Can pentoxifylline be used long-term for management of intermittent claudication?

Can pentoxifylline be used long-term for management of intermittent claudication?

Comment by InpharmD Researcher

Data on the use of pentoxifylline long-term for management of intermittent claudication is limited, although several studies report efficacious use for up to 52 weeks with a lack of notable adverse events. However, effects of use beyond 12 months remain unknown.

Background

A 2020 Cochrane review update evaluated efficacy of pentoxifylline in the treatment of intermittent claudication (IC), assessed via pain‐free walking distance (PFWD) and total walking distance (TWD). A total of 24 double‐blind, randomized controlled trials (RCTs) with 3,377 patients were included that compared pentoxifylline to either placebo or an active pharmacological intervention (flunarizine, aspirin, ginkgo biloba extract, nylidrin hydrochloride, prostaglandin E1, and buflomedil/nifedipine). A majority of studies utilized 1,200 mg/day of pentoxifylline. Duration of treatment varied; when examining PFWD data versus placebo, four studies had a duration of 24 weeks, one study a duration of 26 weeks, and one study a duration of 40 weeks. In these studies, a net improvement for pentoxifylline was typically observed. For studies reporting TWD data versus placebo, six studies had a duration of 24 weeks to 26 weeks, one study a duration of 40 weeks, and two studies a duration of 52 weeks. Similarly, the majority of studies reported improvement in favor of pentoxifylline, although one trial observed no clear improvement with treatment. Differences in dosages and study duration complicate conclusions regarding pentoxifylline’s effect on ankle‐brachial pressure index, quality of life, and adverse events between groups. As there were limited studies on other comparators, conclusions on how clinically meaningful findings are could not be drawn. The authors report uncertainty of pentoxifylline’s treatment effect and tolerability due to the lack of high-quality evidence. [1], [2]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Can pentoxifylline be used long-term for management of intermittent claudication?

Please see Tables 1-2 for your response.

Treatment of intermittent claudication with pentoxifylline: a 12-month, randomized trial--walking distance and microcirculation
Design	Randomized, double-blind, placebo-controlled trial N= 101
Objective	To evaluate the effect of pentoxifylline 1600 mg daily in patients with intermittent claudication in a 12-month trial
Study Groups	Pentoxifylline (n= 56) Placebo (n= 45)
Inclusion Criteria	Severe intermittent claudication with a total walking distance between 50 and 200 m, intermittent claudication lasting more than 4 months, resting Doppler ankle-brachial index (ABI) less than 0.8, decrease in ankle pressure > 15 mmHg after standard exercise test on a treadmill, age 45 to 75 years, documentation of arterial stenoses, plaques and flow reduction due to arteriosclerosis by color duplex imaging
Exclusion Criteria	Exercise-related ischemia, previous coronary or vascular surgery or angioplasty, aneurysms, congestive heart failure, renal failure, diabetes mellitus requiring insulin treatment, maximum walking distance on treadmill changed more than 25% during the 2-week run-in period, arthritis, pulmonary cardiac, neoplastic disease, inflammatory or immunologic diseases
Methods	Patients were randomized to receive either pentoxifylline 1800 mg (three 600 mg tablets daily in three doses) or matching placebo for 12 months. All patients received antiplatelet regimen. The treadmill test was repeated at the end of 6 and 12 months.
Duration	12 months
Outcome Measures	Primary: Absolute change in total walking distance from baseline
Baseline Characteristics		Pentoxifylline (n= 56)	Placebo (n= 45)
	Age, years	63 ± 4	62 ± 3
	Female	35.7%	46.7%
	Months of claudication	2 ± 4	2 ± 2
	Ankle-brachial index (ABI)	0.5 ± 0.1	0.5 ± 0.2
	Smokers at inclusion Past smokers	22% 25%	24% 26%
Results	Endpoint	Pentoxifylline (n= 56)	Placebo (n= 45)	p-value
	Total walking distance, m Baseline 6 months 12 months	66 ± 13 177 ± 18 267 ± 38	67 ± 11 133 ± 12 188 ± 19	--- <0.05 <0.02
	Resting flux 0 months 6 months 12 months	1.4 1.8 1.9	1.5 1.6 1.2	<0.05 <0.02
	After exercise flux 0 months 6 months 12 months	2.2 3.6 4.4	2.3 3.2 3.3	<0.05 <0.02
Adverse Events	N/A
Study Author Conclusions	Between-group analysis favored pentoxifylline considering walking distance and microcirculatory parameters
InpharmD Researcher Critique	It was mentioned that patients participated in an exercise plan which could have also contributed to the benefits seen in the outcome.

References:
[1] De Sanctis MT, Cesarone MR, Belcaro G, et al. Treatment of intermittent claudication with pentoxifylline: a 12-month, randomized trial--walking distance and microcirculation. Angiology. 2002;53 Suppl 1:S7-S12.

Treatment of long-distance intermittent claudication with pentoxifylline: a 12-month, randomized trial
Design	Double-blind, randomized, placebo-controlled trial N= 135
Objective	To evaluate the efficacy of pentoxifylline on walking distance in patients with long-range claudication in a 12-month trial
Study Groups	Pentoxifylline (n = 75) Placebo (n = 60)
Inclusion Criteria	Age between 50 and 65 years, intermittent claudication with total walking distance (TWS) longer than 400 m, claudication lasting more than 3 months, doppler ankle-brachial index (ABI) less than 0.8, decrease in ankle pressure greater than 20 mm Hg after standard exercise test on a treadmill (12% inclination, 3 km/hr, 10 min of exercise), arterial stenoses, plaques, and flow reduction on color-duplex imaging
Exclusion Criteria	Previous coronary or vascular surgery or angiography, aneurysms, congestive heart failure, renal failure, diabetes requiring insulin treatment, arthritis, other pulmonary cardiac, neoplastic, inflammatory, or immunologic diseases, if maximum walking distance on treadmill changes more than ±20% during the 2-week run-in period
Methods	Patients were randomly assigned to one of two treatment regimens. Both groups received antiplatelet therapy (300 mg once daily). Additionally, one group received pentoxifylline (1,800 mg daily, divided into three doses of 600 mg each), while the other received a placebo for a duration of 12 months. The treadmill test, set at 3 km/hr with a 12% incline, was used to assess total walking distance (TWD) at 6 and 12 months.
Duration	12 months
Outcome Measures	TWD (based on the exhaustion point without forcing patients to overperform)
Baseline Characteristics		Pentoxifylline (n =75)	Placebo (n = 60)
	Age, years	62 ± 9	61 ± 8
	Female	38.7%	33.3%
	Months of claudication	6 ± 2	5 ± 1
	Ankle-brachial index	0.61 ± 0.3	0.59 ± 0.2
	Smoking	25%	26%
Results	Endpoint	Pentoxifylline (n =75)	Placebo (n = 60)	p-value
	TWD, m (% increase) Baseline 6 months 12 months	554 ± 66 822 ± 60 (148%) 943 ± 78 (170%)	576 ± 71 638 ± 44 (110%) 755 ± 67 (131%)	--- <0.02 <0.02
	Increase in TWD between the baseline value and the value at 6 and 12 months was significant in both groups (p< 0.05). In the pentoxifylline group TWD was significantly better (p< 0.02) at 6 and 12 months. TWD= total walking distance
Adverse Events	No side effects were observed
Study Author Conclusions	In conclusion, pentoxifylline improved walking distance significantly better than placebo.
InpharmD Researcher Critique	The findings are limited by the small sample size, which was influenced by the number of dropouts due to low participant compliance. Furthermore, the effects beyond 12 months remain unknown.

References:
[1] De Sanctis MT, Cesarone MR, Belcaro G, et al. Treatment of long-distance intermittent claudication with pentoxifylline: a 12-month, randomized trial. Angiology. 2002;53 Suppl 1:S13-S17.