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In people with leg pain while walking, clopidogrel reduces cardiovascular outcomes more than aspirin, and exercise increases walking distance

Jones WS, Schmit KM, Vemulapalli S, et al. Treatment Strategies for Patients With Peripheral Artery Disease AHRQ Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality (US); 2013 May. Report No. 13-EHC090-EF.

Review question

Which treatments are effective for peripheral artery disease with or without intermittent claudication or critical limb ischemia?


Peripheral artery disease is narrowing of the arteries outside the heart. It reduces blood flow, for example, to the legs. It is caused by “hardening of the arteries” (or atherosclerosis), which is a build-up of plaque in the arteries. Some people with peripheral artery disease have no symptoms. Others have pain or cramping in the buttock, thigh or lower leg during exercise (called intermittent claudication). If it becomes more severe, it causes open sores, gangrene, and severe pain even when resting (called critical limb ischemia). Peripheral artery disease may reduce functioning (including the ability to walk) and quality of life. It also increases the risk of myocardial infarction (heart attack), stroke, death, and need for amputation.

How the review was done

The researchers did a systematic review, based on studies available up to August 2012.

They found 83 studies, including 40 randomized controlled trials.

All people had PAD. Some had no symptoms, and others had intermittent claudication or critical limb ischemia.

A variety of treatments were studied. These included medications, such as aspirin, clopidogrel (Plavix®), cilostazol (Pletal®), and pentoxifylline (Pentoxil® or Trental®), exercise therapy, and endovascular intervention and surgical revascularization, which restore blood flow through or around a blocked artery.

What the researchers found

Evidence for many outcomes had low- or insufficient-strength evidence. Only findings based on moderate- or high-strength evidence are reported here.

People with no symptoms

Compared with placebo, aspirin did not reduce deaths, deaths due to cardiovascular causes, nonfatal heart attacks, nonfatal strokes, or vascular events.

People with or without symptoms

Compared with aspirin, clopidogrel plus aspirin did not reduce deaths or cardiovascular events.

People with intermittent claudication

Compared with aspirin, clopidogrel reduced cardiovascular deaths, nonfatal heart attacks, and cardiovascular events.

Compared with usual care, exercise training (e.g., regular walking) increased walking ability by a large amount.

Compared with exercise, endovascular treatment, did not improve walking ability.


In people who have peripheral artery disease with intermittent claudication, clopidogrel reduces cardiovascular deaths, nonfatal heart attacks, and cardiovascular events more than aspirin. Exercise training improves walking ability more than usual care.

Treatments for peripheral artery disease*


Treatment and comparison

Number of studies (people)


People with no symptoms

Aspirin vs placebo

2 studies (3986 people)

No reduction in deaths, deaths due to cardiovascular causes, nonfatal heart attacks, nonfatal strokes, or vascular events

People with or without symptoms

Dual therapy (clopidogrel + aspirin) vs aspirin

1 study (3096 people)

No difference in deaths or cardiovascular events

People with intermittent claudication

Clopidogrel vs aspirin

1 study (6452 people)

Reduced cardiovascular deaths, nonfatal heart attacks, and cardiovascular events


Exercise training vs usual care

9 studies (624 people)

Large improvement in walking ability


Endovascular treatment vs exercise

8 studies (695 people)

No difference in walking ability

*Includes only findings based on high or moderate strength evidence.


A harmless, inactive, and simulated treatment.
Randomized controlled trials
Studies where people are assigned to one of the treatments purely by chance.
Systematic review
A comprehensive evaluation of the available research evidence on a particular topic.
The body's network of blood vessels. It includes the arteries, veins, and capillaries that carry blood to and from the heart.
Vascular death
Death from circulatory problems.

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