Peripheral arterial disease (PAD) is the third most common manifestation of atherosclerosis.1 The atherosclerotic occlusive and thromboembolic pathophysiologic processes narrows and obstructs the arterial lumens. It is more prevalent in the lower extremity than the upper extremities, including the aortoiliac, femoropopliteal, and infrapopliteal arteries.2
PAD primarily arises from atherosclerosis causing insufficient tissue perfusion. Other less common non-atherosclerotic causes are congenital anatomical variations within and external to the vessel wall (i.e., persistent sciatic artery), autoimmune diseases (i.e., vasculitis), collagen vascular disease (i.e., Ehlers-Danlos Syndrome), hereditary or acquired aneurysmal diseases (i.e., fibromuscular dysplasia), radiotherapy, vasospastic agents (i.e., cocaine), tumor invasion, or trauma.3
Epidemiology including risk factors and primary prevention
The worldwide prevalence of PAD in 2015 for age > 25 years was 5.56%, which is approximately 236.62 million, an increase of 17.10% from 2010.1
Risk factors include the following 1,2,4:
- Smoking – most important modifiable risk factor
- Family history and genetic factors
- Chronic kidney disease
- Advanced age
- High homocysteine levels
The American College of Cardiology (ACC)/American Heart Association (AHA) classified the following groups at a higher risk 2:
- Age ≥ 65 years
- Age 50 to 64 years with history of smoking and diabetes
- Age <50 years with diabetes and at least 1 other risk factor for atherosclerosis
- Known atherosclerosis at other sited (e.g., coronary, carotid, subclavian, renal, mesenteric artery stenosis, or abdominal arotic aneurysm)
Primary prevention includes physical activity and diet; blood pressure, cholesterol, and diabetes control; and smoking cessation.
PAD has a complex pathophysiology that involves multiple cells, proteins, and pathways. The key cells to the development of athero-thrombosis are: vascular endothelial cells, vascular smooth muscle cells, fibroblasts, platelets, resident stem cells, pericytes, and inflammatory cells. In patients with PAD, the vascular remodeling, inflammation, and apoptotic pathway responses that promotes angiogenesis and arteriogenesis to increase blood supply to compensate for ischemia are ineffective. This leads to inadequate tissue perfusion, endothelial dysfunction, chronic inflammation, and high oxidative stress. These changes then progress to mitochondrial injury, free radical generation, muscle fiber damage, myofiber degeneration, fibrosis, and tissue damage, which could present as gangrene. 5
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
Not much is known about the clinical manifestations range from asymptomatic to critical limb ischemia. Patients who smoke, have diabetes, early-onset atherosclerosis, or end stage kidney disease, are at higher risk of progressing rapidly and unpredictably with worse prognosis.
There are several classification systems and the two most commonly used are the following:6,7
|I||Asymptomatic, incomplete blood vessel obstruction|
|II||Intermittent mild claudication pain|
|IIa||Claudication at distance >200 meters or 4 min|
|IIb||Claudication at distance <200 meters or 4 min|
|III||Ischemic rest pain, mostly in the feet|
|IV||Necrosis, ulceration and/or gangrene of the limb|
|O||0||Asymptomatic – no hemodynamically significant occlusive disease|
|II||4||Ischemic rest pain (likely due to limited arterial perfusion)|
Specific secondary or associated conditions and complications
Complications of PAD: 8,10
- Acute limb ischemia – sudden drop in blood flow
- Critical limb ischemia – chronic poor blood flow
- Severe Infection
- Heart attack
- Erectile dysfunction
- Blood clots
- Functional impairment
- Decreased quality of life
Essentials of Assessment
Conduct a comprehensive medical history and review of symptoms to evaluate for exertional leg symptoms: claudication, walking impairments, atypical non-joint related lower extremity symptoms, ischemic rest pain, and nonhealing wounds.2,9 It is also important to ask about the common PAD risk factors as noted above.
A thorough vascular exam is necessary2,9:
- Palpate for any abnormal lower extremity pulses (i.e., femoral, popliteal, dorsalis pedis, and posterior tibial)
- Auscultate for audible femoral bruits
- Inspect the legs and feet for non-healing wounds, gangrene, elevation pallor, dependent rubor, delayed capillary refill, hair distribution, and coolness of temperature
PAD may significantly affect patients’ functional independence and quality of life, so it is important to evaluate the patient’s level of assistance to perform activities of daily living and independent activities of daily living. As their mobility can also be compromised, it is key to assess for patient’s gait and ability to ambulate a certain distance without pain as well as their endurance level.10
Laboratory studies are not used to diagnose PAD, but they are helpful to detect associated risk factors such as hemoglobin A1c, lipid profiles, and renal function.
Not recommended for asymptomatic PAD or patients who aren’t candidates for revascularization as it won’t likely change management.
For symptomatic patients who are considered for revascularization, the following imaging modalities are helpful to determine the anatomical location and severity of disease. 2,9
- Duplex (Doppler) ultrasound – Safe and inexpensive with the ability to distinguish between occlusion and stenosis but has a lower spatial resolution. Its pressure gradients and pulse volume waveforms used with ABI measurements can distinguish isolated aortoiliac PAD from femoropopliteal PAD and below-the-knee PAD.
- Computed tomography angiography (CTA) – Better spatial resolution, but arterial calcification limits the interpretation especially below the knee. There’s also a risk of contrast-induced nephropathy, exposure to radiation, and anaphylaxis from the iodine contrast.
- Magnetic resonance angiography (MRA) – Superior spatial resolution where images are not degraded by calcified vessels. Some patients cannot tolerate the length of scanning time. Gadolinium contrasts are also contraindicated for advanced renal disease due to risk of nephrogenic systemic sclerosis.
- Invasive angiography – For patients with chronic limb ischemia or patients with lifestyle limiting claudication with an inadequate response to guideline-directed management and therapy.
Supplemental assessment tools
History and exam findings of PAD needs to be confirmed with the diagnostic testing of ankle-brachial index (ABI). The resting ABI is the initial and only test required to establish the diagnosis. The ABI is a simple, non-invasive exam that measure the systolic blood pressure (BP) of bilateral arms (brachial arteries) and ankles (dorsalis pedis, or posterior tibial arteries) in the supine position with the Doppler. The ABI is calculated by dividing the higher dorsalis pedis pressure or posterior tibial pressure by the higher right or left brachial pressure.
Resting ABI is reported as abnormal (ABI ≤ 0.90), which signifies PAD; borderline (ABI 0.91 – 0.99); normal (ABI 1.00 – 1.40); non-compressible (ABI >1,40).
When ABI >1.40, the toe-brachial index (TBI) is measured for suspected PAD. The TBI is the ratio of systolic BP of the great toe to the higher of the brachial artery pressures. Abnormal TBI is < 0.70 and is diagnostic of PAD.
If patients have exertional on-joint related leg symptoms but has normal or borderline resting ABI, exercise treadmill ABI is recommended. A ≥ 20% decrease in ABI after exercise is an abnormal treadmill ABI and is diagnostic for PAD. An alternative to treadmill testing is the pedal plantar flexion test. 2,9
If amputation of the lower extremity is indicated, transcutaneous oxygen pressure (TcPO) significantly predicts healing. It provides a way to evaluate skin perfusion and cutaneous healing at a specific level. An optimal value of TcPO 38 mm Hg while in a supine position had a sensitivity and specificity of 71% for predicting healing or failure. TcPO should be used to better accurately determine the correct amputation level; however, it should not be used in isolation.11
Early predictions of outcomes
The prognosis of PAD is guarded even with treatment. There is greater functional impairment, faster functional decline, and increased rates of mobility loss compared to those without PAD.20 The disease is progressive and patients with ABI ≤0.9 have 3-fold increased risk of all-cause mortality and cardiovascular mortality in both men and women. The risk of myocardial infarction (MI) and stroke among PAD patients is comparable to the risk of these events in patients with coronary artery disease. 14 Compared to men, women are more likely to have acute MI, longer hospital stays, and requiring rehabilitation or nursing home care. 12,
Active smoking and second-hand exposure to tobacco smoke plays a significant role as an environmental variable in the progression of PAD. Studies have found that tobacco smoke alters the epigenetic state. 15, 16 Therefore, it is strongly advised to quit smoking and continue ongoing restrictions of smoke exposure in public, at work, and at home. 2
Social role and social support system
Intermittent claudication and ischemic ulcers can be very painful, affecting quality of life, mobility, and functional level of independence. There is a sense of burden, powerlessness, social isolation, and compromised independence.17 There are studies showing association of depression with PAD.18 As patients become more debilitated, they will require assistance and support that may include social security disability insurance. PAD is listed under the Cardiovascular System Impairments Category (medical listing 4.12).
Professional and work life may be impaired because of claudication pain and ischemic wounds. This leads to reduced walking capacity and impaired mobility leading to limited exercise and sedentary lifestyle. Asymptomatic patients or those with atypical symptoms also experience progressive functional impairment.19
Rehabilitation Management and Treatments
Available or current treatment guidelines
Comprehensive prevention programs help reduce symptoms, improve exercise capacity, decrease physical disability, and prevent cardiovascular events.9 Aggressive risk factor modification should target obesity, smoking, diabetes, hypertension, hyperlipidemia, and homocysteinemia. A supervised exercise program, structured community or home-based exercise program with behavioral change techniques are recommended. Alternative strategies of exercise include upper-body ergometry, cycling, and pain-free or low-intensity walking that avoids moderate-to-maximum claudication has shown to improve walking ability and functional status. It is also important to teach healthy foot care behaviors (e.g., daily feet inspection, wear proper shoes and socks, avoid barefoot walking). For nighttime pain relief, the legs should be kept below the level of the heart, and the head of the bed should be elevated 10 to 15 cm.
Preventative pharmacologic treatments include antiplatelet therapy with aspirin alone 75-325mg orally daily or clopidogrel alone 75 mg orally daily to reduce MI, stroke and vascular death in patients with symptomatic or asymptomatic PAD. Dual antiplatelet therapy (aspirin, clopidogrel) may be used to reduce limb-related events post revascularization. A statin is indicated for all patients with PAD. Claudication symptoms can be treated with cilostazol 100 mg orally twice daily in the absence of heart failure. Use of pentoxifylline has not been well established. Endovascular revascularization procedures and/or surgery are reserved for PAD that causes life-style limiting claudication, hemodynamically significant aortoiliac occlusive disease, or has been unresponsive to conservative measures.2
At different disease stages
Acute PAD may result from acute compartment syndrome, rupture, thrombosis, or embolus of an atherosclerotic plaque. Immediate angiography to confirm location of occlusion and collateral flow is essential. Embolectomy, thrombolysis, and bypass surgery are options for treatment. Of the patients, 20% to 30% with acute arterial occlusion require amputation within the first 30 days.3
For chronic PAD, supervised claudication rehabilitation is superior to unsupervised training: Begin at 15 min/session increasing to 45-50 minutes/session of treadmill or track walking at least 3 times per week for minimum of 12 weeks. Initial workload is set to speeds that is near maximal claudication within 3 to 5 minutes followed by rest periods as needed. The patient should resume walking when claudication subsides. It is expected to markedly improve walking ability, with results of increased speed, duration, distance, and decreased claudication symptoms. If there are cardiac signs, exercise should stop. Home-based exercise with behavioral change techniques is also an effective alternative for patients unwilling or unable to attend the 3 times a week supervised exercise session.20
Cardiovascular risk reduction is as follows19:
- Diabetes control and proper foot care.
- Hypertension: Antihypertensives, specifically angiotensin-converting enzyme inhibitors and beta-blockers to achieve blood pressure < 140/90 mmHg (<130/80 mmHg for those with diabetes mellitus or chronic kidney disease)
- Hyperlipidemia: Statin to achieve target low-density lipoprotein goal < 100mg/dL (< 70 mg/dL for high risk patients).
- Smoking cessation: Comprehensive smoking intervention program with behavior modification.
- Antiplatelet therapy: Aspirin 75mg-325mg or clopidogrel 75mg to reduce risk of future cardiovascular events (e.g., myocardial infarction, stroke, vascular death in patients with atherosclerotic lower extremity PAD).
Individuals with professional and lifestyle limitations caused by PAD that are not responding to conservative treatments can be considered for endovascular interventions (e.g., percutaneous transluminal angioplasty [PTA]). PTA with or without stent insertion is the primary nonsurgical method for dilating vascular occlusions.
Similarly, candidates for surgery have intermittent claudication that inhibits daily activities, rest pain, and gangrene. Surgery options include thromboendarterectomy, revascularization, and as a last resort, amputation.2
Coordination of care
A multidisciplinary approach with communication between the primary care physician, physiatrist, vascular surgeon, general surgeon (if amputation is a consideration), and the claudication rehabilitation program is essential. This should include addressing modifications for cardiovascular risk factors, pharmacologic and exercise claudication management, lifestyle modifications, and patient-family education.
2017 Medicare Coverage for supervised exercise therapy (SET)25
- Up to 36 sessions lasting 30-60mins over a 12-week period in a hospital outpatient or physicians office. The therapies are to be provided by qualified personnel trained in PAD exercise therapy. These auxiliary personnel are directly supervised by a physician, physician assistant or nurse practitioner/clinical nurse specialist who are trained in both basic/advanced life support techniques.
- Medicare has the potential to cover an additional 36 sessions, but a second referral would be required for renewal of coverage.
Patient & family education
Patients and their family should be educated on PAD, importance of risk factor modification, lifestyle changes, and a rehabilitation exercise program. Referral to support group services should be offered.
Activity and treadmill walking distance should be measured in order to evaluate treatment outcomes. As patients are able to improve their exercise capability, the workload should be increased to ensure continued tolerance of exercise and pain-free walking distance. Range of motion and performance of activities of daily living or ambulation should be tracked as applicable.
For intermittent claudication, a systematic review showed that supervised exercise, endovascular interventions, or surgical bypass compared to medical management alone had greater improvements in the claudication symptoms, walking distance, and quality of life. However, a cost-analysis would be needed to evaluate whether it is worth having earlier interventions for milder symptoms. 23
High intensity lower body resistance training improves treadmill and flat ground walking in persons > 65 years old with PAD. 24
Hemodynamic measurements, including ABI, can help in assessing patency of grafts, angioplasty, or stents.
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
Early detection and diagnosis of PAD is important for better prognosis. Diagnosis with history, physical examination, and ABI measurement is the standard of care. Treatment of mild PAD includes aggressive risk factor modification, smoking cessation, an exercise rehabilitation program, antiplatelet drugs, and cilostazol as needed for claudication symptoms. PTA or surgical bypass are options in PAD that is not responsive to conservative measures with a possibility of amputation in necrotic, septic, or limb-threatening ischemia.
Cutting Edge/ Emerging and Unique Concepts and Practice
Transcutaneous electrical nerve stimulation (TENS)
A prospective double blind multicenter randomized control trial showed potential of using TENs to improve the symptoms of claudication. However, this study was a 3-week trial, so a long-term study would be needed to explore TENS ability of vasodilation, analgesic modulation and neuromodulation. 22
Inorganic nitrate supplements
PAD has a pressor (elevated blood pressure) response during lower and upper extremity exercises. Emerging evidence suggests inorganic nitrate supplements can boost nitric oxide bioavailability, which could improve blood flow and pressor response during exercise. 21
Gaps in the Evidence- Based Knowledge
Improvement in walking distance, duration, and decrease of symptomatology of PAD with exercise has been established; the exact mechanism of improvement is not well understood. It is thought that muscles are conditioned to work by extracting more blood, which increases collateral vessel formation.
- Song P, Rudan D, Zhu Y, et al. Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis. Lancet Glob Heal. 2019;7(8):e1020-e1030. doi:10.1016/S2214-109X(19)30255-4
- 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 [published correction appears in Circulation. 2017 Mar 21;135(12 ):e790]. Circulation. 2017;135(12):e686-e725. doi:10.1161/CIR.0000000000000470
- Ali T, Krokidis ME, Winterbottom A. Peripheral Non-atherosclerotic Arterial Disorders: What Radiologists Need to Know. Acad Radiol. 2017;24(4):497-505. doi:10.1016/j.acra.2016.11.009
- Criqui MH, Aboyans V. Epidemiology of Peripheral Artery Disease. Circ Res. 2015;116(9):1509-1526. doi:10.1161/CIRCRESAHA.116.303849
- Krishna SM, Moxon J V., Golledge J. A review of the pathophysiology and potential biomarkers for peripheral artery disease. Int J Mol Sci. 2015;16(5):11294-11322. doi:10.3390/ijms160511294
- Hardman RL, Jazaeri O, Yi J, Smith M, Gupta R. Overview of classification systems in peripheral artery disease. Semin Intervent Radiol. 2014;31(4):378-388. doi:10.1055/s-0034-1393976
- Patel MR, Conte MS, Cutlip DE, et al. Consensus Definitions From Peripheral Academic Research Consortium (PARC). J Am Coll Cardiol. 2015;65(9):931-941. doi:10.1016/j.exphem.2015.05.018.MicroRNA-223
- Zemaitis MR, Boll JM, Dreyer MA. Peripheral Arterial Disease. [Updated 2020 Jul 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430745/
- Tummala S, Scherbel D. Clinical Assessment of Peripheral Arterial Disease in the Office: What Do the Guidelines Say? Semin Intervent Radiol. 2018;35(5):365-377. doi:10.1055/s-0038-1676453
- Treat-Jacobson D, McDermott MM, Bronas UG, et al. Optimal Exercise Programs for Patients with Peripheral Artery Disease: A Scientific Statement from the American Heart Association. Circulation. 2019;139(4):E10-E33. doi:10.1161/CIR.0000000000000623
- Andrews K, Dib M, Shives T, Hoskin T, Liedl D, Boon A. Noninvasive arterial studies including transcutaneous oxygen pressure measurements with the limbs elevated or dependent to predict healing after partial foot amputation.Am J Phys Med Rehabil.2013;92:385-392.
- Jelani Q ul ain, Petrov M, Martinez SC, Holmvang L, Al-Shaibi K, Alasnag M. Peripheral Arterial Disease in Women: an Overview of Risk Factor Profile, Clinical Features, and Outcomes. Curr Atheroscler Rep. 2018;20(8). doi:10.1007/s11883-018-0742-x
- Parmenter BJ, Dieberg G, Smart NA. Exercise Training for Management of Peripheral Arterial Disease: A Systematic Review and Meta-Analysis. Sport Med. 2015;45(2):231-244. doi:10.1007/s40279-014-0261-z
- Agnelli G, Belch JJF, Baumgartner I, Giovas P, Hoffmann U. Morbidity and mortality associated with atherosclerotic peripheral artery disease: A systematic review. Atherosclerosis. 2020;293(November 2018):94-100. doi:10.1016/j.atherosclerosis.2019.09.012
- Cooke JP, Chen Z. A Compendium on Peripheral Arterial Disease. Circ Res. 2015;116(9):1505-1508. doi:10.1161/CIRCRESAHA.115.306403
- Ngu NL, McEvoy M. Environmental tobacco smoke and peripheral arterial disease: A review. Atherosclerosis. 2017;266:113-120. doi:10.1016/j.atherosclerosis.2017.09.024
- Abaraogu UO, Ezenwankwo EF, Dall PM, Seenan CA. Living a burdensome and demanding life: A qualitative systematic review of the patients experiences of peripheral arterial disease. PLoS One. 2018;13(11):1-21. doi:10.1371/journal.pone.0207456
- Ramirez JL, Grenon SM. Depression and peripheral artery disease: why we should care and what we can do. CVIR Endovasc. 2018;1(1):14. doi:10.1186/s42155-018-0017-1
- Hamburg N, Balady G. Exercise rehabilitation in peripheral artery disease: functional impact and mechanisms of benefits.Circulation. 2011;123:87-97.
- McDermott MM. Exercise Rehabilitation for Peripheral Artery Disease: A REVIEW [published correction appears in J Cardiopulm Rehabil Prev. 2018 Sep;38(5):347]. J Cardiopulm Rehabil Prev. 2018;38(2):63-69. doi:10.1097/HCR.0000000000000343
- Kruse NT, Ueda K, Hughes WE, Casey DP. Eight weeks of nitrate supplementation improves blood flow and reduces the exaggerated pressor response during forearm exercise in peripheral artery disease. Am J Physiol Heart Circ Physiol. 2018;315(1):H101-H108. doi:10.1152/ajpheart.00015.2018
- Besnier F, Sénard JM, Grémeaux V, et al. The efficacy of transcutaneous electrical nerve stimulation on the improvement of walking distance in patients with peripheral arterial disease with intermittent claudication: study protocol for a randomised controlled trial: the TENS-PAD study. Trials. 2017;18(1):373. Published 2017 Aug 10. doi:10.1186/s13063-017-1997-1
- Malgor RD, Alalahdab F, Elraiyah TA, et al. A systematic review of treatment of intermittent claudication in the lower extremities. J Vasc Surg. 2015;61(3):54S-73S. doi:10.1016/j.jvs.2014.12.007
- Parmenter BJ, Mavros Y, Ritti Dias R, et al. Resistance training as a treatment for older persons with peripheral artery disease: a systematic review and meta-analysis. British Journal of Sports Medicine 2020;54:452-461.
- Jensen TS, Chin J, Ashby L, Schafer J, Dolan D. Decision Memo for Supervised Exercise Therapy (SET) for Symptomatic Peripheral Artery Disease (PAD) (CAG-00449N). Centers Medicare Medicaid Serv. 2017:1-58. https://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=287.
Social Security. Disability evaluation under Social Security: 4.00-Cardiovascular System – Adult. 2008. Available at: http://www.ssa.gov/disability/professionals/bluebook/4.00-Cardiovascular-Adult.htm#4_12. Accessed January 1, 2014.
Original Version of the Topic
Marlis Gonzalez-Fernandez, MD, PhD, Tiffany Vu, DO. Rehabilitation of and the effects of exercise on peripheral arterial diseases. 9/20/2014
Cheng-Chuan Chiang, DO
Nothing to Disclose
Marlís González-Fernández, MD, PhD
Nothing to Disclose