Treatment of intermittent claudication

BMJ 2009; 338 doi: https://doi.org/10.1136/bmj.b46 (Published 16 March 2009) Cite this as: BMJ 2009;338:b46
  1. G Karthikeyan, assistant professor1,
  2. John W Eikelboom, associate professor2
  1. 1All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India 110029
  2. 2McMaster University, Hamilton, ON, Canada L8L 2X2
  1. eikelbj{at}mcmaster.ca

    Should start with interventions that improve both symptoms and cardiovascular risk

    Peripheral artery disease of the lower extremities affects more than one in 10 people aged over 55 years.1 2 Half of those affected present with leg symptoms that limit physical activity and impair quality of life.1 The most feared complication is loss of limbs, but only 1-3% of those presenting with intermittent claudication progress to amputation over five years.3 Myocardial infarction and stroke resulting from progressive atherogenesis in other vascular beds are far more common—15% to 30% of people presenting with peripheral artery disease die within five years, mainly from cardiovascular causes.4

    In the linked meta-analysis (doi:10.1136/bmj.b603), De Backer and colleagues assess the effects of the orally active vasodilator naftidrofuryl on pain-free walking distance in patients with intermittent claudication.5

    The most important goal of medical treatment in patients with peripheral artery disease of the lower extremities is the prevention of systemic cardiovascular complications.6 Many treatments that prevent myocardial infarction and stroke also improve leg symptoms (table), but specific treatments for intermittent claudication have been developed. One such treatment is naftidrofuryl, which has been available for more than 20 years in Europe but is not approved in North America. Naftidrofuryl has been evaluated in multiple randomised controlled trials (RCTs) for the treatment of claudication, but its efficacy is uncertain because the trials were small and heterogeneous.

    Effect of behaviour modification and medical treatments for peripheral artery disease on cardiovascular risk reduction and claudication symptoms5

    View this table:

    De Backer and colleagues’ meta-analysis of individual patient data compares the effect of naftidrofuryl 200 mg taken three times daily with that of placebo on pain-free walking distance in patients with intermittent claudication. They indentified 11 potentially eligible RCTs but included only six in their primary analysis; four were excluded because of poor study quality or incomplete availability of individual patient data, and a fifth was included only as part of a sensitivity analysis. The pooled data indicate that naftidrofuryl significantly improved pain-free walking distance compared with placebo (relative risk 1.37, 95% confidence interval 1.27 to 1.49). They also found a similar improvement in maximum walking distance. Results were similar when poor quality studies were included. The authors also reported drug company data indicating that, compared with placebo, naftidrofuryl is associated with a 75% relative increase (25% to 145%) and a 2.85% absolute increase (0.78% to 4.91%) in “gastric” disorders.

    The mechanism of action of naftidrofuryl is not well understood. The increase in walking distance is probably explained by peripheral vasodilatation resulting from inhibition of the 5-hydroxytryptamine 2 receptor, which blocks the effects of serotonin, and possibly inhibition of platelet aggregation. Naftidrofuryl has been reported to reduce angina, which might also contribute to the improvement in walking distance.7

    Several other vasodilators have been evaluated for the management of claudication in patients with peripheral artery disease. The best studied is cilostazol, a phosphodiesterase inhibitor that improves claudication distance by about 50% compared with placebo.8 However, aspirin was not permitted in most trials of cilostazol, and it is unclear how much of the improvement results from vasodilatation rather than the drug’s antiplatelet effects. Cilostazol and naftidrofuryl have not been compared head to head in an RCT. Preliminary data indicate that verapamil, buflomedil, and prostaglandins (alprostadil, epoprostenol, and beraprost) might also improve walking distance in patients with claudication, but these results require confirmation.

    De Backer and colleagues’ results seem to provide convincing evidence for the efficacy of naftidrofuryl in the treatment of patients with claudication. However, several caveats should be considered. Firstly, most of the trials included in the meta-analysis were performed in the 1980s and early 1990s, before the widespread use of antiplatelet agents and statins, which can both prevent cardiovascular events and improve walking distance.4 9 10 It is unclear whether naftidrofuryl provides incremental benefit in patients with peripheral artery disease receiving antiplatelet treatment, a statin, blood pressure lowering treatment, and an angiotensin converting enzyme inhibitor.6 Secondly, naftidrofuryl was evaluated for a mean of only 6.3 months in the trials included in the meta-analysis, and it is unclear whether the benefits are sustained in the long term. Thirdly, the number of patients enrolled to date in randomised trials of naftidrofuryl is modest, and safety data are limited. There were neurological and cardiovascular safety concerns with the intravenous preparation of naftidrofuryl,11 and additional data on the oral preparation would provide reassurance that it is safe.

    What are the implications of De Backer and colleagues’ findings for clinical practice and future research? In the treatment of patients with claudication, the relief of symptoms should proceed along with efforts to reduce the risk of systemic cardiovascular complications. Thus, first line medical treatment of peripheral artery disease should consist of interventions that effectively relieve symptoms and reduce cardiovascular risk (table).

    Patients should be encouraged to “stop smoking and keep walking,” and drugs should include aspirin (or clopidogrel), a statin, a blood pressure lowering agent, and an angiotensin converting enzyme inhibitor.6 Unfortunately these drugs are underused in patients with peripheral artery disease.12 Vasodilators such as naftidrofuryl or cilostazol might be considered in patients who have claudication symptoms that are refractory to conventional treatment. However, their role will probably remain uncertain until it is shown in RCTs that they provide incremental benefit in patients receiving currently established treatments that reduce systemic complications and leg symptoms.


    Cite this as: BMJ 2009;338:b46



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