Oral vasoactive medication in intermittent claudication: utile or futile? De Backer T L, Vander Stichele R H, Warie H H, Bogaert M G

Authors' objectives To evaluate the role of orally administered vasoactive medication in the management of intermittent claudication.

Searching MEDLINE was searched from 1960 to June 1999, using the seven included medications as MeSH. To identify RCTs, the systematic search strategy suggested by the Cochrane Collaboration (see Other Publications of Related Interest no.1) was used initially. The search strategy was then simplified by crossing medication names with the MeSH term 'intermittent claudication'. Additional studies were located by searching International Pharmaceutical Abstracts and the Cochrane Library (Issue 1, 2000), consulting the drug distribution companies for Belgium, examining reference lists of retrieved articles and searching cited articles using the Science Citation Index.

Study selection Study designs of evaluations included in the review Only randomised placebo-controlled trials (RCTs) were included. If the RCT was a crossover study, only the first period of the study was considered. Additional inclusion criteria stipulated: a minimum study duration of 3 months between baseline and outcome assessments, a minimum sample size of 30 participants, and sufficiently detailed reporting of the variability of results in terms of standard deviation (SD), standard error of the mean (SEM) or 95% confidence interval (CI).

Studies were excluded if they presented a major flaw in trial design or internal validity (quality score 'C') according to the validity models utilised.

Specific interventions included in the review Only comparisons of vasoactive drugs available in Belgium with placebo were eligible for inclusion. The vasoactive agents considered were cinnarizine, cyclandelate, isoxsuprine, naftidrofuryl, pentoxifylline, xanthinol nicotinate and buflomedil. Studies on the use of lipid-lowering and antiplatelet-antithrombotic therapy in peripheral arterial obstructive disease were not considered.

The review only included data from studies concerning buflomedil, naftidrofuryl and pentoxifylline, since no studies were found on the remaining medications which met all the stated inclusion criteria. No information was provided on the dosages used in the individual studies.

[A: naftidrofuryl: 600mg daily (in 3 gifts); pentoxifylline: 1200mg daily (in 2 or 3 gifts); buflomedil: 600mg daily (in 2 gifts)]

Participants included in the review The included participants had to be proven to have chronic peripheral arterial occlusive disease in Fontaine stage II. There is a lack of consistent information on the participants in the six included trials of naftidrofuryl versus placebo. In addition, there are no details of the participants in either the two included trials of buflomedil versus placebo, or the two included trials of pentoxifylline versus placebo. [A:For the 2 pentoxifilline studies, mean age was resp. 59y and 64y, gender 80% man and 70% man, PAOD Fontaine Stage II for at least 6 or 3 months (no info on diabetes). For the 2 buflomedil studies, patients were also predominantly male, and between 50y and 70y, walking distance less than 400 meters, PAOD present for at least 6 months. In the second study, all patients suffered from maturity onset diabetes (mean duration 14y).]

Outcomes assessed in the review The primary outcome measure was pain-free walking distance (PFWD) and/or maximum walking distance (MWD), both analysed using a standardised treadmill test. Studies in which either surrogate end points or non-standardised Page: 1 / 5 exercise tests were used to measure walking distance were excluded.

How were decisions on the relevance of primary studies made? The authors do not state how the papers were selected for the review, or how many of the reviewers performed the selection. [A:After an initial screening of the experimental studies by one author, discussions on whether or not a trial was a RCT by design (not whether or not it was a well performed RCT) were resolved by consensus among the 4 authors.]

Assessment of study quality The validity of the studies was assessed, based on the models of Schultz et al. and Jadad et al. (see Other Publications of Related Interest nos.2-3). Studies were rated as: 'C', high risk of bias, and therefore excluded' 'B', moderate risk of bias; or 'A', low risk of bias. The actual validity criteria used for these ratings were not stated. [A:We performed two rounds of quality assessment, aimed to decide whether or not each of the 36 eligible trilas should be included or excluded. 1. Applying disease-specific minimal criteria for PAOD trials (Cameron et al.) a) minimum of 3 months' duration between baseline and outcome assessment b) minimum sample size of 30 patients c) sufficient detail in reporting the variability of results

For each of these criteria the following score was given: 0=if there were no flaws 1=if there were only minor flaws, not leading to exclusion 2=if there were major flaws, leading to exclusion

2. Applying criteria of internal validity in the execution and reporting of RCTs (Schulz and Jadad). (not mentioned explicitly, but references to papers by Schulz and Jadad given): a) use of effective methods of randomisation b) adequate concealment of allocation to patients and physicians c) adequate description of withdrawals and drop-outs

The following score for internal validity was given: 0=if there were no flaws in the trial for each of these criteria 1=if there were only minor flaws in one or more of these criteria 2=if there was a major flaw in either one of these internal validity criteria

The end score was based on the Cochrane Collaboration critical appraisal categorisation of studies, operationalised for this review as follows (and reported in table 1) C=high risk of bias (leading to exclsion), if a score 2 was given on any of the elements of the 2 assessment rounds B=moderate risk of bias (also leading to inclusion) if there were (only) minor flaws (score 1) in any of the criteria. A=low risk of bias (leading to inclusion) if there were no flaws in any of the elements of 2 assessment rounds (score 0)]

The four authors separately evaluated each trial and discussed differences until consensus was reached.

Data extraction A structured abstract was produced for each retrieved RCT. The authors do not state how many of the reviewers performed the data extraction. [A:The first three authors extraced data in a first round, and then discussed the results with the fourth reviewer until consensus was reached]

The mean (plus or minus SD) PFWD and/or MWD at baseline and final assessment were extracted for placebo and active substance groups in all included trials. For each study, the difference in incremental gain between active and placebo groups for PFWD and/or MWD, along with their CIs, was also estimated (see Other Publications of Related Interest no.4). For the naftidrofuryl versus placebo trials, data on participant characteristics and drop-out rates were also extracted.

Methods of synthesis How were the studies combined? A narrative synthesis was presented with studies grouped by medication and by quality score.

The authors made no formal assessment of publication bias, but indicated their belief that it may be present, citing their knowledge of four unpublished trials that they have been unable to retrieve. Page: 2 / 5 How were differences between studies investigated? Heterogeneity was not investigated for the trials concerning buflomedil and pentoxifylline, as the authors stated that there were too few included studies. For the trials concerning naftidrofuryl: within-trial heterogeneity was investigated by examining coefficients of variance on mean baseline and final assessments; and between-trial heterogeneity was investigated by examining overlap between CIs of effect measures, and by examining demographic variables of the participants.

Results of the review The review initially included a total of 36 studies, all placebo- controlled RCTs: of these, 9 were evaluations of naftidrofuryl, 6 were of buflomedil, 18 were of pentoxifylline, 2 were of cyclandelate and 1 was of cinnarizine. After application of quality assessment criteria, 10 studies remained: 6 of naftidrofuryl, 2 of buflomedil and 2 of pentoxifylline. The authors did not report the number of participants, either in total or for individual studies.

Both of the included trials of buflomedil versus placebo had a quality score 'B', showed moderately positive results for PFWD (one statistically significant and the other not), and reported statistically-significant gains in MWD, albeit with wide CIs.

For naftidrofuryl, all 6 included trials had a quality score 'B' and showed moderately positive results for PFWD, 5 with statistical significance. Of the 2 studies which determined MWD, both reported a positive result, although only one was statistically significant. There was large within- and between-trial heterogeneity.

Both of the included trials of pentoxifylline versus placebo had a quality score 'B'. One of these trials showed a marginally positive, non significant gain in PFWD, whereas the other showed negative results. The gain in MWD was non significant for both trials.

Cost information None. [A: The 7 vasodilators, mentioned in the study, were, until March 1997 partially reimbursed by the Belgian State Institute of Disease and Invalidity. The estimates of their consumption (in peripheral arterial disease and in cerebrovascular disease) at that time was 17 Defined Daily Doses for 1,000 inhabitants per day (17 DDD/1,000i/day), involving expenditures (reimbursement+co-payment) of 30 million EURO per year in Belgium (10 million inhabitants). Consumption of these products since then dropped to 12 DDD/1,000i/day.]

Authors' conclusions There is no evidence for the efficacy of oral treatment of peripheral arterial obstructive disease with cinnarizine, cyclandelate, isoxsuprine and xanthinol nicotinate. For pentoxifylline, the available evidence is unconvincing and it is unlikely that further clinical trials for this drug could reverse this failure to provide positive evidence of efficacy in peripheral arterial obstructive disease. For buflomedil, evidence is scarce and the marginally positive results of two trials are undermined by publication bias. For naftidrofuryl, there is somewhat more evidence available, but publication bias cannot be ruled out. This, and the large heterogeneity of the results, both within- and between-trial, preclude any attempt at mathematical pooling.

Health resources should be allocated to prevention and rehabilitation of intermittent claudication, rather than to payment for products with doubtful efficacy.

CRD commentary The review presents a thorough literature search that included attempts to identify unpublished material. The review question was well defined, and a relevant and formal validity assessment was made and reported for included papers. However, the exclusion of a large number of studies after quality assessment suggests the possibility of reviewer bias. Stricter a priori inclusion criteria would have been more appropriate.

The report lacked detail on the methods used to select trials for initial inclusion in the review and for data extraction,

Page: 3 / 5 and on the numbers of reviewers involved in these processes. There is also a lack of reported detail on trial participants for trials other than those concerning naftidrofuryl. Of particular concern is the lack of any reporting on the numbers of trial participants. In addition, the failure of the authors to report the details of the validity criteria means that the nature of the RCTs included in the final assessment of efficacy is unclear, e.g. whether or not they were double-blind.

The narrative summary of included trials was appropriate, clear and concise. However, given the concerns about the process of study exclusion after quality assessment, it is unclear why a meta-analysis had to be rejected.

It is difficult to comment on the authors' negative conclusions with respect to further research due to the insufficient details of trial participant numbers. The authors' conclusions seem particularly harsh with respect to naftidrofuryl, where the between-trial heterogeneity in results may well reflect the heterogeneity of trial participants, as highlighted by the authors.

Implications of the review for practice and research Practice: A national consensus conference, based on this review, concluded that health resources should be allocated to prevention and rehabilitation of intermittent claudication, rather than to reimbursement of those products with doubtful efficacy.

Research: The authors specifically do not recommend further clinical trials of pentoxifylline, and make no other recommendations for further research in this area.

Funding Belgian National Health Insurance Institute.

Bibliographic details De Backer T L, Vander Stichele R H, Warie H H, Bogaert M G. Oral vasoactive medication in intermittent claudication: utile or futile? European Journal of Clinical Pharmacology 2000; 56(3): 199-206

PubMedID 10952473

Other publications of related interest 1. Dickerson K, Sherer R, Lefebvre C. Identifying relevant studies for systematic reviews. BMJ 1994;309:1286-91. 2. Schultz KF, Chalmers IC, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273:408-12. 3. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1-12. 4. Gardner MJ, Altman GD. Statistics with confidence. London: BMJ Books; 1989.

Indexing Status Subject indexing assigned by NLM

MeSH Administration, Oral; Humans; Intermittent Claudication /drug therapy; Nafronyl /therapeutic use; Pentoxifylline /therapeutic use; Pyrrolidines /therapeutic use; Randomized Controlled Trials as Topic

AccessionNumber 12000001441

Date bibliographic record published 31/01/2002

Page: 4 / 5 Date abstract record published 31/01/2002

Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

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