an independent risk factor for distribution pattern and lesion morphology in chronic critical limb ischemia.
      • Sigvant B.
      • Wiberg-Hedman K.
      • Bergqvist D.
      • et al.
      A population-based study of peripheral arterial disease prevalence with special focus on critical limb ischemia and sex differences.
      However, inclusion of the ABI in CV risk stratification resulted in reclassification of the risk category and modification of treatment in approximately 19% of men and 36% of women.
      • Alahdab F.
      • Wang A.T.
      • Elraiyah T.A.
      • et al.
      A systematic review for the screening for peripheral arterial disease in asymptomatic patients.
      The effect of sex and gender on PAD presentation and diagnostic tools such as ABI and TBI warrant further study.
      • 1.
        We suggest using the ABI for asymptomatic adults, older than age 50 years, who have risk factors for PAD (such as smoking or diabetes), to screen for PAD (Weak Recommendation; Low-Quality Evidence).
      • 2.
        We recommend using an ABI and/or a TBI study to confirm the diagnosis of PAD in patients with symptoms of PAD (Strong Recommendation; Moderate-Quality Evidence).
      • 3.
        We suggest using a TBI with tibial waveforms and/or transcutaneous oxygen pressure as adjuncts for patients with symptoms of PAD with calcified arteries to confirm the diagnosis of PAD (Weak Recommendation; Low-Quality Evidence).
      Values and preferences. To improve patient’s quality and quantity of life in the long-term, it is important to diagnose PAD in at-risk asymptomatic, and symptomatic patients to initiate appropriate best, evidence-based, medical therapy.
      Practical tip. The ABI used in the diagnosis of PAD can be easily classified and measured. See Figure 1 and video links provided in the legend.

      1.2 Asymptomatic PAD Screening

      PICO 1.2a: In patients without claudication symptoms, but at high risk for clinically apparent atherosclerotic disease, would routine systematic screening for PAD improve lower limb ischemia outcomes?
      PICO 1.2b: In patients without claudication symptoms, but who have documented atherosclerosis in another vascular bed, would routine systematic screening for PAD improve global CV outcomes?
      The ideal characteristics for a successful population-based screening strategy would include use of a test with high sensitivity that leads to efficacious therapy, if used early in the disease state. Although ABI measurement has very high specificity for detecting PAD, there are no current recommendations for intervention on asymptomatic disease because there has been no demonstration of benefit.
      • Guirguis-Blake J.M.
      • Evans C.V.
      • Redmond N.
      • Lin J.S.
      Screening for peripheral artery disease using the Ankle-Brachial Index updated evidence report and systematic review for the US preventive services task force.
      ,
      • Conte M.S.
      • Pomposelli F.B.
      • Clair D.G.
      • et al.
      Society for Vascular Surgery practice guidelines for atherosclerotic occlusive disease of the lower extremities: management of asymptomatic disease and claudication.
      The Society for Vascular Surgery and the Canadian Society for Vascular Surgery recommend against invasive treatments for asymptomatic PAD (percutaneous or surgery), regardless of ABI or other test results that indicate PAD.
      Canadian Society for Vascular Surgery
      Choosing Wisely Canada Recommendations: Vascular Surgery.
      ,
      • Collet J.P.
      • Cayla G.
      • Ennezat P.V.
      • et al.
      Systematic detection of polyvascular disease combined with aggressive secondary prevention in patients presenting with severe coronary artery disease: the randomized AMERICA study.
      A recent systematic review including studies of asymptomatic patients demonstrated no benefit in major adverse CV events (MACE) or quality of life measures with intervention.
      • Collet J.P.
      • Cayla G.
      • Ennezat P.V.
      • et al.
      Systematic detection of polyvascular disease combined with aggressive secondary prevention in patients presenting with severe coronary artery disease: the randomized AMERICA study.
      A meta-analysis commissioned by the Society for Vascular Surgery did not yield evidence of either cost-effectiveness for ABI screening of asymptomatic patients, or any clear reduction in morbidity or mortality.
      • Alahdab F.
      • Wang A.T.
      • Elraiyah T.A.
      • et al.
      A systematic review for the screening for peripheral arterial disease in asymptomatic patients.
      Individuals with multiple vascular territory involvement or polyvascular disease carry worse prognosis when identified (Fig. 2).
      • Anand S.S.
      • Eikelboom J.W.
      • Dyal L.
      • et al.
      Rivaroxaban plus aspirin versus aspirin in relation to vascular risk in the COMPASS Trial.
      • Bonaca M.P.
      • Nault P.
      • Giugliano R.P.
      • et al.
      Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk).
      • Bonaca M.P.
      • Bhatt D.L.
      • Storey R.F.
      • et al.
      Ticagrelor for prevention of ischemic events after myocardial infarction in patients with peripheral artery disease.
      • Darmon A.
      • Sorbets E.
      • Ducrocq G.
      • et al.
      Association of multiple enrichment criteria with ischemic and bleeding risks among COMPASS-eligible patients.
      To date, there has been no RCT to suggest that the strategy of systematic screening in this setting is effective in lowering rates of CV events, or MALE (evolution to limb-threatening ischemia or limb loss).
      • Collet J.P.
      • Cayla G.
      • Ennezat P.V.
      • et al.
      Systematic detection of polyvascular disease combined with aggressive secondary prevention in patients presenting with severe coronary artery disease: the randomized AMERICA study.
      This is likely because risk factor management and pharmacotherapy are not vastly different when single or multiple vascular beds are involved. Similarly, current guidelines for dyslipidemia, hypertension, or antithrombotic agents have not delineated different treatment streams for patients with vascular disease in multiple vascular territories. However, novel agents, such as PCSK-9 inhibitors and low-dose direct oral anticoagulation were not used in previous studies. It is unknown if diagnosing those at higher risk for events would change management strategies and outcomes.
      Figure thumbnail gr2
      Figure 2Risk of cardiovascular event (screening for coronary artery disease [CAD] and carotid disease in peripheral arterial disease [PAD] patients [death/myocardial infarction/stroke]) in patients with disease in multiple vascular beds (data from a secondary data analysis of the Examining Use of Ticagrelor in Pad [EUCLID] trial).
      • Gutierrez J.A.
      • Mulder H.
      • Jones W.S.
      • et al.
      Polyvascular disease and risk of major adverse cardiovascular events in peripheral artery disease: a secondary analysis of the EUCLID trial.
      CeVD, cerebrovascular disease.
      As we move to precision medicine, the use of the ABI might further refine global CV risk assessment. An abnormal ABI is prognostic, regardless of symptoms. The utility of such a strategy might be dependent on the stage of a patient’s disease. ABIs and CTA delineate flow-limiting lesions. Abnormal results would be a sign of late disease. They are less helpful when trying to detect preclinical or early-stage atherosclerosis in a relatively low risk primary prevention population. However, further refinement of risk estimates in secondary prevention populations could assist in determining the risk-benefit of certain pharmacotherapies and optimize prescription of high-cost treatments. A higher absolute CV risk in a patient with polyvascular disease might justify prescription of a more potent antithrombotic that has a greater bleeding risk,
      • Anand S.S.
      • Eikelboom J.W.
      • Dyal L.
      • et al.
      Rivaroxaban plus aspirin versus aspirin in relation to vascular risk in the COMPASS Trial.
      ,
      • Bonaca M.P.
      • Bhatt D.L.
      • Storey R.F.
      • et al.
      Ticagrelor for prevention of ischemic events after myocardial infarction in patients with peripheral artery disease.
      ,
      • Darmon A.
      • Sorbets E.
      • Ducrocq G.
      • et al.
      Association of multiple enrichment criteria with ischemic and bleeding risks among COMPASS-eligible patients.
      or expensive agents such as PCSK-9 inhibitors. Thus far, we do not have a global vascular risk-estimate tool that has led to ischemic event reduction. A recent cost effectiveness analysis tested the use of ABI screening to detect asymptomatic PAD in patients with recently symptomatic CAD. The analysis showed that patients with asymptomatic PAD had minimal quality of life years gained, with significantly high incremental cost, much above usual willingness to pay thresholds.
      • Minami H.
      • Itoga N.K.
      • George E.L.
      • Garcia-Toca M.
      Cost-effectiveness analysis of Ankle-Brachial Index screening in patients with coronary artery disease to optimize medical management.
      • 4.
        We recommend against implementing a broad, population-based screening strategy for PAD, in patients without signs or symptoms of claudication (Strong Recommendation; High-Quality Evidence).
      Values and preferences. In contrast to general population screening, individual patients with high-risk features such as smoking and diabetes, might benefit from identification of PAD and more aggressive medical management. However, patients do not benefit from revascularization with asymptomatic PAD. Patients’ interest in their future vascular risk should be considered when determining if ABI testing will be undertaken.
      Practical tip. Patients should be assessed and managed for vascular risk factors. Focus should be on the management of CV risk factors rather than the pursuit of revascularization. Currently available tests for PAD do not assess for preclinical disease. Other modalities to assess preclinical disease in coronary and carotid arteries have greater evidence to assist in global CV risk assessment in a primary prevention setting.
      • 5.
        We suggest against routine PAD testing for inferring global CV risk, in patients without symptoms of PAD, who have clinically symptomatic atherosclerosis in another vascular territory (Weak Recommendation; Moderate-Quality Evidence).
      Values and preferences. For patients with polyvascular disease, strong evidence for routine screening of other vascular territories is lacking. There is lack of consensus on how this screening would differentiate treatment. We could not recommend this practice. However, the committee recognizes that in select patients, identifying a second vascular bed might change management and assist in overcoming financial barriers for certain pharmaceuticals.
      Practical tip. Global CV risk reduction should focus on risk factor management as suggested in respective risk factor guidelines.

      1.3 Screening for CAD and carotid disease in PAD patients

      PICO 1.3: Does screening patients with PAD for CAD or cerebrovascular disease reduce myocardial infarction (MI), stroke, or CV death?
      • 6.
        We suggest against routine screening for asymptomatic carotid artery stenosis or asymptomatic CAD, among patients with documented PAD (Weak Recommendation; Low-Quality Evidence).
      Values and preferences. Most patients with PAD require aggressive CV risk factor management to improve long-term outcomes. This is on the basis of the strong epidemiological evidence linking PAD with incident MI and stroke.
      Practical tip. Patients with PAD have a high incidence of concomitant disease in other vascular beds and should be questioned about symptoms attributable to those vascular beds. Patients with polyvascular disease are a particularly high-risk group for future CV events and warrant aggressive management of standard atherosclerotic risk factors, including smoking, hypertension, dyslipidemia, and diabetes.

      2. Management of PAD

      2.1 Smoking cessation

      PICO 2.1: Which smoking cessation interventions (behavioural and drug therapy) are efficacious at reducing MACE and MALE among patients with PAD?
      Of all CV risk factors, tobacco exposure through cigarette smoking is the most strongly associated with the development and progression of PAD and its complications: MACE such as MI, stroke, CV death, and MALE.
      There is a solid foundation of data supporting a variety of smoking cessation interventions. Smoking cessation can prevent PAD and reduce MACE and MALE when PAD becomes symptomatic. Aside from behavioural counselling, pharmacological therapy should be considered, from nicotine replacement therapy (NRT) such as gum and patches, to bupropion and varenicline. Nicotine-containing e-cigarettes (EC) should also be given consideration.
      Behavioural therapy supporting pharmacotherapy does augment the 6-month quitting rate, but the relative risk (RR) is only 1.05-1.20, translating to a 20% quit rate compared with 17% when patients receive no support.
      • Hartmann-Boyce J.
      • Livingstone-Banks J.
      • Ordóñez-Mena J.M.
      • et al.
      Behavioural interventions for smoking cessation: an overview and network meta-analysis.
      Behavioural therapy effectiveness is immensely variable in the literature and has been extensively reviewed in a recent Cochrane review of 312 RCTs with 250,563 participants. The RR of smoking cessation at 6 months is 1.44, ranging from 1.22 to 1.70 with a 6% background rate of quitting.
      • Hartmann-Boyce J.
      • Livingstone-Banks J.
      • Ordóñez-Mena J.M.
      • et al.
      Behavioural interventions for smoking cessation: an overview and network meta-analysis.
      Drug therapies are few and the data are limited mainly to bupropion and varenicline. Bupropion shows an effect on quitting with a RR of 1.64 (additional 6 quitters per 100 after 6 months compared with a nonpharmacological approach).
      • Howes S.
      • Hartmann-Boyce J.
      • Livingstone-Banks J.
      • Hong B.
      • Lindson N.
      Antidepressants for smoking cessation.
      This effect seems less than with varenicline (RR of 0.71).
      • Howes S.
      • Hartmann-Boyce J.
      • Livingstone-Banks J.
      • Hong B.
      • Lindson N.
      Antidepressants for smoking cessation.
      Psychiatric adverse events seem more frequent with bupropion than with placebo (RR, 1.25).
      • Howes S.
      • Hartmann-Boyce J.
      • Livingstone-Banks J.
      • Hong B.
      • Lindson N.
      Antidepressants for smoking cessation.
      A combination of bupropion with NRT or with varenicline marginally appears to enhance the quitting rate but the RRs are respectively 1.19 and 1.21, which are not significant.
      • Brownrigg J.R.W.
      • Hinchliffe R.J.
      • Apelqvist J.
      • et al.
      Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: a systematic review.
      In a network meta-analysis of 267 trials with 101,804 participants, varenicline and combination NRT (ie, combining 2 types of NRT such as patches, tablets, sprays, lozenges, and inhalers) vs placebo were most effective of all drug interventions (varenicline vs placebo odds ratio [OR], 2.88 [95% CI, 2.40-3.47]), accepting nausea as a frequent side effect. This translates to 1 extra quitter for 11 treated people.
      • Cahill K.
      • Lindson-Hawley N.
      • Thomas K.H.
      • Fanshawe T.R.
      • Lancaster T.
      Nicotine receptor partial agonists for smoking cessation.
      Varenicline is similar to combination NRT (OR, 1.06 [95% CI, 0.75-1.48]), and superior to bupropion or single-use NRT, although each of these were superior to placebo (OR for bupropion vs placebo, 1.82 [95% CI, 1.60-2.06]) and NRT vs placebo (OR, 1.84 [95% CI, 1.71-1.99]).
      More recently, nicotine EC have been advocated to reduce smoking addiction. The most recent Cochrane review that compared nicotine EC with NRT showed a positive effect of nicotine EC on quitting with a RR of 1.53 (95% CI, 1.21-1.93) resulting in additional 3 quitters per 100 after 6 months. This effect was higher when compared with behavioural support only/no support, with a RR of 2.61 (95% CI, 1.44-4.74) resulting in additional 6 quitters per 100.
      • Hartmann-Boyce J.
      • McRobbie H.
      • Lindson N.
      • et al.
      Electronic cigarettes for smoking cessation.
      Among patients with PAD, a recent meta-analysis of 6 randomized trials involving 558 patients with PAD in which smoking interventions (behavioural counselling with or without NRT or a community intervention program promoting smoking reduction) were evaluated, suggested smoking cessation interventions increased the chance of quitting smoking (RR, 1.48 [95% CI, 0.84-2.61]),
      • Thanigaimani S.
      • Drovandi A.
      • Golledge J.
      A meta-analysis of randomised controlled trials evaluating the efficacy of smoking cessation interventions in people with peripheral artery disease.
      although the wide CIs indicate a need for more RCTs. Furthermore, a high-quality trial of 124 patients with PAD included in this meta-analysis, in which intensive counselling with a minimum of 6 sessions was tested, was associated with a 2.97 (95% CI, 1.27-6.93) odds of smoking cessation, which was statistically significant.
      • Hennrikus D.
      • Joseph A.M.
      • Lando H.A.
      • et al.
      Effectiveness of a smoking cessation program for peripheral artery disease patients: a randomized controlled trial.
      Considering this, together with the positive effect of individual counselling, compared with usual care groups observed in a meta-analysis of smokers from the general population, which included 27 trials involving 11,100 people in which intensive counselling was effective at bringing about smoking cessation (RR, 1.57; 95% CI, 1.40-1.77), suggests this is an important and effective consideration for smoking cessation strategy for patients with PAD.
      • Lancaster T.
      • Stead L.F.
      Individual behavioural counselling for smoking cessation.
      • 7.
        We recommend smoking cessation to prevent PAD, and to prevent MACE and MALE in patients with PAD (Strong Recommendation; Moderate-Quality Evidence).
      • 8.
        We recommend smoking cessation interventions ranging from intensive counselling, NRT, bupropion, varenicline, and sometimes nicotine EC (Strong Recommendation; High-Quality Evidence).
      Values and preferences. Smoking is one of the most potent risk factors for PAD and is associated with MACE and MALE complications. Studies were selected irrespective of whether the effect of smoking and smoking cessation were specifically focused on PAD patients but also CAD and cardiovascular disease patients or all of these regrouped subpopulations. High value was given to any intervention that led to a significant reduction or cessation of smoking, although the success rate of any given intervention was low compared with treatment of hypertension and dyslipidemia. The value of smoking cessation is considered high not only because of its effect on vascular disease, but also because of the profound effect on preventing many cancers and chronic obstructive pulmonary disease.
      Practical tip. Inquire at every clinical visit about the patient’s smoking status, even if abstinence has been achieved, and offer behavioural support, and present therapeutic options for smoking reduction, and how to access them to patients, because smoking is a major risk factor for CAD and PAD and smoking reduction decreases the risk of MACE and MALE.

      2.2 Glucose control, diabetes, and PAD

      2.2.1 Glucose control and PAD

      PICO 2.2a: Does tight glycemic control (hemoglobin A1c < 7%) reduce incidence of MALE or need for revascularization in patients with PAD?
      Patients with concurrent diabetes and PAD have a three- to fourfold increase in mortality and have a rate of amputation that is 5 times higher than patients with PAD without diabetes.
      • Jude E.B.
      • Oyibo S.O.
      • Chalmers N.
      • Boulton A.J.M.
      Peripheral arterial disease in diabetic and nondiabetic patients: a comparison of severity and outcome.
      • Beks P.J.
      • Mackaay A.J.C.
      • de Neeling J.N.D.
      • de Vries H.
      • Bouter L.M.
      • Heine R.J.
      Peripheral arterial disease in relation to glycaemic level in an elderly Caucasian population: the Hoorn Study.
      • Resnick H.E.
      • Lindsay R.S.
      • McDermott M.M.G.
      • et al.
      Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality: the Strong Heart Study.
      Although promising, no clear association between strict hemoglobin A1c control and reduction in MACE, MALE, or death in patients with PAD has been reported.
      • 9.
        We suggest that tight glycemic control might be beneficial for patients with PAD and diabetes in preventing MALE or need for revascularization (Weak Recommendation; Low-Quality Evidence).

      2.2.2 Diabetes medications and PAD

      PICO 2.2b: Do antihyperglycemic agents result in a reduction in MALE, revascularization, amputation, or MACE, in patients with PAD and diabetes?
      The choice of antihyperglycemic agents in patients with PAD should be individualized to the patient’s wishes, preferences, and financial support/drug coverage. However, diabetes medication should be chosen to provide the optimal CV protection and reduction in MALE.
      • Stone J.A.
      • Houlden R.L.
      • Lin P.
      • Udell J.A.
      • Verma S.
      Cardiovascular protection in people with diabetes.
      Unfortunately, very few hypoglycemic medications have been studied in patients with PAD, although some have shown more promise than others.
      Incretin-based selective inhibitors of dipeptidyl peptidase 4 (DPP-4) medications used in diabetes have not shown a reduction in MACE or MALE in PAD patients. However, a large observational trial of 82,169 patients who started receiving DPP-4 medication did show a 16% reduction in the development of PAD in patients with type 2 diabetes, and a subsequent 35% reduction in amputations among those with established PAD and type 2 diabetes.
      • Chang C.C.
      • Chen Y.T.
      • Hsu C.Y.
      • et al.
      Dipeptidyl peptidase-4 inhibitors, peripheral arterial disease, and lower extremity amputation risk in diabetic patients.
      This vascular protection was only shown in patients receiving combination therapy with metformin. A recent observational study reported a reduction in adverse limb outcomes with glucagon-like peptide 1 (GLP-1) agonists or DPP-4 inhibitors.
      • Lin D.S.H.
      • Lee J.K.
      • Chen W.J.
      Major adverse cardiovascular and limb events in patients with diabetes treated with GLP-1 receptor agonists vs DPP-4 inhibitors.
      There is now a large body of evidence to support the use of the sodium-glucose cotransporter 2 (SGLT-2) inhibitors in patients with PAD and diabetes, in reducing mortality and MACE, and also MALE. In Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction (DECLARE-TIMI), the effects of dapagliflozin was examined in 17,160 patients with diabetes of whom 1025 had concurrent PAD. Patients with PAD and diabetes had higher baseline risk of MACE, hospitalization for heart failure, progression of renal disease, and MALE compared with patients without PAD. The benefit of dapagliflozin in reducing MACE, MALE, and death was consistent regardless of PAD diagnosis in this population. Furthermore, there was no increased risk of adverse limb outcomes in patients with PAD and diabetes randomized to dapagliflozin.
      • Bonaca M.P.
      • Wiviott S.D.
      • Zelniker T.A.
      • et al.
      Dapagliflozin and cardiac, kidney, and limb outcomes in patients with and without peripheral artery disease in DECLARE-TIMI 58.
      In the Canagliflozin Cardiovascular Assessment Study (CANVAS) trial, canagliflozin was associated with an increased risk of amputation among patients with diabetes and PAD, but this has not been observed with other SGLT-2 inhibitors such as empagliflozin and dapagliflozin. Two large meta-analyses reported no overall significant increased risk of amputation with SGLT-2 inhibitors as a class, with the only signal coming from canagliflozin but not the other agents (eg, empagliflozin, dapagliflozin).
      • Dicembrini I.
      • Tomberli B.
      • Nreu B.
      • et al.
      Peripheral artery disease and amputations with sodium-glucose co-transporter-2 (SGLT-2) inhibitors: a meta-analysis of randomized controlled trials.
      ,
      • Huang C.Y.
      • Lee J.K.
      Sodium-glucose co-transporter-2 inhibitors and major adverse limb events: a trial-level meta-analysis including 51 713 individuals.
      • 10.
        We recommend that patients with PAD and type 2 diabetes should be offered a SGLT-2 inhibitor compared with usual diabetic control because of the reduction in MACE without any risk of increased amputation (Strong Recommendation; High-Quality Evidence).
      • 11.
        We suggest that patients with PAD and diabetes might benefit from use of a GLP-1 agonist or DPP-4 inhibitor (Weak Recommendation; Low-Quality Evidence).
      Practical tip. Presently, there is no reason to suspect that empagliflozin or dapagliflozin increase the risk of PAD or lower limb amputations. The risk, or lack of risk, associated with canagliflozin remains to be established.

      2.3 Lipid-lowering and PAD

      PICO 2.3a: In patients with PAD, what is the role of cholesterol-lowering with statins, ezetimibe, niacin, or resins compared with placebo for the reduction of death, CV death, nonfatal MI, nonfatal stroke, or MALE?
      PICO 2.3b: In patients with PAD, what is the role of PCSK-9 inhibitors compared with use of statins with or without ezetimibe for the reduction of death, CV death, nonfatal MI, nonfatal stroke, or MALE?
      Patients with PAD constitute a very high-risk subset of patients with atherosclerotic vascular disease. There is strong and high-quality evidence supporting aggressive lipid-lowering with statins to reduce overall and CV mortality as well as major adverse CV and cerebrovascular events. There is also strong evidence to support this intervention for the purpose of avoiding MALE. There is moderate-quality evidence that aggressive lipid-lowering might improve patient outcomes such as pain-free walking time and overall ambulatory ability. See section 2.3 of the Supplementary Material for further evidence and explanation.
      • 12.
        We recommend that patients with PAD qualify as statin-indicated patients and should receive lipid-modifying therapy for the reduction of death, CV death, nonfatal MI, nonfatal stroke (MACE), and MALE concordant with the recommendations in the 2021 Canadian Cardiovascular Society (CCS) guidelines for the management of dyslipidemia
        • Pearson G.J.
        • Thanassoulis G.
        • Anderson T.J.
        • et al.
        2021 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in adults.
        (Strong Recommendation; High-Quality Evidence).
        • a.
          Maximally tolerated dose of statin therapy
        • b.
          Statin add-on therapies (ezetimibe and/or PCSK-9 inhibitors) if receiving maximally tolerated dose of statin therapy and the low-density lipoprotein cholesterol is ≥ 1.8 mmol/L, non-high-density lipoprotein cholesterol ≥ 2.4 mmol/L or apolipoprotein B100 ≥ 0.7 mg/dL.
      • 13.
        We recommend that patients with PAD, who, despite maximally tolerated dose of statin therapy have a triglyceride level of 1.5-5.6 mmol/L, should be considered for use of icosapent ethyl for the reduction CV death, nonfatal MI, and nonfatal stroke concordant with the recommendations in the 2021 CCS guidelines for the management of dyslipidemia
        • Pearson G.J.
        • Thanassoulis G.
        • Anderson T.J.
        • et al.
        2021 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in adults.
        (Strong Recommendation; Moderate-Quality Evidence).
      Values and preferences. Statin add-on therapy and icosapent ethyl present numerous challenges with respect to cost and access for many patients. They also contribute to the burden of medications and complexity of therapy. Any decision to implement them should be made through open patient-physician discussion. Although not specifically validated in clinical trials, it is reasonable to approach the recommendations for statin add-on therapy in sequence with consideration of ezetimibe followed by PCSK-9 inhibitors if lipid thresholds are not met. But, as emphasized in the 2021 CCS guidelines for the management of dyslipidemia, patients whose levels are significantly above threshold in whom the typical reduction of low-density lipoprotein cholesterol by ezetimibe is not likely to achieve cholesterol levels below threshold might be served more effectively and efficiently by use of a PCSK-9 inhibitor as the add-on of choice while reserving ezetimibe if needed as a third, lipid-lowering agent.
      • Pearson G.J.
      • Thanassoulis G.
      • Anderson T.J.
      • et al.
      2021 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in adults.
      PAD cohorts have been shown consistently to have high risk and high absolute event reductions with PCSK-9 inhibitors.
      • Bonaca M.P.
      • Nault P.
      • Giugliano R.P.
      • et al.
      Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk).
      They benefit from significant event reductions, including adverse limb events, within 3 years, probably because of their far more substantial lipid-lowering compared with ezetimibe, and possibly because of additional benefit when lipoprotein(a) level is elevated. Patient outcomes such as pain-free walk time and overall ambulatory activity are not extensively studied but represent potential additional benefits that might promote acceptance and adherence to these lipid-lowering therapies.
      Evidence for reduction of MALE or PAD patient-relevant outcomes is not yet available for icosapent ethyl. The additional use of this agent has been compared with placebo, not to additional use of ezetimibe or PCSK-9 inhibitors. Moreover, a decision to intensify lipid-lowering using the latter agents in patients receiving maximally tolerated statins might also affect triglycerides, thereby altering the criterion for consideration of icosapent ethyl, which is proven to reduce MACE in the absence of ezetimibe or PCSK-9 inhibitors. Accordingly, for the reduction of MACE, patient-physician decisions that accommodate patient preferences, priorities, and access issues will determine when it is appropriate to consider icosapent ethyl for the PAD patient. See section 2.3 of the Supplementary Material for further evidence and explanation.

      2.4 Hypertension

      PICO 2.4a: How should hypertension be diagnosed in patients with lower extremity PAD?
      Because patients with PAD are at high risk of CV events, hypertension diagnosis and treatment is important as a risk reduction strategy.
      Most clinical studies that described the association between BP control and CV outcomes have used a 24-hour ambulatory BP monitoring (ABPM) assessment to establish a clinical diagnosis of hypertension.
      • Verdecchia P.
      • Reboldi G.
      • Porcellati C.
      • et al.
      Risk of cardiovascular disease in relation to achieved office and ambulatory blood pressure control in treated hypertensive subjects.
      • Rabi D.M.
      • McBrien K.A.
      • Sapir-Pichhadze R.
      • et al.
      Hypertension Canada’s 2020 comprehensive guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children.
      • Staessen J.A.
      • Thijs L.
      • Fagard R.
      • et al.
      Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension.
      Sequential home BP monitoring (HBPM) spaced throughout the day can be used as an alternative. The greater the number of recordings, the more accurately this reflects the true BP when averaged over multiple assessments.
      • Agarwal R.
      • Tu W.
      Minimally sufficient numbers of measurements for validation of 24-hour blood pressure monitoring in chronic kidney disease.
      Out-of-office BP measurements have a better prognostic value compared with office-based assessments.
      • Verdecchia P.
      • Reboldi G.
      • Porcellati C.
      • et al.
      Risk of cardiovascular disease in relation to achieved office and ambulatory blood pressure control in treated hypertensive subjects.
      ,
      • Mulè G.
      • Caimi G.
      • Cottone S.
      • et al.
      Value of home blood pressures as predictor of target organ damage in mild arterial hypertension.
      Moreover, 24-hour ABPM improves CV risk stratification compared with office-based BP assessments.
      • Verdecchia P.
      • Reboldi G.
      • Porcellati C.
      • et al.
      Risk of cardiovascular disease in relation to achieved office and ambulatory blood pressure control in treated hypertensive subjects.
      ,
      • Verdecchia P.
      Prognostic value of ambulatory blood pressure: current evidence and clinical implications.
      Hence, the Hypertension Canada 2020 guidelines advocate for a standardized protocol in which BP is measured at 20- to 30-minute intervals throughout the day.
      • Rabi D.M.
      • McBrien K.A.
      • Sapir-Pichhadze R.
      • et al.
      Hypertension Canada’s 2020 comprehensive guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children.
      If ABPM monitoring is unavailable or not tolerated, HBPM can be used as an alternative.
      Hypertension can be diagnosed after multiple out-of-office assessments. Hypertension is diagnosed if the mean ambulatory daytime BP is ≥ 135/85 mm Hg, or if the 24-hour mean BP is ≥ 130/80 mm Hg (Fig. 3).
      Figure thumbnail gr3
      Figure 3Diagnostic algorithm for hypertension as per the Hypertension Canada guidelines.
      • Rabi D.M.
      • McBrien K.A.
      • Sapir-Pichhadze R.
      • et al.
      Hypertension Canada’s 2020 comprehensive guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children.
      All measurement values in the algorithm are reported as mm Hg. ∗ If AOBP is used, use the mean calculated and displayed by the device. If OBPM is used, take at least 3 readings, discard the first and calculate the mean of the remaining measurements. A history and physical exam should be performed and diagnostic tests ordered. Serial office measurements over 3-5 visits can be used if ABPM or HBPM are not available. Home BP series: 2 readings are taken each morning and evening for 7 days (28 total). Discard first-day readings and average the last 6 days’ readings. § In patients with suspected masked HTN, ABPM or HBPM could be considered to rule out masked HTN. ABPM, ambulatory blood pressure monitoring; AOBP, automated office blood pressure; BP, blood pressure; HBPM, home blood pressure monitoring; HTN, hypertension; OBPM, office blood pressure measurement; WCH, white coat hypertension.
      Reproduced from Rabi et al.
      • Rabi D.M.
      • McBrien K.A.
      • Sapir-Pichhadze R.
      • et al.
      Hypertension Canada’s 2020 comprehensive guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children.
      with permission from Elsevier.
      Patients with PAD are at an elevated risk of future vascular events, and a target of ≥ 140/90 mm Hg should be considered as the treatment threshold.
      The SPRINT Research Group
      A randomized trial of intensive versus standard blood-pressure control.
      PICO 2.4b: In patients with PAD without an indication for a specific antihypertensive agent, what is the ideal BP target?
      Antihypertensive therapy should be administered to patients with hypertension and PAD to reduce the risk of MI, stroke, heart failure, and CV death.
      • Bavry A.A.
      • Anderson R.D.
      • Gong Y.
      • et al.
      Outcomes among hypertensive patients with concomitant peripheral and coronary artery disease: findings from the international VErapamil-SR/ trandolapril study.
      ,
      • Feringa H.H.H.
      • van Waning V.H.
      • Bax J.J.
      • et al.
      Cardioprotective medication is associated with improved survival in patients with peripheral arterial disease.
      There are no large-scale RCTs that specifically assessed BP targets in patients with lower extremity PAD.
      In a subgroup of patients with PAD from the Systolic Blood Pressure Intervention Trial (SPRINT),
      • Frary J.M.C.
      • Pareek M.
      • Byrne C.
      • et al.
      Intensive blood pressure control appears to be effective and safe in patients with peripheral artery disease: the Systolic Blood Pressure Intervention Trial.
      intensive BP lowering to a systolic BP target < 120 mm Hg was associated with a reduction in the primary outcome of CV death and all-cause mortality. Because of the higher baseline risk among patients with PAD, the absolute risk reduction was larger in patients with PAD compared with those without PAD. However, intensive BP control also led to a greater absolute increased risk of adverse events in patients with PAD.
      • 14.
        We suggest favouring HBPM measurement or a 24-hour ABPM over office BP measurement for diagnosis and management of hypertension in patients with PAD. If there is a difference in BP measurements between arms, the higher value should be used for diagnosis and treatment considerations (Weak Recommendation; Low-Quality Evidence).
      • 15.
        We suggest that the approach to initiation and titration of antihypertensive agents should follow the Hypertension Canada guidelines
        • Rabi D.M.
        • McBrien K.A.
        • Sapir-Pichhadze R.
        • et al.
        Hypertension Canada’s 2020 comprehensive guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children.
        (Weak Recommendation; Low-Quality Evidence).
      • 16.
        We suggest treating hypertension to a target of less than 140/90 mm Hg in patients with PAD without compelling indications for specific agents or targets (Weak Recommendation; Low-Quality Evidence).
      Practical tip. In select patients, intensive systolic BP targets (< 120 mm Hg) might be considered. However, we suggest that caution be exercised if systolic BP is < 110 mm Hg because this is associated with an increase rate of adverse events (eg, MACE and MALE) in patients with PAD.
      PICO 2.4c: In patients with PAD without an indication for a specific antihypertensive agent, what is the preferred approach to achieve optimal BP control?
      Optimal hypertension management requires a holistic approach. Lifestyle modifications and pharmacological agents are the mainstay of treatment.

      2.4.1 Lifestyle modification

      Diet, exercise, weight management, alcohol reduction, stress management, and self-monitoring play an important role in managing BP. See Supplemental Table S1 for targets.

      2.4.2 Pharmacological

      Angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium antagonists, and diuretics are all suited for BP-lowering treatment in patients with PAD
      • Whelton P.K.
      • Carey R.M.
      • Aronow W.S.
      • et al.
      2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary.
      ,
      • Williams B.
      • Mancia G.
      • Spiering W.
      • et al.
      2018 ESC/ESH guidelines for the management of arterial hypertension.
      ; see Figure 4, from Hypertension Canada.
      Figure thumbnail gr4
      Figure 4Treatment options for patients with hypertension without a compelling indication for a specific agent as per the Hypertension Canada guidelines.
      Hypertension Canada
      2020 - 2022 Hypertension highlights: a practical guide informed by the Hypertension Canada Guidelines for the Prevention, Diagnosis, Risk Assessment, and Treatment of Hypertension.
      ACE-I, angiotensin-converting enCzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; SPC, single pill combination.
      Reprinted with permission from Hypertension Canada.
      In the absence of contraindications, we recommend that patients with PAD and hypertension be treated with ACE inhibitors or ARBs as first choice agents. ACE inhibitors and ARBs have been shown to reduce MACE in patients with arterial peripheral vascular diseases.
      • Yusuf S.
      • Joseph P.
      • Dans A.
      • et al.
      Polypill with or without aspirin in persons without cardiovascular disease.
      ACE inhibitor or ARB use is also associated with reduced MACE among patients with critical limb ischemia.
      • Armstrong E.J.
      • Chen D.C.
      • Singh G.D.
      • Amsterdam E.A.
      • Laird J.R.
      Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use is associated with reduced major adverse cardiovascular events among patients with critical limb ischemia.
      Most patients with hypertension require multiple agents for optimal BP control. Use of combination pills therapy improves adherence, BP, and CV outcomes compared with usual pharmacological care.
      • Yusuf S.
      • Joseph P.
      • Dans A.
      • et al.
      Polypill with or without aspirin in persons without cardiovascular disease.
      ,
      • Muñoz D.
      • Uzoije P.
      • Reynolds C.
      • et al.
      Polypill for cardiovascular disease prevention in an underserved population.
      • 17.
        We recommend that PAD patients with hypertension be treated with ACE inhibitors or ARBs as the first choice in the absence of contraindications (Strong Recommendation; Moderate-Quality Evidence).

      2.4.3 Special considerations in PAD patients

      As mentioned previously, in the SPRINT trial, aggressive BP control among patients with PAD was associated with an increased risk of the primary outcome, CV death, and all-cause mortality compared with patients without PAD. As such, the optimal target is likely between 120 mm Hg and 140 mm Hg.
      A theoretical risk exists with the use of β-blockers in patients with limb ischemia. Previous guidelines have suggested avoiding the use of β-blockers in those with severe PAD. However, large systematic reviews on the topic have not shown increased harm with the use of β-blockers among patients with PAD. As such, they are not contraindicated and might be useful in PAD patients with concomitant CV disorders, where they are indicated as a second-line option.
      • Paravastu S.C.V.
      • Mendonca D.A.
      • da Silva A.
      Beta blockers for peripheral arterial disease.
      ,
      • Soga Y.
      • Iida O.
      • Takahara M.
      • Hirano K.
      • Suzuki K.
      • Kawasaki D.
      Beta-blocker treatment does not worsen critical limb ischemia in patients receiving endovascular therapy.

      2.5 Antithrombotic therapy

      A substantial amount of evidence has emerged since the 2005 Canadian Cardiovascular Congress Consensus Conference for the management of PAD. The advent of newer thienopyridines and direct oral anticoagulants (DOACs), as well as their investigation within atherosclerotic PAD, has vastly expanded the tools available to practitioners. This has come with a concomitant shift in the understanding of the pathophysiology of lower extremity PAD. A large proportion of severe vascular occlusions are mediated by thrombotic occlusive disease, even in the absence of major atherosclerotic lesions, reframing PAD as a condition of “athero-thrombo-embolism” and informing the choice of antithrombotics investigated and used clinically.
      Lower extremity PAD is continually appreciated as but 1 manifestation of systemic atherosclerosis. As such, the efficacy of antithrombotics in lower extremity PAD are evaluated according to MACE and MALE outcomes. The benefit of antithrombotics in lower extremity PAD in conferring global vascular protection must be weighed against the risk of major and/or fatal bleeding.

      2.5.1 Asymptomatic lower extremity PAD

      PICO 2.5a: In adult patients with asymptomatic PAD does a single antiplatelet agent compared with placebo affect rates of MACE, MALE, or bleeding?
      Patients with a low ABI, but without clinical limb symptoms or previous vascular intervention, are considered to have asymptomatic lower extremity PAD.
      • 18.
        We recommend against routine antithrombotic therapy (antiplatelet or anticoagulant) for patients with isolated asymptomatic lower extremity PAD (Strong Recommendation; High-Quality Evidence).
      Practical tip. Atypical symptoms are common for lower extremity PAD, making a directed history (and consideration for noninvasive imaging when appropriate) essential for PAD classification.
      Practical tip. Patients with asymptomatic lower extremity PAD often have atherosclerotic coronary artery or cerebrovascular disease, and might merit antithrombotic therapy for these indications.

      2.5.2 Stable symptomatic lower extremity PAD

      PICO 2.5b: In adult patients with stable symptomatic lower extremity PAD (no recent or imminent revascularization), what is the optimal antithrombotic therapy considering the outcomes of MACE, MALE, or bleeding?
      Patients with intermittent claudication, without recent (< 6 months) endovascular or surgical peripheral artery revascularization, and without acute symptoms of rest pain or tissue loss, are considered to have stable lower extremity PAD. Although single antiplatelet therapy has been the mainstay of antithrombotic therapy for symptomatic PAD patients,
      CAPRIE Steering Committee
      A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee.
      ,
      • Baigent Colin
      • Blackwell Lisa
      • et al.
      Antithrombotic Trialists’ (ATT) Collaboration
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      recent large trials that have tested low-dose DOACs together with aspirin have provided important new evidence.
      • Hess C.N.
      • Debus E.S.
      • Nehler M.R.
      • et al.
      Reduction in acute limb ischemia with rivaroxaban versus placebo in peripheral artery disease after lower extremity revascularization: insights from VOYAGER PAD.
      ,
      • Anand S.S.
      • Bosch J.
      • Eikelboom J.W.
      • et al.
      Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial.
      • 19.
        We recommend treatment with rivaroxaban 2.5 mg twice daily in combination with aspirin (80-100 mg daily) for management of patients with symptomatic lower extremity PAD who are at high risk for ischemic events (high-risk comorbidities such as polyvascular disease, diabetes, history of heart failure, or renal insufficiency) and/or high-risk limb presentation post peripheral revascularization, limb amputation, rest pain, ischemic ulcers) and at low bleeding risk (Strong Recommendation; High-Quality Evidence).
      • 20.
        We recommend combination treatment with rivaroxaban 2.5 mg twice daily and aspirin or single antiplatelet therapy for patients with symptomatic lower extremity PAD and low bleeding risk in the absence of high-risk limb presentation or high-risk comorbidities (Strong Recommendation; High-Quality Evidence).
      Values and preferences. This recommendation places high value on the overall Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial findings, which showed a significant net clinical benefit with combination low-dose rivaroxaban and aspirin among a heterogenous patient population with PAD. Patients who place a high value on minimizing ischemic risk, such as MI, stroke, acute limb ischemia, or major vascular amputation, might opt for rivaroxaban 2.5 mg twice daily in combination with aspirin. Patients who place a high value on bleeding avoidance and minimizing pill burden might opt for single antiplatelet therapy alone.
      Practical tip. Rivaroxaban 2.5 mg twice daily in combination with aspirin should be avoided in patients with strong cytochrome P450 family 3 subfamily A member 4 (CYP3A4) or p-glycoprotein medication interactions, those with recent stroke (< 1 month,) any previous hemorrhagic stroke, and with an estimated glomerular filtration rate < 15 mL/min. Although patients with severe heart failure (New York Heart Association classification III-IV or left ventricular ejection fraction < 30%) were excluded from the COMPASS trial, it might be reasonable to use rivaroxaban 2.5 mg twice daily in combination with aspirin, if otherwise indicated, and alternative etiologies for arterial occlusive disease have been excluded.
      Practical tip. At this time, the combination of rivaroxaban 2.5 mg twice daily and aspirin is not considered to be sufficiently equivalent to anticoagulation for management of atrial fibrillation or acute venous thrombosis. Optimal antithrombotic choices for these conditions can be found in the 2020 CCS/Canadian Heart Rhythm Society comprehensive guidelines for the management of atrial fibrillation and the Thrombosis Canada clinical guides, respectively.
      • Andrade J.G.
      • Aguilar M.
      • Atzema C.
      • et al.
      The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society comprehensive guidelines for the management of atrial fibrillation.
      ,
      Thrombosis Canada. Clinical Guides.
      • 21.
        We recommend single antiplatelet therapy with either aspirin (75-325 mg) or clopidogrel (75 mg) be considered for patients with symptomatic lower extremity PAD at high bleeding risk who remain eligible for antithrombotic therapy (Strong Recommendation; High-Quality Evidence).
      Values and preferences. This recommendation places a high value on the reduction of vascular events despite elevated bleeding risk. Patients at extremely high bleeding risk might not tolerate single antiplatelet therapy alone and might best be served by no antithrombotic therapy, particularly if vascular risk is low.
      • 22.
        We suggest that clopidogrel (75 mg daily)
        CAPRIE Steering Committee
        A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee.
        should be the preferred agent when single antiplatelet therapy is deemed to be the optimal antithrombotic choice (Weak Recommendation; Moderate-Quality Evidence).
      • 23.
        We suggest that dual antiplatelet therapy (DAPT; aspirin and clopidogrel or aspirin and ticagrelor) be used for patients with symptomatic lower extremity PAD at high risk for vascular events, at low bleeding risk, and who have contraindications to rivaroxaban (Weak Recommendation; Moderate-Quality Evidence).
      Values and preferences. This recommendation places greater weight on prevention of ischemic events (particularly coronary events) than on the risk of bleeding. The combination of ticagrelor and aspirin likely has greater ischemic benefit yet higher bleeding risk as contrasted with the combination of clopidogrel and aspirin, with choice of therapy directed by individual patient profile and preferences.
      Practical tip. Patients with recent (< 1 year) coronary revascularization and stable lower extremity PAD should have the choice of antithrombotic therapy guided by the 2018 CCS/Canadian Association of Interventional Cardiology focused update on the guidelines for the use of antiplatelet therapy,
      • Andrade J.G.
      • Verma A.
      • Mitchell L.B.
      • et al.
      2018 Focused update of the Canadian Cardiovascular Society guidelines for the management of atrial fibrillation.
      although patients with symptomatic lower extremity PAD should merit particular consideration for ticagrelor and aspirin in combination.
      • 24.
        We recommend against the additional use of full-dose anticoagulation with antiplatelet therapy for the purpose of decreasing MACE and MALE events in patients with stable lower extremity PAD (Strong Recommendation; High-Quality Evidence).
      Practical tip. Vascular and bleeding risk are not static and should be regularly reevaluated by primary care and vascular care practitioners, with dynamic adjustment of antithrombotic therapy as appropriate.
      Practical tip. Patients with stable lower extremity PAD who require full-dose anticoagulation for nonvascular indications might not require antiplatelet therapy. Although not robustly evaluated within the lower extremity PAD literature, analogous patients with stable CAD (no CV events in > 1 year) who required full-dose anticoagulation experienced harm with the additional use of an antiplatelet agent with anticoagulation.
      • Yasuda S.
      • Kaikita K.
      • Akao M.
      • et al.
      Antithrombotic therapy for atrial fibrillation with stable coronary disease.

      2.5.3 Therapy after elective lower extremity revascularization

      2.5.3.1 Endovascular revascularization

      PICO 2.5c: In adult patients who undergo elective endovascular revascularization for lower extremity PAD, what is the optimal antithrombotic therapy to prevent MACE, MALE, bleeding, or need for repeat intervention, in the early postoperative period (within 12 months)?
      The Antithrombotic Trialists’ Collaboration reported a numerical but not statistically significant reduction in MACE associated with single antiplatelet therapy vs placebo (odds reduction, 29%) after peripheral angioplasty.
      • Baigent C.
      • Sudlow C.
      • Collins R.
      • Peto R.
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      A subsequent Cochrane review identified 2 small trials that compared aspirin and dipyridamole, respectively, vs placebo after endovascular revascularization, with pooled analysis showing a similar nonsignificant result for lesion patency at 6 months.
      • Robertson L.
      • Ghouri M.A.
      • Kovacs F.
      Antiplatelet and anticoagulant drugs for prevention of restenosis/reocclusion following peripheral endovascular treatment.
      In the Management of Peripheral Arterial Interventions with Mono or Dual Antiplatelet Therapy (MIRROR) trial, DAPT using aspirin and clopidogrel was compared with aspirin alone in 80 patients after endovascular lower extremity revascularization. DAPT improved target lesion revascularization rates at 6 months (5% vs 8%; P = 0.04) but not at 1 year.
      • Hartmann-Boyce J.
      • Livingstone-Banks J.
      • Ordóñez-Mena J.M.
      • et al.
      Behavioural interventions for smoking cessation: an overview and network meta-analysis.
      Despite the lack of robust RCT data, DAPT after endovascular stenting is often extrapolated from the CV literature and mandated in trials investigating varying endovascular options.
      • Dake M.D.
      • Ansel G.M.
      • Jaff M.R.
      • et al.
      Durable clinical effectiveness with paclitaxel-eluting stents in the femoropopliteal artery: 5-year results of the Zilver PTX randomized trial.
      Two small trials (n = 160 and n = 167, respectively) that compared full-dose oral anticoagulation with DAPT after endovascular revascularization showed no significant difference in lesion patency with increased bleeding events.
      • Do D.D.
      • Mahler F.
      Low-dose aspirin combined with dipyridamole versus anticoagulants after femoropopliteal percutaneous transluminal angioplasty.
      ,
      • Pilger E.
      • Lammer J.
      • Bertuch H.
      • et al.
      Nd:YAG laser with sapphire tip combined with balloon angioplasty in peripheral arterial occlusions: long-term results.
      Both trials were significantly underpowered with respect to their primary end point.
      Literature from patients who required full-dose anticoagulation and coronary artery stenting has shown full oral anticoagulant (OAC) in combination with single antiplatelet therapy can be an optimal strategy in select groups of patients.
      • Lopes R.D.
      • Heizer G.
      • Aronson R.
      • et al.
      Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation.
      • Cannon C.P.
      • Bhatt D.L.
      • Oldgren J.
      • et al.
      Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation.
      • Gibson C.M.
      • Mehran R.
      • Bode C.
      • et al.
      Prevention of bleeding in patients with atrial fibrillation undergoing PCI.
      • Mehta S.R.
      • Bainey K.R.
      • Cantor W.J.
      • et al.
      2018 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology focused update of the guidelines for the use of antiplatelet therapy.
      Although less robust evidence exists after lower extremity stenting, the pilot Edoxaban in Peripheral Arterial Disease (ePAD) trial showed no significant difference in re-stenosis/reocclusion with edoxaban 60 mg compared with clopidogrel, largely on the background of aspirin therapy.
      • Moll F.
      • Baumgartner I.
      • Jaff M.
      • et al.
      Edoxaban plus aspirin vs dual antiplatelet therapy in endovascular treatment of patients with peripheral artery disease: results of the ePAD trial.
      In the Vascular Outcomes Study of ASA [Acetylsalicylic Acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER PAD) trial outlined in the following section, two-thirds of the patient population underwent endovascular intervention, making this the largest such trial conducted to date.
      • Bonaca M.P.
      • Bauersachs R.M.
      • Anand S.S.
      • et al.
      Rivaroxaban in peripheral artery disease after revascularization.

      2.5.3.2 Open revascularization

      After infrainguinal arterial bypass surgery, a meta-analysis showed improved graft patency with aspirin, with or without dipyridamole (OR, 0.42; 95% CI, 0.22-0.83).
      • Bedenis R.
      • Lethaby A.
      • Maxwell H.
      • Acosta S.
      • Prins M.H.
      Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery.
      Data for alternative antiplatelet regimens are limited. In the Clopidogrel and Acetylsalicylic Acid in Bypass Surgery for Peripheral Arterial Disease (CASPAR) trial, clopidogrel and aspirin in combination vs aspirin alone was assessed in patients who underwent infrainguinal bypass surgery, and although no effect on MALE was seen in the overall population, a significant reduction was observed in a subgroup of patients who received prosthetic bypass grafts (hazard ratio [HR], 0.65; 95% CI, 0.45-0.95).
      • Belch J.J.F.
      • Dormandy J.
      Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial.
      The 2 largest trials in open revascularization include the Dutch Bypass, Oral Anticoagulants or Aspirin (Dutch BOA) and VOYAGER PAD trial.
      • Hess C.N.
      • Debus E.S.
      • Nehler M.R.
      • et al.
      Reduction in acute limb ischemia with rivaroxaban versus placebo in peripheral artery disease after lower extremity revascularization: insights from VOYAGER PAD.
      ,
      Efficacy of oral anticoagulants compared with aspirin after infrainguinal bypass surgery (The Dutch Bypass Oral anticoagulants or Aspirin study): a randomised trial.
      Treatment with vitamin K antagonist (VKA) monotherapy (international normalized ratio, 3.0-4.5) compared with aspirin monotherapy did not significantly decrease graft occlusion or MACE, and significantly increased major bleeding (HR, 1.96; 95% CI, 1.42-2.71), in the overall Dutch BOA trial.
      Efficacy of oral anticoagulants compared with aspirin after infrainguinal bypass surgery (The Dutch Bypass Oral anticoagulants or Aspirin study): a randomised trial.
      Subgroup analysis did, however, show improved patency with VKA in venous conduit bypass (HR, 0.69; 95% CI, 0.54-0.88), and with acetylsalicylic acid in nonvenous conduit grafts (HR, 1.26; 95% CI, 1.03-1.55).
      Efficacy of oral anticoagulants compared with aspirin after infrainguinal bypass surgery (The Dutch Bypass Oral anticoagulants or Aspirin study): a randomised trial.
      Multiple smaller trials have assessed oral anticoagulation with single antiplatelet therapy vs single antiplatelet therapy or DAPT and have shown mixed results. The largest of these studies showed increased mortality with the combination of OAC and acetylsalicylic acid without improved graft patency.
      • Sarac T.P.
      • Huber T.S.
      • Back M.R.
      • et al.
      Warfarin improves the outcome of infrainguinal vein bypass grafting at high risk for failure.
      • Johnson W.C.
      • Williford W.O.
      Benefits, morbidity, and mortality associated with long-term administration of oral anticoagulant therapy to patients peripheral arterial bypass procedures: a prospective randomized study.
      • Monaco M.
      • di Tommaso L.
      • Pinna G.B.
      • Lillo S.
      • Schiavone V.
      • Stassano P.
      Combination therapy with warfarin plus clopidogrel improves outcomes in femoropopliteal bypass surgery patients.
      The VOYAGER PAD trial randomized patients after endovascular or open revascularization to combination therapy with rivaroxaban 2.5 mg twice daily and aspirin or aspirin alone, with the option to additionally use clopidogrel up to a maximum of 6 months at the treating physicians’ discretion.
      • Bonaca M.P.
      • Bauersachs R.M.
      • Anand S.S.
      • et al.
      Rivaroxaban in peripheral artery disease after revascularization.
      Compared with aspirin alone, the combination of rivaroxaban and aspirin reduced composite MACE and MALE events (HR, 0.85; 95% CI, 0.76-0.96), driven largely by a significant reduction in acute limb ischemia (HR, 0.67; 95% CI, 0.55-0.82).
      • Bonaca M.P.
      • Bauersachs R.M.
      • Anand S.S.
      • et al.
      Rivaroxaban in peripheral artery disease after revascularization.
      Although there was no significant difference in the primary safety outcome of Thrombolysis in Myocardial Infarction (TIMI) major bleeding, the secondary safety outcome of the International Society on Thrombosis and Haemostasis major bleeding was increased (HR, 1.42; 95% CI, 1.10-1.84), albeit without significant increases in intracranial or fatal bleeding.
      • Bonaca M.P.
      • Bauersachs R.M.
      • Anand S.S.
      • et al.
      Rivaroxaban in peripheral artery disease after revascularization.
      There was no significant heterogeneity in primary efficacy or bleeding outcomes on the basis of an open or endovascular approach.
      • Bonaca M.P.
      • Bauersachs R.M.
      • Anand S.S.
      • et al.
      Rivaroxaban in peripheral artery disease after revascularization.
      Notably, most revascularization procedures were performed for the indication of worsening claudication (76.6%), and up to one-third of patients had critical limb ischemia.
      • Bonaca M.P.
      • Bauersachs R.M.
      • Anand S.S.
      • et al.
      Rivaroxaban in peripheral artery disease after revascularization.
      Approximately 50% of the VOYAGER trial participants were given clopidogrel. The mean duration of clopidogrel use was 30 days, and the use of concomitant clopidogrel after revascularization did not alter the efficacy of rivaroxaban and aspirin compared with aspirin alone in reducing MACE or MALE events (P for interaction = 0.92), nor rates of acute limb ischemia (P for interaction = 0.93).
      • Hiatt W.R.
      • Bonaca M.P.
      • Patel M.R.
      • et al.
      Rivaroxaban and aspirin in peripheral artery disease lower extremity revascularization: impact of concomitant clopidogrel on efficacy and safety.
      This was consistent for open and endovascular procedures. However, in those with longer courses of clopidogrel there was a trend toward increased major bleeding. More than 30 days of clopidogrel use came with a 2.71% absolute risk increase of major bleeding (HR, 3.20; 95% CI, 1.44-7.13), whereas < 30 days of clopidogrel conferred a 0.46% absolute risk increase of major bleeding (HR, 1.30; 95% CI, 0.68-2.47; P for interaction = 0.07).
      • Hiatt W.R.
      • Bonaca M.P.
      • Patel M.R.
      • et al.
      Rivaroxaban and aspirin in peripheral artery disease lower extremity revascularization: impact of concomitant clopidogrel on efficacy and safety.
      • 25.
        We recommend rivaroxaban 2.5 mg twice daily in combination with aspirin (80-100 mg daily), with or without short-term clopidogrel use, for patients with lower extremity PAD after elective endovascular revascularization (Strong Recommendation; Moderate-Quality Evidence).
      • 26.
        We recommend treatment with rivaroxaban 2.5 mg twice daily in combination with aspirin (80-100 mg daily) for patients with lower extremity PAD after elective open revascularization (Strong Recommendation; High-Quality Evidence).
      Values and preferences. This recommendation places high value on a single large well constructed RCT as opposed to multiple smaller low-quality studies. This recommendation also places high value on minimizing ischemic risk in the setting of acceptable increases to overall bleeding risk.
      Practical tip. The additional use of clopidogrel (75 mg daily) with rivaroxaban 2.5 mg twice daily and aspirin (80-100 mg daily) can be considered in patients who undergo complex endovascular stenting. Should clopidogrel be used, it should be continued for a maximum of 30 days in the absence of other indications.
      Practical tip. Rivaroxaban 2.5 mg twice daily in combination with aspirin should be avoided in patients with strong CYP3A4 or p-glycoprotein medication interactions, stroke within 1 month, any previous hemorrhagic stroke, or estimated glomerular filtration rate < 15 mL/min.
      Practical tip. Patients who start treatment with rivaroxaban 2.5 mg twice daily in combination with aspirin after revascularization should preferably continue this therapy long-term in the absence of bleeding or ischemic manifestations, because previous revascularization represents a high-risk limb presentation for patients with stable lower extremity PAD.
      • 27.
        We suggest DAPT with aspirin (75-325 mg) and clopidogrel (75 mg) for at least 1 month in patients with lower extremity PAD after elective endovascular revascularization who are unable to receive low-dose rivaroxaban (Weak Recommendation; Very Low-Quality Evidence).
      Values and preferences. This recommendation places high value on expert opinion and indirect extrapolation from the CAD literature. Direct evaluation of DAPT after endovascular revascularization remains limited.
      Practical tip. Duration of DAPT might be affected by procedural factors such as use and complexity of stenting, as well as patient factors such as global ischemic and bleeding risk. It should be noted that the effect of stenting complexity or technology of drug-eluting stents (DES) on antithrombotic effect remains minimally studied.
      • 28.
        We suggest either a VKA or single antiplatelet therapy for patients with lower extremity PAD after elective open revascularization who are unable to receive low dose rivaroxaban (Weak Recommendation; Very Low-Quality Evidence).
      Values and preferences. This recommendation places greater value on overall trial results as opposed to discrepant results within patient subgroups. This recommendation is made acknowledging that robust evidence is not available to guide when VKA or single antiplatelet therapy would be of greater ischemic benefit, yet VKA therapy comes with a notably increased bleeding risk compared with single antiplatelet therapy. Therefore, this recommendation places a high value on expert opinion and intraoperative surgical decision-making for determining the optimal antithrombotic regimen in this scenario.
      Practical tip. VKA might be particularly considered for patients who receive infrainguinal bypass using an autologous vein conduit with high-risk features including poor quality conduit, long conduit, disadvantaged distal runoff, or previous failed open revascularization.
      Practical tip. Full-dose DOAC therapy has not been studied in the setting of open peripheral revascularization. However, in high-risk patients deemed unsuitable for VKA therapy, full-dose DOAC may be considered as an alternative therapy.

      2.5.4 Therapy after urgent/emergent lower extremity revascularization

      PICO 2.5d: What is the optimal antithrombotic therapy among adult patients who undergo urgent or emergent revascularization (of any kind) for lower extremity PAD considering the outcomes of MACE, MALE, bleeding, or need for repeat intervention?
      Limited comparative data exist to assess antithrombotic regimens in patients who require urgent or emergent revascularization despite their elevated risk of recurrent ischemic events and overall mortality.
      • 29.
        We suggest any of: (1) full-dose anticoagulation in combination with single antiplatelet therapy; (2) rivaroxaban 2.5 mg twice daily in combination with aspirin, with or without short-term use of clopidogrel; or (3) DAPT for patients with lower extremity PAD after urgent or emergent revascularization (Weak Recommendation; Very Low-Quality Evidence).
      Values and preferences. This recommendation acknowledges the lack of high-quality data informing antithrombotic treatment after urgent or emergent lower extremity revascularization and the noted heterogeneity in practice.
      • Agarwal R.
      • Tu W.
      Minimally sufficient numbers of measurements for validation of 24-hour blood pressure monitoring in chronic kidney disease.
      Practical tip. Evaluation of the risk of re-thrombosis after urgent or emergent lower extremity revascularization should take into consideration the surgical procedure performed (ie, embolectomy or thrombectomy, bypass vs stenting), intraoperative findings (ie, residual distal occlusive disease, length and quality of conduit, infrapopliteal placement of conduit), as well as patient characteristics (ie, previous failed revascularizations, bleeding risk).
      • McClure G.R.
      • Kaplovitch E.
      • Chan N.
      • et al.
      A national Canadian survey of antithrombotic therapy after urgent and emergent limb revascularization.
      For patients deemed high-risk for re-thrombosis and low-risk for bleeding, full-dose anticoagulation in combination with single antiplatelet therapy should be particularly considered.
      Practical tip. In patients who require urgent or emergent lower extremity revascularization because of acute limb ischemia, care should be taken to rule out nonatherothromboembolic causes of limb ischemia, such as but not limited to cardioembolic cause, to inform the optimal antithrombotic therapy.

      2.6 Exercise therapy for intermittent claudication

      PICO 2.6: Among patients with PAD who have intermittent claudication, is supervised exercise, home, or community-based exercise therapy more efficacious than usual care, on outcomes of: total walking time and distance, claudication, need for revascularization, and quality of life?
      Leg pain during activity is a major determinant of functional capacity among patients with PAD, negatively affecting their ability to perform activities of daily living and their quality of life. Thus, addressing functional impairment is crucial in the management of PAD patients with noncritical leg symptoms. A robust body of data support medical interventions aimed to improve walking and quality of life in patients with PAD. Because cilostazol is not yet available in Canada, and other potential medical interventions such as pentoxifylline, carnitine, propionyl-L carnitine, and chelation therapy have not been recommended in recent US
      • Gerhard-Herman M.D.
      • Gornik H.L.
      • Barrett C.
      • et al.
      2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      and European
      • Aboyans V.
      • Ricco J.B.
      • Bartelink M.L.E.L.
      • et al.
      2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS): document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteriesEndorsed by: the European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS).
      guidelines because of lack of benefit or insufficient, potentially biased data, this section focuses on exercise therapy for the management of PAD patients with intermittent claudication.
      • 30.
        We recommend supervised exercise programs as first-line therapy for patients with PAD and intermittent claudication, with the objective of improving maximal and pain-free walking distance and time, as well as quality of life (Strong Recommendation; High-Quality Evidence).
      • 31.
        We recommend that a structured home-based or community exercise program can be offered to improve leg symptoms and quality of life when supervised exercise programs are not available, or not desired by the patient (Strong Recommendation; High-Quality Evidence).
      • 32.
        We recommend that walking should be the preferred form of exercise in exercise programs for intermittent claudication (Strong Recommendation; High-Quality Evidence).
      • 33.
        We suggest that, in patients with intermittent claudication who are unable to pursue walking exercise therapy, other forms of exercise such as cycle ergometer, arm ergometer, pole-striding, Nordic walking, or dynamic leg exercises can also be beneficial to improve leg symptoms (Weak Recommendation; Moderate-Quality Evidence).
      • 34.
        We suggest that resistance training can be used in addition to, but not substitute, walking therapy in exercise programs for patients with intermittent claudication (Weak Recommendation; Moderate-Quality Evidence).
      Values and preferences. High value is placed on a robust body of evidence that supports exercise therapy as first-line for improvement of walking, claudicant leg symptoms, and quality of life in patients with PAD. Preference is given to supervised exercise therapies that use walking as the primary form of exercise, but emerging evidence also supports home-based or community-based exercise as long as structure and guidance are provided throughout the duration of the program, as well as other forms of exercise when walking cannot be achieved or is not desirable.
      Practical tip. Exercise habits should be asked at every visit with a health practitioner.
      Practical tip. Every patient with intermittent claudication should be referred to a supervised exercise rehabilitation program tailored to individuals with PAD, when available. When such a program is not locally available, structured guidance for home-based exercise should be provided by clinicians.
      Practical tip. Structured exercise guidance, either supervised or home or community-based, should include a minimum of 2 weekly sessions of at least 30 minutes duration, and be pursued for a minimum of 12 weeks of therapy.
      Practical tip. The authors acknowledge the lack of uniformity in exercise protocols for intermittent claudication. On the basis of our experience administering exercise therapy for PAD, patients are encouraged to walk on the treadmill or track for 8- to 9-minute bouts, with speed and/or incline sufficient to cause 3-4 of 5 claudicant pain toward the end of the 8- to 9-minute interval. Patients then rest until pain dissipates, and then resume a new bout of walking, repeating the cycles until 3 bouts are complete. Over the course of the program, walking speed and/or incline is adjusted by the therapist to continue achieving the aforementioned parameters.
      Practical tip. After patients complete the exercise program, they should be encouraged to continue walking for at least 30 minutes a day, at least 3 times a week, to maintain the walking and quality of life benefits gained during exercise therapy.

      3. Revascularization Procedures for PAD

      3.1 Preoperative assessment and risk stratification

      3.1.1 Guideline rationale, development, and over-riding principles

      Since the publication of the 2017 CCS guidelines on perioperative cardiac risk assessment and management for patients who undergo noncardiac surgery,
      • Duceppe E.
      • Parlow J.
      • MacDonald P.
      • et al.
      Canadian Cardiovascular Society guidelines on perioperative cardiac risk assessment and management for patients who undergo noncardiac surgery.
      new evidence has emerged for evaluating clinical risk indices specific to patients who undergo peripheral vascular surgery. The scope of this section includes the evaluation of available evidence for preoperative assessment and risk stratification of patients who undergo nonurgent vascular surgery for PAD along the following themes: clinical risk indices, cardiac biomarkers, and noninvasive testing.
      The recommendations pertain to adult patients, 18 years of age or older, who undergo elective open or endovascular arterial revascularization procedures of the lower extremities.
      Patients who require emergency lower extremity arterial revascularization should not have their surgery delayed by a preoperative risk assessment. The risks to life or limb that could result from a delay in surgery are often greater than the risks of not assessing and subsequently optimizing a patient’s preoperative cardiac status. However, operative risks must be explained to the patient and their family.
      Conversely, patients who undergo scheduled, nonemergency lower extremity arterial revascularization surgery should undergo cardiac risk assessment.
      Physicians or surgeons with training and competency in cardiac risk assessment should perform preoperative assessments.

      3.1.2 Risk tools

      PICO 3.1a: Which risk tool(s) best predict(s) perioperative CV risk and mortality?
      Individuals who undergo surgery for PAD have a higher preoperative CV risk compared with other noncardiac surgeries. Various tools have been developed and evaluated to predict the perioperative risk of vascular surgery patients. Tools that included preoperative components only were considered. The following were examined: the Vascular Study Group of New England Cardiac Risk Index (VSG-CRI), the Vascular Quality Initiative Cardiac Risk Index (VQI-CRI), and frailty scores (single domain and multidomain). The evidence for Revised Cardiac Risk Index (RCRI) was also reassessed with a focus on PAD to determine whether its predictive value differs compared with a heterogenous pool of noncardiac surgeries. The summary of the findings and GRADE Evidence Profile for the 3 clinical risk scores are available on ccs.ca.

      RCRI

      For vascular surgery, RCRI consistently underestimated the risk of MACE with poor discriminatory ability with the median area under the curve of 0.64 (range, 0.58-0.70; see ccs.ca for table). A number of serious limitations were identified in these studies, and the resulting bias would have been expected to falsely amplify the ability of RCRI to predict MACE. However, despite these limitations, RCRI still had poor prediction even in the largest study with subgroup analysis of lower extremity bypass.

      VSG-CRI risk tool

      This is a simple scoring algorithm that was derived from a vascular surgery cohort; the Vascular Study Group of New England. It was developed by assigning weighted points to each statistically significant predictor from a multivariate analysis and stratified patients prepared to undergo vascular surgery into 1 of 6 risk categories (0-3, 4, 5, 6, 7, 8) and predicted risk of MACE (2.2%, 3.5%, 6%, 6.6%, 8.9%, 14.3%), respectively. MACE were defined as in-hospital MI, clinically significant arrhythmia, or congestive heart failure (Fig. 5).
      Figure thumbnail gr5
      Figure 5The Vascular Study Group of New England Cardiac Risk Index (VSG-CRI) score. CABG, coronary artery bypass grafting; CAD, coronary artery disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; PCI, percutaneous coronary intervention.
      Reproduced from Bertges et al.
      • Bertges D.J.
      • Goodney P.P.
      • Zhao Y.
      • et al.
      The Vascular Study Group of New England Cardiac Risk Index (VSG-CRI) predicts cardiac complications more accurately than the Revised Cardiac Risk Index in vascular surgery patients.
      with permission from Elsevier.

      INFRA VQI-CRI risk score

      This risk score was developed from the Vascular Quality Initiative, the largest vascular surgery-specific database assembled to date representing data from the United States and Canada.
      • Bertges D.J.
      • Neal D.
      • Schanzer A.
      • et al.
      The Vascular Quality Initiative Cardiac Risk Index for prediction of myocardial infarction after vascular surgery.
      An all-procedure model and procedure-specific models were developed (eg, Infrainguinal [INFRA] VQI-CRI for infrainguinal bypass procedures) to predict postoperative MI. The risk tools are freely available online and can be downloaded for offline use through the app, Calculate by QxMD, at https://qxmd.com/calculate/calculator_323/vascular-quality-initiative-vqi-cardiac-risk-index-cri-infra-inguinal-bypass.

      Frailty scores

      The following tools were examined: single-domain (modified Frailty Index [mFI], and the Groningen Frailty Indicator [GFI]).
      • Scarborough J.E.
      • Bennett K.M.
      • Englum B.R.
      • Pappas T.N.
      • Lagoo-Deenadayalan S.A.
      The impact of functional dependency on outcomes after complex general and vascular surgery.
      • Brahmbhatt R.
      • Brewster L.P.
      • Shafii S.
      • et al.
      Gender and frailty predict poor outcomes in infrainguinal vascular surgery.
      • Visser L.
      • Banning L.B.D.
      • el Moumni M.
      • Zeebregts C.J.
      • Pol R.A.
      The effect of frailty on outcome after vascular surgery.
      • Houghton J.S.M.
      • Nickinson A.T.O.
      • Morton A.J.
      • et al.
      Frailty factors and outcomes in vascular surgery patients: a systematic review and meta-analysis.
      Functional dependency is classified as independent if no assistance is needed and dependent if there is some or full dependency for functions. The mFI comprises 11 items, of which 9 are comorbidities, along with measures of functional dependency and cognition variables. The score is calculated by adding 1 point for the presence of each variable, then dividing the sum by 11 (Table 4). Frailty is defined as mFI ≥ 0.25.
      Table 4Modified Frailty Index (mFI)
      • Eslami M.H.
      • Saadeddin Z.
      • Rybin D.V.
      • Doros G.
      • Siracuse J.J.
      • Farber A.
      Association of frailty index with perioperative mortality and in-hospital morbidity after elective lower extremity bypass.
      VariableNSQIP categoriesYes = 1; no = 0
      Functional and cognitive impairment
      • Preoperative functional health status
      • Impaired sensorium
      Comorbidities
      • Diabetes mellitus
      • History of COPD
      • Current pneumonia
      • Congestive heart failure ≤ 30 days before surgery
      • History of angina ≤ 1 month before surgery
      • Hypertension requiring medication
      • History of transient ischemic attacks
      • Cerebrovascular accident or stroke with neurologic deficit
      • History of revascularization or amputation for peripheral vascular disease
      • Rest pain or gangrene
      Total item score
      mFI is calculated as (total item score)/11.
      COPD, chronic obstructive pulmonary disease; NSQIP, National Surgical Quality Improvement Program.
      Reproduced from Eslami et al.
      • Eslami M.H.
      • Saadeddin Z.
      • Rybin D.V.
      • Doros G.
      • Siracuse J.J.
      • Farber A.
      Association of frailty index with perioperative mortality and in-hospital morbidity after elective lower extremity bypass.
      with permission from Elsevier.
      The GFI includes 16 items organized into 8 different groups. This tool would require further validation studies in peripheral arterial surgery before developing a recommendation regarding its use.
      Other prediction tools such as Vascular-Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (V-POSSUM) (with only preoperative components), Preoperative Score to Predict Postoperative Mortality (POSPOM), and modified RCRI, were considered but studies of those prediction tools were small, of low quality, and lacked validation using large databases.
      • Kertai M.D.
      • Boersma E.
      • Klein J.
      • van Urk H.
      • Poldermans D.
      Optimizing the prediction of perioperative mortality in vascular surgery by using a customized probability model.
      • Teixeira I.M.
      • Teles A.R.
      • Castro J.M.
      • Azevedo L.F.
      • Mourão J.B.
      Physiological and Operative Severity Score for the enumeration of Mortality and Morbidity (POSSUM) system for outcome prediction in elderly patients undergoing major vascular surgery.
      • Reis P.
      • Lopes A.I.
      • Leite D.
      • et al.
      Incidence, predictors and validation of risk scores to predict postoperative mortality after noncardiac vascular surgery, a prospective cohort study.
      • 35.
        We recommend against using RCRI for preoperative assessment of cardiac risk in peripheral arterial surgery (Strong Recommendation; Moderate-Quality Evidence). Alternate options include the VSG-CRI and INFRA VQI-CRI (see the following recommendations).
      • 36.
        When evaluating cardiac risk:
        • a)
          We suggest that clinicians use the VSG-CRI to predict MACE in patients who undergo peripheral vascular surgery (Weak Recommendation; Low-Quality Evidence); or
        • b)
          We suggest that clinicians use the INFRA VQI-CRI score to predict postoperative MI in patients who receive peripheral vascular surgery (Weak Recommendation; Low-Quality Evidence).
      • 37.
        We recommend against using the RCRI for preoperative assessment of 30-day mortality in peripheral arterial surgery (Strong Recommendation; Low-Quality Evidence) and alternatively suggest using frailty scores (functional dependency or mFI) over other available risk prediction scores for 30-day mortality assessment (Weak Recommendation; Low-Quality Evidence for functional dependency; Moderate-Quality Evidence for mFI).
      Values and preferences. Higher preference and value are given to tools that are readily available and are quick to complete in the context of preoperative care clinics. Preference was also given to tools derived directly from the population of interest (ie, infrainguinal revascularization) because of data that support more reliable prediction than those developed from heterogenous surgical populations.
      Practical tip. Although a single risk tool to assess the risk of cardiac events and 30-day mortality would be clinically useful, such a tool was not identified in the current literature search. For 30-day mortality risk assessment, frailty scores are suggested, and for cardiac risk assessment the VSG-CRI or INFRA VQI-CRI are suggested. An online and free calculator is available to assist clinicians with using the INFRA VQI-CRI risk score for postoperative MI prediction.

      3.1.3 Cardiac biomarkers

      PICO 3.1b: What is the role of preoperative cardiac biomarkers in risk prediction?
      Cardiac biomarkers have been shown to help predict MACE in vascular surgery.
      • Rodseth R.N.
      • Biccard B.M.
      • le Manach Y.
      • et al.
      The prognostic value of pre-operative and post-operative B-type natriuretic peptides in patients undergoing noncardiac surgery: B-type natriuretic peptide and N-terminal fragment of pro-B-type natriuretic peptide: a systematic review and individual patient data meta-analysis.
      Brain natriuretic peptide (BNP) and N-terminal fragment pro hormone BNP (NT-proBNP) have shown some promising results (see ccs.ca for evidence tables). The recommendations are largely consistent with the CCS 2017 perioperative guidelines for non-cardiac surgery with a suggested threshold of preoperative NT-proBNP ≥ 300 mg/L or BNP ≥ 92 mg/L associated with an estimate risk of 21.8% (95% CI, 19.0%-24.8%) for composite of death and nonfatal MI at 30-days postoperatively.
      • Rodseth R.N.
      • Biccard B.M.
      • le Manach Y.
      • et al.
      The prognostic value of pre-operative and post-operative B-type natriuretic peptides in patients undergoing noncardiac surgery: B-type natriuretic peptide and N-terminal fragment of pro-B-type natriuretic peptide: a systematic review and individual patient data meta-analysis.
      • 38.
        We suggest that clinicians consider measuring BNP or NT-proBNP before peripheral arterial surgery to enhance perioperative cardiac risk estimation (Weak Recommendation; Low-Quality Evidence).
      Values and preferences. Cost, accessibility, and reliability of the thresholds were considered for this recommendation. BNP and NT-proBNP are inexpensive and widely available tests. Patients might benefit from further stratification using biomarkers to guide perioperative care and surveillance of cardiac events perioperatively.
      Practical tip. Clinicians might consider clinical monitoring postoperatively in individuals with an elevated perioperative troponin level, preoperative NT-proBNP ≥ 300 mg/L or BNP ≥ 92 mg/L because of the significantly increased risk in these patient groups.
      • Rodseth R.N.
      • Biccard B.M.
      • le Manach Y.
      • et al.
      The prognostic value of pre-operative and post-operative B-type natriuretic peptides in patients undergoing noncardiac surgery: B-type natriuretic peptide and N-terminal fragment of pro-B-type natriuretic peptide: a systematic review and individual patient data meta-analysis.
      Point of care testing is an alternative for obtaining BNP/NT-proBNP levels within minutes in the preoperative setting or where testing is not available through core laboratories.

      3.1.4 Noninvasive cardiac testing

      PICO 3.1c: What is the role of preoperative noninvasive cardiac testing?
      The literature search did not identify new, robust studies that examined the utility of noninvasive cardiac testing for peripheral arterial surgery.
      Practical tip. In the absence of new and robust evidence to inform noninvasive testing for peripheral arterial surgery, we suggest referring to the CCS 2017 guidelines for noncardiac surgery.
      Efficacy of oral anticoagulants compared with aspirin after infrainguinal bypass surgery (The Dutch Bypass Oral anticoagulants or Aspirin study): a randomised trial.
      It is essential to continue to apply clinical judgement and current standards of practice for ordering noninvasive testing preoperatively while keeping in mind that the general risk of noncardiac surgery does not reflect the relatively increased cardiac and mortality risk of patients who undergo peripheral arterial surgery.

      3.2 Indications for revascularization

      PICO 3.2: What are the indications for revascularization procedures in patients with PAD on the basis of their clinical presentation (intermittent claudication, critical limb ischemia, acute limb ischemia, or asymptomatic)?

      3.2.1 Intermittent claudication

      Symptoms of claudication can manifest as pain, weakness, or numbness in the lower extremity induced with activity, usually walking. Common muscle groups involved include the calf, thigh, or buttock regions depending on the level of atherosclerotic disease (see section 1.1). The natural history of intermittent claudication generally includes a 2%-3% annual risk of progression to chronic limb-threatening ischemia after the first year of diagnosis.
      • Norgren L.
      • Hiatt W.R.
      • Dormandy J.A.
      • Nehler M.R.
      • Harris K.A.
      • Fowkes F.G.R.
      Inter-society consensus for the management of peripheral arterial disease (TASC II).
      • Aquino R.
      • Johnnides C.
      • Makaroun M.
      • et al.
      Natural history of claudication: long-term serial follow-up study of 1244 claudicants.
      • Jelnes R.
      • Gaardsting O.
      • Jensen K.H.
      • BÆkgaard N.
      • Tønnesen K.H.
      • Schroeder T.
      Fate in intermittent claudication: outcome and risk factors.
      In addition, the annual risk of amputation is ≤ 1% in these patients.
      • Norgren L.
      • Hiatt W.R.
      • Dormandy J.A.
      • Nehler M.R.
      • Harris K.A.
      • Fowkes F.G.R.
      Inter-society consensus for the management of peripheral arterial disease (TASC II).
      ,
      • Aquino R.
      • Johnnides C.
      • Makaroun M.
      • et al.
      Natural history of claudication: long-term serial follow-up study of 1244 claudicants.
      Although the management of intermittent claudication is predominantly risk factor modification,
      • Hussain M.A.
      • Al-Omran M.
      • Mamdani M.
      • et al.
      Efficacy of a guideline-recommended risk-reduction program to improve cardiovascular and limb outcomes in patients with peripheral arterial disease.
      ,
      • Kullo I.J.
      • Rooke T.W.
      Peripheral artery disease.
      revascularization can be considered in patients who continue to have lifestyle-limiting symptoms despite best medical management with an acceptable risk profile, reasonable expectation for functional improvement and life expectancy, and in whom a trial of nonoperative therapy with an exercise program on the basis of data from RCTs has failed.
      • 39.
        We suggest that revascularization may be considered in patients with intermittent claudication affecting vocational, recreational, or daily living activities who have an acceptable risk profile, reasonable expectation for function and life expectancy, and in whom a trial of nonoperative therapy with an exercise program and optimal medical therapy has failed (Weak Recommendation; Moderate-Quality Evidence).
      • 40.
        We recommend that the choice of revascularization procedure for intermittent claudication should be individualized, have the expectation of low perioperative morbidity, and have a reasonable likelihood of providing sustained symptomatic benefit (Strong Recommendation; Low-Quality Evidence).
      Values and preferences. This recommendation emphasizes that early intervention on lesions in individuals with claudication has not been shown to favourably alter the patient’s natural history or propensity to develop chronic limb-threatening ischemia.

      3.2.2 Chronic limb-threatening ischemia

      Unlike claudication, chronic limb-threatening ischemia has a worse natural history with increased propensity for tissue and limb loss.
      • Shishehbor M.H.
      • White C.J.
      • Gray B.H.
      • et al.
      Critical limb ischemia: an expert statement.
      Chronic limb-threatening ischemia is the most advanced form of PAD and patients with chronic limb-threatening ischemia often present with signs of severe arterial insufficiency such as ischemic rest pain, tissue loss, or gangrene.
      • Farber A.
      • Eberhardt R.T.
      The current state of critical limb ischemia: a systematic review.
      Despite advances in pharmacological risk reduction therapy for PAD over the past 2 decades,
      • Hussain M.A.
      • Al-Omran M.
      • Creager M.A.
      • Anand S.S.
      • Verma S.
      • Bhatt D.L.
      Antithrombotic therapy for peripheral artery disease: recent advances.
      ,
      • Olin J.W.
      • White C.J.
      • Armstrong E.J.
      • Kadian-Dodov D.
      • Hiatt W.R.
      Peripheral artery disease: evolving role of exercise, medical therapy, and endovascular options.
      chronic limb-threatening ischemia patients continue to have high mortality (22% over 1 year) and major amputation (22% over 1 year) rates without revascularization.
      • Abu Dabrh A.M.
      • Steffen M.W.
      • Undavalli C.
      • et al.
      The natural history of untreated severe or critical limb ischemia.
      As such, in addition to CV risk reduction (see sections 2.1-2.6), prompt revascularization is the cornerstone of management for this condition.
      • Forsythe R.O.
      • Apelqvist J.
      • Boyko E.J.
      • et al.
      Effectiveness of revascularisation of the ulcerated foot in patients with diabetes and peripheral artery disease: a systematic review.
      Patients with chronic limb-threatening ischemia should be urgently assessed by vascular specialists who have expertise in endovascular, open, and hybrid surgical techniques for peripheral revascularization. A thoughtful approach to selecting the type of revascularization procedure involves a timely assessment of patient, disease, and procedural factors (see section 3.4).
      In addition to revascularization, special attention is required for the management of any associated tissue loss, gangrene, or infection. In patients who present with a deep foot infection or wet gangrene, urgent foot debridement or minor amputation should be considered before revascularization. Close follow-up, appropriate wound care, and frequent reassessment for further debridement are essential in ensuring ischemic and diabetic foot wounds heal after revascularization.
      Some chronic limb-threatening ischemia patients might benefit from primary major amputation over a revascularization attempt, such as those with advanced nonreconstructable disease, nonambulatory status, severe sepsis due to progressive limb infection, and those who are unfit for revascularization (often nursing home or bedridden patients).
      • 41.
        We recommend that all patients with chronic limb-threatening ischemia should be urgently referred to vascular specialists for consideration of revascularization (Strong Recommendation; Low-Quality Evidence).
      Values and preferences. This recommendation places a high value on timely evaluation of chronic limb-threatening ischemia patients by vascular specialists to decrease pain, improve wound healing, and ultimately prevent limb loss.
      • 42.
        We recommend that in patients with chronic limb-threatening ischemia, endovascular, open, or hybrid revascularization should be considered on the basis of the anatomical pattern of disease, degree of ischemia, expected durability of the procedure, perioperative risk, and patient life expectancy (Strong Recommendation; Low-Quality Evidence).
      • 43.
        We recommend wound debridement and/or minor amputation simultaneously with revascularization or in a staged manner depending on the degree of tissue loss, gangrene, and/or infection (Strong Recommendation; Low-Quality Evidence).
      Practical tip. Urgent debridement or minor amputation before revascularization is recommended if deep foot infection or wet gangrene is present.
      • 44.
        We recommend primary major amputation in chronic limb-threatening ischemia patients with nonreconstructible disease, nonsalvageable limb, nonambulatory status, severe sepsis, or for palliation for those with a short life expectancy and who are unfit for revascularization (Strong Recommendation; Low-Quality Evidence).
      Values and preferences. This recommendation places a high value on primary amputation for chronic limb-threatening ischemia patients who are unlikely to benefit from revascularization.

      3.2.3 Acute limb ischemia

      Acute limb ischemia, which occurs because of a sudden decrease in limb perfusion (usually within minutes to hours), is distinct from chronic limb-threatening ischemia because there is inadequate collateral circulation present to maintain imminent limb viability. Patients with acute limb ischemia have a poor prognosis, because delays in diagnosis or treatments are associated with high rates of major amputation and mortality.
      • Creager M.A.
      • Kaufman J.A.
      • Conte M.S.
      Clinical practice. Acute limb ischemia.
      Revascularization options include percutaneous catheter-directed thrombolytic therapy or mechanical thrombus extraction or aspiration, surgical thrombectomy, and surgical reconstruction. Treatment strategies are usually individualized and dependent on the degree and duration of ischemia present, viability of the limb, anatomical factors, patient risk profile, and availably of surgical and endovascular expertise.

      3.2.4 Asymptomatic PAD

      Often, PAD lesions and/or reduced ABI are identified during screening or as incidental findings. This finding in and of itself is low risk but is a marker for elevated risk of other CV events such as CV death, MI, and stroke.
      • Criqui M.H.
      • Aboyans V.
      Epidemiology of peripheral artery disease.
      The focus for these patients should be on optimal medical therapy to reduce the risk of MACE; revascularization is generally not indicated unless progression is rapid.
      • 45.
        We recommend not offering revascularization to patients with asymptomatic PAD (Strong Recommendation; Low-Quality Evidence).
      Practical tip. In patients with asymptomatic PAD, counsel and implement CV risk reduction therapies, in addition to providing education on signs and symptoms of progressive PAD.

      3.3 Techniques for revascularization

      PICO 3.3a: What are the available revascularization procedures in treating patients with PAD and their outcomes?

      3.3.1 Endovascular revascularization

      PICO 3.3b: What are the available endovascular revascularization procedures in treating patients with PAD and their outcomes?

      3.3.1.1 Overview for endovascular revascularization

      Endovascular therapies represent an area of innovation and advancement in the management of patients with PAD. These minimally invasive procedures use variations of balloon dilatation and stent technologies, via small pinhole incisions usually performed as day surgery cases. These procedures have become an especially attractive option for severely comorbid patients with chronic limb-threatening ischemia or claudication, in whom an open surgical revascularization procedure would not have been tolerated, is not feasible as a result of anatomy or conduit availability, or is undesirable because of concomitant morbidity and recovery time. Although less invasive, these endovascular therapies continue to face challenges with respect to limited durability compared with open surgical repair.
      • Antoniou G.A.
      • Chalmers N.
      • Georgiadis G.S.
      • et al.
      A meta-analysis of endovascular versus surgical reconstruction of femoropopliteal arterial disease.
      ,
      • Bradbury A.W.
      • Adam D.J.
      • Bell J.
      • et al.
      Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: an intention-to-treat analysis of amputation-free and overall survival in patients randomized to a bypass surgery-first or a balloon angioplasty-first revascularization strategy.
      The objective of endovascular therapy is to target lesions that are hemodynamically significant, usually in the range of 75%-100% occlusion, with the goal of creating inline flow to the affected muscle group or ischemic tissue in the lower extremity. In addition to considering patient factors, anatomical characteristics of lesions considered favourable for endovascular therapy include short lesion length, stenosis (vs chronic total occlusions), proximal lesions (iliac vs femoropopliteal vs tibial), those with minimal calcification, and good distal runoff. Common femoral and profunda artery lesions are generally not considered for standard endovascular therapy.
      • Conte M.S.
      • Bradbury A.W.
      • Kolh P.
      • et al.
      Global vascular guidelines on the management of chronic limb-threatening ischemia.
      • Löfberg A.M.
      • Karacagil S.
      • Ljungman C.
      • et al.
      Percutaneous transluminal angioplasty of the femoropopliteal arteries in limbs with chronic critical lower limb ischemia.
      • Capek P.
      • McLean G.K.
      • Berkowitz H.D.
      Femoropopliteal angioplasty. Factors influencing long-term success.
      • Clark T.W.I.
      • Groffsky J.L.
      • Soulen M.C.
      Predictors of long-term patency after femoropopliteal angioplasty: results from the STAR registry.

      3.3.1.2 Endovascular procedures

      See the 3.3.1.2 Endovascular Procedures section of the Supplementary Material for endovascular procedures.

      3.3.1.3 Outcomes of endovascular revascularization

      Endovascular revascularization outcomes are heterogeneous and, in many aspects, difficult to quantify. The immediate results of crossing a lesion and providing a treatment resulting in minimal residual stenosis are simple to measure as a procedural success. Other outcome measures such as patient-reported subjective outcomes, hemodynamic improvement, wound healing, and even vessel patency are limited by the inconsistency of definitions. The indication of the procedure, chronic limb-threatening ischemia vs claudication, can also affect outcomes because the severity and natural history of the disease is often worse in the former.
      Outcomes are separated into anatomical regions: aortoiliac, infrainguinal, and infrapopliteal. The endovascular treatment of the aortoiliac segment has become the preferred option for the anatomically suitable because of the low incidence of morbidity and mortality compared with open surgical options.
      • Conte M.S.
      • Bradbury A.W.
      • Kolh P.
      • et al.
      Global vascular guidelines on the management of chronic limb-threatening ischemia.
      ,
      • de Vries S.O.
      • Hunink M.G.M.
      Results of aortic bifurcation grafts for aortoiliac occlusive disease: a meta-analysis.
      ,
      • Jongkind V.
      • Akkersdijk G.J.M.
      • Yeung K.K.
      • Wisselink W.
      A systematic review of endovascular treatment of extensive aortoiliac occlusive disease.
      The common femoral artery area historically has been treated only with open surgery. This practice is currently challenged by studies indicating comparable results with endovascular treatment. The anatomic challenge of a flexible location beneath the inguinal ligament and the potential of covering the profunda femoral artery during possible stent placement must be weighed against the excellent results from a straightforward, open procedure. The consensus remains for operative intervention aside from high-risk anatomy or patient factors.
      • Boufi M.
      • Ejargue M.
      • Gaye M.
      • Boyer L.
      • Alimi Y.
      • Loundou A.D.
      Systematic review and meta-analysis of endovascular versus open repair for common femoral artery atherosclerosis treatment.
      The superficial femoral artery segment has multiple challenges, including lengthening or shortening, compression, and twisting of the vessel during regular everyday activity. These dynamic challenges have led to stent fractures, which might lead to premature occlusion and restenosis.
      • Scheinert D.
      • Scheinert S.
      • Sax J.
      • et al.
      Prevalence and clinical impact of stent fractures after femoropopliteal stenting.
      RCTs have suggested that balloon angioplasty is comparable with bare-metal stents (BMS) for short lesions but for longer disease segments greater than 5-6 cm, nitinol BMS show extended patency.
      • Schillinger M.
      • Sabeti S.
      • Loewe C.
      • et al.
      Balloon angioplasty versus implantation of nitinol stents in the superficial femoral artery.
      ,
      • Laird J.R.
      • Katzen B.T.
      • Scheinert D.
      • et al.
      Nitinol stent implantation versus balloon angioplasty for lesions in the superficial femoral artery and proximal popliteal artery: twelve-month results from the RESILIENT randomized trial.
      BMS, although improved, suffer from recurrent in-stent restenosis in the medium- and long-term, leading to relatively low long-term patency.
      • Abdoli S.
      • Katz S.
      • Ochoa C.
      Long-term patency and clinical outcomes of nitinol stenting for femoropopliteal atherosclerotic disease.
      Covered stents, which prevent tissue ingrowth aside from the proximal and distal edges, might provide some advantage. Nonrandomized industry-sponsored studies showed 1-year primary patency and secondary patency at 73% and 92% percent, respectively.
      • Saxon R.R.
      • Chervu A.
      • Jones P.A.
      • et al.
      Heparin-bonded, expanded polytetrafluoroethylene-lined stent graft in the treatment of femoropopliteal artery disease: 1-year results of the VIPER (Viabahn Endoprosthesis with Heparin Bioactive Surface in the Treatment of Superficial Femoral Artery Obstructive Disease) trial.
      A smaller RCT did not show a benefit compared with BMS for long lesions.
      • Geraghty P.J.
      • Mewissen M.W.
      • Jaff M.R.
      • Ansel G.M.
      Three-year results of the VIBRANT trial of VIABAHN endoprosthesis versus bare nitinol stent implantation for complex superficial femoral artery occlusive disease.
      Frequent restenosis of treated lesions has led to randomized trials for drug-eluting technologies, including balloon and stent platforms. Recent data for DES have shown excellent results with 1- and 5-year patency rates at 86% and 66%, respectively. Symptomatic improvement occurred in 92% and 80% of patients during that same period. Registry and single-arm data have also shown dramatic benefits for DES.
      • Dake M.D.
      • Ansel G.M.
      • Jaff M.R.
      • et al.
      Durable clinical effectiveness with paclitaxel-eluting stents in the femoropopliteal artery: 5-year results of the Zilver PTX randomized trial.
      ,
      • Stavroulakis K.
      • Torsello G.
      • Bosiers M.
      • Argyriou A.
      • Tsilimparis N.
      • Bisdas T.
      2-Year outcomes of the Eluvia drug-eluting stent for the treatment of complex femoropopliteal lesions.
      Drug-eluting balloons have also shown benefits compared with standard balloon angioplasty in randomized trials.
      • Schneider P.A.
      • Laird J.R.
      • Tepe G.
      • et al.
      Treatment effect of drug-coated balloons is durable to 3 years in the femoropopliteal arteries: long-term results of the IN.PACT SFA randomized trial.
      • Rosenfield K.
      • Jaff M.R.
      • White C.J.
      • et al.
      Trial of a paclitaxel-coated balloon for femoropopliteal artery disease.
      • Tepe G.
      • Zeller T.
      • Albrecht T.
      • et al.
      Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg.
      A meta-analysis of drug-eluting balloons vs balloon angioplasty showed a significant reduction in restenosis rates in the former group. It also showed that higher drug concentrations of paclitaxel were associated with a superior reduction in restenosis than lower doses (3.0 vs 2.0 μg/mm2).
      • Caradu C.
      • Lakhlifi E.
      • Colacchio E.C.
      • et al.
      Systematic review and updated meta-analysis of the use of drug-coated balloon angioplasty versus plain old balloon angioplasty for femoropopliteal arterial disease.
      A concern about higher mortality rates associated with drug-eluting technologies has led several governing bodies to add warnings to their use.
      • Dan K.
      • Shlofmitz E.
      • Khalid N.
      • et al.
      Paclitaxel-related balloons and stents for the treatment of peripheral artery disease: insights from the Food and Drug Administration 2019 Circulatory System Devices Panel Meeting on late mortality: paclitaxel devices in PAD treatment.
      ,
      • Katsanos K.
      • Spiliopoulos S.
      • Kitrou P.
      • Krokidis M.
      • Karnabatidis D.
      Risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg: a systematic review and meta-analysis of randomized controlled trials.
      However, more recent data have brought these safety concerns into question.
      • Choi H.
      • Lee H.
      • Lee S.S.
      • Ahn J.
      • Joh J.H.
      • Lee M.Y.
      Association of mortality with drug-coated devices in femoropopliteal artery based on the nationwide data.
      ,
      • Schneider P.A.
      • Laird J.R.
      • Doros G.
      • et al.
      Mortality not correlated with paclitaxel exposure: an independent patient-level meta-analysis of a drug-coated balloon.
      A recent network meta-analysis that compared 14 different treatment modalities (ie, atherectomy, brachytherapy, cryoplasty, cutting balloons, drug-coated balloons, bare nitinol stents, DES, covered stents, and combinations), showed DES and covered stents to be the best modalities at 12 months and 24 months, respectively, for restenosis and target lesion revascularization.
      • Zhou Y.
      • Zhang Z.
      • Lin S.
      • et al.
      Comparative effectiveness of endovascular treatment modalities for de novo femoropopliteal lesions: a network meta-analysis of randomized controlled trials.
      Infrapopliteal endovascular treatment has been associated with a high incidence of restenosis of the treated vessel, where primary patency rates range from 22% to 92% at 1 year.
      • Lipsitz E.C.
      • Veith F.J.
      • Ohki T.
      The value of subintimal angioplasty in the management of critical lower extremity ischemia: failure is not always associated with a rethreatened limb.
      ,
      • Schmidt A.
      • Ulrich M.
      • Winkler B.
      • et al.
      Angiographic patency and clinical outcome after balloon-angioplasty for extensive infrapopliteal arterial disease.
      Although rates of restenosis or occlusion are high, limb salvage can be obtained and maintained despite relatively poor vessel patency rates.
      • 46.
        We recommend endovascular therapy in appropriately selected patients with claudication or chronic limb-threatening ischemia (Strong Recommendation; Low-Quality Evidence).
      • 47.
        We recommend against performing endovascular therapy in the common femoral or profunda femoris arteries (Strong Recommendation; Low-Quality Evidence).
      • 48.
        We recommend against performing endovascular therapy for lesions in asymptomatic patients or lesions that are not hemodynamically significant (Strong Recommendation; Low-Quality Evidence).
      Values and preferences. This recommendation places a high value on offering a revascularization option in appropriately selected patients that balances the inherent advantages of reduced morbidity, mortality, and faster recovery with the disadvantages of limited durability and increased potential for reinterventions.
      Practical tip. Patients with claudication that are selected for endovascular therapy ideally have short stenotic or occlusive lesions in the iliac or superficial femoral artery and reasonable expectation for functional capacity. Endovascular therapy is a reasonable minimally invasive option for limb salvage in patients with chronic limb-threatening ischemia and limited life expectancy, increased number of comorbidities, limited conduit options, or hostile tissue environments including active infection, scarring from multiple repeat surgeries, or radiation.

      3.3.2 Open and hybrid surgical revascularization

      PICO 3.3c: What are the available open surgical and hybrid (endovascular and open surgical) revascularization procedures in treating patients with PAD and their outcomes?

      3.3.2.1 Open surgical revascularization

      Despite the increasing use of endovascular interventions, open surgery remains an important therapeutic option in selected patients with PAD. Atherosclerotic disease of the lower extremities is usually described or divided into inflow (aortoiliac) and outflow (infrainguinal) disease.
      Endarterectomy is a technique in which the plaque is directly removed from the artery. This is a local open surgical repair and can be used as the sole procedure to treat short segment stenoses or occlusions. The artery can be closed primarily after the endarterectomy but is usually closed with a vein or prosthetic patch angioplasty to increase the diameter of the artery. Endarterectomy can also be used to treat and improve the inflow or outflow vessel(s) in conjunction with surgical bypass procedures. The common femoral artery is the most common lower extremity artery treated with endarterectomy as a sole procedure or at the time of bypass.
      Aortoiliac (inflow) disease can be successfully treated surgically with the use of larger-calibre prosthetic bypasses that are associated with good patency rates (aortofemoral 90% at 5 years) and superior to endovascular revascularization in a recent meta-analysis.
      • de Vries S.O.
      • Hunink M.G.M.
      Results of aortic bifurcation grafts for aortoiliac occlusive disease: a meta-analysis.
      ,
      • Premaratne S.
      • Newman J.
      • Hobbs S.
      • Garnham A.
      • Wall M.
      Meta-analysis of direct surgical versus endovascular revascularization for aortoiliac occlusive disease.
      Lower but acceptable 5-year graft patency are noted with less direct inflow from femoral-femoral (60%-80%) or axillo-femoral bypasses (80%).
      • Perler B.A.
      • Burdick J.F.
      • Williams G.M.
      Femoro-femoral or ilio-femoral bypass for unilateral inflow reconstruction?.
      • Blaisdell F.W.
      Development of femoro-femoral and axillo-femoral bypass procedures.
      • Samson R.H.
      • Showalter D.P.
      • Lepore M.R.
      • Nair D.G.
      • Dorsay D.A.
      • Morales R.E.
      Improved patency after axillofemoral bypass for aortoiliac occlusive disease.
      • Nguyen K.P.
      • Perrone K.H.
      • Rahman A.
      • et al.
      The role of axillofemoral bypass in current vascular surgery practice.
      However, all bypasses are associated with a low but significant incidence of operative, wound, and graft complications, which are avoided using the endovascular route. Aortoiliac disease is therefore generally first treated using endovascular techniques (angioplasty with or without stent) but if this is not possible or has failed, then surgical bypass can be considered in selected patients with acceptable risk profiles.
      Infrainguinal (outflow) disease can be treated with bypass generally originating from the common femoral artery as inflow and terminating at the above- or below-knee popliteal, or tibial or pedal vessels. Open bypass procedures might be considered for long-segment occlusions that cannot be treated with endovascular techniques or local repairs alone.
      Bypass patency is generally highest with the use of autogenous (saphenous or other) vein grafts. These bypasses have patency rates that range from 60% to 80% at 5 years for popliteal vein bypasses.
      • Almasri J.
      • Adusumalli J.
      • Asi N.
      • et al.
      A systematic review and meta-analysis of revascularization outcomes of infrainguinal chronic limb-threatening ischemia.
      Patency decreases significantly with more distal tibial or pedal artery bypasses, and therefore should only be performed for chronic limb-threatening ischemia. Patency rates are lower with the use of prosthetics at these levels and are avoided if possible.
      • Almasri J.
      • Adusumalli J.
      • Asi N.
      • et al.
      A systematic review and meta-analysis of revascularization outcomes of infrainguinal chronic limb-threatening ischemia.

      3.3.2.2 Hybrid procedures

      “Hybrid” procedures involve the concurrent use of surgical and endovascular techniques for revascularization. They offer the advantages of less invasive procedures (potential for less local and systemic morbidity, and quicker recovery time) in circumstances in which endovascular treatment alone might be insufficient or is not anatomically feasible. In these procedures, an angioplasty with or without stent is performed proximal or distal to a surgical bypass or endarterectomy during the same sitting to optimize inflow or outflow. This offers a more complete revascularization while limiting surgical exposure and operative time. Recently, these hybrid procedures have been increasingly used as revascularization options for patients.
      • Fereydooni A.
      • Zhou B.
      • Xu Y.
      • Deng Y.
      • Dardik A.
      • Ochoa Chaar C.I.
      Rapid increase in hybrid surgery for the treatment of peripheral artery disease in the Vascular Quality Initiative database.
      Choosing between exclusively surgical, endovascular, or hybrid revascularization will depend on patient anatomy and condition, and will take into consideration the feasibility, near-term risks, and long-term durability of the procedure(s).
      Surgical revascularization for intermittent claudication
      • 49.
        We recommend that surgical bypass to the popliteal artery (when indicated) should be performed with an autogenous vein in preference to prosthetic graft material for the treatment of intermittent claudication (Strong Recommendation; High-Quality Evidence).
      • 50.
        We recommend against performing femoral-tibial artery bypasses for the treatment of intermittent claudication (Strong recommendation; Moderate-Quality Evidence).
      Surgical revascularization for chronic limb-threatening ischemia
      • 51.
        We recommend that surgical bypass to the popliteal or infrapopliteal arteries should be performed with an autogenous vein for chronic limb-threatening ischemia (Strong Recommendation; High-Quality Evidence).
      • 52.
        We suggest that in patients with chronic limb-threatening ischemia for whom endovascular revascularization is not feasible and a suitable autogenous vein is not available, prosthetic material can be effective for bypass to the below-knee popliteal and tibial arteries as a last resort in cases of limb salvage (Strong Recommendation; Moderate-Quality Evidence).
      Values and preferences. This recommendation emphasizes the use of an autogenous vein as the best conduit for surgical bypass regardless of the indication. The choice of surgical conduit can significantly affect longer-term patency and limb salvage. For example, an autogenous saphenous vein has the best long-term patency rates in open revascularization procedures. The use of arm or composite vein grafts results in decreased but acceptable patency. The use of prosthetic bypasses below the knee generally results in poor long-term patency rates.
      • 53.
        We suggest a staged (proximal revascularization of aortic inflow first) approach to surgical procedures is reasonable in patients with ischemic rest pain (Weak Recommendation; Low-Quality Evidence).
      Values and preferences. This recommendation emphasizes that the extent of revascularization will depend on the severity of presentation. Patients with rest pain, in contrast to patients with significant ulcers or gangrene, might not require all levels of disease to be revascularized to resolve their symptoms. If indicated, and technically or anatomically feasible, endovascular treatment of aorta-iliac disease before, or concurrent with, infrainguinal surgical procedures offers a less invasive approach that can improve inflow and can contribute to the success of revascularization.

      3.4 Choosing between open surgical and endovascular procedures

      PICO 3.4: How to choose between open surgical and endovascular procedures in patients with PAD who require revascularization procedures?

      3.4.1 Evidence for open surgical vs endovascular revascularization

      3.4.1.1 Claudication

      There are no contemporary trials that have compared surgical with endovascular revascularization in patients with claudication related to aortoiliac and/or infrainguinal artery occlusive disease. Because of the previously discussed recommendation of offering the lowest possible risk intervention when moving forward with revascularization for debilitating claudication, it is unlikely that equipoise needed for a trial will ever exist.

      3.4.1.2 Chronic limb-threatening ischemia

      Only 1 RCT has been completed on this topic and open surgical bypass was compared with balloon angioplasty in patients with chronic limb-threatening ischemia due to infrainguinal arterial occlusive disease.
      • Bradbury A.W.
      • Adam D.J.
      • Beard J.D.
      • et al.
      Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial.
      There were no differences in amputation-free survival at 1 or 5 years. However, post hoc analysis suggested greater amputation-free survival with bypass surgery starting 2 years after randomization.
      • Farber A.
      • Eberhardt R.T.
      The current state of critical limb ischemia: a systematic review.
      This finding supports the superior durability of surgical bypass relative to balloon angioplasty in patients with chronic limb-threatening ischemia.
      There are, however, no trials that have compared open surgical vs endovascular revascularization that include: (1) aortoiliac disease; (2) the full spectrum of open (eg, endarterectomy) and hybrid revascularization (eg, iliac stent and femoral patch angioplasty); or (3) the full spectrum of contemporary endovascular revascularization approaches.

      3.4.2 Decision determinants for open vs endovascular

      After appropriate imaging is obtained and a decision has been made for revascularization, careful consideration of anatomic, patient, and procedural factors is essential to select the optimal revascularization strategy (Table 5).
      • 54.
        We recommend that when selecting endovascular vs open revascularization strategies for PAD, one must consider anatomic, patient, and procedural factors, in addition to operator expertise and resource availability (Strong Recommendation; Low-Quality Evidence).
      Values and preferences. This recommendation places a high value on individualizing revascularization strategies for PAD patients.
      Table 5Factors favouring endovascular vs open revascularization in patients with PAD
      Favours endovascular
      • Focal aortoiliac occlusive disease
      • Focal femoropopliteal and/or infrapopliteal disease
      • Intermittent claudication indication
      • Inadequate vein conduit for bypass
      • Prohibitive surgical risk
      • Expected survival < 2 years
      Favours open
      • Diffuse aortoiliac occlusive disease
      • Diffuse infrainguinal and/or infrapopliteal disease
      • Significant CFA and/or PFA disease
      • Adequate vein conduit for bypass
      • Failed endovascular revascularization(s)
      • Expected survival > 2 years
      CFA, common femoral artery; PAD, peripheral arterial disease; PFA, profunda femoris artery.
      Practical tip. Hybrid revascularization can be considered in those with common femoral or profunda femoral occlusive disease requiring endarterectomy, in addition to inflow and/or outflow disease amenable to endovascular therapy.

      3.4.3 Upcoming trials

      Two ongoing clinical trials of endovascular vs open revascularization for patients with PAD have the potential to change practice in the near future. The Best Endovascular vs Best Surgical Therapy for Patients With Critical Limb Ischemia (BEST-CLI) and Bypass vs Angioplasty in Severe Ischemia of the Leg (BASIL)-2.
      • Menard M.T.
      • Farber A.
      • Assmann S.F.
      • et al.
      Design and rationale of the Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia (BEST-CLI) Trial.
      ,
      • Popplewell M.A.
      • Davies H.
      • Jarrett H.
      • et al.
      Bypass versus Angio plasty in Severe Ischaemia of the Leg - 2 (BASIL-2) trial: study protocol for a randomised controlled trial.

      Conclusion

      In summary, the 2022 CCS guidelines for PAD should provide clinicians with guidance in the following areas: (1) diagnosis and screening of PAD; (2) optimal medical management for patients with PAD; (3) strategies to decrease risk and improve symptoms with smoking cessation therapies, medical therapies, and exercise programs; and (4) decisions regarding indications for interventions, assessing perioperative risk, and choosing between endovascular vs surgical approaches to revascularization. Approximately one-quarter (15/56) of the research questions received a strong recommendation with high-quality evidence, whereas 29% (16/56) were classified as weak recommendation with very low- or low-quality evidence, which illustrates the need for more evidence generation, particularly in preoperative risk assessment and interventional management of PAD patients. A gap in the medical management of patients with PAD has been reported by American and Canadian physicians for 20 years, and we hope that these guidelines will provide primary care, medical specialists, and vascular surgeons with the tools required to help close the treatment gap, and to improve the prognosis of patients with PAD.

      Acknowledgements

      The authors thank Sarah Visintini (Berckman Librarian at the University of Ottawa Heart Institute), for helping with the literature search for the exercise therapy section of this guideline. The authors also recognize Henry Lam for providing input on the search strategy and conducting the literature search, and Hannah Brooks for her support and work in screening and evaluating the search results for this project. The authors acknowledge and thank the volunteer contributions of panel members and all additional individuals involved in the guidelines process.

      Supplementary Material

      References

        • Canadian Cardiovascular Society
        Framework for Application of GRADE in CCS Guideline Development.
        (Available at:) (Accessed April 1, 2021)
        • Hennion D.R.
        • Siano K.A.
        Diagnosis and treatment of peripheral arterial disease.
        Am Fam Physician. 2013; 88: 306-310
        • Lend G.C.
        • Fowkes F.G.R.
        The Edinburgh Claudication Questionnaire: an improved version of the WHO/Rose questionnaire for use in epidemiological surveys.
        J Clin Epidemiol. 1992; 45: 1101-1109
        • Bauersachs R.
        • Debus S.
        • Nehler M.
        • et al.
        A targeted literature review of the disease burden in patients with symptomatic peripheral artery disease.
        Angiology. 2020; 71: 303-314
        • Aboyans V.
        • Criqui M.H.
        • Abraham P.
        • et al.
        Measurement and interpretation of the Ankle-Brachial Index: a scientific statement from the American Heart Association.
        Circulation. 2012; 126: 2890-2909
        • Khan N.A.
        • Rahim S.A.
        • Anand S.S.
        • Simel D.L.
        • Panju A.
        Does the clinical examination predict lower extremity peripheral arterial disease?.
        JAMA. 2006; 295: 536-546
        • Tehan P.E.
        • Santos D.
        • Chuter V.H.
        A systematic review of the sensitivity and specificity of the toe-brachial index for detecting peripheral artery disease.
        Vasc Med. 2016; 21: 382-389
        • Herraiz-Adillo Á.
        • Cavero-Redondo I.
        • Álvarez-Bueno C.
        • Pozuelo-Carrascosa D.P.
        • Solera-Martínez M.
        The accuracy of toe brachial index and ankle brachial index in the diagnosis of lower limb peripheral arterial disease: a systematic review and meta-analysis.
        Atherosclerosis. 2020; 315: 81-92
        • Chuter V.H.
        • Searle A.
        • Barwick A.
        • et al.
        Estimating the diagnostic accuracy of the ankle–brachial pressure index for detecting peripheral arterial disease in people with diabetes: a systematic review and meta-analysis.
        Diabet Med. 2021; 38e14379
        • Normahani P.
        • Mustafa C.
        • Shalhoub J.
        • et al.
        A systematic review and meta-analysis of the diagnostic accuracy of point-of-care tests used to establish the presence of peripheral arterial disease in people with diabetes.
        J Vasc Surg. 2021; 73: 1811-1820
        • Higgins P.
        • Higgins A.
        Epidemiology of peripheral arterial disease in women.
        J Epidemiol. 2003; 13: 1-14
        • Ortmann J.
        • Nüesch E.
        • Traupe T.
        • Diehm N.
        • Baumgartner I.
        Gender is an independent risk factor for distribution pattern and lesion morphology in chronic critical limb ischemia.
        J Vasc Surg. 2012; 55: 98-104
        • Sigvant B.
        • Wiberg-Hedman K.
        • Bergqvist D.
        • et al.
        A population-based study of peripheral arterial disease prevalence with special focus on critical limb ischemia and sex differences.
        J Vasc Surg. 2007; 45: 1185-1191
        • Alahdab F.
        • Wang A.T.
        • Elraiyah T.A.
        • et al.
        A systematic review for the screening for peripheral arterial disease in asymptomatic patients.
        J Vasc Surg. 2015; 61: 42S-53S
        • Guirguis-Blake J.M.
        • Evans C.V.
        • Redmond N.
        • Lin J.S.
        Screening for peripheral artery disease using the Ankle-Brachial Index updated evidence report and systematic review for the US preventive services task force.
        JAMA. 2018; 320: 184-196
        • Conte M.S.
        • Pomposelli F.B.
        • Clair D.G.
        • et al.
        Society for Vascular Surgery practice guidelines for atherosclerotic occlusive disease of the lower extremities: management of asymptomatic disease and claudication.
        J Vasc Surg. 2015; 61: 2S-41S
        • Canadian Society for Vascular Surgery
        Choosing Wisely Canada Recommendations: Vascular Surgery.
        (Available at:) (Accessed February 20, 2022)
        • Collet J.P.
        • Cayla G.
        • Ennezat P.V.
        • et al.
        Systematic detection of polyvascular disease combined with aggressive secondary prevention in patients presenting with severe coronary artery disease: the randomized AMERICA study.
        Int J Cardiol. 2018; 254: 36-42
        • Anand S.S.
        • Eikelboom J.W.
        • Dyal L.
        • et al.
        Rivaroxaban plus aspirin versus aspirin in relation to vascular risk in the COMPASS Trial.
        J Am Coll Cardiol. 2019; 73: 3271-3280
        • Bonaca M.P.
        • Nault P.
        • Giugliano R.P.
        • et al.
        Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk).
        Circulation. 2018; 137: 338-350
        • Bonaca M.P.
        • Bhatt D.L.
        • Storey R.F.
        • et al.
        Ticagrelor for prevention of ischemic events after myocardial infarction in patients with peripheral artery disease.
        J Am Coll Cardiol. 2016; 67: 2719-2728
        • Darmon A.
        • Sorbets E.
        • Ducrocq G.
        • et al.
        Association of multiple enrichment criteria with ischemic and bleeding risks among COMPASS-eligible patients.
        J Am Coll Cardiol. 2019; 73: 3281-3291
        • Minami H.
        • Itoga N.K.
        • George E.L.
        • Garcia-Toca M.
        Cost-effectiveness analysis of Ankle-Brachial Index screening in patients with coronary artery disease to optimize medical management.
        J Vasc Surg. 2021; 74 (2030-9.e2)
        • Gutierrez J.A.
        • Mulder H.
        • Jones W.S.
        • et al.
        Polyvascular disease and risk of major adverse cardiovascular events in peripheral artery disease: a secondary analysis of the EUCLID trial.
        JAMA Netw Open. 2018; 1e185239
        • Hartmann-Boyce J.
        • Livingstone-Banks J.
        • Ordóñez-Mena J.M.
        • et al.
        Behavioural interventions for smoking cessation: an overview and network meta-analysis.
        Cochrane Database Syst Rev. 2021; 1: CD013229
        • Howes S.
        • Hartmann-Boyce J.
        • Livingstone-Banks J.
        • Hong B.
        • Lindson N.
        Antidepressants for smoking cessation.
        Cochrane Database Syst Rev. 2020; 4: CD000031
        • Brownrigg J.R.W.
        • Hinchliffe R.J.
        • Apelqvist J.
        • et al.
        Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: a systematic review.
        Diabetes Metab Res Rev. 2016; 32: 119-127
        • Cahill K.
        • Lindson-Hawley N.
        • Thomas K.H.
        • Fanshawe T.R.
        • Lancaster T.
        Nicotine receptor partial agonists for smoking cessation.
        Cochrane Database Syst Rev. 2016; 2016: CD006103
        • Hartmann-Boyce J.
        • McRobbie H.
        • Lindson N.
        • et al.
        Electronic cigarettes for smoking cessation.
        Cochrane Database Syst Rev. 2021; 4: CD010216
        • Thanigaimani S.
        • Drovandi A.
        • Golledge J.
        A meta-analysis of randomised controlled trials evaluating the efficacy of smoking cessation interventions in people with peripheral artery disease.
        J Vasc Surg. 2022; 75: 721-729.e7
        • Hennrikus D.
        • Joseph A.M.
        • Lando H.A.
        • et al.
        Effectiveness of a smoking cessation program for peripheral artery disease patients: a randomized controlled trial.
        J Am Coll Cardiol. 2010; 56: 2105-2112
        • Lancaster T.
        • Stead L.F.
        Individual behavioural counselling for smoking cessation.
        Cochrane Database Syst Rev. 2017; 3: CD001292
        • Jude E.B.
        • Oyibo S.O.
        • Chalmers N.
        • Boulton A.J.M.
        Peripheral arterial disease in diabetic and nondiabetic patients: a comparison of severity and outcome.
        Diabetes Care. 2001; 24: 1433-1437
        • Beks P.J.
        • Mackaay A.J.C.
        • de Neeling J.N.D.
        • de Vries H.
        • Bouter L.M.
        • Heine R.J.
        Peripheral arterial disease in relation to glycaemic level in an elderly Caucasian population: the Hoorn Study.
        Diabetologia. 1995; 38: 86-96
        • Resnick H.E.
        • Lindsay R.S.
        • McDermott M.M.G.
        • et al.
        Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality: the Strong Heart Study.
        Circulation. 2004; 109: 733-739
        • Stone J.A.
        • Houlden R.L.
        • Lin P.
        • Udell J.A.
        • Verma S.
        Cardiovascular protection in people with diabetes.
        Can J Diabetes. 2018; 42: S162-S169
        • Chang C.C.
        • Chen Y.T.
        • Hsu C.Y.
        • et al.
        Dipeptidyl peptidase-4 inhibitors, peripheral arterial disease, and lower extremity amputation risk in diabetic patients.
        American Journal of Medicine. 2017; 130: 348-355
        • Lin D.S.H.
        • Lee J.K.
        • Chen W.J.
        Major adverse cardiovascular and limb events in patients with diabetes treated with GLP-1 receptor agonists vs DPP-4 inhibitors.
        Diabetologia. 2021; 64: 1949-1962
        • Bonaca M.P.
        • Wiviott S.D.
        • Zelniker T.A.
        • et al.
        Dapagliflozin and cardiac, kidney, and limb outcomes in patients with and without peripheral artery disease in DECLARE-TIMI 58.
        Circulation. 2020; 142: 734-747
        • Dicembrini I.
        • Tomberli B.
        • Nreu B.
        • et al.
        Peripheral artery disease and amputations with sodium-glucose co-transporter-2 (SGLT-2) inhibitors: a meta-analysis of randomized controlled trials.
        Diabetes Res Clin Pract. 2019; 153: 138-144
        • Huang C.Y.
        • Lee J.K.
        Sodium-glucose co-transporter-2 inhibitors and major adverse limb events: a trial-level meta-analysis including 51 713 individuals.
        Diabetes Obes Metab. 2020; 22: 2348-2355
        • Pearson G.J.
        • Thanassoulis G.
        • Anderson T.J.
        • et al.
        2021 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in adults.
        Can J Cardiol. 2021; 37: 1129-1150
        • Verdecchia P.
        • Reboldi G.
        • Porcellati C.
        • et al.
        Risk of cardiovascular disease in relation to achieved office and ambulatory blood pressure control in treated hypertensive subjects.
        J Am Coll Cardiol. 2002; 39: 878-885
        • Rabi D.M.
        • McBrien K.A.
        • Sapir-Pichhadze R.
        • et al.
        Hypertension Canada’s 2020 comprehensive guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children.
        Can J Cardiol. 2020; 36: 596-624
        • Staessen J.A.
        • Thijs L.
        • Fagard R.
        • et al.
        Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension.
        JAMA. 1999; 282: 539-546
        • Agarwal R.
        • Tu W.
        Minimally sufficient numbers of measurements for validation of 24-hour blood pressure monitoring in chronic kidney disease.
        Kidney Int. 2018; 94: 1199-1204
        • Mulè G.
        • Caimi G.
        • Cottone S.
        • et al.
        Value of home blood pressures as predictor of target organ damage in mild arterial hypertension.
        Eur J Cardiovasc Prev Rehab. 2002; 9: 123-129
        • Verdecchia P.
        Prognostic value of ambulatory blood pressure: current evidence and clinical implications.
        Hypertension. 2000; 35: 844-851
        • The SPRINT Research Group
        A randomized trial of intensive versus standard blood-pressure control.
        N Engl J Med. 2015; 373: 2103-2116
        • Bavry A.A.
        • Anderson R.D.
        • Gong Y.
        • et al.
        Outcomes among hypertensive patients with concomitant peripheral and coronary artery disease: findings from the international VErapamil-SR/ trandolapril study.
        Hypertension. 2010; 55: 48-53
        • Feringa H.H.H.
        • van Waning V.H.
        • Bax J.J.
        • et al.
        Cardioprotective medication is associated with improved survival in patients with peripheral arterial disease.
        J Am Coll Cardiol. 2006; 47: 1182-1187
        • Frary J.M.C.
        • Pareek M.
        • Byrne C.
        • et al.
        Intensive blood pressure control appears to be effective and safe in patients with peripheral artery disease: the Systolic Blood Pressure Intervention Trial.
        Eur Heart J Cardiovasc Pharmacother. 2021; 7: e38-e40
        • Whelton P.K.
        • Carey R.M.
        • Aronow W.S.
        • et al.
        2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary.
        J Am Soc Hypertens. 2018; 12 (579.e1-73)
        • Williams B.
        • Mancia G.
        • Spiering W.
        • et al.
        2018 ESC/ESH guidelines for the management of arterial hypertension.
        Eur Heart J. 2018; 39: 3021-3104
        • Yusuf S.
        • Joseph P.
        • Dans A.
        • et al.
        Polypill with or without aspirin in persons without cardiovascular disease.
        N Engl J Med. 2021; 384: 216-228
        • Armstrong E.J.
        • Chen D.C.
        • Singh G.D.
        • Amsterdam E.A.
        • Laird J.R.
        Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use is associated with reduced major adverse cardiovascular events among patients with critical limb ischemia.
        Vasc Med. 2015; 20: 237-244
        • Muñoz D.
        • Uzoije P.
        • Reynolds C.
        • et al.
        Polypill for cardiovascular disease prevention in an underserved population.
        N Engl J Med. 2019; 381: 1114-1123
        • Hypertension Canada
        2020 - 2022 Hypertension highlights: a practical guide informed by the Hypertension Canada Guidelines for the Prevention, Diagnosis, Risk Assessment, and Treatment of Hypertension.
        (Available at:)
        • Paravastu S.C.V.
        • Mendonca D.A.
        • da Silva A.
        Beta blockers for peripheral arterial disease.
        Eur J Vasc Endovasc Surg. 2009; 38: 66-70
        • Soga Y.
        • Iida O.
        • Takahara M.
        • Hirano K.
        • Suzuki K.
        • Kawasaki D.
        Beta-blocker treatment does not worsen critical limb ischemia in patients receiving endovascular therapy.
        J Atheroscler Thromb. 2014; 22: 481-489
        • CAPRIE Steering Committee
        A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee.
        Lancet. 1996; 348: 1329-1339
        • Baigent Colin
        • Blackwell Lisa
        • et al.
        • Antithrombotic Trialists’ (ATT) Collaboration
        Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
        Lancet. 2009; 373: 1849-1860
        • Hess C.N.
        • Debus E.S.
        • Nehler M.R.
        • et al.
        Reduction in acute limb ischemia with rivaroxaban versus placebo in peripheral artery disease after lower extremity revascularization: insights from VOYAGER PAD.
        Circulation. 2021; 144: 1831-1841
        • Anand S.S.
        • Bosch J.
        • Eikelboom J.W.
        • et al.
        Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial.
        Lancet. 2018; 391: 219-229
        • Andrade J.G.
        • Aguilar M.
        • Atzema C.
        • et al.
        The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society comprehensive guidelines for the management of atrial fibrillation.
        Can J Cardiol. 2020; 36: 1847-1948
      1. Thrombosis Canada. Clinical Guides.
        (Available at:)
        https://thrombosiscanada.ca/clinicalguides/#
        Date accessed: September 12, 2021
        • Andrade J.G.
        • Verma A.
        • Mitchell L.B.
        • et al.
        2018 Focused update of the Canadian Cardiovascular Society guidelines for the management of atrial fibrillation.
        Can J Cardiol. 2018; 34: 1371-1392
        • Yasuda S.
        • Kaikita K.
        • Akao M.
        • et al.
        Antithrombotic therapy for atrial fibrillation with stable coronary disease.
        N Engl J Med. 2019; 381: 1103-1113
        • Baigent C.
        • Sudlow C.
        • Collins R.
        • Peto R.
        Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
        BMJ. 2002; 324: 71-86
        • Robertson L.
        • Ghouri M.A.
        • Kovacs F.
        Antiplatelet and anticoagulant drugs for prevention of restenosis/reocclusion following peripheral endovascular treatment.
        Cochrane Database Syst Rev Published online. 2012; 2012: CD002071
        • Dake M.D.
        • Ansel G.M.
        • Jaff M.R.
        • et al.
        Durable clinical effectiveness with paclitaxel-eluting stents in the femoropopliteal artery: 5-year results of the Zilver PTX randomized trial.
        Circulation. 2016; 133 ([discussion: 1483]): 1472-1483
        • Do D.D.
        • Mahler F.
        Low-dose aspirin combined with dipyridamole versus anticoagulants after femoropopliteal percutaneous transluminal angioplasty.
        Radiology. 1994; 193: 567-571
        • Pilger E.
        • Lammer J.
        • Bertuch H.
        • et al.
        Nd:YAG laser with sapphire tip combined with balloon angioplasty in peripheral arterial occlusions: long-term results.
        Circulation. 1991; 83: 141-147
        • Lopes R.D.
        • Heizer G.
        • Aronson R.
        • et al.
        Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation.
        N Engl J Med. 2019; 380: 1509-1524
        • Cannon C.P.
        • Bhatt D.L.
        • Oldgren J.
        • et al.
        Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation.
        N Engl J Med. 2017; 377: 1513-1524
        • Gibson C.M.
        • Mehran R.
        • Bode C.
        • et al.
        Prevention of bleeding in patients with atrial fibrillation undergoing PCI.
        N Engl J Med. 2016; 375: 2423-2434
        • Mehta S.R.
        • Bainey K.R.
        • Cantor W.J.
        • et al.
        2018 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology focused update of the guidelines for the use of antiplatelet therapy.
        Can J Cardiol. 2018; 34: 214-233
        • Moll F.
        • Baumgartner I.
        • Jaff M.
        • et al.
        Edoxaban plus aspirin vs dual antiplatelet therapy in endovascular treatment of patients with peripheral artery disease: results of the ePAD trial.
        J Endovasc Ther. 2018; 25: 158-168
        • Bonaca M.P.
        • Bauersachs R.M.
        • Anand S.S.
        • et al.
        Rivaroxaban in peripheral artery disease after revascularization.
        N Engl J Med. 2020; 382: 1994-2004
        • Bedenis R.
        • Lethaby A.
        • Maxwell H.
        • Acosta S.
        • Prins M.H.
        Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery.
        Cochrane Database Syst Rev. 2015; 2015: CD00053
        • Belch J.J.F.
        • Dormandy J.
        Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial.
        J Vasc Surg. 2010; 52 (833.e1-2): 825-833
      2. Efficacy of oral anticoagulants compared with aspirin after infrainguinal bypass surgery (The Dutch Bypass Oral anticoagulants or Aspirin study): a randomised trial.
        Lancet. 2000; 355: 346-351
        • Sarac T.P.
        • Huber T.S.
        • Back M.R.
        • et al.
        Warfarin improves the outcome of infrainguinal vein bypass grafting at high risk for failure.
        J Vasc Surg. 1998; 28: 446-457
        • Johnson W.C.
        • Williford W.O.
        Benefits, morbidity, and mortality associated with long-term administration of oral anticoagulant therapy to patients peripheral arterial bypass procedures: a prospective randomized study.
        J Vasc Surg. 2002; 35: 413-421
        • Monaco M.
        • di Tommaso L.
        • Pinna G.B.
        • Lillo S.
        • Schiavone V.
        • Stassano P.
        Combination therapy with warfarin plus clopidogrel improves outcomes in femoropopliteal bypass surgery patients.
        J Vasc Surg. 2012; 56: 96-105
        • Hiatt W.R.
        • Bonaca M.P.
        • Patel M.R.
        • et al.
        Rivaroxaban and aspirin in peripheral artery disease lower extremity revascularization: impact of concomitant clopidogrel on efficacy and safety.
        . 2020; 142: 2219-2230
        • McClure G.R.
        • Kaplovitch E.
        • Chan N.
        • et al.
        A national Canadian survey of antithrombotic therapy after urgent and emergent limb revascularization.
        Can J Cardiol. 2021; 37: 504-507
        • Gerhard-Herman M.D.
        • Gornik H.L.
        • Barrett C.
        • et al.
        2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
        Circulation. 2017; 135: e686-e725
        • Aboyans V.
        • Ricco J.B.
        • Bartelink M.L.E.L.
        • et al.
        2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS): document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteriesEndorsed by: the European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS).
        Eur Heart J. 2018; 39: 763-816
        • Duceppe E.
        • Parlow J.
        • MacDonald P.
        • et al.
        Canadian Cardiovascular Society guidelines on perioperative cardiac risk assessment and management for patients who undergo noncardiac surgery.
        Can J Cardiol. 2017; 33: 17-32