Peripheral arterial disease
Peripheral arterial disease (PAD) affects approximately 8 to 10 million people in the United States, with an age-adjusted prevalence of 12%, which increases to 20% in persons over 70 years.1 Mortality is increased in both symptomatic and asymptomatic patients with PAD, when compared with those without PAD,2 primarily because of an increased risk of death from cardiovascular disease.
Several studies have found that the diagnosis of PAD confers a threefold to fivefold increased risk of cardiovascular mortality in patients when compared with age-matched controls.3 Even in the absence of a previous myocardial infarction or ischemic stroke, the risk of cardiovascular death for those with PAD is similar to the risk for those known to have coronary artery or cerebrovascular disease.4 Furthermore, patients with known coronary artery disease and PAD who undergo percutaneous coronary intervention with intracoronary stents have lower procedural success and higher in-hospital major cardiovascular complications than patients with coronary artery disease alone.5
Additionally, as the severity of PAD increases, so, too, does the risk of morbidity and mortality. The lower the ankle-brachial index (ABI), the higher the risk of cardiovascular events.6 Those with the lowest ABI values have an annual mortality rate approaching 25%,7 which is higher than that for several malignancies. Tobacco use and diabetes mellitus are the strongest risk factors for PAD, and dyslipidemia, hypertension, and advanced age are also major risk factors.1 Although the prevalence of PAD is high within the primary care setting, physician awareness of their patients' PAD is relatively low.8 This, in turn, leads to missed opportunities for the use of effective secondary preventive measures.
The most common symptom of PAD is intermittent claudication, which is described as a cramping pain in the calf, thigh, or buttocks that occurs with walking or other forms of exercise and remits very quickly with the cessation of activity and rest. Features in the patient history may assist the clinician in distinguishing classic vascular claudication from neurogenic claudication caused by spinal stenosis (table 1). Disease of the aortoiliac arteries may present with Leriche's syndrome, which consists of claudication of the buttocks and thighs, as well as impotence, resulting from impaired flow to the pudendal artery.
Patients with the most extreme manifestation of PAD, critical limb ischemia, present with pain while at rest, tissue loss, or gangrene, and the ischemia can be limb-threatening. Only about one third of all patients with PAD experience claudication, whereas over one half are asymptomatic.6
Physical examination of the lower extremities can provide important clues to the diagnosis of PAD. In a review of published studies,9 abnormal pedal pulses, a unilaterally cool extremity, prolonged venous filling time, and the presence of a femoral bruit were found to be useful in the diagnosis of PAD. However, the capillary refill test, foot discoloration, atrophic skin, and hairless extremities were found to be not helpful.
Screening measures such as the World Health Organization/Rose Questionnaire on intermittent claudication and the self-administered Edinburgh Claudication Questionnaire have been used, but not commonly, because they underestimate the true prevalence of PAD.10
The ankle-brachial index (ABI) is a simple, inexpensive, noninvasive test with a very high degree of sensitivity and specificity. It is helpful for screening asymptomatic patients at risk, diagnosing PAD in patients with suggestive symptoms, and assessing the effects of interventions.
An appropriately sized blood pressure cuff is inflated over the ankle of a patient in the supine position. Then, with the use of a 5- to 10-mHz hand-held Doppler, pressure measurements are obtained in the posterior tibial and dorsalis pedis arteries. The ABI of each lower extremity is determined by dividing the lower- extremity pressure by the higher of the systolic brachial pressure measurements.
A normal ABI value is greater than 1.0. Values less than 0.9 are consistent with claudication in patients with symptoms that are suggestive of PAD. ABI values of 0.81 to 0.9 are consistent with mild obstructive disease, values of 0.51 to 0.8 with moderate obstructive disease, and values less than 0.5 with severe obstructive disease. Those with the most severe obstructive disease (ABI <0.5) may experience pain at rest and may be unable to heal ischemic wounds without intervention.
The sensitivity can be increased if the ABI is repeated after the patient exercises, such as walking on a treadmill at 1.5 to 2.0 miles per hour at a 10% to 15% incline for up to 5 minutes. Contraindications to exercise testing include unstable coronary syndromes, critical leg ischemia, and pain at rest.
Although the ABI is an excellent tool, it fares less well in patients with stiff, noncompressible, calcified vessels, such as the elderly and those with diabetes mellitus. If the ABI is greater than 1.3, this should be suspected and other diagnostic testing should be used. Because the digital arteries of the toes are often spared from medial calcinosis in diabetic patients, a toe-brachial index may be useful.
Segmental leg pressures
Although a low ABI implies obstructed arterial flow in the affected lower extremity, it does not provide more precise anatomic location. When multiple pressure measurements are obtained along the extremity, the site of the arterial obstruction can be more precisely located.
Segmental leg pressures can be obtained by placing appropriately sized pneumatic cuffs on (1) the proximal thigh just below the perineum, (2) the distal thigh, just above the patella, (3) the proximal calf, just below the knee, (4) the lower calf, just superior to the ankle, and (5) the first toe. A significant arterial obstruction can be detected in the vessels between the pneumatic cuffs if there is a decrease in pressure of 20 to 30 mm Hg between adjacent segments.11
Doppler waveform analysis
Similar to segmental leg pressures, the finding of an abnormally dampened arterial waveform between adjacent segments implies arterial obstruction between the areas where the waveforms were obtained. Specific blood vessels can often be identified as being responsible for a patient's symptoms or findings and targeted for intervention.
Color duplex imaging
Color duplex imaging combines pulsed and color imaging with real-time B-mode imaging. Color Doppler provides information regarding the direction of flow and presence of turbulence, whereas B-mode imaging provides anatomic detail of the vessel. Although color duplex imaging is valuable in the evaluation of suspected PAD, it requires a longer time for evaluation, a more skilled technologist, and more expensive equipment when compared with segmental leg pressures or waveform analysis.
Magnetic resonance imaging
Technologic advances in magnetic resonance imaging have improved its diagnostic capability with respect to PAD so much that at some institutions, magnetic resonance angiography has obviated the need for conventional angiography before surgery, thereby eliminating the risks of angiography, such as arterial puncture, embolization of atherosclerotic plaque, and contrast nephropathy.
A meta-analysis found MRA to be highly accurate for diagnosing lower-extremity PAD when compared with conventional angiography or intra-arterial digital subtraction angiography. Three-dimensional gadolinium-enhanced MRA was found to be superior to two-dimensional MRA.12 A summary of commonly used diagnostic testing is listed in table 2.
Use of noninvasive diagnostic testing in management of ulcers
Information beyond the diagnosis of PAD can be obtained by noninvasive evaluation. Although the success or failure of wound healing is affected by a variety of factors (eg, presence of infection, coincident venous disease, patient adherence and nutritional status, aggressiveness of health care provider), prognostic information can be obtained that can direct whether a conservative or invasive approach is necessary for the healing of lower-extremity wounds.
If amputation is required, information provided by the noninvasive assessment can help determine the level of amputation to ensure adequate healing. Isch-emic lesions in patients with an ABI of 0.4 or less are unlikely to heal without revascularization procedures. Furthermore, approximately 80% of distal ischemic lesions will heal if the ankle pressure is at least 80 mm Hg.13,14 In contrast, when the ankle pressure is below 50 to 55 mm Hg, healing rates of only up to 11% can be expected.13,15,16
Measurements of toe pressures can also be helpful in determining the likelihood of healing for patients with ischemic injury of the toes or forefoot and for those in whom minor forefoot amputations are planned. When toe pressures are greater than 30 mm Hg, healing rates of 86% to 90% have been found,13,15,16 whereas toe pressures of 20 to 30 mm Hg are associated with healing rates of 14% to 50%, and pressures less than 20 mm Hg are associated with rates of 0% to 29%.17
Transcutaneous oxygen tension (tcPO2) measurements can be useful in predicting the likelihood that an amputation will heal. Measurements greater than 10 mm Hg have been associated with successful healing in 75% to 94% of patients, whereas lower levels were associated with failure of healing in 51% to 100% of patients.18,19 Other studies, however, have found that higher tcPO2 levels, ranging from 20 to 50 mm Hg, were predictive of the successful healing of ulcers and amputations.20
Therapy for patients with PAD is not only targeted to the affected extremity, but also directed to the atherosclerotic process, since vascular beds throughout the body may be diseased. Both pharmacologic and nonpharmacologic interventions should be used to improve the quality of life, avoid amputations, and decrease the risk of cardiovascular disease and death.
Exercise and medical therapy for claudication
For many patients with claudication, the pain of walking limits their ability to perform their daily activities and may lead to physical deconditioning, dependence on others, or becoming housebound. Although little is known about exercise training for asymptomatic patients with PAD or those with critical leg ischemia, exercise training has been shown to be beneficial in increasing walking distance in patients with claudication.21 The greatest improvements in walking ability have been shown to occur in programs in which each session lasts more than 30 minutes, sessions occur at least three times per week, sessions last 6 months or more, and subjects walked until near-maximal pain was experienced.
Possible mechanisms underlying the benefits of exercise training include improvements in endothelial function, blood viscosity, and skeletal muscle metabolism; reduced inflammation; and perhaps vascular angiogenesis.21 In addition, exercise training exerts favorable effects on blood pressure, lipids, and glycemic control and helps with weight loss.
Pentoxyfylline, a xanthine derivative, has been shown to increase walking distance in patients with PAD, although its mechanism of action is poorly understood, its long-term efficacy is not known, and its effects are often not dramatic.22 A newer agent, cilostazol, has been shown to be superior to pentoxyfylline in improving maximal walking distance,23 but it is more expensive. Cilostazol, a phosphodiesterase III inhibitor, although generally well tolerated, is contraindicated in patients with congestive heart failure, because a chemically related agent has been shown to increase mortality in these patients.
Aspirin, in doses of 81 to 325 mg daily, can be used not only to modify the natural history of chronic lower extremity arterial obstruction, but to decrease the incidence of associated cardiovascular events.
Another antiplatelet agent, clopidogrel, has been shown to be superior to aspirin in reducing the composite end point of ischemic stroke, myocardial infarction, or vascular death in a large cohort of subjects with symptom-atic PAD, recent ischemic stroke, or recent myocardial infarction.24 In a subgroup analysis, the largest benefit was realized in the symptomatic PAD subgroup. However, in this large multicenter study, though the benefit of clopidogrel over aspirin was statistically significant, the absolute benefit was small. At this time it is not clear whether the combination of clopidogrel and aspirin is superior to clopidogrel alone in decreasing cardiovascular end points. A recent study25 found that the combination of clopidogrel and aspirin was not more effective in reducing cardiovascular events in asymptomatic patients at risk for cardiovascular disease than aspirin alone. However, there was a suggestion of benefit in symptomatic patients.
Risk factor modification
Risk factor modification plays an essential role in the care of patients with PAD, and clinicians need to identify and treat atherosclerotic risk factors. Ample evidence supports the benefits of smoking cessation, which should be emphasized for all smokers, with or without PAD. Nicotine replacement therapy or the antidepressant bupropion, combined with behavioral modification, should be strongly encouraged.
Dyslipidemia is a major risk factor for vascular disease and should be treated aggressively. In patients with claudication, lipid lowering has been shown to reduce disease progression and claudication. Furthermore, in the Heart Protection Study,26 subjects with PAD and no known CAD who were treated with simvastatin had about a 25% reduction in cardiovascular events when compared with subjects taking placebo, a reduction similar to those with known cardiovascular disease. Whereas the goal for low-density lipoprotein cholesterol in patients with PAD has been less than 100 mg/dL, it was suggested recently that this be reduced to less than 70 mg/dL in those felt to be at very high risk.27
Diabetes mellitus and hypertension are risk factors for vascular disease. Although tight control of diabetes has not conclusively been shown to be beneficial in PAD outcomes, it should be attempted, when possible, on account of its known beneficial effects on microvascular complications. Similarly, although hypertension is associated with cardiovascular disease, it is not known whether the treatment of hypertension alters the progression of established disease. However, in the Heart Outcomes Prevention Evaluation study, the angiotensin-converting enzyme inhibitor ramipril was shown to prevent cardiovascular events in patients with clinical as well as subclinical PAD.28
Referral for more aggressive intervention
Patients with pain at rest, nonhealing lower-extremity ulcers associated with a low ABI, or severe, debilitating claudication should be referred to a vascular surgeon or interventional radiologists for consideration of more aggressive intervention.
Peripheral arterial disease is a common disorder, which in addition to its propensity to adversely affect a patient's quality of life, is associated with cardiovascular disease and death. Clinicians need a heightened awareness of the presence of both asymptom-atic and symptomatic disease and should screen patients at risk with the ankle-brachial index, a simple yet highly sensitive and specific test. Pentoxyfylline or cilostazol should be considered for patients with claudication in order to improve their maximal walking distance. Whenever possible, all patients with PAD should be treated with exercise therapy, antiplatelet therapy, and aggressive risk factor modification targeting smoking, dyslipidemia, diabetes mellitus, and hypertension.
- Criqui MH . Peripheral arterial disease—epidemiologic aspects Vasc Med 2001; 6( 3 Suppl): 3-7
- Rockson SG , Cooke JP . Peripheral arterial insufficiency: mechanisms, natural history, and therapeutic options Adv Intern Med 1998; 43: 253-77
- Mukherjee D, Lingam P, Chetcuti S, et al. Missed opportunities to treat atherosclerosis in patients undergoing peripheral vascular interventions: insights from the University of Michigan Peripheral Vascular Disease Quality Improvement Initiative (PVD-QI2) Circulation 2002; 106( 15): 1909-12
- Newman AB, Shemanski L, Manolio TA, et al. Ankle-arm index as a predictor of cardiovascular disease and mortality in the Cardiovascular Health Study. The Cardiovascular Health Study Group Arterioscler Thromb Vasc Biol 1999; 19( 3): 538-45
- Singh M, Lennon RJ, Darbar D, et al. Effect of peripheral arterial disease in patients undergoing percutaneous coronary intervention with intracoronary stents Mayo Clin Proc 2004; 79( 9): 1113-8
- Hiatt WR . Medical treatment of peripheral arterial disease and claudication N Engl J Med 2001; 344( 21): 1608-21
- Dormandy J, Heeck L , Vig S. The fate of patients with critical leg ischemia Semin Vasc Surg 1999; 12( 2): 142-7
- Hirsch AT, Criqui MH, Treat-JacobsonD, et al. Peripheral arterial disease detection, awareness, and treatment in primary care JAMA 2001; 286( 11): 1317-24
- McGee SR, Boyko EJ . Physical examination and chronic lower-extremity ischemia: a critical review Arch Intern Med 1998; 158( 12): 1357-64
- Dormandy JA, Rutherford RB . Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Consensus (TASC) J Vasc Surg 2000; 31( 1 Pt 2): S5-S14, S93-Sl01
- Barnes RW . Noninvasive diagnostic assessment of peripheral vascular disease Circulation 1991; 83( Suppl 2): I20-7
- Koelamay MJ, Lijmer JG, Stoker J, et al. Magnetic resonance angiography for the evaluation of lower extremity arterial disease: a meta-analysis JAMA 2001; 285( 10): 1338-45
- Rose SC . Noninvasive vascular laboratory for evaluation of peripheral arterial occlusive disease: part II—clinical applications: chronic usually atherosclerotic lower extremity ischemia J Vasc Interv Radio1 2000; 11( 10): 1257-75
- Nicholas GG, Myers JL, DeMuthWE Jr . The role of vascular laboratory criteria in the selection of patients for lower extremity amputation Ann Surg 1982; 195( 4): 469-73
- Carter SA . The relationship of distal systolic pressures to healing of skin lesions in limbs with arterial occlusive disease, with special reference to diabetes mellitus Scan J Clin Lab Invest 1973; 128( Suppl): 239-43
- Baker WH, Barnes RW . Minor forefoot amputation in patients with low ankle pressure Am J Surg 1977; 133( 3): 331-2
- Holstein P, Noer I, Tonnesen KH, et al. Distal blood pressure in severe arterial insufficiency: strain-gauge, radioisotopes, and other methodsIn: BerganJJ, YaoST, eds. Gangrene and severe ischemia of the lower extremities New York: Grunes & Stratton 1978: 95-114
- Harward TR, Volny J, Golbranson F, et al. Oxygen inhalation-induced transcutaneous P02 changes as a predictor of amputation level J Vasc Surg 1985; 2( 1): 220-7
- Karanfilian RG, Lynch TG, Zirul VT, et al. The value of laser Doppler velocimetry and transcutaneous oxygen tension determination in predicting healing of ischemic forefoot ulcerations and amputations in diabetic and nondiabetic patients J Vasc Surg 1986; 4( 5): 511-6
- Ballard JL, Eke CC, Bunt TJ, et al. A prospective evaluation of transcutaneous oxygen measurements in the management of diabetic foot problems J Vasc Surg 1995; 22( 4): 485-92
- Stewart KJ, Hiatt WR, Regensteiner JG, et al. Exercise training for claudication N Engl J Med 2002; 347( 24): 1941-51
- Gillings D, Koch G, Reich T, et al. Another look at pentoxyfylline efficacy data for intermittent claudication J Clin Pharmacol 1987; 27: 601-609
- Dawson DL, Cutler BS, Hiatt WR, et al. A comparison of cilostazol and pentoxifylline for treating intermittent claudication Am J Med 2000; 109: 523-30
- A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee Lancet 1996; 348( 9038): 1329-39
- Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events N Engl J Med 2006; 354: 1706-17
- Heart Protection Study Collaborative Group . MRC/BHF Heart Protection Study of cholesterol lowering with simvastain in 20,536 high-risk individuals: a randomized placebo-controlled trial Lancet 2002; 360( 9326): 7-22
- Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines Circulation 2004; 110( 2): 227-39
- OstergrenJ, Sleight P, Dagenais G, et al. Impact of ramipril in patients with evidence of clinical or subclinical peripheral arterial disease Eur Heart J 2004; 25( 1): 17-24