Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease

Peripheral arterial disease, also known as peripheral vascular disease, is a condition in which arteries that carry blood to the legs or arms are narrowed or blocked. The main cause of peripheral arterial disease is atherosclerosis. The major risk factors for peripheral arterial disease are smoking, diabetes mellitus and pre-existing cardiovascular disease. Other factors include increasing age, male sex, ethnicity, hypertension, hypercholesterolaemia, renal insufficiency and a sedentary lifestyle

The Fontaine scheme classifies 4 stages of peripheral arterial disease. Peripheral arterial disease can be asymptomatic (Fontaine stage 1) or symptomatic (Fontaine stages 2 to 4). The most common symptom of peripheral arterial disease is intermittent claudication (Fontaine stage 2), which is characterised by pain in the legs or buttocks that occurs with exercise and is relieved with rest. Two further stages exist: pain in the extremities at rest (ischaemic rest pain, Fontaine stage 3) and necrosis and gangrene (Fontaine stage 4).

The pain associated with intermittent claudication occurs because of a lack of oxygen in the leg muscles owing to the impaired blood supply. Rest normalises blood flow and relieves the pain. Intermittent claudication is most commonly associated with disease in the femoropopliteal segment of the arterial circulation. Peripheral arterial disease can also be present at the aorto–iliac level causing pain in the thigh, hip or buttock. Peripheral arterial disease can also cause foot pain. Around 20% of people aged 55 to 75 years have evidence of peripheral arterial disease in the legs and a quarter of these have symptoms.

Intermittent claudication worsens people's quality of life because it restricts their mobility. People with peripheral arterial disease, and specifically with intermittent claudication, are at increased risk of myocardial infarction and stroke. Additionally, people with intermittent claudication are at higher risk from cardiovascular mortality than people with asymptomatic peripheral arterial disease.

The diagnosis of intermittent claudication includes a clinical history that assesses the presence and character of the pain. A clinician may also measure a patient's ankle-brachial pressure index, that is, the ratio of the blood pressure in the lower leg to the blood pressure in the arm at rest. A value of 0.9 indicates disease, and high values (that is, greater than 1.3) may reflect arterial stiffening associated with disease.

Evaluating the presence and progression of disease takes into account symptoms and signs (for example, the development of ischaemic ulcers). As an objective measure, walking on a treadmill, either at a fixed speed and slope, or a fixed speed and increasing slope, determines how far a patient can walk before developing claudication pain and how far a patient can walk with pain before having to stop.

A number of interventions are used to manage intermittent claudication. Stopping smoking and increasing exercise can help reduce symptoms of claudication. People are more likely to benefit from supervised exercise programmes than from unsupervised exercise. Vasoactive drugs including cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate have marketing authorisations for the symptomatic relief of intermittent claudication and are considered in this appraisal. Angioplasty (that is, mechanical widening of the blood vessel) or other revascularisation (for example, arterial bypass) may be undertaken for people whose symptoms continue despite treatment. To reduce the risk of a heart attack or stroke, interventions include helping patients stop smoking, lowering cholesterol, controlling blood pressure, offering aspirin, and, in people with diabetes, controlling glycaemia.