An evaluation of patients with severe intermittent claudication and the effect of treatment with naftidrofuryl. [Naftidrofuryl in arterial occlusive disease. Controlled multicenter double-blind study with oral administration]. [Effect of naftidrofuryl on physiological walking distance in patients with intermittent claudication]. Effects of regular physical training in a supervised class and additional intravenous prostaglandin E1 and naftidrofuryl infusion therapy in patients with intermittent claudication--a controlled study. Treatment of stage II chronic arterial disease of the lower limbs with the serotonergic antagonist naftidrofuryl: results after 6 months of a controlled, multicenter study.
A randomized placebo-controlled study was undertaken in 188 patients with severe intermittent claudication attending two vascular clinics in Manchester and Liverpool. After a 4-week run-in period, patients received active or placebo treatment for 24 weeks. Patients were assessed on a treadmill prior to the 4-week run-in period, at randomization, and at 8, 16, and 24 weeks. Outcome was measured in terms of change in pain-free walking distance, maximum walking distance, and pressure indices. In this severe claudication population, in which the patients presented with a mean pain-free walking distance of 60 m, an intention-to-treat analysis demonstrated that the outcome in the naftidrofuryl-treated group was significantly better than in the group receiving placebo (p = 0.045). Additionally, 7% of patients in the naftidrofuryl group deteriorated compared with 22% in the placebo group (p = 0.005). Of the various risk factors that were recorded during the study--smoking habits, the presence of hypertension, diabetes, obesity, and duration of illness--only duration of illness had a significant influence on outcome. Maximum walking distances alone were not significantly influenced by treatment, but the use of a combined index of pain-free walking distance, maximum walking distance, and pressure indices to record success or failure confirmed a significant treatment effect (p = 0.047). A higher incidence of minor gastrointestinal symptoms was recorded in the naftidrofuryl-treated group. Treatment with naftidrofuryl was shown to prevent or slow the deterioration observed in a group of patients with severe claudication over a 24-week period. The efficacy of naftidrofuryl ( Dusodril ) for treatment of stage II arterial occlusive disease was evaluated in a controlled multi-centre study in a total of 104 out-patients with angiographically documented localization of occlusion. The therapeutic effect was assessed over three months by measurements of walking distance using standardized treadmill conditions. Further parameters were venoocclusive plethysmography and Doppler ultrasonography measurement of pressures. The complaint-free walking distance increased significantly during daily application of 600 mg naftidrofuryl orally (n = 54) during the 12-week assessment period when compared to the placebo group (n = 50). Taking the intraindividual variability of 17.2 m in assessment of walking distance into account, the increase of painless walking of 93 m after treatment for 12 weeks in the active-drug group is considered the result of treatment-induced increased performance. To evaluate the physiological walking distance measured with the Peripheral Arterial Disease Holter Control device (PADHOC) after 12 months of treatment with naftidrofuryl in a double blind placebo controlled, parallel group study, in patients presenting with intermittent claudication.
                The outpatients selected were of both sexes, aged 40 to 80, with a chronic, stable intermittent claudication and an ankle brachial index between 0.60 and 0.90. They received naftidrofuryl 200 mg tid or placebo for 12 months. Outcome measures included physiological painfree and maximal walking distances using the PADHOC device. The principle of this device is the measurement of the intermalleolar distances using ultrasound telemetry. The PADHOC measures the walking distance and the speed profile in an ambulatory subject.
                182 patients were randomised and 168 entered the intention to treat analysis. The two groups were well matched for demographic variables, risk factors and history of vascular disease. After 12-month treatment, patients who received naftidrofuryl had a 107% improvement of geometric physiological pain-free walking distance versus 12% in the placebo group (P < 0.001) and 74% improvement of geometric maximal physiological walking distance versus 1% in the placebo group (P < 0.001).
                This study demonstrates the efficacy of naftidrofuryl versus placebo in patients with intermittent claudication using a new device measuring the walking distances of the patients in a more physiological way than the treadmill test. The aim of this study was to investigate if PGE1 i.v.-therapy after active physical training further increases the walking distance in PAOD stage IIb according to Fontaine. 48 outpatients with intermittent claudication underwent a standardized active walking training of about 6 months twice weekly. Afterwards patients were randomly given once daily an i.v. infusion of 60 micrograms PGE1 (3 ampoules prostavasin) or 600 mg naftidrofuryl. The therapy lasted for 3 weeks with the exception of Saturdays and Sundays. Besides laboratory and doppler parameters, painfree and maximum walking distance (treadmill, 10% incline, 3.5 km/h) were determined. Results: Under active physical training the patients' walking distance increased significantly to more than double the baseline levels. Further significant increase of the painfree walking distance was seen after a 3 week treatment with PGE1 from 136 to 270 m (99%) as well as with naftidrofuryl from 117 to 230 m (97%). While this difference was not significant there was a significant difference in favour to PGE1 after the follow-up period (p less than 0.01). In the PGE1-group the painfree walking distance showed a further increase (from 270m to 306m) whereas it decreased in the naftidrofuryl-group (from 230m to 210m). At the same time under PGE1 the ankle/arm index increased significantly in comparison to naftidrofuryl (p less than 0.01). Side effects differed significantly in respect of the frequency and severity. In the PGE1-group in 20.8% of the patients side effects occurred, whereas in 91.6% of the patients in the naftidrofuryl-group side effects were observed. In no case therapy had to be discontinued because of side effects. A study was carried out in patients with intermittent claudication (Fontaine's stage II). The atheromatous origin of the disease was confirmed and localized by angiography or Doppler. One hundred eight-three patients were selected initially (day -30) with a pain-free walking distance on a treadmill (at a speed of 3 km/h and a slope of 10%) ranging from 150 to 300 m. During the first month (washout period) all patients received two placebo tablets daily. At the end of this run-in period (day -30; day 0) and after checking walking distance stability (allowed variation: 20% between the two measurements), patients were included in the study. According to this criterion, 112 patients were selected and 94 remained during the whole study. The study was designed in double-blind, using two parallel, randomly selected groups. Fifty-two patients received naftidrofuryl (2 x 316.5 mg tablets daily with meals) for 6 months; 42 patients received placebo under the same conditions. During this period, clinical and paraclinical examinations were carried out every quarter (day 90 and day 180). After checking the initial homogeneity of the naftidrofuryl and placebo groups, the comparison between the two groups indicates a significant improvement in the naftidrofuryl group after 3 months and 6 months of treatment, for the pain-free walking distance. For the maximal walking distance, a significant improvement was found at day 180. Nonparametric analysis (chi 2 test) also indicated a significant improvement for the naftidrofuryl group. These results confirm that naftidrofuryl is beneficial in the treatment of patients with chronic arterial disease.
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.