Peripheral artery disease (PAD) has a worldwide prevalence of more than 200 million, with at least 8 million of those residing within the United States.^1,2 Although awareness has improved, PAD is still associated with significant morbidity, mortality, and quality of life impairment. Thus, it is incumbent upon the cardiovascular care team member to be acquainted with the diagnosis and management of PAD.

In 2016, the American College of Cardiology (ACC) and American Heart Association (AHA) updated guidelines regarding the management of patients with PAD due to atherosclerotic disease.³ This is the first comprehensive update since the 2005 ACC/AHA guidelines and takes an incremental step forward from the focused update issued in 2011.^4,5 The new guidelines draw upon evidence accumulated over the last ten years, including several large clinical trials, as well as expert opinion. A summary of the recommendations can be found in Table 1.

Table 1: A Summary of Guidelines from the 2016 Update

Class I

In patients with history or physical examination findings suggestive of PAD, the resting ABI, with or without segmental pressures and waveforms, is recommended to establish the diagnosis.

Patients with exertional non-joint-related leg symptoms and normal or borderline resting ABI (>0.90 and ≤1.40) should undergo exercise treadmill ABI testing to evaluate for PAD.

Duplex ultrasound, CTA, or MRA of the lower extremities is useful to diagnose anatomic location and severity of stenosis for patients with symptomatic PAD in whom revascularization is considered.

Antiplatelet therapy with aspirin alone (75-325 mg per day) or clopidogrel alone (75 mg per day) is recommended to reduce MI, stroke, and vascular death in patients with symptomatic PAD.

Treatment with a statin medication is indicated for all patients with PAD.

Antihypertensive therapy should be administered to patients with hypertension and PAD to reduce the risk of MI, stroke, heart failure, and cardiovascular death.

Patients with PAD who smoke cigarettes or use other forms of tobacco should be advised at every visit to quit.

Management of diabetes mellitus in the patient with PAD should be coordinated between members of the healthcare team.

Cilostazol is an effective therapy to improve symptoms and increase walking distance in patients with claudication.

In patients with claudication, a supervised exercise program is recommended to improve functional status and quality of life and to reduce leg symptoms.

Endovascular procedures are effective as a revascularization option for patients with lifestyle-limiting claudication and hemodynamically significant aortoiliac occlusive disease.

In patients with CLI, revascularization should be performed when possible to minimize tissue loss.

In patients with ALI, systemic anticoagulation with heparin should be administered unless contraindicated.

Catheter-based thrombolysis is effective for patients with ALI and a salvageable limb.

Class IIa

In patients at increased risk of PAD but without history or physical examination findings suggestive of PAD, measurement of the resting ABI is reasonable.

In patients with PAD, a structured community- or home-based exercise program with behavioral change techniques can be beneficial to improve walking ability and functional status.

Revascularization is a reasonable treatment option for the patient with lifestyle-limiting claudication with an inadequate response to guideline-directed medical therapy.

Surgical procedures are reasonable as a revascularization option for patients with lifestyle-limiting claudication with inadequate response to guideline-directed medical therapy, acceptable perioperative risk, and technical factors suggesting advantages over endovascular procedures.

Class IIb

The effectiveness of dual-antiplatelet therapy (aspirin and clopidogrel) to reduce the risk of cardiovascular ischemic events in patients with symptomatic PAD is not well established.

Class III

In patients not at increased risk of PAD and without history or physical examination findings suggestive of PAD, the ABI is not recommended.

Invasive and noninvasive angiography (i.e., CTA, MRA) should not be performed for the anatomic assessment of patients with asymptomatic PAD.

Anticoagulation should not be used to reduce the risk of cardiovascular ischemic events in patients with PAD.

Endovascular and surgical procedures should not be performed in patients with PAD solely to prevent progression to CLI.

Dr. Gerhard-Herman et al. provide a number of decision trees to aid evaluation and treatment. First, they propose a systematic approach to the diagnosis of PAD. Those patients with a history or physical exam findings suggestive of PAD should receive a resting ankle-brachial index (ABI) to establish the diagnosis.⁶ A resting ABI may also be considered in patients at high risk of PAD but without symptoms (Table 2). Exercise treadmill ABI testing is reserved for those patients with exertional symptoms but a normal or borderline resting ABI.⁷ Other types of testing, including transcutaneous oxygen pressure or skin perfusion pressure, may be appropriate in certain clinical settings but are not typically first-line tests.⁸

Table 2: High Risk Characteristics for Peripheral Artery Disease

Age older than age 65 Age 50-65 with at least one risk factor for atherosclerosis (diabetes mellitus, history of smoking, hyperlipidemia, or hypertension) or family history Age less than 50 with diabetes and one risk factor for atherosclerosis Known atherosclerosis in another vascular bed

Once the diagnosis of PAD is made, the authors recommend several evidence-based interventions to improve functional status and reduce the risk for cardiovascular ischemic events (Table 3). These include single antiplatelet therapy, either aspirin (75-325 mg daily) or clopidogrel (75 mg) alone.^9,10 The guidelines also recommend a statin and, when appropriate, blood pressure and hyperglycemia management.^11-13 Cilostazol, an inhibitor of platelet aggregation, is also included in the update. It can be an effective treatment of leg symptoms and walking impairment.¹⁴ Finally, the guidelines recommend smoking cessation counseling for patients at every visit, as well as pharmacotherapy as needed to aid quitting.¹⁵

Table 3: Evidence-Based Medical Interventions in Peripheral Artery Disease

Intervention	Patient Population
Single anti-platelet therapy (ASA 81-325 mg or clopidogrel 75 mg)	ALL
Statin	ALL
Antihypertensives	PAD and HTN
Glycemic control	PAD and DM
Cilostazol	Symptomatic PAD
Smoking cessation counseling	ALL
Supervised or structured exercise	ALL
Revascularization	CLI or ALI May be considered in symptomatic PAD if failed other therapies

Supervised exercise, which is directly supervised in a hospital or outpatient facility, and structured exercise receive greater emphasis in the 2016 update. Supervised exercise is recommended for all patients with PAD, and should be discussed as a treatment option prior to attempts at revascularization.¹⁶ Structured or home-based exercise, on the other hand, may be considered as an alternative treatment modality but has not been shown to be as efficacious.¹⁷ Efforts are underway to get payer coverage for supervised exercise in patients with symptomatic PAD, also referred to as claudication.

Because PAD represents a spectrum, we see a range of presentations from asymptomatic atherosclerotic disease, to claudication, to critical limb ischemia (CLI), and finally to a true medical emergency, acute limb ischemia (ALI). Revascularization, whether surgical or endoscopic, is a treatment approach to be considered in patients who have progressed to symptomatic PAD. Gerhard et al. emphasize that only a minority of patients with claudication will progress to CLI.¹⁸ Therefore, in patients with claudication but without evidence of ischemia, revascularization should only be considered in those patients with lifestyle-limiting symptoms. The guidelines do not suggest any diagnostic threshold at which revascularization would be appropriate, but rather should be based on a conversation between the provider and patient and after an attempt at guideline determined medical therapy and supervised exercise.

Revascularization is indicated, and in fact urgently needed, in cases of limb ischemia that may threaten tissue. CLI is defined as ischemic symptoms at rest for at least two weeks. Surgical or endovascular revascularization is recommended to restore in-line blood flow to the affected limb, which can decrease ischemic pain and improve wound healing. The BASIL (Bypass versus Angioplasty in Severe Ischemia of the Leg) trial showed that both surgical and endovascular revascularization had similar rates of amputation.¹⁹ However, this study was limited to angioplasty alone, and more contemporary randomized clinical trials will compare modern endovascular procedures, including atherectomy and stenting.

ALI, on the other hand, is a true medical emergency, and requires prompt evaluation by a vascular clinician.²⁰ Systemic anticoagulation with heparin should be started immediately, unless contraindicated, followed by surgical or endovascular revascularization if the limb is still salvageable. In cases in which the limb is not salvageable, amputation should be the first procedure performed. In both CLI and ALI, referral to a medical center with expertise in vascular disease is an important aspect of early management.

The new guidelines were developed from mounting evidence that specific medical interventions can improve quality of life and reduce morbidity and mortality from atherosclerotic disease in other vascular beds. Gerhard et al. create a framework from which cardiovascular team members can confidently manage lower extremity vascular disease. The guidelines also reveal areas of future opportunity that guidelines do not currently address. These include identification of risk factors that lead to the progression of PAD, patient-centered outcome research comparing surgical and endovascular approaches, and new medical therapies to relieve the symptoms of claudication.

References

1. Writing Group Members, Mozaffarian D, Benjamin EJ, et al. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation 2016;133:e38-360.
2. Fowkes FG, 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. Lancet 2013;382:1329-40.
3. Gerhard-Herman MD, Gornik HL, 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. J Am Coll Cardiol 2017;69:1465-508.
4. Hirsch AT, Kaskal ZJ, Hertzer NR, et al. ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease) endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. J Am Coll Cardiol 2006;47:1239-312.
5. Rooke TW, Hirsch AT, Misra S, et al. 2011 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Peripheral Artery Disease (updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011;58:2020-45.
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8. Shishehbor MH, Hammad TA, Zeller T, Baumgartner I, Scheinert D, Rocha-Singh KJ. An analysis of IN.PACT DEEP randomized trial on the limitations of the societal guidelines-recommended hemodynamic parameters to diagnose critical limb ischemia. J Vasc Surg 2016;63:1311-7.
9. Berger JS, Krantz MJ, Kittelson JM, Hiatt WR. Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: a meta-analysis of randomized trials. JAMA 2009;301:1909-19.
10. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-39.
11. Ramos R, Garcia-Gil M, Comas-Cufi M, et al. Statins for prevention of cardiovascular events in a low-risk population with low brachial index. J Am Coll Cardiol 2016;67:630-40.
12. Bavry AA, Anderson RD, 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.
13. Singh S, Armstrong EJ, 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. Vasc Med 2014;19:307-14.
14. Bedenis R, Stewart M, Cleanthis M, Robless P, Mikhailidis DP, Stansby G. Cilostazol for intermittent claudication. Cochrane Database Syst Rev 2014:CD003748.
15. Hennrikus D, Joseph AM, Lando HA, et al. Effectiveness of a smoking cessation program for peripheral artery disease patients: a randomized controlled trial. J Am Coll
16. Murphy TP, Cutlip DE, Regensteiner JG, et al. Supervised exercise, stent revascularization, or medical therapy for claudication due to aortoiliac peripheral artery disease: the CLEVER study. J Am Coll Cardiol 2015;65:999-1009.
17. Parmenter BJ, Dieberg G, Smart NA. Exercise training for management of peripheral arterial disease: a systematic review and meta-analysis. Sports Med 2015;45:231-44.
18. Leng GC, Lee AJ, Fowkes FG, et al. Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population. Int J Epidemiol 1996;25:1172-81.
19. Adam DJ, Beard JD, Cleveland T, et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet 2005;366:1925-34.
20. Blaisdell FW. The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review. Cardiovasc Surg 2002;10:620-30.

Keywords: Amputation, Angiography, Angioplasty, Ankle Brachial Index, Antihypertensive Agents, Atherectomy, Blood Platelets, Blood Pressure, Constriction, Pathologic, Diabetes Mellitus, Heart Failure, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperglycemia, Hyperlipidemias, Hypertension, Ocimum basilicum, Peripheral Arterial Disease, Risk Factors, Smoking, Smoking Cessation, Stroke, Tetrazoles, Ticlopidine

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