Intravenous naftidrofuryl for critical limb ischaemia

Peripheral arterial disease affects 5% of men and women by late middle age. In approximately 25% of those affected the condition will progress to critical limb ischaemia (rest pain, ulceration and gangrene) within five years. The vasoactive drug naftidrofuryl is a serotononergic receptor antagonist which may be beneficial in the treatment of severe lower limb disease such as critical limb ischaemia.

To determine whether the vasoactive drug, naftidrofuryl, when administered intravenously is effective in alleviating symptoms and reducing progression of disease in patients with critical limb ischaemia.

Randomised controlled trials were identified using the search strategy of the Peripheral Vascular Diseases Review group, including MEDLINE and EMBASE searches and reviewing reference lists in papers. In addition, publications were identified through pharmaceutical companies.

All randomised controlled trials of critical limb ischaemia in which patients were randomly allocated to intravenous naftidrofuryl or control (either pharmacological, inert placebo or conservative therapy) were included. Patients with intermittent claudication were not eligible for inclusion. Trials were selected by one reviewer and checked independently.

Fifteen trials were identified, but eight were excluded because of poor methodology. The seven remaining trials involved a total of 229 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 weighted 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 (weighted mean difference -0.42, 95% confidence interval -1.19 to 0.35). Similarly, improvement in rest pain or skin necrosis occurred, but these effects were also not significant. The effect on mean ankle systolic ankle pressure was inconclusive.

Based on the results of these trials, it cannot be confirmed that intravenous naftidrofuryl is effective in the treatment of patients 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 peripheral arterial disease in 1995 because of reported side effects.