A specialist in internal medicine recommended naftidrofuryl (DUSODRIL, generics) for one of my patients for peripheral arterial occlusive disease (PAOD). In doing so, he referred to the guideline of the German Society of Angiology (1)... There the active substance is actually recommended for symptomatic PAOD. Based on my previous knowledge, the benefit was rather insignificant. Your evaluation in arznei-telegramm comes from 2000 (a-t 2000; 31: 87), the studies quoted in the guideline are from 2001. What should we think of the recommendation in the guideline?

Dr. med. J. SEFFRIN (General Practitioner)
D-64331 Weiterstadt
Conflict of interest: none

1 Deutsche Gesellschaft für Angiologie - Gesellschaft für Gefäßmedizin (German Society of Angiology - Society of Vascular Medicine): Diagnostik und Therapie der peripheren arteriellen Verschlusskrankheit (pAVK) (Diagnosis and treatment of peripheral arterial occlusive disease [PAOD]). S3 guideline, as at April 2009; to be found at: http://leitlinien.net

The vasodilator naftidrofuryl (DUSODRIL, generics) available since the 1960s is licensed for peripheral arterial occlusive disease (PAOD) Fontaine stage II (intermittent claudication) if other measures such as walking training cannot be implemented (1). Owing to the possible risk of a steal effect, there have long been reservations about the use of vasodilators in patients with PAOD, the prognosis of which is largely determined by coronary and cerebrovascular complications (2). Intravenous naftidrofuryl had to be withdrawn from the market because of fatal cardiovascular complications (see a-t 1995; No. 1: 8).

The PAOD guideline of the German Society of Angiology recommends the vasodilator for a walking distance of less than 200 metres (Fontaine stage IIb) and severely impaired quality of life (3). With regard to benefit, it is based on a Cochrane Review on naftidrofuryl, according to which the pain-free walking distance is lengthened by 37% compared with placebo, given a mean baseline of 140 metres (4). This effect, which in our opinion is hardly clinically relevant, is based on a meta-analytical evaluation of individual patient data from six randomised studies, which were made available by the manufacturer Lipha-Merck. None of the studies evaluated includes only patients who cannot undergo walking training, as required by the European Medicines Agency (5). The concomitant treatment in the predominantly very old studies is unlikely to conform to current standards which provide for platelet aggregation inhibitors and statins. Details of this aspect are given in only two studies: in one of two more recent studies, administration of platelet aggregation inhibitors was required (6), in one out of four older studies they were expressly not allowed (7). The methodology of these four older studies is extremely flawed, without reliable information about randomisation and without an intention-to-treat analysis. According to the Cochrane Review, in a few of these studies patients were even excluded from the evaluation retrospectively because of criteria defined later (4).

The patient data made available by Lipha-Merck were said to encompass the intention-to-treat population of all six studies - a total of 1,083 patients. However, the review does not give a transparent, reproducible account of the study procedures, especially on the question of how many patients were actually randomised, how many were excluded, when and for what reasons they were excluded or how many were lost to follow-up. This provides a highly contradictory picture that does not enable the reader to make head or tail of the sequence of events. This lack of transparency, together with the fact that the Cochrane analysis is based solely on information from the naftidrofuryl manufacturer and that the pool of data largely comes from the era before the introduction of Good Clinical Practice, greatly reduces trust in the review.

One of the two more recent studies with 182 patients uses a non-standardised method for measuring the pain-free walking distance, which is reportedly lengthened by 95% by naftidrofuryl versus placebo from an initial mean distance of just under 400 metres. It is the longest of the six studies with a 12-month treatment period. In this study, severe adverse effects are almost twice as common with naftidrofuryl as with placebo (21% vs. 12%) (6). It is only apparent from the Cochrane Review that these effects represent cardiovascular events (4). The second of the more recent, placebo-controlled trials (8) is a single-centre study involving 181 patients. In six months naftidrofuryl, compared with placebo, lengthens the pain-free walking distance by 75% from an initial average of 190 metres. There is no information about blinding of the randomisation or about concomitant treatment, particularly concurrent walking training. 22% of the study participants dropped out prematurely. A follow-up observation of these patients with regard to cardiovascular events does not appear to have taken place. Once again severe adverse effects, which are equally common in both groups (12% vs. 13%), can only be classified as cardiovascular events with the aid of the Cochrane Review.

In view of the outlined deficiencies, we do not regard any benefit as sufficiently proven, even in the two more recent studies. The studies available to date are too small overall and too flawed to allow damage caused by oral naftidrofuryl in PAOD patients to be excluded.

  The pool of data on the vasodilator naftidrofuryl (DUSODRIL, generics) in the symptomatic treatment of intermittent claudication comprises mainly old, small-scale, short-term studies. In view of the appreciable deficiencies, even in two more recent studies, we regard a benefit of naftidrofuryl in peripheral arterial occlusive disease (PAOD) as not sufficiently proven.

  The size and the quality of the existing data pool also do not permit an adequate assessment of the safety of naftidrofuryl in PAOD.

(R = randomized study, M = metaanalysis)

    1

Merck Serono: Fachinformation DUSODRIL, as at Sept. 2009

    2

LOWE, G.D.O.: BMJ 1990; 300: 524-8

    3

Deutsche Gesellschaft für Angiologie - Gesellschaft für Gefaessmedizin: Diagnostik und Therapie der peripheren arteriellen Verschlusskrankheit (pAVK). S3-Leitlinie, Stand Apr. 2009; to find under: http://leitlinien.net

M 4

De BACKER, T.L.M. et. al.: Naftidrofuryl for intermittent claudication. The Cochrane Database of Systematic Reviews, as at Dec. 2007, access May 2010

    5

EMA: Note for Guidance on Clinical Investigation of Medicinal Products for the Treatment of Peripheral Arterial Occlusive Disease, Apr. 2002; http://www.ema.europa.eu/pdfs/human/ewp/071498en.pdf

R  6

BOCCALON, H. et al.: Ann. Cardiol. Angéiol. 2001; 50: 175-82

R  7

MAASS, U. et al.: Dtsch. med. Wochenschr. 1984; 109: 745-50

R  8

KIEFFER, E. et al.: Int. Angiol. 2001; 20: 58-65