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Canadian Journal of Cardiology

Building Your Peripheral Artery Disease Toolkit: Medical Management of Peripheral Artery Disease in 2022

Published:February 09, 2022DOI:https://doi.org/10.1016/j.cjca.2022.02.004

      Abstract

      Peripheral artery disease (PAD) is associated with substantial morbidity, including a high risk of cardiovascular and limb events and death. A growing body of evidence has demonstrated the benefits of antithrombotic therapy, lipid lowering, blood pressure control, diabetes management, smoking cessation, and exercise programs on improving symptoms and reducing these complications. Guidelines make specific recommendations on how to use these strategies to prevent adverse cardiovascular and limb outcomes in patients with PAD. Unfortunately, antithrombotic therapies, statins, optimal antihypertensives, smoking cessation counselling and therapies, and exercise programs have all been consistently shown to be underutilised in PAD patients both in Canada and globally. A variety of barriers to optimal utilisation of evidence-based medical therapies have been described at the patient, health care provider, and system levels. These include lack of knowledge among patients and health care providers, and lack of access to secondary prevention programs. We review the evidence for preventive therapies in PAD, evidence for underutilisation of these therapies, and barriers to their use. Core elements of PAD secondary prevention clinics are proposed, and a summary of optimal medical therapies and relevant tools is provided. This review may help clinicians who treat patients with PAD to develop a toolkit to overcome these barriers in order to improve utilisation of medical therapies, with the ultimate goal of improving outcomes for PAD patients.

      Résumé

      La maladie artérielle périphérique (MAP) est associée à une morbidité substantielle, avec notamment un risque élevé d'événements cardiovasculaires et d'événements touchant les membres, ainsi que de décès. De plus en plus d'évidences ont démontré les avantages d'un traitement antithrombotique, d'une réduction des taux lipidiques, du contrôle de la pression artérielle, d'une prise en charge du diabète, de l'arrêt du tabac et des programmes d'exercice physique pour atténuer les symptômes et en réduire les complications. Les lignes directrices font des recommandations spécifiques sur la façon d'utiliser ces stratégies pour prévenir les effets indésirables au niveau des membres et du système cardiovasculaire chez les patients atteints de MAP. Malheureusement, il a été démontré que les traitements antithrombotiques, les statines, les meilleurs antihypertenseurs, les conseils et les thérapies de désaccoutumance au tabac et les programmes d'activité physique sont autant d'outils sous-utilisés chez les patients atteints de MAP, tant au Canada que dans le monde. Divers obstacles à l'utilisation optimale des thérapies médicales, fondées sur des données probantes, ont été détaillés au niveau des patients, des fournisseurs de soins de santé et du système. Cela inclut le manque de connaissances des patients et des fournisseurs de soins de santé, et du manque d'accès aux programmes de prévention secondaire. Nous réalisons la synthèse des évidences concernant les thérapies préventives dans la MAP, les preuves de la sous-utilisation de ces thérapies et les obstacles à leur utilisation. Les éléments fondamentaux des cliniques de prévention secondaire pour la prise en charge de la MAP sont proposés, et un résumé des thérapies médicales optimales et des outils pertinents est proposé. Cet examen peut aider les cliniciens qui traitent les patients atteints de MAP à développer une boîte à outils pour surmonter ces obstacles afin d'améliorer l'utilisation des thérapies médicales, dans le but ultime d'améliorer le pronostic des patients atteints de MAP.
      Peripheral artery disease (PAD) is defined by the narrowing and obstruction of the noncoronary and nonintracranial arteries, and it is estimated to affect more than 200 million people worldwide.
      • Fowkes F.G.R.
      • Rudan D.
      • Rudan I.
      • et al.
      Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis.
      In Canada, it has been estimated that 1 in 20 people over the age of 50 years have PAD,
      • Makowsky M.
      • McMurtry M.S.
      • Elton T.
      • et al.
      Prevalence and treatment patterns of lower extremity peripheral arterial disease among patients at risk in ambulatory health settings.
      with prevalence likely to be rising with increasing age and rates of diabetes.
      • Blais C.
      • Rochette L.
      • Ouellet S.
      • Huynh T.
      Complex evolution of epidemiology of vascular diseases, including increased disease burden: from 2000 to 2015.
      Manifestations of PAD in the lower extremities include intermittent claudication, which causes significant functional impairment and a reduction in health-related quality of life.
      • Meru A.V.
      • Mittra S.
      • Thyagarajan B.
      • Chugh A.
      Intermittent claudication: an overview.
      Patients may also develop critical limb ischemia (CLI), which is characterised by resting leg pain and tissue loss (ulcers, gangrene) and often requires surgical intervention (ie, revascularisation or amputation).
      • Kinlay S.
      Management of critical limb ischemia.
      One year after revascularisation for CLI in Canada, more than 25% of patients undergo amputation or die.
      • Li B.
      • Rizkallah P.
      • Eisenberg N.
      • Forbes T.L.
      • Roche-Nagle G.
      Rates of intervention for claudication versus chronic limb-threatening ischemia in Canada and United States [e-pub ahead of print].
      Even in the absence of symptoms, the development of PAD indicates the presence of more widespread atherosclerosis.
      • Abramson B.L.
      • Huckell V.
      • Anand S.
      • et al.
      Canadian Cardiovascular Society Consensus Conference: peripheral arterial disease—executive summary.
      For this reason, in addition to major adverse limb events (MALE), PAD patients are also at risk for major adverse cardiovascular (CV) events (MACE) and increased mortality.
      • Criqui M.H.
      • Aboyans V.
      Epidemiology of peripheral artery disease.
      The cumulative incidence risk of MACE among patients with PAD alone is similar to those with established coronary artery disease (CAD), and this risk is increased 2-fold in patients with both PAD and CAD.
      • Eikelboom J.W.
      • Connolly S.J.
      • Bosch J.
      • et al.
      Rivaroxaban with or without aspirin in stable cardiovascular disease.
      Canadian data reveal that age-adjusted mortality is higher for patients with PAD than for patients with CAD or ischemic stroke in this country.
      • Blais C.
      • Rochette L.
      • Ouellet S.
      • Huynh T.
      Complex evolution of epidemiology of vascular diseases, including increased disease burden: from 2000 to 2015.
      The morbidity and mortality associated with PAD can be combatted with the effective use of secondary preventative therapies including lifestyle modification and medications such as antithrombotic, lipid-lowering, and antihypertensive drugs (Table 1). However, these therapies are underutilised, both in Canada and globally.
      • Li B.
      • Rizkallah P.
      • Eisenberg N.
      • Forbes T.L.
      • Roche-Nagle G.
      Rates of intervention for claudication versus chronic limb-threatening ischemia in Canada and United States [e-pub ahead of print].
      ,
      • Kaplovitch E.
      • Collins A.
      • McClure G.
      • et al.
      Medical therapy following urgent/emergent revascularization in Peripheral artery disease patients (Canadian Limb Ischemia Registry (CANALISE I).
      Barriers to implementation of therapies can be classified as occurring at the level of the patient, health care provider, or health system (Fig. 1). Patients and health care providers may face capability barriers related to knowledge or capacity to act, and intention barriers related to attitudes or motivations.
      • Michie S.
      • Johnston M.
      • Abraham C.
      • et al.
      Making psychological theory useful for implementing evidence based practice: a consensus approach.
      This narrative review outlines the current evidence supporting the use of medical therapies for prevention of adverse CV and limb events in patients with PAD, and barriers to their implementation. Strategies are then suggested to build a PAD toolkit to deliver better preventive care to this population.
      Table 1Summary of optimal evidence-based medical therapy for reduction of vascular events in stable symptomatic PAD, with selected published guidelines
      The following guidelines provide recommendations on all of the categories in this table: 2017 European Society of Cardiology guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery13; and 2016 American Heart Association/American College of Cardiology guideline on the management of patients with lower extremity peripheral artery disease.12
      and tools
      Smoking cessation
      Structured exercise therapy
      Antithrombotics
      • Single antiplatelet therapy (eg, 75 mg clopidogrel daily) or combination low-dose aspirin daily and 2.5 mg rivaroxaban twice daily in patients with symptomatic PAD, with preference for combination therapy in those at higher risk of ischemic events without high risk of bleeding
      Lipid-lowering therapy
      • Statin therapy (eg, 40 mg rosuvastatin daily)
      • Consider adding PCSK9 inhibitor in patients at high risk of ischemic events with LDL-C > 1.8 mmol/L despite maximal tolerated statin
      Antihypertensives
      • Hypertension should be controlled according to current guidelines
      • Consider ACEi or ARB first line
        • Hypertension Canada’s 2020 comprehensive hypertension 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.
      Diabetes management
      • Comprehensive coordinated care plan for diabetes control
      • Guideline-based pharmacotherapy including SGLT2 inhibitor or GLP-1 receptor agonist
        • 2019 European Society of Cardiology (ESC)/European Association for the Study of Diabetes (EASD) guideline on diabetes, prediabetes, and cardiovascular diseases
          • Cosentino F.
          • Grant P.J.
          • Aboyans V.
          • et al.
          2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
      • Regular foot screening
      ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; LDL-C, low-density lipoprotein cholesterol; PAD, peripheral artery disease; SGLT2, sodium-glucose cotransporter 2.
      The following guidelines provide recommendations on all of the categories in this table: 2017 European Society of Cardiology guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery
      • 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 arteries. Endorsed 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).
      ; and 2016 American Heart Association/American College of Cardiology guideline on the management of patients with lower extremity peripheral artery disease.
      • 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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      Figure thumbnail gr1
      Figure 1Barriers to optimal utilisation of evidence-based secondary preventive therapies for patients with peripheral artery disease (PAD). SET, structured exercise therapy.

      Lifestyle Modification

      Smoking cessation

      All PAD patients who smoke should be encouraged to quit.
      • 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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      ,
      • 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 arteries. Endorsed 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).
      Continued smoking is associated with increased mortality and decreased amputation-free survival
      • Armstrong E.J.
      • Wu J.
      • Singh G.D.
      • et al.
      Smoking cessation is associated with decreased mortality and improved amputation-free survival among patients with symptomatic peripheral artery disease.
      and can have negative impacts on postsurgical outcomes.
      • Willigendael E.M.
      • Teijink J.A.W.
      • Bartelink M.L.
      • et al.
      Smoking and the patency of lower extremity bypass grafts: a meta-analysis.
      The use of nicotine replacement therapy or other medications (eg, bupropion, varenicline) is safe and effective, and can be offered in conjunction with intensive counselling and/or a referral to a smoking cessation program.
      • 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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      ,
      • 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 arteries. Endorsed 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).
      A recent systematic review of smoking cessation trials in PAD found that methods previously tested in other populations may not necessarily be effective for patients with PAD,
      • 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 more intensive counselling and use of varenicline may improve chances of success.
      • 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.
      Guidelines recommend that PAD patients who smoke should be advised to quit, and assisted with a smoking cessation plan that includes pharmacotherapy.
      • 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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      ,
      • 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 arteries. Endorsed 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).

      Barriers to smoking cessation

      Implementation of smoking cessation counselling is suboptimal. Even in specialised vascular specialty clinics, only 75.2% of newly referred PAD patients who were current smokers were counselled on smoking cessation.
      • Saxon J.T.
      • Safley D.M.
      • Mena-Hurtado C.
      • et al.
      Adherence to guideline-recommended therapy—including supervised exercise therapy referral across peripheral artery disease specialty clinics: insights from the international PORTRAIT registry.
      Rates of counselling are worse for patients without comorbid CAD. Berger and Ladapo found that PAD patients with comorbid CAD were more likely to receive smoking cessation counseling (odds ratio 4.4) at a given visit, compared with patients with PAD alone.
      • Berger J.S.
      • Ladapo J.A.
      Underuse of prevention and lifestyle counseling in patients with peripheral artery disease.
      Possible patient-level explanations for reduced effectiveness of smoking cessation interventions in PAD patients include lack of knowledge regarding smoking as a causative factor,
      • Eyholzer S.
      • Perrenoud B.
      • Dwyer A.A.
      Patient perceptions of peripheral artery disease: a cross-sectional study of hospitalized adults.
      a higher level of addiction in this population, and environmental factors such as higher smoking rates among other members of the household and social circle.
      • 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.
      Innovative interventions, such as SMS- or app-based counseling strategies, have been shown to be beneficial,
      • Whittaker R.
      • McRobbie H.
      • Bullen C.
      • Rodgers A.
      • Gu Y.
      • Dobson R.
      Mobile phone text messaging and app-based interventions for smoking cessation.
      but their effectiveness may vary in different populations.
      • Bermon A.
      • Uribe A.F.
      • Pérez-Rivero P.F.
      • et al.
      Efficacy and safety of text messages targeting adherence to cardiovascular medications in secondary prevention: TXT2HEART Colombia randomized controlled trial.
      Although these potential patient-level barriers should motivate increased attempts by health care systems to encourage smoking cessation, we find that the opposite is true, with PAD patients receiving less counselling on smoking cessation than patients with CAD.
      • Berger J.S.
      • Ladapo J.A.
      Underuse of prevention and lifestyle counseling in patients with peripheral artery disease.
      The high site-by-site variability in implementation of smoking cessation counselling suggests that health system factors, such as access to smoking cessation programs, play a role.
      • Saxon J.T.
      • Safley D.M.
      • Mena-Hurtado C.
      • et al.
      Adherence to guideline-recommended therapy—including supervised exercise therapy referral across peripheral artery disease specialty clinics: insights from the international PORTRAIT registry.
      A review of smoking cessation interventions found that published interventions were less successful in women than in men, suggesting a need to consider gender when designing and implementing smoking cessation interventions.
      • Smith P.H.
      • Bessette A.J.
      • Weinberger A.H.
      • Sheffer C.E.
      • McKee S.A.
      Sex/gender differences in smoking cessation: a review.

      Structured exercise therapy

      Exercise therapy in the form of a supervised exercise program is an additional lifestyle modification that should be encouraged in PAD patients experiencing claudication.
      • 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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      ,
      • 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 arteries. Endorsed 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).
      These programs are typically more effective than home-based programs,
      • Hageman D.
      • Fokkenrood H.J.
      • Gommans L.N.
      • van den Houten M.M.
      • Teijink J.A.
      Supervised exercise therapy versus home-based exercise therapy versus walking advice for intermittent claudication.
      perhaps because of differences in intensity or opportunity for encouragement/motivation. However, logistical obstacles (eg, transportation to the facility) exist for some patients, and unsupervised programs should still be considered if those are more practical for a given patient.
      • Parvar S.L.
      • Fitridge R.
      • Dawson J.
      • Nicholls S.J.
      Medical and lifestyle management of peripheral arterial disease.
      The benefits of exercise are numerous; regular physical activity is associated with reduced all-cause mortality,
      • Chang P.
      • Nead K.T.
      • Olin J.W.
      • Myers J.
      • Cooke J.P.
      • Leeper N.J.
      Effect of physical activity assessment on prognostication for peripheral artery disease and mortality.
      and exercise programs result in significant improvements in functional capacity.
      • Lane R.
      • Harwood A.
      • Watson L.
      • Leng G.C.
      Exercise for intermittent claudication.
      In the Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) trial, the difference in peak walking time between patients receiving supervised exercise vs stent revascularisation was nonsignificant (P = 0.16) at 18-month follow-up.
      • Murphy T.P.
      • Cutlip D.E.
      • Regensteiner J.G.
      • et al.
      Supervised exercise, stent revascularization, or medical therapy for claudication due to aortoiliac peripheral artery disease: the CLEVER study.
      This highlights that noninvasive approaches can be considered even in the treatment of function-limiting claudication. Guidelines recommend structured exercise programs to improve symptoms and function.
      • 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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      ,
      • 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 arteries. Endorsed 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).

      Barriers to structured exercise therapy

      Studies have found that patients with PAD are less likely to start and complete exercise therapy programs,
      • Devrome A.N.
      • Aggarwal S.
      • McMurtry M.S.
      • et al.
      Cardiac rehabilitation in people with peripheral arterial disease: a higher risk population that benefits from completion.
      and patients with PAD experience less improvement in cardiorespiratory fitness than those with CAD alone.
      • Nguyen C.H.
      • Marzolini S.
      • Oh P.
      • Thomas S.G.
      A retrospective comparison of fitness and exercise progression in patients with coronary and peripheral artery disease in cardiac rehabilitation.
      A few studies have qualitatively examined barriers to PAD patients’ use of preventive therapies. At the patient level, claudication pain itself is a barrier. The pain that is associated with walking for people with claudication discourages participation in exercise programs.
      • Galea M.N.
      • Bray S.R.
      • Ginis K.A.M.
      Barriers and facilitators for walking in individuals with intermittent claudication.
      ,
      • Galea Holmes M.N.
      • Weinman J.A.
      • Bearne L.M.
      “You cannot walk with cramp!” A qualitative exploration of individuals’ beliefs and experiences of walking as treatment for intermittent claudication.
      A systematic review suggests that alternative exercise regimens that do not involve development of maximal claudication pain improve adherence and completion rates.
      • Lin E.
      • Nguyen C.H.
      • Thomas S.G.
      Completion and adherence rates to exercise interventions in intermittent claudication: traditional exercise versus alternative exercise—a systematic review.
      Transportation to supervised exercise program sites may be more difficult for people with PAD, which may be alleviated by use of home-based exercise programs that use pedometers.
      • Chan C.
      • Sounderajah V.
      • Normahani P.
      • et al.
      Wearable activity monitors in home based exercise therapy for patients with intermittent claudication: a systematic review.
      Women are less likely to complete the therapy than men owing to unaddressed patient-level barriers including difficulty with transportation and family responsibilities.
      • Khadanga S.
      • Gaalema D.E.
      • Savage P.
      • Ades P.A.
      Underutilization of cardiac rehabilitation in women: barriers and solutions.
      At the provider level, surveys have found that health care practitioners lack knowledge regarding PAD-specific exercise protocols.
      • Ahden S.
      • Ngo V.
      • Hoskin J.
      • et al.
      Inclusion of people with peripheral artery disease in cardiac rehabilitation programs: a pan-Canadian survey.
      Health care providers appear to refer women with cardiac disease less frequently than men to exercise programs.
      • Khadanga S.
      • Gaalema D.E.
      • Savage P.
      • Ades P.A.
      Underutilization of cardiac rehabilitation in women: barriers and solutions.
      The biggest barrier is systemic lack of access to exercise programs. Surveys and systematic reviews demonstrate that most PAD patients do not have access to supervised exercise programs.
      • Ahden S.
      • Ngo V.
      • Hoskin J.
      • et al.
      Inclusion of people with peripheral artery disease in cardiac rehabilitation programs: a pan-Canadian survey.
      • Abaraogu U.O.
      • Abaraogu O.D.
      • Dall P.M.
      • et al.
      Exercise therapy in routine management of peripheral arterial disease and intermittent claudication: a scoping review.
      • Makris G.C.
      • Lattimer C.R.
      • Lavida A.
      • Geroulakos G.
      Availability of supervised exercise programs and the role of structured home-based exercise in peripheral arterial disease.
      Where they do have access, the programs often do not have PAD-specific protocols, education among staff is often limited, and funding is poor.
      • Ahden S.
      • Ngo V.
      • Hoskin J.
      • et al.
      Inclusion of people with peripheral artery disease in cardiac rehabilitation programs: a pan-Canadian survey.
      Referral for supervised exercise therapy was found to be especially sensitive to site-by-site availability of exercise programs for these patients, even in specialised vascular clinics.
      • Saxon J.T.
      • Safley D.M.
      • Mena-Hurtado C.
      • et al.
      Adherence to guideline-recommended therapy—including supervised exercise therapy referral across peripheral artery disease specialty clinics: insights from the international PORTRAIT registry.

      Diet

      The body of literature investigating the role of diet in the generation and propagation of PAD is heterogeneous. Most of these studies lack impact owing to their small sizes or observational designs. Previous studies, such as the Northern Manhattan Study (NOMAS)
      • Gardener H.
      • Wright C.B.
      • Cabral D.
      • et al.
      Mediterranean diet and carotid atherosclerosis in the Northern Manhattan Study.
      and the Coronary Diet Intervention With Olive Oil and Cardiovascular Prevention (CORDIOPREV) study,
      • Jimenez-Torres J.
      • Alcalá-Diaz J.F.
      • Torres-Peña J.D.
      • et al.
      Mediterranean diet reduces atherosclerosis progression in coronary heart disease: an analysis of the CORDIOPREV randomized controlled trial.
      among others, have suggested that the Mediterranean diet may reduce the progression of carotid atherosclerosis as measured by carotid intimal medial thickness (CIMT). However, this remains a surrogate marker, and the role of serial CIMT assessments has not been established in clinical practice, nor has it been shown to affect clinical outcomes. The effect of dietary intake on plaque development and progression has not been well studied in the PAD cohort.
      The only randomised controlled trial which has reported on the role of diet and the presence of PAD is a subgroup analysis of the Prevención con Dieta Mediterránea (PREDIMED) study.
      • Ruiz-Canela M.
      • Estruch R.
      • Corella D.
      • Salas-Salvadó J.
      • Martínez-González M.A.
      Association of Mediterranean diet with peripheral artery disease: the PREDIMED randomized trial.
      In this primary prevention study, randomisation to a Mediterranean diet was associated with a significantly lower risk of PAD development. However, the trial suffered from inconsistencies in methodology leading to the subsequent retraction and republication of the overall study.
      • Martínez-González M.A.
      Protocol deviations, reanalyses, and corrections to PREDIMED trial derivative study on peripheral artery disease.
      The Lyon Diet Heart Study was a randomised trial of secondary prevention in patients with prior myocardial infarction (MI).
      • Kris-Etherton P.
      • Eckel R.H.
      • Howard B.V.
      • St Jeor S.
      • Bazzarre T.L.
      Nutrition Committee Population Science Committee and Clinical Science Committee of the American Heart Association. AHA science advisory: Lyon Diet Heart Study. Benefits of a Mediterranean-style, National Cholesterol Education Program/American Heart Association step I dietary pattern on cardiovascular disease.
      Although the Mediterranean diet was shown to improve the rate of CV death and nonfatal MI, PAD-specific outcomes have not been reported. Further randomised controlled trials are required to clarify the role of the Mediterranean diet in the development and progression of PAD.
      The limited evidence for dietary interventions in PAD patients is reflected in the absence of recommendations for dietary counselling in PAD guidelines.
      • 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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      ,
      • 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 arteries. Endorsed 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).

      Medications

      Antiplatelet agents

      The rationale for the use of antiplatelet therapy in PAD is derived from the role of platelets in atherothrombosis, and the proven efficacy of these drugs in other atherosclerotic disease states (ischemic stroke, CAD).
      • Abramson B.L.
      • Huckell V.
      • Anand S.
      • et al.
      Canadian Cardiovascular Society Consensus Conference: peripheral arterial disease—executive summary.
      Current European and American guidelines for the treatment of PAD recommend the use of single antiplatelet therapy (SAPT; 75-325 mg/day aspirin or 75 mg/day clopidogrel) in symptomatic PAD patients.
      • 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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      ,
      • 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 arteries. Endorsed 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).
      This guidance is supported by a meta-analysis of 18 prospective randomised trials (5269 PAD patients) assessing the effectiveness of aspirin (alone or with dipyridamole) vs placebo in which a reduction in odds for cardiac events (pooled relative risk [RR] 0.88, 95% confidence interval [CI] 0.76-1.04) was observed.
      • Berger J.S.
      • Krantz M.J.
      • Kittelson J.M.
      • Hiatt W.R.
      Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: a meta-analysis of randomized trials.
      Previous data from the Antithrombotic Trialists’ Collaboration demonstrated that the use of antiplatelet therapy in general (aspirin or other drugs) is associated with a 23% relative risk reduction (8% absolute) of serious vascular events in PAD patients (P = 0.004).
      Antithrombotic Trialists’ Collaboration
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      The Clopidogrel vs Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial forms the basis for inclusion of clopidogrel into guidelines, in which a PAD subgroup on clopidogrel rather than aspirin experienced a 23.8% relative risk reduction (95% CI 8.9-36.2; P = 0.0028) in stroke, MI, or vascular death with a similar safety profile.
      CAPRIE Steering Committee
      A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
      The Examining Use of Ticagrelor in PAD (EUCLID) trial did not find a benefit of ticagrelor over clopidogrel for either MACE or MALE.
      • Hiatt W.R.
      • Fowkes F.G.R.
      • Heizer G.
      • et al.
      Ticagrelor versus clopidogrel in symptomatic peripheral artery disease.
      The efficacy of SAPT in asymptomatic PAD patients is not well established.
      • Kaplovitch E.
      • Rannelli L.
      • Anand S.S.
      Antithrombotics in stable peripheral artery disease.
      Studies investigating the use of dual antiplatelet therapy (DAPT) in stable PAD, with the addition of either clopidogrel, ticagrelor, or vorapaxar to aspirin, suggest that while there are some benefits in terms of reducing CV and limb events, these are counterbalanced by an excess major bleeding risk.
      • Kaplovitch E.
      • Rannelli L.
      • Anand S.S.
      Antithrombotics in stable peripheral artery disease.
      • Cacoub P.P.
      • Bhatt D.L.
      • Steg P.G.
      • Topol E.J.
      • Creager M.A.
      Patients with peripheral arterial disease in the CHARISMA trial.
      • Bonaca M.P.
      • Scirica B.M.
      • Creager M.A.
      • et al.
      Vorapaxar in patients with peripheral artery disease: results from TRA2°P-TIMI 50.

      Anticoagulants

      Oral anticoagulants have proven benefit in reducing CV events in CAD
      • Anand S.S.
      • Yusuf S.
      Oral anticoagulants in patients with coronary artery disease.
      and have since been studied in patients with PAD in combination with antiplatelet therapy. In the Warfarin Antiplatelet Vascular Evaluation (WAVE) trial, which assessed the combination of warfarin (target international normalized ratio 2-3) and antiplatelet therapy vs antiplatelet alone, no significant difference in MI, stoke, or death from CV causes was observed (RR 0.92, 95% CI 0.73-1.16; P = 0.48).
      • Anand S.
      • Yusuf S.
      • Xie C.
      • et al.
      Oral anticoagulant and antiplatelet therapy and peripheral arterial disease.
      Furthermore, a significant increase in life-threatening bleeding was noted in the combination group (RR 3.41, 95% CI 1.84-6.35), limiting the utility of adding warfarin. These findings were consistent with the Dutch Bypass, Oral Anticoagulants or Aspirin (Dutch BOA) trial of moderate- to high-intensity warfarin compared with aspirin alone in patients after infrainguinal open surgical revascularisation, which found no clear evidence of efficacy and an excess of life-threatening bleeding.
      Efficacy of oral anticoagulants compared with aspirin after infrainguinal bypass surgery (the Dutch Bypass Oral Anticoagulants or Aspirin Study): a randomised trial.
      A strategy of adding a low dose of direct oral anticoagulants to antiplatelet therapy was proven to reduce MACE in patients with recent coronary events.
      • Mega J.L.
      • Braunwald E.
      • Wiviott S.D.
      • et al.
      Rivaroxaban in patients with a recent acute coronary syndrome.
      In the subsequent Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial, patients with stable atherosclerotic disease (PAD or CAD) were randomly assigned to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily) alone (1:1:1).
      • Eikelboom J.W.
      • Connolly S.J.
      • Bosch J.
      • et al.
      Rivaroxaban with or without aspirin in stable cardiovascular disease.
      Among the subgroup of 7470 patients with PAD the combination of low-dose rivaroxaban and aspirin was associated with a reduction in MACE (hazard ratio [HR] 0.72, 95% CI 0.57-0.90) and MALE (HR 0.54, 95% CI 0.35-0.84) compared with aspirin alone.
      • 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.
      An increased risk of major bleeding was observed in patients receiving the combination therapy, but no excess in severe bleeding, including fatal bleeding, symptomatic bleeding into a critical organ, or surgical site bleeding requiring reoperation, was observed. Even when MALE did occur, combination therapy reduced recurrent MALE by 43% (P = 0.01) and, total vascular amputations by 58% (P = 0.01).
      • Anand S.S.
      • Caron F.
      • Eikelboom J.W.
      • et al.
      Major adverse limb events and mortality in patients with peripheral artery disease: the COMPASS trial.
      Patients at high risk of MACE and MALE, such as those with concomitant heart failure, diabetes, renal insufficiency, and polyvascular disease, experienced the greatest risk reduction from rivaroxaban plus aspirin therapy.
      • Anand S.S.
      • Eikelboom J.W.
      • Dyal L.
      • et al.
      Rivaroxaban plus aspirin versus aspirin in relation to vascular risk in the COMPASS trial.
      These findings are applicable to many real-world PAD patients; in the Reduction of Atherothrombosis for Continued Health (REACH) registry, 68.4% of real-world PAD patients met eligibility for the COMPASS trial.
      • Darmon A.
      • Bhatt D.L.
      • Elbez Y.
      • et al.
      External applicability of the COMPASS trial: an analysis of the reduction of atherothrombosis for continued health (REACH) registry.
      The predominant reasons for exclusion included high bleeding risk (contraindication to rivaroxaban), need for full-dose anticoagulant use, and requirement for DAPT (after acute coronary syndrome [ACS], or percutaneous coronary intervention with stent).
      • Darmon A.
      • Bhatt D.L.
      • Elbez Y.
      • et al.
      External applicability of the COMPASS trial: an analysis of the reduction of atherothrombosis for continued health (REACH) registry.
      Kaplovitch et al. summarises best antithrombotic therapy for stable symptomatic PAD considering the newest clinical evidence (ie, COMPASS).
      • Kaplovitch E.
      • Rannelli L.
      • Anand S.S.
      Antithrombotics in stable peripheral artery disease.
      SAPT in the form of aspirin or clopidogrel remains standard in mild disease, with the evidence for clopidogrel being slightly superior. The use of rivaroxaban (2.5 mg twice daily) in combination with aspirin should now be considered in patients who are at high risk for MACE and MALE and at low risk for bleeding.
      • Kaplovitch E.
      • Rannelli L.
      • Anand S.S.
      Antithrombotics in stable peripheral artery disease.
      Patients with PAD who endure an ACS or an acute cerebrovascular event should be managed according to those corresponding guidelines.
      • Hess C.N.
      • Hiatt W.R.
      Antithrombotic therapy for peripheral artery disease in 2018.
      For example, in patients with PAD and CAD, DAPT (aspirin and ticagrelor) is often used in the 6-12 months following ACS. There is evidence to support the continuation of long-term DAPT in those patients,
      • 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.
      but given the benefit of low-dose rivaroxaban and aspirin in reducing MACE and MALE, returning to the COMPASS regimen after 6 or 12 months is reasonable.
      • McClure G.R.
      • Kaplovitch E.
      • Narula S.
      • Bhagirath V.C.
      • Anand S.S.
      Rivaroxaban and aspirin in peripheral vascular disease: a review of implementation strategies and management of common clinical scenarios.
      The use of antithrombotic therapy after vascular surgery for PAD patients is less well defined, but a course of DAPT after peripheral revascularisation is reasonable, according to the 2017 American Heart Association guidelines.
      • 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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      However, after those guidelines were published, strong evidence from the Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER PAD) trial revealed similar benefits and risks for PAD patients after lower-extremity infrainguinal peripheral revascularisation (endovascular or surgical) as found for stable patients in the COMPASS trial. Acute limb ischemia, major amputation, MI, ischemic stroke, or death from CV events occurred less frequently in the rivaroxaban plus aspirin group at 3 years (17.3% vs 19.9%, HR 0.85, 95% CI 0.76-0.96; P = 0.009).
      • Bonaca M.P.
      • Bauersachs R.M.
      • Anand S.S.
      • et al.
      Rivaroxaban in peripheral artery disease after revascularization.
      Meta-analysis of the 2 trials revealed consistent beneficial effects with the use of that combination.
      • Anand S.S.
      • Hiatt W.
      • Dyal L.
      • et al.
      Low-dose rivaroxaban and aspirin among patients with peripheral artery disease: a meta-analysis of the COMPASS and VOYAGER trials [e-pub ahead of print].

      Statins

      The initiation of statin therapy in all patients with PAD is supported by current guidelines.
      • 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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      ,
      • 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 arteries. Endorsed 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).
      In the Heart Protection Study, 20,536 adults with vascular disease (6748 PAD patients) were randomly assigned to receive either 40 mg simvastatin daily or placebo.
      Heart Protection Study Collaborative Group
      Randomized trial of the effects of cholesterol-lowering with simvastatin on peripheral vascular and other major vascular outcomes in 20,536 people with peripheral arterial disease and other high-risk conditions.
      In those patients with PAD receiving simvastatin, a 22% relative reduction (95% CI 15%-29%) in the rate of first major vascular event (MI, coronary death, stroke, or revascularisation) was observed, and this effect was significant across different PAD subgroups.
      Heart Protection Study Collaborative Group
      Randomized trial of the effects of cholesterol-lowering with simvastatin on peripheral vascular and other major vascular outcomes in 20,536 people with peripheral arterial disease and other high-risk conditions.
      Observational data from the REACH registry demonstrates that statin users have a significantly lower risk of adverse limb outcomes (worsening claudication/new episode of CLI, new percutaneous/surgical revascularisation, or amputation) at 4 years compared with non–statin users (HR 0.82, 95% CI 0.72-0.92; P = 0.0013).
      • Kumbhani D.J.
      • Steg P.G.
      • Cannon C.P.
      • et al.
      Statin therapy and long-term adverse limb outcomes in patients with peripheral artery disease: insights from the REACH registry.
      The impact of unmeasured confounding, such as the “healthy user” effect, cannot be overlooked. However, this was thought to play a minor role, because the patients receiving statins had more comorbidities and a greater severity of disease.

      PCSK-9 inhibitors

      Newly developed PCSK-9 inhibitors have emerged as an additional tool that can be used to lower low-density lipoprotein cholesterol (LDL-C). Forty-eight weeks after randomisation to either evolocumab (either 140 mg every 2 weeks or 420 mg monthly, subcutaneous injection) or placebo in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, patients in the treatment arm experienced a reduction in the risk of CV death, MI, stroke, hospitalisation for unstable angina, or coronary revascularisation (HR 0.85, 95% CI 0.79-0.92; P < 0.001).
      • Sabatine M.S.
      • Giugliano R.P.
      • Keech A.C.
      • et al.
      Evolocumab and clinical outcomes in patients with cardiovascular disease.
      The reduction in the primary end point was consistent across different baseline LDL-C levels, even in the quartile of participants with a low baseline median LDL-C of 1.9 mmol/L. A subanalysis of the 3642 patients with PAD revealed a 27% composite relative risk reduction in MACE and MALE among PAD patients (HR 0.73, 95% CI 0.60-0.88; 10.9% vs 15.0%, absolute risk reduction 4.1%; no. needed to treat: 25).
      • 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).
      Strikingly, there appeared to be an approximately linear relationship between LDL-C levels and reduction of MACE/MALE, all the way down to an LDL-C of 10 mg/dL (0.6 mmol/L). PCSK-9 inhibition with alirocumab also reduced limb events in patients after acute coronary syndrome (HR 0.69, 95% CI 0.54-0.89; P = 0.004), and the benefit was associated with baseline lipoprotein(a) but not LDL-C levels.
      • Schwartz G.G.
      • Steg P.G.
      • Szarek M.
      • et al.
      Peripheral artery disease and venous thromboembolic events after acute coronary syndrome: role of lipoprotein(a) and modification by alirocumab: prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial.

      Blood pressure control

      Elevated blood pressure (BP) is one of the main risk factors for the development of PAD, and PAD patients who are hypertensive have poorer outcomes.
      • Murabito J.M.
      • Evans J.C.
      • Nieto K.
      • et al.
      Prevalence and clinical correlates of peripheral arterial disease in the Framingham Offspring Study.
      Current guidelines endorse the use of blood pressure–lowering medications in PAD patients with hypertension to reduce the risk of MI, stroke, heart failure, and CV death.
      • 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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      ,
      • 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 arteries. Endorsed 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).
      ,
      • 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.
      Angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) are typically used as first-line therapies owing to their beneficial effects in this population. In the Heart Outcomes Prevention Evaluation (HOPE) trial, patients with vascular disease or diabetes who were randomised to receive ramipril (10 mg daily) rather than placebo experienced a 22% relative reduction in MACE (RR 0.78, 95% CI 0.70-0.86; P < 0.001).
      • Yusuf S.
      • Sleight P.
      • Pogue J.
      • et al.
      Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.
      A subgroup analysis revealed that ramipril was beneficial in both clinical and subclinical (ankle-brachial index [ABI] < 0.9, no symptoms) PAD, and the absolute benefit of ramipril was twice as large in those with a low ABI (50 vs 24 per 1000 events prevented).
      • Ostergren J.
      • Sleight P.
      • Dagenais G.
      • et al.
      Impact of ramipril in patients with evidence of clinical or subclinical peripheral arterial disease.
      ARBs are a safe and effective alternative, and a trial that investigated the use of telmisartan vs ramipril in patients with vascular disease found no significant difference in CV outcomes.
      • Yusuf S.
      • Teo K.K.
      • Pogue J.
      • et al.
      Telmisartan, ramipril, or both in patients at high risk for vascular events.
      High-quality evidence to inform the optimal BP target specifically in PAD patients is lacking. A subgroup analysis of Systolic Blood Pressure Intervention Trial (SPRINT) trial found a reduction in the composite of MACE and heart failure, but an increase in serious adverse events, with intensive BP control (systolic BP target < 120 vs 135-139 mm Hg) in the PAD subpopulation.
      • Frary J.
      • Byrne C.
      • Vaduganathan M.
      • et al.
      Intensive versus standard blood pressure control in patients with peripheral artery disease: the Systolic Blood Pressure Intervention Trial (SPRINT).
      A post hoc analysis of the International Verapamil SR/Trandolapril Study (INVEST) trial, which was designed to compare hypertension treatment strategies in CAD, included 2699 patients with PAD. A J-shape relationship was observed between systolic BP achieved and the primary outcome of all-cause mortality, MI, or stroke, with the lowest frequency of the outcome observed in patients with a BP of 135-145/60-90 mm Hg.
      • 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.

      Glycemic control

      Diabetes is a strong risk factor for PAD, and increasing rates of diabetes may be driving an increasing share of hospitalisations for PAD.
      • Jacob-Brassard J.
      • Al-Omran M.
      • Hussain M.A.
      • et al.
      Temporal trends in hospitalization for lower extremity peripheral artery disease in Ontario: the importance of diabetes.
      A subanalysis of the EUCLID trial revealed that each 1% elevation of HbA1c was associated with a 14.2% increased risk of MACE.
      • Low Wang C.C.
      • Blomster J.I.
      • Heizer G.
      • et al.
      Cardiovascular and limb outcomes in patients with diabetes and peripheral artery disease: the EUCLID trial.
      In diabetic patients undergoing infrapopliteal balloon angioplasty, lower rates of primary patency (16% vs 46%; P = 0.005) and higher rates of MALE (35% vs 23%; P = 0.05) were observed among patients with a fasting blood glucose above the median.
      • Singh S.
      • Armstrong E.J.
      • Sherif W.
      • et al.
      Association of elevated fasting glucose with lower patency and increased major adverse limb events among patients with diabetes undergoing infrapopliteal balloon angioplasty.
      In terms of choice of medication, sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial effects in diabetics with high CV risk. In the Canagliflozin Cardiovascular Assessment Study (CANVAS) trial, which assessed the efficacy of canagliflozin vs placebo in participants with type 2 diabetes and high CV risk, a reduction in MI, stroke, or CV mortality (HR 0.86, 95% CI 0.75-0.97; P < 0.001 for noninferiority; P = 0.02 for superiority) but increase in amputation rate (HR 1.97, 95% CI 1.41-2.75) was observed.
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      The mechanistic explanation for this particular finding is unknown.
      • 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.
      However, no difference in amputation rate was observed in the Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) trial among patients with type 2 diabetes and chronic kidney disease taking canagliflozin vs placebo (HR 1.11, 95% CI 0.79-1.56).
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      One observational study suggests that in adults over 65 years of age with baseline CVD who start taking canagliflozin vs a glucagon-like peptide 1 (GLP-1) receptor agonist, the number needed to treat for an additional harmful outcome is high (556 patients at 6 months).
      • Fralick M.
      • Kim S.C.
      • Schneeweiss S.
      • et al.
      Risk of amputation with canagliflozin across categories of age and cardiovascular risk in three US nationwide databases: cohort study.
      The magnitude of this risk may be outweighed by the immense cardioprotective effects of these medications. The concern regarding amputation and SGLT2 inhibitors appears to be specific to canagliflozin,
      • Sunner S.S.
      • Welsh R.C.
      • Bainey K.R.
      Medical management of peripheral arterial disease: deciphering the intricacies of therapeutic options.
      and a recent analysis of dapagliflozin revealed that it has clinical benefits in CV outcomes regardless of PAD status, without an incremental risk of amputation.
      • 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 subgroup of PAD patients from the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA-REG OUTCOME) trial, treatment with empagliflozin vs placebo resulted in statistically significant reductions in all-cause mortality (HR 0.62, 95% CI 0.44-0.88) and CV death (HR 0.57, 95% CI 0.37-0.88).
      • Verma S.
      • Mazer C.D.
      • Al-Omran M.
      • et al.
      Cardiovascular outcomes and safety of empagliflozin in patients with type 2 diabetes mellitus and peripheral artery disease: a subanalysis of EMPA-REG OUTCOME.
      GLP-1 receptor agonists are other glucose-lowering medications that also reduce adverse cardiac outcomes in high-risk diabetic patients.
      • Badjatiya A.
      • Merrill P.
      • Buse J.B.
      • et al.
      Clinical outcomes in patients with type 2 diabetes mellitus and peripheral artery disease: results from the EXSCEL trial.
      Guidelines recommend comprehensive care plans coordinated among team members for patients with PAD and comorbid diabetes.
      • 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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

      Therapies to improve walking distance

      There is some evidence to support the use of cilostazol, a vasodilator, to improve walking distance in patients with stable intermittent claudication, but no benefit in reducing CV events has been found for it, and it is contraindicated in patients with left ventricular dysfunction and heart failure.
      • Brown T.
      • Forster R.B.
      • Cleanthis M.
      • et al.
      Cilostazol for intermittent claudication.
      Cilostazol’s clinical utility is limited by side-effects (headache), contraindications (heart failure), and marginal benefit compared with distance gained through supervised exercise.
      • Bevan G.H.
      • White Solaru K.T.
      Evidence-based medical management of peripheral artery disease.
      Pentoxifylline is a medication that increases red cell deformability, and theoretically may improve peripheral blood flow, but current guidelines do not endorse its use in improving walking distance, owing to limited conclusive evidence.
      • Broderick C.
      • Forster R.
      • Abdel-Hadi M.
      • Salhiyyah K.
      Pentoxifylline for intermittent claudication.

      Barriers to implementation of recommended medications

      Despite evidence-based guidelines espousing the use of preventive medications for PAD patients,
      • 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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      ,
      • 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 arteries. Endorsed 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).
      studies have revealed persistently low adherence to these guidelines over decades. Of 647 patients with PAD included in an analysis of the U.S. National Health and Nutrition Examination Survey database from 1999 to 2004, only 30.5% were using a statin, 35.8% were using aspirin, and 24.9% were using an ACEi or ARB.
      • Pande R.L.
      • Perlstein T.S.
      • Beckman J.A.
      • Creager M.A.
      Secondary prevention and mortality in peripheral artery disease: National Health and Nutrition Examination Study 1999 to 2004.
      Similarly, in an analysis of 1982 visits of patients with PAD in national outpatient databases in the U.S. from 2005 to 2012, a statin was used in 33.1%, any antiplatelet therapy was used in 35.7%, and an ACEi or ARB in 28.4%.
      • Berger J.S.
      • Ladapo J.A.
      Underuse of prevention and lifestyle counseling in patients with peripheral artery disease.
      Data from Denmark reveal better adherence to guidelines, although utilisation was still suboptimal, with 53% of patients on antiplatelet agents, 40% on a statin, and 20% on an ACEi or ARB.
      • Subherwal S.
      • Patel M.R.
      • Kober L.
      • et al.
      Missed opportunities: despite improvement in use of cardioprotective medications among patients with lower-extremity peripheral artery disease, underuse remains.
      Adherence rates may be higher in specialised vascular clinics, with prospective data from the Patient-Centered Outcomes Related to Treatment Practices in Peripheral Arterial Disease: Investigating Trajectories (PORTRAIT) study of PAD patients treated at vascular care sites in the U.S., The Netherlands, and Australia revealing that 89% patients were on antiplatelets and 83% on statins.
      • Saxon J.T.
      • Safley D.M.
      • Mena-Hurtado C.
      • et al.
      Adherence to guideline-recommended therapy—including supervised exercise therapy referral across peripheral artery disease specialty clinics: insights from the international PORTRAIT registry.
      Data also reveal that patients with PAD are less likely than similar patients with CAD to use these therapies, despite equal or greater benefit with their use. For example, Berger et al. found that PAD patients with comorbid CAD were more likely to receive antiplatelets, statin, and ACEi/ARB (odds ratio 2.6 for each) at a given visit compared with patients with PAD alone.
      • Berger J.S.
      • Ladapo J.A.
      Underuse of prevention and lifestyle counseling in patients with peripheral artery disease.
      At the patient level, although there is little data specific to PAD, one study found that more than 30% of patients with PAD older than 65 years were no longer taking antiplatelet therapy 5 years after initial prescription,
      • Wawruch M.
      • Murin J.
      • Tesar T.
      • et al.
      Non-persistence with antiplatelet medications among older patients with peripheral arterial disease.
      and among those who did persist with therapy, 15% had less than 80% of days covered.
      • Wawruch M.
      • Murin J.
      • Tesar T.
      • et al.
      Adherence to antiplatelet medications among persistent and non-persistent older patients with peripheral arterial disease.
      Several factors may contribute to poor adherence to prescribed therapy. Awareness of PAD as a diagnosis and understanding of the disease has been found to be poor even among patients attending clinics for PAD.
      • Byskosh N.
      • Pamulapati V.
      • Xu S.
      • et al.
      Identifying gaps in disease knowledge among patients with peripheral artery disease [e-pub ahead of print].
      ,
      • Builyte I.U.
      • Baltrunas T.
      • Butkute E.
      • et al.
      Peripheral artery disease patients are poorly aware of their disease.
      Descriptive studies show that many patients with PAD, even in the context of recent hospitalisation for limb ischemia, express weak belief in the necessity of medication.
      • Eyholzer S.
      • Perrenoud B.
      • Dwyer A.A.
      Patient perceptions of peripheral artery disease: a cross-sectional study of hospitalized adults.
      Patient education can improve utilisation of guideline-based therapies, and a network meta-analysis found that patient education as a component of cardiac rehabilitation reduced the hazards of MI and hospitalisation. However, there is a lack of standardisation of patient education interventions, likely related to the heterogeneous preferences and needs of patients, leading to difficulty in delivering evidence-based patient education in PAD.
      • Byskosh N.
      • Pamulapati V.
      • Xu S.
      • et al.
      Identifying gaps in disease knowledge among patients with peripheral artery disease [e-pub ahead of print].
      Cost may also affect the use of medications, as patients with PAD have lower socioeconomic status than patients with CAD.
      • Eid M.A.
      • Mehta K.S.
      • Goodney P.P.
      Epidemiology of peripheral artery disease.
      In a Canadian survey, 70% of vascular surgeons cited cost as their principal concern regarding prescription of combination low-dose rivaroxaban and aspirin.
      • McClure G.R.
      • Kaplovitch E.
      • Chan N.
      • et al.
      A national Canadian survey of antithrombotic therapy after urgent and emergent limb revascularization.
      Providing medications at no cost improved adherence among patients who cited cost as a barrier in a randomised controlled trial.
      • Persaud N.
      • Bedard M.
      • Boozary A.
      • et al.
      Adherence at 2 years with distribution of essential medicines at no charge: the CLEAN Meds randomized clinical trial.
      Research into health care provider–level barriers to medication prescription in PAD is limited, but may include capability barriers (such as lack of knowledge and skills) and intention barriers (lack of motivation owing to previous failed attempts, doubts about the efficacy or importance of preventive therapies, and habits).
      • Khatib R.
      • Schwalm J.D.
      • Yusuf S.
      • et al.
      Patient and healthcare provider barriers to hypertension awareness, treatment and follow up: a systematic review and meta-analysis of qualitative and quantitative studies.
      “Diffusion of responsibility,” in which there is lack of clarity regarding who will be ensuring optimisation of secondary prevention of vascular outcomes, may act as another barrier for primary care physicians and vascular surgeons,
      • Dua A.
      • Gologorsky R.
      • Savage D.
      • et al.
      National assessment of availability, awareness, and utilization of supervised exercise therapy for peripheral artery disease patients with intermittent claudication.
      as has been shown in other disease states.
      • Semb A.G.
      • Rollefstad S.
      • Ikdahl E.
      • et al.
      Diabetes mellitus and cardiovascular risk management in patients with rheumatoid arthritis: an international audit.
      In a Canadian study, hospitalisation for PAD resulted in high rates of antithrombotics use at discharge, but no improvement was seen in prescription of statins (60.8% vs 56.3%; P = 0.23) or ACEis/ARBs (48.7% vs 50.6%; P = 0.58) when comparing preadmission and postdischarge prescriptions.
      • Kaplovitch E.
      • Collins A.
      • McClure G.
      • et al.
      Medical therapy following urgent/emergent revascularization in Peripheral artery disease patients (Canadian Limb Ischemia Registry (CANALISE I).
      This suggests that inpatient providers may focus on certain medications, assuming others will be managed by outpatient providers. Lack of access to comprehensive secondary prevention programs, such as exists for cardiac rehabilitation, limits opportunities to provide comprehensive secondary prevention for PAD patients.
      Of particular concern is the low rate of prescription of evidence-based therapies for women with PAD. Although these data are limited, there are parallels with women with CAD, who also are less likely to receive prescriptions for guideline-recommended antiplatelet or statin therapy, and are less likely to have their hypertension controlled, despite similar observed benefits in trials as for men.
      • Thakkar A.
      • Agarwala A.
      • Michos E.D.
      Secondary prevention of cardiovascular disease in women: closing the gap.
      Although all of the reasons for these sex differences are poorly understood, underrepresentation of women in clinical trials may result in therapies that are optimised and marketed for men more than for women.
      • Khadanga S.
      • Gaalema D.E.
      • Savage P.
      • Ades P.A.
      Underutilization of cardiac rehabilitation in women: barriers and solutions.

      How can barriers to optimal use of secondary prevention therapies in PAD be overcome?

      Strategies to optimise secondary prevention therapies in PAD should address barriers at patient, health care provider, and system levels. An approach similar to that of the Ontario Core Elements for Stroke Prevention Clinics,
      Ontario Regional Stroke Networks. Core elements—Ontario stroke prevention clinics.
      and consistent with the Cardiac Care Network of Ontario Standards for the Provision of Cardiovascular Rehabilitation,
      Cardiac Care Network of Ontario
      Standards for the provision of cardiovascular rehabilitation in Ontario. September 2014.
      can be taken. The following core elements for PAD secondary prevention clinics are proposed: 1) access to a secondary prevention program; 2) an established system for referral to the program; 3) intake assessment that includes risk factor screening; 4) patient education on manifestations, risk factors, and therapies for PAD; 5) medication optimisation; 6) a smoking cessation plan; 7) access to comprehensive diabetes care; 8) access to an evidence-based exercise program; 9) communication and coordination with other health care team members; and 10) quality assurance (Table 2).
      Table 2Proposed core elements for PAD secondary prevention clinics
      1) Access to a secondary prevention program

      A clinic with an explicit mandate to optimise preventive therapy for PAD patients should be identified and made accessible for PAD patients.
      2) Referral system

      A system to prompt and accept referrals from inpatient and outpatient environments should be established. Clear criteria for referrals should be communicated.
      3) Intake assessment

      Screening for smoking status, hypertension, diabetes, current activity levels and limitations, lipid profile, and diet should occur at intake.
      4) Patient education

      Patients should be educated about PAD manifestations, risk factors, and therapies, with consideration of their individual learning needs and preferences.
      5) Medication optimisation

      Procedures for medication reconciliation, recognition of suboptimal prescribing, and optimisation should be followed.
      6) Smoking cessation

      Smoking status should be reviewed, smokers should be counselled to quit at every visit, and those who are interested should be offered pharmacotherapy.
      7) Diabetes care

      Patients with diabetes should receive comprehensive coordinated care, including guideline-based foot screening.
      8) Exercise

      Patients should be referred to a PAD-specific structured exercise program, which may take place in collaboration with a cardiac rehabilitation program.
      9) Communication with health team members

      The intake assessment and any recommended changes to the medical plan should be documented and communicated to other members of the patient’s health team. At discharge from the clinic, clear follow-up instructions should be communicated.
      10) Quality assurance

      Data on the proportion of patients offered and utilising each component of evidence-based secondary prevention should be collected and regularly reviewed.
      PAD, peripheral artery disease.
      The first step is to identify a clinic that can see patients specifically to optimise preventive therapy for PAD patients. This may be a vascular surgery clinic, vascular medicine clinic, or part of a cardiac rehabilitation program. Accessibility for PAD patients, including transportation options and distance from parking to the site, should be considered.
      • Galea M.N.
      • Bray S.R.
      • Ginis K.A.M.
      Barriers and facilitators for walking in individuals with intermittent claudication.
      ,
      • Galea Holmes M.N.
      • Weinman J.A.
      • Bearne L.M.
      “You cannot walk with cramp!” A qualitative exploration of individuals’ beliefs and experiences of walking as treatment for intermittent claudication.
      A system to prompt and accept referrals from vascular surgery wards, vascular surgery clinics, and primary care clinics should be established and clearly communicated. Patients who have undergone revascularisation or amputation are at highest risk of CV events and may be targeted for more intensive secondary prevention efforts. We are currently studying the use of a discharge checklist to be used after revascularisation that includes assessment of major risk factors, ensures consideration of antithrombotic therapy, statins, and counselling on smoking cessation, and referral to a comprehensive secondary prevention program (Medical Care GAPs in Peripheral Arterial Disease – Checklist implementation Pilot Trial) GAP-PAD Check Pilot Trial.
      Once patients are seen in the prevention clinic, their intake assessment should include screening for smoking status, hypertension, diabetes, current activity levels and limitations, lipid profile, and diet.
      Cardiac Care Network of Ontario
      Standards for the provision of cardiovascular rehabilitation in Ontario. September 2014.
      Patients should receive educational materials in print or electronically about PAD manifestations, risk factors, and therapies.
      The clinic should use a medication reconciliation procedure to accurately capture current medications. Tools for medication reconciliation are available from the Institute for Safe Medication Practices Canada.
      Institute for Safe Medication Practices Canada
      Medication Reconciliation (MedRec).
      Patients who are not prescribed or on suboptimal doses of statin, ACEi or ARB, and antithrombotics, should receive evidence-based therapy as outlined above. Prescription of lower-cost brands of approved medications may improve adherence.
      • Musich S.
      • Cheng Y.
      • Wang S.S.
      • et al.
      Pharmaceutical cost-saving strategies and their association with medication adherence in a Medicare Supplement population.
      Adherence to, and tolerance of, guideline-recommended therapies should be routinely assessed.
      Smoking status should be reviewed with every PAD patient, and those who are currently smoking and interested in quitting should be offered nicotine replacement therapy, bupropion, or varenicline. The Centers for Disease Control and Prevention website hosts tools for clinicians to help patients with smoking cessation,
      Centers for Disease Control and Prevention
      Clinical cessation tools.
      and in Canada, the Ottawa Model for Smoking Cessation
      Ottawa Model for Smoking Cessation. About OMSC.
      can help to improve provision of smoking cessation services. A free smokers’ helpline is available in Canada at +1-866-366-3667 and SmokersHelpline.ca.
      Canadian Cancer Society
      Smokers’ Helpline.
      Patients with diabetes should receive coordinated and comprehensive management, especially those with CLI, in whom improved glycemic control reduces the risk of amputation and failure of revascularisation.
      • 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 arteries. Endorsed 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).
      ,
      • Cosentino F.
      • Grant P.J.
      • Aboyans V.
      • et al.
      2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
      Guideline-based regular foot screening should be ensured.
      • Bus S.A.
      • Lavery L.A.
      • Monteiro-Soares M.
      • et al.
      Guidelines on the prevention of foot ulcers in persons with diabetes (IWGDF 2019 update).
      Interested patients should be referred to an evidence-based exercise program. The Vascular Disease Foundation (VDF) and the American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) have produced a toolkit that outlines protocols and considerations to set up supervised exercise programs tailored to PAD patients.
      Vascular Disease Foundation; American Association of Cardiovascular and Pulmonary Rehabilitation
      PAD exercise training toolkit: a guide for health care professionals.
      Other providers involved in care of the patient should be routinely identified. Notes from the secondary prevention clinic should be communicated to these team members, and a mechanism should be created to ensure handover of ongoing secondary prevention efforts once the patient is discharged from the clinic.
      • 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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      Finally, performance should be regularly reviewed for adherence to guidelines; ideally, data on the proportion of patients who are offered each component of evidence-based secondary prevention should be collected. Patient satisfaction surveys can provide data on how to improve adherence.

      Conclusion

      Although evidence-based guidelines identify life-saving therapies to prevent adverse CV events in PAD patients, these therapies are underutilised. A variety of patient-, provider-, and system-level barriers contribute to this underutilisation. By building a PAD toolkit, some of these barriers can be overcome, and morbidity and mortality can be reduced for patients with PAD.

      Funding Sources

      Dr Anand holds a Tier 1 Canada Research Chair in Ethnic Diversity and Cardiovascular Disease, and a Heart & Stroke Foundation/Michael G. DeGroote Chair in Population Health Research McMaster University.

      Disclosures

      Dr Bhagirath discloses grants from Pfizer Canada and honoraria from Bayer. Dr Anand receives honoraria for speaking and consultancy from Bayer and Janssen. The other authors have no conflicts of interest to disclose.

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