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Drug treatment of peripheral arterial disease

Bandolier is always interested to hear about interventions that don't work. If the evidence is strong, then we can drop the intervention and get on with thinking about things that do work. So when we were told that a drug treatment for treatment of peripheral artery disease was ineffective, we sought the evidence.

Background

Risk factors for peripheral artery disease are much the same as for cardiovascular or cerebrovascular disease. They are age, smoking, hypertension, hyperlipidaemia, diabetes, obesity, physical inactivity and family history. Of these, by far the most important is cigarette smoking; the relative risk is about 9 for those smoking more than 15 cigarettes a day.

Peripheral artery disease produces symptoms of pain, ache, cramp or severe fatigue in one or both legs occasioned by walking (intermittent claudication), so that those affected slacken their walking pace, or stop altogether. Pain-free walking distance (PFWD) on a treadmill at standard pace and incline is one of the tests used in determining disease severity.

Surgical treatments

In the 20-30% of patients who experience progressive deterioration, surgical treatments may include arterial grafts to remove the blockage in the peripheral arteries. Blockages tend to occur in large arteries with a high pressure, and at the bifurcation of arteries. In extreme cases (3-6%) amputation of the affected limb may be necessary [1].

Surgical treatments are expensive. In a paper examining the lack of information on the cost-effectiveness of drug treatments, Drummond & Davies from the Centre for Health Economics at York estimated that the average overall cost of treating limb ischaemia with a graft was between £6,600 and £11,000, depending on the site of the arterial blockage, while the cost of an amputation was close to £11,000 [2].

Naftidrofuryl

This drug has been licensed for use in peripheral vascular disease since the early 1970s at a dose of about 600 mg a day. A retrospective single-patient data analysis of five randomised controlled studies has looked at its effectiveness [3]. Bandolier could find no other studies or reviews in the recent (post 1990) literature apart from a single RCT which forms part of the review.

Readers should know that the work was sponsored by the manufacturer. The analysis appears to be of high standard. The authors say that they:

  • made new case-record forms for all patients, with the data recorded by a person with no knowledge about whether the treatment was active or placebo
  • included all demographic data, associated risk factors, and important clinical measurements
  • included any critical events that occurred during the course of the study - defined as local deterioration, a cardiovascular critical event (fatal or non-fatal myocardial infarction, angina newly diagnosed, cerebrovascular accident, transient ischaemic attack or sudden death), surgical interventions (during the course of the study or immediately afterwards), and treatment discontinuation.
  • included more patients than were in the original published studies to obtain an "intention-to-treat" analysis, and all patients who were randomised were included.

Studies

Five studies with 888 patients were included - 447 receiving naftidrofuryl and 441 placebo. They were double-blind parallel-group studies of three months (D1 and D2 in Germany) or 6 months duration (F1, F2 in France and GB in the UK). Patients were usually men (85%); about 60% were smokers, 23% obese, 31% had hypertension, 12% angina, 13% diabetes and 39% hyperlipidaemia. Patients in the UK had the most severe disease and the shortest PFWD. Bandolier could find no mention of how exercise and smoking were handled.

Outcomes and results

Efficacy was assessed on three different measures.

Pain free walking distance

Treatment was considered successful if the patients completed the full treatment period, were not lost to follow up and the PFWD increased by more than 50%. All other outcomes were considered as failures.

On an intention-to-treat basis, 175/447 treated patients achieved a successful outcome, compared with 129/441 on placebo (odds ratio 1.54, 95%CI 1.16 - 2.03). This produces a number-needed-to-treat (NNT) for one patient to benefit compared with placebo of 10.3 (95%CI 6.3 - 29).

Change in walking distance

This outcome examined the change in PFWD between the initial and final assessments, or the last visit before treatment stopped in 834 patients in whom this data was available. The analysis is shown in a L'Abbé plot for individual trials. Points above the line of equality demonstrate a positive effect of naftidrofuryl. In the paper, analysis of variance showed this to be statistically significant.

Occurrence of critical cardiovascular events

These occurred in 50 patients taking placebo and 32 taking naftidrofuryl. Analysing without any exclusions, this was a significantly lower rate for naftidrofuryl (odds ratio 0.61, 95%CI 0.39 - 0.96). The NNT was 24 (13 - 266).

Comment

This was a retrospective analysis of single-patient data, regarded as being an excellent method. It did not claim to be a systematic search for all RCTs, but a recent review of naftidrofuryl [4] failed to find any other studies which approximated the stringent German guidelines for the assessment of pharmacological interventions for peripheral arterial disease.

Pain-free walking distances are a proxy measurement for some features of the illness. They may be a useful measure, because the increase ability to get about enhances the activities of daily living and quality of life. Perhaps we haven't found it yet, but there seems to be more research to be done, and good guidelines on how to do it.

Stop smoking, keep walking

Stopping people smoking and giving them exercise training are known to be beneficial, shown in a good systematic review [5].These are the mainstay of conservative management of intermittent clausication [1]; controlled trials of exercise increased PFWD by 88-190% in six studies, with little change in non-excercise controls [5].

Pharmacological interventions that strengthen these beneficial effects may well have its place. Systematic review of pentoxifylline also showed drug-related benefits in walking distance [5. There is no cost-effectiveness data on which we can draw [2], but the daily drug costs are about 60p.

References:

  1. Merec. Drug treatment of intermiottent claudication. May 1994. Vol 5 No 5.
  2. M Drummond, L Davies. Economic evaluation of drugs in peripheral vascular disease and stroke. Journal of Cardiovascular Pharmacology 1994 23 (Suppl3) S4-S7.
  3. P Lehert, S Comte, S Gamand, TM Brown. Naftdrofuryl in intermittent claudication: a retrospective analysis. Journal of Cardiovascular Pharmacology 1994 23 (Suppl 3) S48-S52.
  4. LB Barradell, RN Brogden. Oral naftidrofuryl. Drugs & Aging 1996 8:299-322.
  5. K Radack, RJWyderski. Conservative management of intermittent claudication. Annals of Internal Medicine 1990 113: 135-46.




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