What is intermittent claudication?
Intermittent claudication is cramping pain in your lower leg that happens when you walk and usually goes away after a few minutes of rest. Both legs may be affected at the same time, although the pain may be worse in one leg. It happens because there is not enough blood flowing to the leg muscles. It is a symptom of peripheral arterial disease: a common condition in which fatty deposits build-up on the walls of arteries (blood vessels) and restrict the flow of blood through them.
How is intermittent claudication treated?
Intermittent claudication is usually treated with exercise and medicines that reduce the chance of blood clots in a blocked blood vessel, or that reduce symptoms and help people to walk further. People with serious claudication may need to have surgery.
Why we did this Cochrane Review
Pentoxifylline is a medicine taken orally (by mouth) that makes the blood less thick and sticky. This helps blood to flow more easily through small vessels such as arteries, and lets more oxygen reach the muscles. Pentoxifylline is licensed for treating intermittent claudication, although more evidence of its benefits is needed before its use is recommended in treatment guidelines.
What did we do?
We searched for studies that looked at the use of pentoxifylline to treat intermittent claudication. We wanted to find out if pentoxifylline:
– could help people to walk further, by measuring how far they could walk before feeling pain in their legs;
– affected the relationship of blood pressure at the ankle compared with that in the arm (ankle-brachial pressure index (ABI) – a measure of peripheral arterial disease);
– affected people's quality of life (well-being); and
– caused any side effects.
We looked for randomised controlled studies, in which the treatments people received were decided at random. This type of study usually gives the most reliable evidence about the effects of a treatment.
We included evidence published up to 28 January 2020.
What we found
We found 24 studies in 3377 people with intermittent claudication, conducted mostly in Europe and the USA. Seventeen studies compared pentoxifylline treatment with a dummy treatment (placebo); seven studies compared pentoxifylline with another medicine. The studies lasted from four weeks to 40 weeks.
Differences in how the studies were conducted and how they measured the results meant that we could not combine all their results. We assessed results from the 17 studies comparing pentoxifylline with placebo, but we could not compare pentoxifylline with any of the other medicines.
What are the results of our review?
Compared with a placebo, most studies showed that pentoxifylline treatment may help people to walk further without pain: 11 studies in 1890 people measured how far they could walk without pain; 14 studies in 2110 people measured how far they could walk.
For measurements of ABI, there were no clear differences between pentoxifylline and placebo treatment (5 studies, 902 people).
Three studies in 1179 people assessed well-being related to being able to walk. Two large studies showed no clear difference between pentoxifylline and placebo treatment, and one smaller study showed pentoxifylline probably improved people's well-being, though it was unclear how that was measured.
Side effects reported in the studies varied greatly: some studies reported no major side effects and most reported no side effects with pentoxifylline or with placebo (9 studies; 1837 people).
How reliable are these results?
We are not confident in the results for whether pentoxifylline helps people to walk further, or about its side effects, because we found limitations in the ways that the studies were designed and reported. These results are likely to change when more evidence becomes available.
We are moderately confident that pentoxifylline treatment was similar to placebo in its effects on difference in ankle-brachial pressure index, and on people's well-being. These results might change when more evidence is available.
Pentoxifylline may help people with intermittent claudication to walk further without pain, but we are uncertain about whether it works better than a placebo or other medicines. We did not find enough reliable evidence about any side effects.
There is a lack of high-certainty evidence for the effects of pentoxifylline compared to placebo, or other treatments, for IC. There is low-certainty evidence that pentoxifylline may improve PFWD and TWD compared to placebo, but no evidence of a benefit to ABI or QoL (moderate-certainty evidence). Pentoxifylline was reported to be generally well tolerated (low-certainty evidence). Given the large degree of heterogeneity between the studies, the role of pentoxifylline for people with IC Fontaine class II remains uncertain.
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 people with PAD, but results of these studies are variable. This is the second 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 people with stable intermittent claudication, Fontaine stage II.
For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases, and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 28 January 2020. There were no language restrictions.
We included all double-blind, randomised controlled trials (RCTs) comparing pentoxifylline versus placebo or any other pharmacological intervention in people with IC Fontaine stage II.
Two review authors independently selected studies for inclusion, assessed the included studies, matched data and resolved disagreements by discussion. Review authors assessed the methodological quality of studies using the Cochrane 'Risk of bias' tool and collected results related to the outcomes of interest, pain-free walking distance (PFWD), total walking distance (TWD), ankle-brachial pressure index (ABI), quality of life (QoL) and side effects. Comparison of studies was based on duration and dose of pentoxifylline. We used GRADE criteria to assess the certainty of the evidence.
We identified no new eligible studies for this update. This review includes 24 studies with 3377 participants. Seventeen studies compared pentoxifylline versus placebo. The seven 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). Risk of bias for the individual studies was generally unclear because there was a lack of methodological reporting for many of the included studies, especially regarding randomisation and allocation methods. Most included studies 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 for comparisons which included more than one study, was not possible.
Pentoxifylline compared to placebo
Of 17 studies comparing pentoxifylline with placebo, 11 reported PFWD and 14 reported TWD; the difference in percentage improvement in PFWD for pentoxifylline over placebo ranged from –33.8% to 73.9% and in TWD ranged from 1.2% to 155.9%. It was not possible to pool the data of the studies because data were insufficient and findings from individual trials were unclear. Most included studies suggested a possible improvement in PFWD and TWD for pentoxifylline over placebo (both low-certainty evidence).
The five studies which evaluated pre-exercise ABI comparing pentoxifylline and placebo found no evidence of a difference (moderate-certainty evidence). Two of the three studies that evaluated QoL between people who received pentoxifylline and placebo were larger studies that used validated QoL tools and generally found no evidence of a difference between groups. One small, short-term study, which did not specify which QoL tool was used, reported improved QoL in the pentoxifylline group (moderate-certainty evidence). Pentoxifylline generally was well tolerated; the most commonly reported side effects consisted of gastrointestinal symptoms such as nausea (low-certainty evidence).
Certainty of the evidence from this review was low or moderate, with downgrading due to risk of bias concerns, inconsistencies between studies and the inability to evaluate imprecision because meta-analysis could not be undertaken.
The seven remaining studies compared pentoxifylline with either flunarizine, aspirin, Gingko biloba extract, nylidrin hydrochloride, prostaglandin E1, or buflomedil and nifedipine; data were too limited to allow any meaningful conclusions to be made.