Peripheral arterial disease is relatively common, particularly in late middle age. Blockages in the leg arteries can reduce blood flow in the legs enough to cause cramping leg pain that limits walking (termed intermittent claudication). They can become severe and cause critical limb ischaemia, pain at rest, leg ulceration and gangrene that requires amputation. When a patient with critical limb ischaemia is being assessed for vascular surgery or if they are unsuitable or refuse surgery, they are treated conservatively as with bed rest. Drug therapy may be used to relieve symptoms and reduce progression of disease. Vasodilator drugs such as prostaglandins increase local blood flow to the leg but may not improve blockages (stenoses). Naftidrofuryl is also vasoactive and blocks serotonin. It has been used intravenously in severe critical limb ischaemia for rapid effect.
The review authors identified eight controlled trials that randomly allocated a total of 269 participants from five different countries to receive intravenous naftidrofuryl, other treatments, and placebo alone or with another treatment. There was no clear indication that short-term intravenous naftidrofuryl significantly improves either symptoms of ischaemic rest pain or skin necrosis. Treatment with naftidrofuryl tended to reduce pain, measured using a scale or with analgesic consumption, and improve rest pain and skin necrosis but the effects were not clear (statistically significant). The trials were generally of low methodological quality, included small numbers of predominantly elderly participants with varying levels of severity of critical limb ischaemia and used different measures of effect. The duration of treatment was short, from three to 42 days, most often seven days. Other treatments were haemodilution, anti-coagulant medication, prostaglandins, bed rest and reflex heating, and gingko biloba. Side effects included mild blood clotting (thrombophlebitis) at the injection site and in one trial two participants experienced renal insufficiency. Intravenous naftidrofuryl was withdrawn as a treatment for severe peripheral arterial disease in 1995 because of reported side effects.
Based on the results of these trials, it cannot be confirmed that intravenous naftidrofuryl is effective in the treatment of people with critical limb ischaemia. However, these results were based on trials of generally low methodological quality which had only a small number of participants, the duration of treatment was extremely short, and the methods varied between the trials. The wide range of endpoints effectively precluded any meaningful pooling of the results. Intravenous naftidrofuryl was withdrawn as a treatment for severe peripheral arterial disease in 1995 because of reported side effects.
Peripheral arterial disease affects five per cent of men and women by late middle age. Approximately 25% of those affected will develop critical limb ischaemia (rest pain, ulceration and gangrene) within five years. Naftidrofuryl is a vasoactive drug which may be beneficial in the treatment of critical limb ischaemia.
To determine whether naftidrofuryl, when administered intravenously, is effective in alleviating symptoms and reducing progression of disease in patients with critical limb ischaemia.
The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2012) and CENTRAL (2012, Issue 4). We searched the reference lists of articles. We also contacted pharmaceutical companies for any unpublished trials.
All randomised controlled trials of critical limb ischaemia in which participants were randomly allocated to intravenous naftidrofuryl or control (either pharmacological, inert placebo or conservative therapy) were included. People with intermittent claudication were not included.
Sixteen trials were identified, but eight were excluded because of poor methodology. The eight included trials involved a total of 269 participants from five different countries. The following outcomes were reported: pain reduction, rest pain/necrosis, progression of disease in terms of incidence of surgical reconstruction/amputation, mortality and side effects. On extraction of the data, odds ratios and mean differences were estimated where appropriate.
Treatment with naftidrofuryl tended to show reduction of pain evaluated by both analogue score and analgesic consumption, but the effect was statistically non-significant (mean difference (MD): 0.42; 95% confidence interval (CI)1.19 to 0.35). Similarly, improvement in rest pain or skin necrosis occurred, but these effects were also non-significant. The effect on mean ankle systolic pressure was inconclusive.