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.
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.
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 .
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 .
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
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
- 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
- included more patients than were in the original published studies to
obtain an "intention-to-treat" analysis, and all patients who were randomised
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.
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