Etiology of Peripheral Arterial Disease
Prevalence of peripheral arterial disease (PAD) is about 12% in the US; men are affected more commonly than women.
Risk factors are the same as those for atherosclerosis:
Cigarette smoking (including passive smoking) or other forms of tobacco use
Dyslipidemia (high low-density lipoprotein [LDL] cholesterol, low high-density lipoprotein [HDL] cholesterol)
Family history of atherosclerosis
High homocysteine level
Increasing age
Male sex
Obesity
Atherosclerosis is a systemic disorder; 50 to 75% of patients with PAD also have clinically significant coronary artery disease (CAD) or cerebrovascular disease. However, CAD may be silent in part because PAD may prevent patients from exerting themselves enough to trigger angina.
Symptoms and Signs of Peripheral Arterial Disease
Intermittent claudication is the typical manifestation of peripheral arterial disease. Intermittent claudication is a painful, aching, cramping, uncomfortable, or tired feeling in the legs that occurs during walking and is relieved by rest. Claudication usually occurs in the calves but can occur in the feet, thighs, hips, buttocks, or, rarely, arms. Claudication is a manifestation of exercise-induced reversible ischemia, similar to angina pectoris. As PAD progresses, the distance that can be walked without symptoms may decrease, and patients with severe PAD may experience pain during rest, reflecting irreversible ischemia. Rest pain is usually worse distally, is aggravated by leg elevation (often causing pain at night), and lessens when the leg is below heart level. The pain may be burning, tightening, or aching, although this finding is nonspecific.
About 20% of patients with peripheral arterial disease are asymptomatic, sometimes because they are not active enough to trigger leg ischemia. Some patients have atypical symptoms (eg, nonspecific exercise intolerance, hip or other joint pain).
Mild PAD often causes no signs. Moderate to severe PAD commonly causes diminished or absent peripheral (popliteal, tibialis posterior, dorsalis pedis) pulses.
When below heart level, the foot may appear dusky red (called dependent rubor). In some patients, elevating the foot causes loss of color and worsens ischemic pain; when the foot is lowered, venous filling is prolonged (> 15 seconds). Edema is usually not present unless the patient has kept the leg immobile and in a dependent position to relieve pain. Patients with chronic PAD may have thin, pale (atrophic) skin with hair thinning or loss. Distal legs and feet may feel cool. The affected leg may sweat excessively and become cyanotic, probably because of sympathetic nerve overactivity.
DR P. MARAZZI/SCIENCE PHOTO LIBRARY
As ischemia worsens, ulcers may appear (typically on the toes or heel, occasionally on the leg or foot), especially after local trauma. The ulcers tend to be surrounded by black, necrotic tissue (dry gangrene). They are usually painful, but people with peripheral neuropathy (eg, due to diabetes or alcohol use disorder) may not feel them. Infection of ischemic ulcers (wet gangrene) occurs readily, causing rapidly progressive cellulitis.
The level of arterial occlusion influences location of symptoms. Aortoiliac PAD may cause buttock, thigh, or calf claudication; hip pain; and, in men, erectile dysfunction (Leriche syndrome). In femoropopliteal PAD, claudication typically occurs in the calf; pulses below the femoral artery are weak or absent. In PAD of more distal arteries, femoropopliteal pulses may be present, but foot pulses are absent.
Arterial occlusive disease occasionally affects the arms, epecially the left proximal subclavian artery, causing arm fatigue with exercise and occasionally embolization to the hands.
Diagnosis of Peripheral Arterial Disease
Ankle-brachial index
Ultrasonography
Angiography before surgery
© 2017 Elliot K. Fishman, MD.
Peripheral arterial disease is suspected clinically but is underrecognized because many patients have atypical symptoms or are not active enough to have symptoms. Spinal stenosis may also cause leg pain during walking but can be distinguished because the pain (called pseudoclaudication) requires sitting, not just rest, for relief, and distal pulses remain intact.
Diagnosis is confirmed by noninvasive testing. First, bilateral arm and ankle systolic blood pressure (BP) is measured; because ankle pulses may be difficult to palpate, a Doppler probe may be placed over the dorsalis pedis or posterior tibial arteries. Doppler ultrasonography is often used, because pressure gradients and pulse volume waveforms can help distinguish isolated aortoiliac PAD from femoropopliteal PAD and below-the-knee PAD.
The ankle-brachial index is the ratio of ankle systolic BP to arm systolic BP. A low (≤ 0.90) ankle-brachial index indicates PAD, which can be classified as
Mild: 0.71 to 0.90
Moderate: 0.41 to 0.70
Severe: ≤ 0.40)
If the index is normal (0.91 to 1.30) but suspicion of PAD remains high, the index is determined after exercise stress testing. A high index (> 1.30) may indicate noncompressible leg vessels (as occurs in Mönckeberg arteriosclerosis with calcification of the arterial wall).
If the index is > 1.30 but suspicion of PAD remains high, additional tests (eg, Doppler ultrasonography, measurement of BP in the first toe using a toe cuff) are done to check for arterial stenoses or occlusions. Ischemic lesions are unlikely to heal when systolic BP is < 55 mm Hg in patients without diabetes or < 70 mm Hg in patients with diabetes; below-the-knee amputations usually heal if BP is ≥ 70 mm Hg.
Peripheral arterial insufficiency can also be assessed by transcutaneous oximetry (TcO2). A TcO2 level < 40 mm Hg (5.32 kPa) is predictive of poor healing, and a value < 20 mm Hg (2.66 kPa) is consistent with critical limb ischemia.
Angiography provides details of the location and extent of arterial stenoses or occlusion; it is a prerequisite for surgical correction or percutaneous transluminal angioplasty (PTA). It is not a substitute for noninvasive testing because it provides no information about the functional significance of abnormal findings. Magnetic resonance angiography and CT angiography are noninvasive alternatives to catheter contrast angiography.
Treatment of Peripheral Arterial Disease
Risk factor modification
Exercise
Antiplatelet drugs
Angiotensin-converting enzyme (ACE) inhibitors
Percutaneous transluminal angioplasty (PTA) or surgery for severe disease
All patients require aggressive risk factor modification for relief of peripheral arterial disease symptoms and prevention of cardiovascular disease (CVD), including
Smoking cessation, which is essential
Control of diabetes, dyslipidemia, and hypertension
Structured exercise therapy
Dietary changes
Statins, ACE inhibitors, and aspirin are given to reduce the risk of CVD (see Treatment of Atherosclerosisaspirin reduced CVD events and major adverse limb events, including amputation (1). In patients with severe peripheral artery disease that required lower-extremity revascularization, another study demonstrated that postoperative therapy with rivaroxaban 2.5 mg orally twice a day plus aspirin significantly lowered the incidence of the composite outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes compared to aspirin alone (2).
Beta-blockers are safe unless PAD is very severe (3).
Exercise—35 to 50 minutes of treadmill or track walking in an exercise-rest-exercise pattern 3 to 4 times a week—is an important but underused treatment. Supervised exercise programs are probably superior to unsupervised programs. Exercise can increase symptom-free walking distance and improve quality of life. Mechanisms probably include increased collateral circulation, improved endothelial function with microvascular vasodilation, decreased blood viscosity, improved red blood cell filterability, decreased ischemia-induced inflammation, and improved oxygen extraction.
Patients are advised to keep the legs below heart level. For pain relief at night, the head of the bed can be elevated about 10 to 15 cm (4 to 6 inches) to improve blood flow to the feet.
Patients are also advised to avoid cold and drugs (eg, cocaine
Preventive foot care is crucial, especially for patients with diabetes. It includes daily foot inspection for injuries and lesions; treatment of calluses and corns by a podiatrist; daily washing of the feet in lukewarm water with mild soap, followed by gentle, thorough drying; and avoidance of thermal, chemical, and mechanical injury, especially that due to poorly fitting footwear. Foot ulcer management is discussed elsewhere.
Drug treatment
Antiplatelet drugs3). Some data suggest that the combination of aspirin4).
pentoxifylline nor cilostazol is a substitute for risk factor modification and exercise. Use of pentoxifylline is controversial because evidence of its effectiveness is mixed. A trial of ≥ 2 months may be warranted because adverse effects are uncommon and mild. The most common adverse effects of cilostazol are headache and diarrhea. Cilostazol is contraindicated in patients with severe heart failure.
ACE inhibitors and angiotensin II receptor blockers (ARBs) have several beneficial effects. They are antiatherogenic and are potent vasodilators. Among patients undergoing vascular intervention for chronic limb-threatening ischemia, those on ACE inhibitors or ARBs had improved amputation-free and overall survival (5).
Other drugs that may relieve claudication are being studied; they include L-arginine (the precursor of endothelium-dependent vasodilator), nitric oxide, vasodilator prostaglandins, and angiogenic growth factors (eg, vascular endothelial growth factor [VEGF], basic fibroblast growth factor [bFGF]). In patients with severe limb ischemia, long-term parenteral use of vasodilator prostaglandins may decrease pain and facilitate ulcer healing.
Percutaneous transluminal angioplasty (PTA)
PTA with or without stent insertion is the primary nonsurgical method for dilating vascular occlusions. PTA with stent insertion may keep the artery open better than balloon compression alone, with a lower rate of reocclusion. Stents work best in large arteries with high flow (iliac and renal); they are less useful for smaller arteries and for long occlusions.
Indications for PTA are similar to those for surgery:
Intermittent claudication that inhibits daily activities and does not respond to risk factor modification and noninvasive treatments
Rest pain
Gangrene
Suitable lesions are flow-limiting, short iliac stenoses (< 3 cm) and short, single or multiple stenoses of the superficial femoropopliteal segment. Complete occlusions (up to 10 or 12 cm long) of the superficial femoral artery can be successfully dilated, but results are better for occlusions ≤ 5 cm. PTA is also useful for localized iliac stenosis proximal to a bypass of the femoropopliteal artery.
PTA is less useful for diffuse disease, long occlusions, and eccentric calcified plaques. Such lesions are particularly common in patients with diabetes, often affecting small arteries.
With appropriate patient selection, PTA for iliac, thigh, and calf artery stenosis has a high success rate. A systematic review and meta-analysis documented a limb salvage rate of 95% after 12 months, target lesion revascularization rate of 14 to 25%, and a survival rate of 90% (6). However, the restenosis rate was 33 to 62%; repeat PTA may be successful.
Surgery
Surgery is indicated for patients
Who can safely tolerate a major vascular procedure
With severe symptoms that do not respond to noninvasive treatments
The goal is to relieve symptoms, heal ulcers, and avoid amputation. Because many patients have underlying coronary artery disease, which places them at risk of acute coronary syndromes during surgical procedures for PAD, patients usually undergo cardiac evaluation prior to surgery.
Thromboendarterectomy (surgical removal of an occlusive lesion) is used for short, localized lesions in the aortoiliac, common femoral, or deep femoral arteries.
Revascularization (eg, femoropopliteal bypass grafting) uses synthetic or natural materials (often the saphenous or another vein) to bypass occlusive lesions. Revascularization helps prevent limb amputation and relieve claudication.
Sympathectomy may be effective in patients who cannot undergo major vascular surgery, when a distal occlusion causes severe ischemic pain. Chemical sympathetic blocks are as effective as surgical sympathectomy, so the latter is rarely done.
Amputation is a procedure of last resort, indicated for uncontrolled infection, unrelenting rest pain, and progressive gangrene. Amputation should be as distal as possible, preserving the knee for optimal use with a prosthesis.
External compression therapy
External pneumatic compression of the lower limb to increase distal blood flow is an option for limb salvage in patients who have severe PAD and are not candidates for surgery. Theoretically, it controls edema and improves arterial flow, venous return, and tissue oxygenation, but data supporting its use are lacking. Pneumatic cuffs or stockings are placed on the lower leg and inflated rhythmically during diastole, systole, or part of both periods for 1 to 2 hours several times a week.
Stem cell transplantation
Bone marrow stem cells can differentiate into small blood vessels. Clinical trials are investigating autologous iliac crest bone marrow stem cell transplantation into legs of patients with critical limb ischemia. Although this therapy may not be appropriate for every patient, it may prove to be an alternative for some who would otherwise need major amputation; results of initial smaller trials have been encouraging but some blinded, placebo-controlled trials have failed to show benefit (7, 8).
Gene therapy
Gene therapy is also being studied (9, 10). Gene transfer of DNA encoding VEGF may promote collateral blood vessel growth.
Treatment references
1. Anand S, Bosch J, Eikelboom JW, et al, on behalf of the COMPASS Investigators: Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomized, double-blind, placebo controlled trial. Lancet 391(10117):218–229, 2018. doi: 10.1016/S0140-6736(17)32409-1
2. Bonaca MP, Bauersachs RM, Anand SS, et al: Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med 382:1994–2004, 2020. doi: 10.1056/NEJMoa2000052
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. Circulation 155:e686–e725, 2017.
4. Hiatt WR, Bonaca MP, Patel MR, et al. Rivaroxaban and Aspirin in Peripheral Artery Disease Lower Extremity Revascularization. Circulation142 (23):2219-2230, 2020. doi/10.1161/CIRCULATIONAHA.120.050465
5. Khan SZ, O'Brien-Irr MS, Rivero M, et al. Improved survival with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in chronic limb-threatening ischemia. J Vasc Surg 2020;72(6):2130-2138. doi:10.1016/j.jvs.2020.02.041
6. Ipema J, Huizing E, Schreve MA, de Vries JPM, Ünlü Ç. Editor's Choice - Drug Coated Balloon Angioplasty vs. Standard Percutaneous Transluminal Angioplasty in Below the Knee Peripheral Arterial Disease: A Systematic Review and Meta-Analysis. Eur J Vasc Endovasc Surg. 2020;59(2):265-275. doi:10.1016/j.ejvs.2019.10.002
7. Rigato M, Monami M, Fadini GP: Autologous cell therapy for peripheral arterial disease: Systematic review and meta-analysis of randomized, nonrandomized, and noncontrolled studies. Circ Res 120(8):1326–1340, 2017. doi: 10.1161/CIRCRESAHA.116.309045
8. Teraa M, Sprengers RW, Schutgens RE, et al: Effect of repetitive intra-arterial infusion of bone marrow mononuclear cells in patients with no-option limb ischemia: The randomized, double-blind, placebo-controlled Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial. Circulation 131(10):851–860, 2015. doi: 10.1161/CIRCULATIONAHA.114.012913
9. Forster R, Liew A, Bhattacharya V, Shaw J, Stansby G: Gene therapy for peripheral arterial disease. Cochrane Database Syst Rev 2018;10(10):CD012058. Published 2018 Oct 31. doi:10.1002/14651858.CD012058.pub2
10. Shimamura M, Nakagami H, Sanada F, Morishita R. Progress of Gene Therapy in Cardiovascular Disease. Hypertension 2020;76(4):1038-1044. doi:10.1161/HYPERTENSIONAHA.120.14478
Key Points
Peripheral arterial disease (PAD) occurs almost always in the lower extremities.
50 to 75% of patients also have significant cerebral and/or coronary atherosclerosis.
When symptomatic, PAD causes intermittent claudication, which is discomfort in the legs that occurs during walking and is relieved by rest; it is a manifestation of exercise-induced reversible ischemia, similar to angina pectoris.
Severe PAD may cause pain during rest, reflecting irreversible ischemia, or ischemic ulcers on the feet.
A low (≤ 0.90) ankle-brachial index (ratio of ankle to arm systolic blood pressure) indicates PAD.
Percutaneous transluminal angioplasty with or without stent insertion may dilate vascular occlusions; sometimes surgery (endarterectomy or bypass grafting) is necessary.
