Pentoxifylline for intermittent claudication

Abstract

Intermittent claudication (IC) is a symptom of peripheral arterial disease (PAD) and is associated with high morbidity and mortality. Pentoxifylline, one of many drugs used to treat IC, acts by decreasing blood viscosity, improving erythrocyte flexibility and promoting microcirculatory flow and tissue oxygen concentration. Many studies have evaluated the efficacy of pentoxifylline in treating individuals with PAD, but results of these studies are variable. This is an update of a review first published in 2012. To determine the efficacy of pentoxifylline in improving the walking capacity (i.e. pain‐free walking distance and total (absolute, maximum) walking distance) of individuals with stable intermittent claudication, Fontaine stage II. For this update, the Cochrane Vascular Group Trials Search Co‐ordinator searched the Specialised Register (last searched April 2015) and the Cochrane Register of Studies (2015, Issue 3). All double‐blind, randomised controlled trials (RCTs) comparing pentoxifylline versus placebo or any other pharmacological intervention in patients with IC Fontaine stage II. Two review authors separately assessed included studies,. matched data and resolved disagreements by discussion. Review authors assessed the methodological quality of studies by using the Cochrane 'Risk of bias' tool and collected results related to pain‐free walking distance (PFWD) and total walking distance (TWD). Comparison of studies was based on duration and dose of pentoxifylline. We included in this review 24 studies with 3377 participants. Seventeen studies compared pentoxifylline versus placebo. In the seven remaining studies, pentoxifylline was compared with flunarizine (one study), aspirin (one study), Gingko biloba extract (one study), nylidrin hydrochloride (one study), prostaglandin E1 (two studies) and buflomedil and nifedipine (one study). The quality of the evidence was generally low, with large variability in reported findings.. Most included studies did not report on random sequence generation and allocation concealment, did not provide adequate information to allow selective reporting to be judged and did not report blinding of assessors. Heterogeneity between included studies was considerable with regards to multiple variables, including duration of treatment, dose of pentoxifylline, baseline walking distance and participant characteristics; therefore, pooled analysis was not possible. Of 17 studies comparing pentoxifylline with placebo, 14 reported TWD and 11 reported PFWD; the difference in percentage improvement in TWD for pentoxifylline over placebo ranged from 1.2% to 155.9%, and in PFWD from ‐33.8% to 73.9%. Testing the statistical significance of these results generally was not possible because data were insufficient. Most included studies suggested improvement in PFWD and TWD for pentoxifylline over placebo and other treatments, but the statistical and clinical significance of findings from individual trials is unclear. Pentoxifylline generally was well tolerated; the most commonly reported side effects consisted of gastrointestinal symptoms such as nausea. Given the generally poor quality of published studies and the large degree of heterogeneity evident in interventions and in results, the overall benefit of pentoxifylline for patients with Fontaine class II intermittent claudication remains uncertain. Pentoxifylline was shown to be generally well tolerated. Based on total available evidence, high‐quality data are currently insufficient to reveal the benefits of pentoxifylline for intermittent claudication. Pentoxifylline for intermittent claudication Background Atherosclerosis, or hardening of the arteries, results in narrowing and blockage of the arteries and can reduce the blood supply to the legs, causing peripheral arterial disease. Intermittent claudication (IC) is a cramp‐like pain felt in the leg muscles that is brought on by walking and is relieved by standing still or resting. Pentoxifylline is a drug that is used to relieve IC while improving people's walking capacity. It decreases blood viscosity and improves red blood cell flexibility, promoting microcirculatory blood flow and increasing oxygen in the tissues. This review looked at all available evidence from randomised controlled trials on the efficiency of pentoxifylline for treatment of IC. Study characteristics and key results This review included 24 studies with 3377 participants (current until April 2015). Seventeen studies compared pentoxifylline with placebo, and the remaining studies compared pentoxifylline with flunarizine (one study), aspirin (one study), Gingko biloba extract (one study), nylidrin hydrochloride (one study), prostaglandin E1 (two studies) and buflomedil and nifedipine (one study). Large differences between included studies in how investigators measured and reported study findings made it impossible to combine results. Most of the included studies suggested mild to moderate improvement in pain‐free walking distance and total walking distance for pentoxifylline over placebo (and other treatments, which included Gingko biloba, buflomedil, iloprost, nylidrin, aspirin and prostaglandin E1). The statistical significance of findings from individual trials was unclear, and researchers observed large variability between studies in the effects of pentoxifylline. The most commonly reported side effects were gastrointestinal symptoms, mainly nausea, and the drug was well tolerated. Quality of the evidence The quality of included studies was generally low, and very large variability between studies was noted in reported findings including duration of trials, doses of pentoxifylline and distances participants could walk at the start of trials. Most included studies did not report on randomisation techniques or how treatment allocation was concealed, did not provide adequate information to permit judgement of selective reporting and did not report blinding of outcome assessors. Given all these factors, the role of pentoxifylline in intermittent claudication remains uncertain, although this medication was generally well tolerated by participants.