How to Refine Your Approach to Peripheral Arterial Disease

Home , Differential diagnosis

Dustin K. Smith, DO; Michael J. Arnold, MD; Job Larson, MD How to refine your approach Jacksonville Family Medicine Residency Program, Naval Hospital Jacksonville, FL (Dr. to peripheral arterial disease Smith); Uniformed Services University of the Health Sciences, Bethesda, MD Early recognition, management of comorbid conditions, (Dr. Arnold); Naval Hospital Naples, Italy (Dr. Larson) and appropriate treatment of peripheral arterial disease

dustinksmith@yahoo. can help you improve your patient’s outcome. com

The authors reported no potential conflict of interest relevant to this article. eripheral arterial disease (PAD), the progressive disor- The views expressed in this PRACTICE der that results in ischemia to distal vascular territories article are those of the authors RECOMMENDATIONS and do not necessarily reflect as a result of atherosclerosis, spans a wide range of pre- the official policy or position of ❯ Use the ankle-brachial P the Department of the Navy, sentations, from minimally symptomatic disease to limb isch- index for diagnosis in Uniformed Services University of emia secondary to acute or chronic occlusion. the Health Sciences, Department patients with history/ of Defense, or the United States The prevalence of PAD is variable, due to differing diag- government. physical exam findings suggestive of peripheral nostic criteria used in studies, but PAD appears to affect 1 in doi: 10.12788/jfp.0115 1 arterial disease (PAD). A every 22 people older than age 40. However, since PAD inci- ❯ dence increases with age, it is increasing in prevalence as the Strongly encourage smoking 1-3 cessation in patients with US population ages. PAD as doing so reduces PAD is associated with increased hospitalizations and de- 4 5-year mortality and creased quality of life. Patients with PAD have an estimated amputation rates. B 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.3 ❯ Use structured exercise ❚ programs for patients with Screening. Although PAD is underdiagnosed and ap- 3 intermittent claudication pears to be undertreated, population-based screening for PAD prior to consideration of in asymptomatic patients is not recommended. A Cochrane re- revascularization; doing view found no studies evaluating the benefit ofasymptomatic so offers similar benefit population-based screening.5 Similarly, in 2018, the USPSTF and lower risks. A performed a comprehensive review and found no studies to ❯ Recommend support routine screening and determined there was insuffi- revascularization for cient evidence to recommend it.6,7 patients who have limb ischemia or lifestyle-limiting claudication despite medical Risk factors and and exercise therapy. B associated comorbidities

Strength of recommendation (SOR) PAD risk factors, like the ones detailed below, have a poten- A Good-quality patient-oriented tiating effect. The presence of 2 risk factors doubles PAD risk, evidence while 3 or more risk factors increase PAD risk by a factor B Inconsistent or limited-quality 1 patient-oriented evidence of 10. ❚ C Consensus, usual practice, Increasing age is the greatest single risk factor for opinion, disease-oriented PAD.1,2,8,9 Researchers using data from the National Health and evidence, case series Nutrition Examination Survey (NHANES) found that the prevalence of PAD increased from 1.4% in individuals ages 40 to 49 years to almost 17% in those age 70 or older.1

500 THE JOURNAL OF FAMILY PRACTICE | DECEMBER 2020 | VOL 69, NO 10 Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.

❚ Demographic characteristics. Most smokers.1 Risk increases linearly with cumu- studies demonstrate a higher risk for PAD lative years of smoking.1,2,9,10 in men.1-3,10 African-American patients have ❚ Diabetes is another significant modi- more than twice the risk for PAD, compared fiable risk factor, increasing PAD risk by 2.5 with Whites, even after adjustment for the times.2 Diabetes is also associated with in- increased prevalence of associated diseases creases in functional limitation from claudi- such as hypertension and diabetes in this cation, risk for acute coronary syndrome, and population.1-3,10 progression to amputation.1 ❚ Genetics. A study performed by the ❚ Hypertension nearly doubles the risk National Heart Lung and Blood Institute for PAD, and poor control further increases suggested that genetic correlations between this risk.2,9,10 twins were more important than environ- ❚ Chronic kidney disease (CKD). Patients mental factors in the development of PAD.11 with CKD have a progressively higher preva- IMAGE: ©KOSTUDIOS ❚ Smoking. Most population studies lence of PAD with worsening renal function.1 show smoking to be the greatest modifi- There is also an association between CKD able risk factor for PAD. An analysis of the and increased morbidity, revascularization NHANES data yielded an odds ratio (OR) of failure, and increased mortality.1 4.1 for current smokers and of 1.8 for former ❚ Two additional risk factors that are

MDEDGE.COM/FAMILYMEDICINE VOL 69, NO 10 | DECEMBER 2020 | THE JOURNAL OF FAMILY PRACTICE 501 less well understood are dyslipidemia and Diagnostic testing chronic inflammation. There is conflicting An ankle-brachial index (ABI) test should be data regarding the role of individual compo- performed in patients with history or physi- nents of cholesterol and their effect on PAD, cal exam findings suggestive of PAD. A resting although lipoprotein (a) has been shown to ABI is performed with the patient in the su- be an independent risk factor for both the pine position, with measurement of systolic development and progression of PAD.12 Simi- blood pressure in both arms and ankles using larly, chronic inflammation has been shown a Doppler ultrasound device. TABLE 213 out- to play a role in the initiation and progression lines ABI scoring and interpretation. of the disease, although the role of inflamma- An ABI > 1.4 is an invalid measurement, tory markers in evaluation and treatment is indicating that the arteries are too calcified unclear and assessment for these purposes is to be compressed. These highly elevated ABI not currently recommended.12,13 measurements are common in patients with diabetes and/or advanced CKD. In these patients, a toe-brachial index (TBI) test should Diagnosis be performed, because the digital arteries are Clinical presentation almost always compressible.13 Lower extremity pain is the hallmark symp- Patients with symptomatic PAD who are tom of PAD, but presentation varies. The clas- under consideration for revascularization African- sic presentation is claudication, pain within may benefit from radiologic imaging of the American a defined muscle group that occurs with ex- lower extremities with duplex ultrasound, patients have ertion and is relieved by rest. Claudication is computed tomography angiography, or more than twice most common in the calf but also occurs in magnetic resonance angiography to deter- the risk for PAD, the buttock/thigh and the foot. mine the anatomic location and severity of compared with However, most patients with PAD present stenosis.13 Whites, even with pain that does not fit the definition of clau- after adjustment dication. Patients with comorbidities, physical for the increased inactivity, and neuropathy are more likely to Management of PAD prevalence present with atypical pain.14 These patients may Lifestyle interventions of associated demonstrate critical or acute limb ischemia, For patients with PAD, lifestyle modifications diseases in this characterized by pain at rest and most often are an essential—but challenging—compo- population. localized to the forefoot and toes. Patients with nent of disease management. critical limb ischemia may also present with ❚ Smoking cessation. As with other nonhealing wounds/ulcers or gangrene.15 atherosclerotic diseases, PAD progression ❚ Physical exam findings can support is strongly correlated with smoking. A tri- the diagnosis of PAD, but none are reliable al involving 204 active smokers with PAD enough to rule the diagnosis in or out. Find- showed that 5-year mortality and amputa- ings suggestive of PAD include cool skin, tion rates dropped by more than half in those presence of a bruit (iliac, femoral, or poplite- who quit smoking within a year, with num- al), and palpable pulse abnormality. Multiple bers needed to treat (NNT) of 6 for mortal- abnormal physical exam findings increase ity and 5 for amputation.19 Because of this the likelihood of PAD, while the absence of dramatic effect, American College of Cardi- a bruit or palpable pulse abnormality makes ology/American Heart Association (ACC/ PAD less likely.16 In patients with PAD, an as- AHA) guidelines encourage providers to ad- sociated wound/ulcer is most often distal in dress smoking at every visit and use cessation the foot and usually appears dry.17 programs and medication to increase quit ❚ The differential diagnosis for intermit- rates.13 tent leg pain is broad and includes neurolog- ❚ Exercise may be the most important in- ic, musculoskeletal, and venous etiologies. tervention for PAD. A 2017 Cochrane review TABLE 118 lists some common alternate diag- found that supervised, structured exercise noses for patients presenting with leg pain or programs increase pain-free and maximal claudication. walking distances by at least 20% and also im-

502 THE JOURNAL OF FAMILY PRACTICE | DECEMBER 2020 | VOL 69, NO 10 PERIPHERAL ARTERIAL DISEASE

TABLE 1 Differential diagnosis for leg pain or claudication18 Condition Location Characteristics Effect of exercise Effect of rest Effect of position Chronic Calf muscles Tight, bursting Usually occurs Subsides very Relief with rest compartment pain after prolonged slowly syndrome exercise Venous Entire leg, worse Tight, bursting Occurs after Subsides slowly Relief speeded by claudication in calf pain walking elevation Spinal stenosis Often bilateral Pain and weakness May mimic Recovery variable, Relief by lumbar buttocks, posterior claudication usually longer than spine flexion leg in claudication Nerve root Radiates down leg Sharp, lancinating Induced by Often present at Improved by compression pain walking (as well as rest change in position sitting or standing) Hip arthritis Lateral hip, thigh Aching discomfort Occurs after Not quickly Improved when varying degree of relieved not weight- exercise bearing Foot/ankle Ankle, foot, arch Aching pain Occurs after Not quickly May improve arthritis varying degree of relieved when not weight- exercise bearing Symptomatic Behind knee, Swelling, Occurs with Present at rest None Baker cyst down calf tenderness exercise

TABLE 2 Interpretation of the ankle-brachial index13 ABI score Interpretation Next step ≤ 0.9 Abnormal Diagnosis of PAD 0.91 - 0.99 Borderline Exercise ABI (if high clinical suspicion) 1 - 1.4 Normal Evaluate for other causes > 1.4 Noncompressible TBI ABI, ankle-brachial index; PAD, peripheral arterial disease; TBI, toe-brachial index prove physical and mental quality of life.20 In supervised exercise and no clear improve- a trial involving 111 patients with aortoiliac ment in patients given home exercise or ad- PAD, supervised exercise plus medical care vice to walk.23 A recent study examined the led to greater functional improvement than effect of having patients use a wearable fit- either revascularization plus medical care ness tracker for home exercise and demon- or medical care alone.21 In a 2018 Cochrane strated no benefit over usual care.24 review, neither revascularization or revascu- ❚ Diet. There is some evidence that di- larization added to supervised exercise were etary interventions can prevent and possibly better than supervised exercise alone.22 ACC/ improve PAD. A large randomized controlled AHA guidelines recommend supervised ex- trial showed that a Mediterranean diet low- ercise programs for claudication prior to ered rates of PAD over 1 year compared to a considering revascularization.13 TABLE 313 out- low-fat diet, with an NNT of 336 if supple- lines the components of a structured exercise mented with extra-virgin olive oil and 448 program. if supplemented with nuts.25 A small trial of Unfortunately, the benefit of these pro- 25 patients who consumed non-soy legumes grams has been difficult to reproduce without daily for 8 weeks showed average ABI im- supervision. Another 2018 Cochrane review provement of 6%, although there was no con- demonstrated significant improvement with trol group.26 CONTINUED

MDEDGE.COM/FAMILYMEDICINE VOL 69, NO 10 | DECEMBER 2020 | THE JOURNAL OF FAMILY PRACTICE 503 TABLE 3 Elements of a structured exercise program13 ACC/AHA guidelines recommend supervised exercise programs for claudication prior to considering revascularization. Hospital or outpatient facility; can be part of cardiac rehabilitation program Directly supervised by qualified health care providers Sessions a minimum of 30-40 min Sessions performed at least 3 times/wk for at least 12 wk Warm-up and cool-down included in sessions Exercise modality–varied between studies Aerobic exercises Treadmill walking without avoiding or purposely causing claudication Treadmill walking, graded to avoid claudication Walking (outdoors or indoor track) Cycle ergometer Arm crank exercises Polestriding (walking with ski poles in cross-country ski movement) A trial involving Anaerobic exercises 204 active Strength training smokers with Calisthenics PAD showed that 5-year ACC/AHA, American College of Cardiology/American Heart Association. mortality and amputation Medical therapy to address mortality with nonaspirin antiplatelet agents rates dropped by peripheral and cardiovascular events vs aspirin (NNT = 94) without increase in ma- more than half Standard medical therapy for coronary artery jor bleeding.29 Only British guidelines specifi- in those who disease (CAD) is recommended for patients cally recommend clopidogrel over aspirin.31 quit smoking with PAD to reduce cardiovascular and limb Dual antiplatelet therapy has not shown within a year. events. For example, treatment of hyperten- consistent benefits over aspirin alone. ACC/ sion reduces cardiovascular and cerebrovas- AHA guidelines state that dual antiplatelet cular events, and studies verify that lowering therapy is not well established for PAD but blood pressure does not worsen claudication may be reasonable after revascularization.13 or limb perfusion.13 TABLE 413,27-30 outlines the Voraxapar is a novel antiplatelet agent options for medical therapy. that targets the thrombin-binding receptor ❚ Statins reduce cardiovascular events on platelets. However, trials show no signifi- in PAD patients. A large study demonstrated cant coronary benefit, and slight reductions that 40 mg of simvastatin has an NNT of 21 to in acute limb ischemia are offset by increases prevent a coronary or cerebrovascular event in major bleeding.13 in PAD, similar to the NNT of 23 seen in treat- For patients receiving medical therapy, ment of CAD.27 Statins also reduce adverse limb ongoing evaluation and treatment should be outcomes. A registry of atherosclerosis patients based on claudication symptoms and clinical showed that statins have an NNT of 56 to pre- assessment. vent amputation in PAD and an NNT of 28 to prevent worsening claudication, critical limb Medical therapy for claudication ischemia, revascularization, or amputation.28 Several medications have been proposed for ❚ Antiplatelet therapy with low-dose symptomatic treatment of intermittent clau- aspirin or clopidogrel is recommended for dication. Cilostazol is a phosphodiesterase symptomatic patients and for asymptomatic inhibitor with the best risk-benefit ratio. A patients with an ABI ≤ 0.9.13 A Cochrane re- Cochrane review showed improvements in view demonstrated significantly reduced maximal and pain-free walking distances

504 THE JOURNAL OF FAMILY PRACTICE | DECEMBER 2020 | VOL 69, NO 10 PERIPHERAL ARTERIAL DISEASE

TABLE 4 Medical therapy to address peripheral and cardiovascular events13,27-30 Element Cardiac effect Limb effect Hypertension management Reduce MACE No harm High-dose statin Reduce MACE Reduce ischemia and amputation Antiplatelet agent, preferably Reduce MACE Reduce chronic limb ischemia clopidogrel MACE, major acute coronary event. compared to placebo and improvements in bidity, length of hospitalization, and cost quality of life with cilostazol 100 mg taken than surgical repair. However, surgical mor- twice daily.32 Adverse effects included head- tality was lower after 2 years.40 ACC/AHA ache, dizziness, palpitations, and diarrhea.29 guidelines recommend either surgery or en- Pentoxifylline is another phosphodi- dovascular procedures and propose initial esterase inhibitor with less evidence of im- endovascular treatment followed by surgery provement, higher adverse effect rates, and if needed.13 After revascularization, the pa- more frequent dosing. It is not recommended tient should be followed periodically with For chronic limb for treatment of intermittent claudication.13,33 a clinical evaluation and ABI measurement ischemia, a large ❚ Supplements. Padma 28, a Tibetan with further consideration for routine duplex trial showed herbal formulation, appears to improve maxi- ultrasound surveillance.13 angioplasty had mal walking distance with adverse effect rates lower initial similar to placebo.34 Other supplements, in- morbidity, cluding vitamin E, ginkgo biloba, and omega-3 Outcomes length of fatty acids, have no evidence of benefit.35-37 Patients with PAD have variable outcomes. hospitalization, About 70% to 80% of patients with this diag- and cost than When revascularization nosis will have a stable disease process with surgical repair. is needed no worsening of symptoms, 10% to 20% will Surgical mortality Patients who develop limb ischemia or lifestyle- experience worsening symptoms over time, was lower after 2 limiting claudication despite conservative 5% to 10% will require revascularization years. therapy are candidates for revascularization. within 5 years of diagnosis, and 1% to 5% Endovascular techniques include angioplasty, will progress to critical limb ischemia, which stenting, atherectomy, and precise medication has a 5-year amputation rate of 1% to 4%.2 delivery. Surgical approaches mainly consist of Patients who require amputation have poor thrombectomy and bypass grafting. For inter- outcomes: Within 2 years, 30% are dead and mittent claudication despite conservative care, 15% have had further amputations.18 ACC/AHA guidelines state endovascular pro- In addition to the morbidity and mortali- cedures are appropriate for aortoiliac disease ty from its own progression, PAD is an impor- and reasonable for femoropopliteal disease, tant predictor of CAD and is associated with but unproven for infrapopliteal disease.13 a significant elevation in morbidity and mor- Acute limb ischemia is an emergency re- tality from CAD. One small but well-designed quiring immediate intervention. Two trials re- prospective cohort study found that patients vealed identical overall and amputation-free with PAD had a more than 6-fold increased survival rates for percutaneous thrombolysis and risk of death from CAD than did patients surgical thrombectomy.38,39 ACC/AHA guide- without PAD.41 JFP lines recommend anticoagulation with heparin ACKNOWLEDGEMENT followed by the revascularization technique that The authors thank Francesca Cimino, MD, FAAFP, for her help in reviewing this manuscript. will most rapidly restore arterial flow.13 CORRESPONDENCE For chronic limb ischemia, a large trial Dustin K. Smith, DO, 2080 Child Street, Jacksonville, FL 32214; showed angioplasty had lower initial mor- [email protected] CONTINUED

MDEDGE.COM/FAMILYMEDICINE VOL 69, NO 10 | DECEMBER 2020 | THE JOURNAL OF FAMILY PRACTICE 505 References 1. Eraso LH, Fukaya E, Mohler ER 3rd, et al. Peripheral arterial dis- endoluminal revascularization (CLEVER) study. Circulation. ease, prevalence and cumulative risk factor profile analysis. Eur J 2012;125:130-139. Prev Cardiol. 2014;21:704-711. 22. Fakhry F, Fokkenrood HJP, Pronk S, et al. Endovascular revascu- 2. Pasternak RC, Criqui MH, Benjamin EJ, et al; American Heart As- larization versus conservative management for intermittent clau- sociation. Atherosclerotic Vascular Disease Conference: Writing dication. Cochrane Database Syst Rev. 2018;(3):CD010512. Group I: epidemiology. Circulation. 2004;109:2605-2612. 23. Hageman D, Fokkenrood HJ, Gommans LN, et al. Supervised ex- 3. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arte- ercise therapy versus home-based exercise therapy versus walk- rial disease detection, awareness, and treatment in primary care. ing advice for intermittent claudication. Cochrane Database Syst JAMA. 2001;286:1317-1324. Rev. 2018;(4):CD005263. 4. Olin JW, Sealove BA. Peripheral artery disease: current insight 24. McDermott MM, Spring B, Berger JS, et al. Effect of a home- into the disease and its diagnosis and management. Mayo Clin based exercise intervention of wearable technology and tele- Proc. 2010;85:678-692. phone coaching on walking performance in peripheral artery 5. Andras A, Ferkert B. Screening for peripheral arterial disease. Co- disease: the HONOR randomized clinical trial. JAMA. 2018;319: chrane Database Syst Rev. 2014;(4):CD010835. 1665-1676. 6. Guirguis-Blake JM, Evans CV, Redmond N, et al. Screening for pe- 25. Ruiz-Canela M, Estruch R, Corella D, et al. Association of Mediter- ripheral artery disease using ankle-brachial index: updated evi- ranean diet with peripheral artery disease: the PREDIMED ran- dence report and systematic review for the US Preventive Services domized trial. JAMA. 2014;311:415-417. Task Force. JAMA. 2018;320:184-196. 26. Zahradka P, Wright B, Weighell W, et al. Daily non-soy legume 7. US Preventive Services Task Force. Screening for peripheral artery consumption reverses vascular impairment due to peripheral disease and cardiovascular disease risk assessment with ankle- artery disease. Atherosclerosis. 2013;230:310-314. brachial index: US Preventive Services Task Force recommenda- 27. Heart Protection Study Collaborative Group. Randomized trial of tion statement. JAMA. 2018;230:177-183. the effects of cholesterol-lowering with simvastatin on peripheral 8. American Heart Association Writing Group 2. Atherosclerotic vascular and other major vascular outcomes in 20536 people with Peripheral Vascular Disease Symposium II: screening for athero- peripheral arterial disease and other high-risk conditions. J Vasc sclerotic vascular diseases: should nationwide programs be insti- Surg. 2007;45:645-655. tuted? Circulation. 2008;118:2830-2836. 28. Kumbhani DJ, Steg G, Cannon CP, et al. Statin therapy and One small but 9. Berger JS, Hochman J, Lobach I, et al. Modifiable risk factor bur- long-term adverse limb outcomes in patients with peripheral den and the prevalence of peripheral artery disease in different artery disease: insights from the REACH registry. Eur Heart J. well-designed vascular territories. J Vasc Surg. 2013;58:673-681. 2014;35:2864-2872. prospective 10. Joosten MM, Pai JK, Bertoia ML, et al. Associations between con- 29. Wong PF, Chong LY, Mikhailidis DP, et al. Antiplatelet agents ventional cardiovascular risk factors and risk of peripheral artery for intermittent claudication. Cochrane Database Syst Rev. cohort study disease in men. JAMA. 2012;308:1660-1667. 2011;(11):CD001272. found that 11. Carmelli D, Fabsitz RR, Swan GE, et al. Contribution of genetic 30. Critical Leg Ischaemia Prevention Study (CLIPS) Group, Catalano and environmental influences to ankle-brachial blood pressure M, Born G, Peto R. Prevention of serious vascular events by as- patients with index in the NHLBI Twin Study. National Heart, Lung, and Blood pirin amongst patients with peripheral arterial disease: randomized, double-blind trial. J Intern Med. 2007;261:276-284. PAD had a more Institute. Am J Epidemiol. 2000;151:452-458. 12. Aboyans V, Criqui MH, Denenberg JO, et al. Risk factors for pro- 31. Morley RL, Sharma A, Horsch AD, et al. Peripheral artery disease. than 6-fold gression of peripheral arterial disease in large and small vessels. BMJ. 2018;360:j5842. increased risk of Circulation. 2006;113:2623-2629. 32. Bedenis R, Stewart M, Cleanthis M, et al. Cilostazol for intermittent 13. Gerald-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC claudication. Cochrane Database Syst Rev. 2014;(10):CD003748. death from CAD guideline on the management of patients with lower extrem- 33. Salhiyyah K, Forster R, Senanayake E, et al. Pentoxifylline ity peripheral artery disease: a report of the American College of for intermittent claudication. Cochrane Database Syst Rev. than did patients Cardiology/American Heart Association Task Force on Clinical 2015;(9):CD005262. without PAD. Practice Guidelines. Circulation. 2017;135:e726-e779. 34. Stewart M, Morling JR, Maxwell H. Padma 28 for intermittent 14. McDermott MM, Greenland P, Liu K, et al. Leg symptoms in pe- claudication. Cochrane Database Syst Rev. 2016;(3):CD007371. ripheral arterial disease: associated clinical characteristics and 35. Kleijnen J, Mackerras D. Vitamin E for intermittent claudication. functional impairment. JAMA. 2001;286:1599-1606. Cochrane Database Syst Rev. 1998;(1):CD000987. 15. Cranley JJ. Ischemic rest pain. Arch Surg. 1969;98:187-188. 36. Nicolai SPA, Kruidenior LM, Bendermacher BLW, et al. Ginkgo 16. Khan NA, Rahim SA, Anand SS, et al. Does the clinical examina- biloba for intermittent claudication. Cochrane Database Syst Rev. tion predict lower extremity peripheral arterial disease? JAMA. 2013;(6):CD006888. 2006;295:536-546. 37. Campbell A, Price J, Hiatt WR. Omega-3 fatty acids for intermittent 17. Wennberg PW. Approach to the patient with peripheral arterial claudication. Cochrane Database Syst Rev. 2013;(7):CD003833. disease. Circulation. 2013;128:2241-2250. 38. American Surgical Association, New York Surgical Society, Phila- 18. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-society consensus delphia Academy of Surgery, Southern Surgical Association (US), for the management of peripheral arterial disease (TASC II). Eur J Central Surgical Association. Results of a prospective randomized Vas Endovasc Surg. 2007;33:S1-S75. trial evaluating surgery versus thrombolysis for ischemia of the 19. Armstrong EJ, Wu J, Singh GD, et al. Smoking cessation is asso- lower extremity: the STILE trial. Ann Surg. 1994;220:251-268. ciated with decreased mortality and improved amputation-free 39. Ouriel K, Veith FJ, Sasahara AA. Thrombolysis or peripheral ar- survival among patients with symptomatic peripheral artery dis- terial surgery: phase I results. TOPAS Investigators. J Vasc Surg. ease. J Vasc Surg. 2014;60:1565-1571. 1996;23:64-73. 20. Lane R, Harwood A, Watson L, et al. Exercise for intermittent 40. Bradbury AW, Ruckley CV, Fowkes FGR, et al. Bypass versus an- claudication. Cochrane Database Syst Rev. 2017;(12):CD000990. gioplasty in severe ischaemia of the leg (BASIL): multicentre, ran- 21. Murphy TP, Cutlip DE, Regensteiner JG, et al; CLEVER Study domised, controlled trial. Lancet. 2005;366:1925-1934. Investigators. Supervised exercise versus primary stenting for 41. Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of claudication resulting from aortoiliac peripheral artery disease: 10 years in patients with peripheral arterial disease. N Engl J Med. six-month outcomes from the claudication: exercise versus 1992;326:381-386.

Visit us @ mdedge.com/familymedicine

506 THE JOURNAL OF FAMILY PRACTICE | DECEMBER 2020 | VOL 69, NO 10