What are the effects of treatments for persons with chronic peripheral arterial disease?

BENEFICIAL

Antiplatelet Agents

Systematic reviews showed that antiplatelet agents (i.e., aspirin, clopidogrel, aspirin plus dipyridamole, aspirin plus glycoprotein IIb/IIIa antagonist, or ticlopidine) reduced major cardiovascular events over an average of about two years compared with control treatment. Systematic reviews also showed that aspirin and ticlopidine reduced the risk from arterial occlusion and revascularization procedures compared with placebo or no treatment. The balance of benefits and harms is in favor of treatment for most persons with symptomatic peripheral arterial disease because, as a group, they are at a higher risk of cardiovascular events.

Exercise

Systematic reviews and subsequent randomized controlled trials (RCTs) including persons with chronic stable claudication showed that regular exercise at least three times weekly for three to six months improved total walking distance and maximal exercise time after three to 12 months compared with no exercise. One RCT showed that vitamin E plus regular exercise increased walking duration at six months compared with placebo. One RCT showed that a “stop smoking and keep walking” intervention increased maximal walking distance at 12 months compared with usual care.

LIKELY TO BE BENEFICIAL

3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors (Statins)

Three RCTs including persons with peripheral arterial disease showed that statins (i.e., simvastatin, atorvastatin, and pravastatin) reduced cardiovascular events including nonfatal myocardial infarction, coronary death, total coronary events, and fatal and nonfatal stroke compared with placebo. One RCT showed that simvastatin increased the time to onset of claudication at 12 months compared with placebo. One RCT showed that simvastatin increased pain-free walking distance and total walking distance at six months compared with placebo. One RCT showed that atorvastatin increased pain-free walking time at 12 months compared with placebo.

Percutaneous Transluminal Angioplasty (Transient Benefit Only)

Two small RCTs, identified by a systematic review, including persons with mild to moderate intermittent claudication showed limited evidence that percutaneous transluminal angioplasty improved walking distance after six months compared with no angioplasty but showed no significant difference after two or six years. Two small RCTs, identified by a systematic review, and four additional RCTs including persons with stenosis between the femoral and popliteal arteries or between the aorta and iliac arteries showed no significant difference between angioplasty alone and angioplasty plus stent placement in patency rates, occlusion rates, or clinical improvement. The RCTs may have lacked power to detect a clinically important effect. One RCT showed no significant difference between percutaneous transluminal angioplasty plus lovastatin and percutaneous transluminal angioplasty alone in restenosis rates at 12 months. One systematic review showed that, in persons with chronic progressive peripheral arterial disease, percutaneous transluminal angioplasty was less effective than surgery in improving patency after 12 to 24 months but showed no significant difference after four years. The review showed no difference in mortality after 12 to 24 months.

Smoking Cessation

RCTs of advice to stop smoking would be considered unethical. The consensus view is that smoking cessation improves symptoms in persons with intermittent claudication. One systematic review of observational studies showed inconclusive results comparing smoking cessation and smoking continuation in terms of increasing absolute claudication distance and reducing the risk of symptom progression.

TRADE-OFF BETWEEN BENEFITS AND HARMS

Cilostazol

Six RCTs showed that cilostazol improved claudication distance at 12 to 24 weeks compared with placebo. However, adverse effects (e.g., headache, diarrhea, palpitations) were common. One RCT showed limited evidence that cilostazol increased initial and absolute claudication distance compared with pentoxifylline.

UNKNOWN EFFECTIVENESS

Bypass Surgery (Compared with Percutaneous Transluminal Angioplasty)

One systematic review showed that bypass surgery in persons with chronic progressive peripheral arterial disease improved primary patency after 12 to 24 months compared with percutaneous transluminal angioplasty, but it showed no significant difference after four years. The review showed no significant difference in mortality after 12 to 24 months. Although the consensus view is that bypass surgery is the most effective treatment for persons with debilitating symptomatic peripheral arterial disease, we found inadequate RCTs reporting long-term clinical outcomes to confirm this view.

Pentoxifylline

One systematic review and one subsequent RCT showed insufficient evidence to compare pentoxifylline with placebo. One RCT showed limited evidence that pentoxifylline was less effective at improving initial and absolute claudication distance after 24 weeks than cilostazol.

Definition

Peripheral arterial disease develops when there is significant narrowing of arteries distal to the arch of the aorta. This narrowing can be caused by atheroma, arteritis, local thrombus formation, or embolization from the heart or from more central arteries. This chapter includes treatment options for persons with symptoms of reduced blood flow to the leg that are likely caused by atheroma. These symptoms range from calf pain during exercise (intermittent claudication) to pain at rest, skin ulceration, or symptoms of ischemic necrosis (gangrene) in persons with critical limb ischemia.

Incidence

Peripheral arterial disease is more common in persons older than 50 years than in younger persons and is more common in men than in women. The prevalence of peripheral arterial disease of the legs (assessed by noninvasive tests) is about 13.9 to 16.9 percent in men and 11.4 to 20.5 percent in women older than 55 years.^1,2 The overall annual incidence of intermittent claudication is 4.1 to 12.9 per 1,000 men and 3.3 to 8.2 per 1,000 women.³

Etiology

Factors associated with peripheral arterial disease include age, sex, cigarette smoking, diabetes, hypertension, hyperlipidemia, obesity, and physical inactivity. The strongest associations are with smoking (relative risk [RR], 2.0 to 4.0) and diabetes (RR, 2.0 to 3.0).⁴ Acute limb ischemia may be caused by thrombosis within a peripheral artery or by embolic occlusion.

Prognosis

Symptoms of intermittent claudication can resolve spontaneously, remain stable over many years, or progress rapidly to critical limb ischemia. About 15 percent of persons with intermittent claudication eventually develop critical limb ischemia, which endangers the viability of the limb. The annual incidence of critical limb ischemia in Denmark and Italy in 1990 was 0.25 to 0.45 per 1,000 persons.^5,6 Coronary heart disease is the major cause of death in persons with peripheral arterial disease of the legs. Over five years, about 20 percent of persons with intermittent claudication have a nonfatal cardiovascular event (i.e., myocardial infarction or stroke).⁷ The mortality rate of persons with peripheral arterial disease is two to three times higher than that of age- and sex-matched control patients. Overall mortality is 30 percent five years after a peripheral arterial disease diagnosis and 70 percent 15 years after diagnosis.⁷