Naftidrofuryl for intermittent claudication

Patients with narrowed arteries of the lower limbs may be hampered by pain in their calves after relatively short walks. This limits the distance they can walk, and hence their quality of life. This is a sure sign of atherosclerosis. These patients are at greater risk of cardiovascular death and should take preventive measures. The symptoms of the disease can be alleviated by smoking cessation and exercise. The question is whether specific drugs such as naftidrofuryl also reduce symptoms, more than placebo. To answer the question, we collected all published reports of randomized trials where the drug was compared with placebo. In addition, we went back to the original data of individual patients and made one big database with all data from all patients from all trials. We included seven studies with a total of 1266 patients. The improvement of pain-free walking distance was 37% larger in the naftidrofuryl group than the improvement observed in the placebo group. In the naftidrofuryl group 55% of the patients improved by more than 50%, compared with 30% of patients on placebo. Naftidrofuryl 200 mg (taken three times a day by mouth) improved walking distance in the six months after the start of therapy.

Authors' conclusions: 

Oral naftidrofuryl has a statistically significant and clinically meaningful, although moderate, effect of improving walking distance in the six months after initiation of therapy for people with intermittent claudication. Access by researchers to data from RCTs that are suitable for IPD analysis should be possible through repositories of data from pharmacological trials. Regular formal appraisal of the balance of risk and benefit is needed for older pharmaceutical products.

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Background: 

Lifestyle changes and cardiovascular prevention measures are a primary treatment for intermittent claudication (IC). Symptomatic treatment with vasoactive agents (Anatomic Therapeutic Chemical Classification (ATC) for medicines from the World Health Organisation class CO4A) is controversial.

Objectives: 

To evaluate evidence on the efficacy and safety of oral naftidrofuryl (ATC CO4 21) versus placebo on the pain-free walking distance (PFWD) of people with IC by using a meta-analysis based on individual patient data (IPD).

Search strategy: 

For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched October 2012) and CENTRAL (2012, Issue 9).

For the original review the authors handsearched the European Journal of Vascular and Endovascular Surgery (1984 to 1994) and checked relevant bibliographies. They contacted the registration holder of naftidrofuryl and the authors of identified trials for any unpublished data.

Selection criteria: 

We included only randomized controlled trials (RCTs) with low or moderate risk of bias for which the IPD were available.

Data collection and analysis: 

We collected data from the electronic data file or from the case report form and checked the data by a statistical quality control procedure. All randomized patients were analyzed following the intention-to-treat (ITT) principle. The geometric mean of the relative improvement in PFWD was calculated for both treatment groups in all identified studies.

The effect of the drug was assessed compared with placebo on final walking distance (WDf) using multilevel and random-effect models and adjusting for baseline walking distance (WD0). For the responder analysis, therapeutic success was defined as an improvement of walking distance of at least 50%.

Main results: 

We included seven studies in the IPD (n = 1266 patients). One of these studies (n = 183) was only used in the sensitivity analysis so that the main analysis included 1083 patients. The ratio of the relative improvement in PFWD (naftidrofuryl compared with placebo) was 1.37 (95% confidence interval (CI) 1.27 to 1.49, P < 0.001). The absolute difference in responder rate, or proportion successfully treated, was 22.3% (95% CI 17.1% to 27.6%). The calculated number needed to treat was 4.5 (95% CI 3.6 to 5.8).

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