Improving Functional Outcomes in Patients with Intermittent Claudication

Pharmacologic Therapies

In the UK, 4 drugs are licensed for the symptomatic relief of intermittent claudication: pentoxifylline, inositol nicotinate, cilostazol, and naftidrofuryl oxalate (in the US, naftidrofuryl oxalate is not FDA approved, and inositol is labeled GRAS [generally regarded as safe]). Pentoxifylline (Trental 400, Sanofi-Aventis) is an oral peripheral vasodilator derived from methylxanthine. To date, most studies have found no significant difference in walking distances between pentoxifylline and placebo groups, and a recent meta-analysis suggested that pentoxifylline only increased maximum walking distance by 11% (95% credible interval, –1 to 24%) relative to placebo [51]. Inositol nicotinate (Hexopal, Genus Pharmaceuticals) is an oral peripheral vasodilator that slows the release of nicotinic acid. A recent Health Technology Assessment highlighted that there have only been a few trials of this drug in claudication patients, and that the available data show limited efficacy [52]. It is also relatively expensive and has potential side effects of nausea/vomiting, skin rashes, and headache. Cilostazol (Pletal, Otsuka Pharmaceuticals) is an oral phosphodiesterase type 3 inhibitor, which is reported to have both antiplatelet and vasodilator effects [53]. In a systematic review and meta-analysis of drug therapies for intermittent claudication, Momsen et al reported a dose-dependent positive effect of cilostazol, with mean differences for maximum walking distance of 36 m (95% CI, 30 to 41 m) and 70 m (95% CI, 47 to 93), respectively, for 50 and 100 mg doses taken twice daily [50]. In a separate review, cilostazol was shown to increase maximum walking distance by 25% relative to placebo (95% credible interval, 20 to 114%), and pain-free walking distance by 13% [52]. Naftidrofuryl oxalate (Praxilene, Merck Serono) is an oral peripheral vasodilator that selectively blocks vascular and platelet 5-hydroxytryptamine 2 (5-HT2) receptors. The meta-analysis of Stevens et al, which included 2 trials of naftidrofuryl oxalate for claudication, indicated that this drug increased maximum walking distance by 60% (95% credible interval, 20 to 114%) and pain-free walking distance by 49% (95% credible interval, 23 to 81%) relative to placebo [51]. Comparative analyses indicated that the improvements were of a greater magnitude than those observed with pentoxifylline and cilostazol. An economic evaluation also suggested that naftidrofuryl oxalate “dominated” cilostazol and pentoxifylline, and has an incremental cost per QALY (quality-adjusted life-years) gained of around $9720 compared with no vasoactive drug [52]. However, Hong and Mackey recently concluded that the clinical data for both naftidrofuryl and cilostazol are plagued by flaws related to lack of protocol standardization, objective endpoints, and strict eligibility criteria in study subjects, making identification of a true treatment effect difficult [54].

Other studies have investigated the functional effects of drugs that are commonly used to reduce the risk of cardiovascular events in patients with PAD, including antiplatelet, antihypertensive and lipid-lowering agents. The meta-analysis of Momsen et al assessed the effects of antiplatelet agents on walking distances in intermittent claudication [55]. The included studies involved 5 different drugs (ticlopidine, cloricromene, mesoglycan, indobufen and defibrotide), and while some studies did not show a statistically significant benefit of antiplatelet therapy, the pooled estimate showed a modest increase in maximum walking distance favoring treatment of 59 m (95% CI, 37 to 81 m). The same paper also assessed the effects of 4 lipid-lowering drugs: atorvastatin, simvastatin, policosanol, and avasimibe [55]. Despite variable results according to the specific drug used, the effect estimates favored lipid-lowering agents in all studies and was statistically significant in all but one study. The pooled effect estimate was in favor of intervention, with a clinically relevant increase in maximum walking distance of 163 m (95% CI, 83 to 242 m). Two recent meta-analyses have also reviewed the functional effects of ACE inhibitors in patients with intermittent claudication [56,57], and although data are conflicting, a recent large trial of 212 patients reported that ramipril increased claudication onset time by 75 seconds (95% CI, 60 to 89 seconds) and peak walking time by 255 seconds (215 to 295 seconds) [58]. These changes were independent of the small change in blood pressure that occurred with ramipril treatment.