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Overview – Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease
NATIONAL INSTITUTE FOR HEALTH AND CLINICAL
EXCELLENCE
Overview
Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol
nicotinate for the treatment of intermittent claudication in
people with peripheral arterial disease
This document is a summary of the evidence and views submitted by
consultees and the Assessment Group. It highlights key issues for discussion
at the first Appraisal Committee meeting. NICE prepares the overview before
it receives consultees’ comments on the assessment report. The sources of
evidence used in the preparation of this document are given in appendix A.
1 Background
1.1 The condition
Peripheral arterial disease (PAD), also known as peripheral vascular disease,
is a condition in which there is blockage of the arteries that carry blood to the
legs and arms. The main cause is atherosclerosis, which is narrowing of the
arteries caused by fatty deposits on the arterial walls.
The Fontaine classification scheme includes four different stages of PAD.
PAD can be asymptomatic (Fontaine classification I) or symptomatic
(Fontaine classification II–IV). The most common symptom of PAD is
intermittent claudication (Fontaine classification II), which is characterised by
pain in the legs or buttocks that occurs with exercise and is relieved with rest.
People with severe pain at rest (ischaemic rest pain, Fontaine
classification III) can progress to necrosis and gangrene (Fontaine
classification IV).
The pain that people experience with intermittent claudication is a result of the
narrowed arteries not delivering adequate blood to leg muscles and so pain
comes from the oxygen starved muscles. Pain is relieved with rest because of
normalisation of the blood flow. Intermittent claudication is most commonly
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Overview – Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease
associated with PAD in the femoropopliteal segment. PAD can also be
present at the aorto-iliac level causing pain in the thigh, hip or buttock. In rare
cases PAD can be located in the foot.
The major risk factors of intermittent claudication are smoking and diabetes
mellitus. Other factors include hypertension, hypercholesterolaemia, obesity,
renal insufficiency, hyperhomocysteinaemia, raised C-reactive protein and
sedentary lifestyle. People with intermittent claudication are at increased risk
of myocardial infarction and stroke. Additionally, people with intermittent
claudication are at higher risk from cardiovascular mortality than patients with
PAD who do not have intermittent claudication.
The prevalence of intermittent claudication increases with age and is more
common in men than women. Intermittent claudication has a detrimental effect
on people’s quality of life because of their restricted mobility. Around 20% of
people aged 55–75 years have evidence of PAD in the legs and a quarter of
them have symptoms.
The diagnosis of intermittent claudication includes an assessment of the
presence or absence and type of pain that a patient experiences. A
measurement of patient’s ankle-brachial pressure index (ABPI) at rest is also
taken.
1.2 Current management
A number of interventions are used for the conventional management of
intermittent claudication. Treatment should be targeted at reducing the risk
from cardiovascular events such as smoking cessation, cholesterol lowering,
glycaemic control, weight reduction and blood pressure control. Antiplatelet
and statin therapy may be given as a long term prophylaxis of myocardial
infarction and stroke. The management of claudication symptoms includes the
recommendation to exercise. Supervised exercise programmes are the most
effective form of exercise but are not widely available in England and Wales.
Additionally, antiplatelet drugs and statins might be offered as long-term
prophylaxis of myocardial infarction and stroke. Vasoactive drugs (that is
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Overview – Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease
2 The technologies
Summary description of technologies
Generic name Cilostazol Naftidrofuryl oxalate Pentoxifylline Inositol nicotinate Brand name (^) Pletal Praxilene Trental 400 Hepoxal Brand manufacturer Otsuka Pharmaceuticals Merk Serono Sanofi-Aventis Genus Pharmaceuticals Generic manufacturer
- Actavis UK. Kent Pharmaceuticals. Mylan Teva. Apotex UK Mylan Dose 200 mg daily (100 mg twice daily). 300 mg or 600 mg daily (one or two 100 mg capsules three times daily). Recommended initial dose: 1200 mg daily (one tablet of 400 mg three times daily); 800 mg daily dose (two 400 mg tablets daily) may prove sufficient in some patients. 3 g daily (2 to 3 divided doses daily). Dose might be increased to 4 g daily if necessary. Acquisition cost (British national formulary 60)
(100 mg, 56- tablet pack) Merk Serono £8.10 (net price 84 - capsule pack) £5.30 (net price 84 - capsule pack) £19.68 (400 mg, net price 90-tablet pack) £30.76 (500 mg, net price 100- tablet pack) £51.03 (750 mg, net price 112- tablet pack).
Cilostazol (Pletal, Otsuka Pharmaceuticals) is a phosphodiesterase III
inhibitor. Cilostazol is a direct arterial vasodilator and it also inhibits platelet
aggregation. It is administered orally. Cilostazol has a UK marketing
authorisation for the improvement of the maximal and pain-free walking
distances in patients with intermittent claudication, who do not have rest pain
and who do not have evidence of peripheral tissue necrosis (that is, for
peripheral arterial disease Fontaine stage II). Cilostazol is contraindicated in
people with severe renal impairment: creatinine clearance of 25 ml/min or
lower, moderate or severe hepatic impairment, congestive heart failure,
pregnancy. Cilostazol is also contraindicated in patients with any known
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Overview – Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease
predisposition to bleeding and with any history of ventricular tachycardia,
ventricular fibrillation or multifocal ventricular ectopics. For full details of side
effects and contraindications see the summary of product characteristics.
Naftidrofuryl oxalate (Praxilene, Merk Serono) is a peripheral vasodilator
which selectively blocks vascular and platelet 5-hydroxytryptamine (5-HT2)
receptors. Naftidrofuryl oxalate has a UK marketing authorisation for
peripheral vascular disorders: intermittent claudication, night cramps, rest
pain, incipient gangrene, trophic ulcers, Raynaud's Syndrome, diabetic
arteriopathy and acrocyanosis. Naftidrofuryl oxalate is contraindicated in
people with a history of hyperoxaluria or recurrent calcium-containing stones.
For full details of side effects and contraindications see the summary of
product characteristics.
Pentoxifylline (Trental 400, Sanofi-Aventis) is a peripheral vasodilator that is
derived from methylxanthine. Pentoxifylline has a UK marketing authorisation
for the treatment of peripheral arterial disease, including intermittent
claudication and rest pain. Pentoxifylline is contraindicated in people with
cerebral haemorrhage, extensive retinal haemorrhage, acute myocardial
infarction and severe cardiac arrhythmias. For full details of side effects and
contraindications see the summary of product characteristics.
Inositol nicotinate (Hepoxal, Genus Pharmaceuticals) is a peripheral
vasodilator that is thought to work by slowing the release of nicotinic acid.
Inositol nicotinate has a UK marketing authorisation for the symptomatic relief
of severe intermittent claudication and Raynaud's phenomenon. Inositol
nicotinate is contraindicated in people who have suffered a recent myocardial
infarction or are in the acute phase of a cerebrovascular accident. It also
contraindicated in patients hypersensitive to the active ingredient. For full
details of side effects and contraindications see the summary of product
characteristics.
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Overview – Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease 3.1.2 Assessment Group report
Systematic review of existing clinical effectiveness evidence
The Assessment Group identified four Cochrane reviews; three reviews of
cilostazol (Pratt, 2001; Robless et al, 2008; Pande et al, 2010) and one review
of naftidrofuryl oxalate (De-Backer-Tine et al, 2008). All of the trials included in
the three reviews of cilostazol were included in the systematic review
undertaken by the Assessment Group. Only three out of the six trials included
in the review of naftidrofury oxalate were included in the systematic review
undertaken by the Assessment Group because the naftidrofuryl oxalate dose
was not in line with the UK marketing authorisation, or the population included
patients with severe pain at rest (ischemic rest pain).
Assessment Group’s systematic literature review
The Assessment Group conducted a systematic review of cilostazol,
naftidrofuryl oxalate, pentoxifylline and inositol nicotinate within their licensed
indications for the treatment of intermittent claudication in people with PAD
whose symptoms continue despite a period of conventional management.
A total of 26 RCTs in 36 publications were indentified. Placebo-controlled
trials were available for all four of the vasoactive drugs being assessed in the
appraisal. The only head-to head comparison between the vasoactive drugs
was that of cilostazol versus pentoxifylline. The included studies provided data
for the following comparisons:
11 RCTs of cilostazol 200 mg versus placebo
three RCTs of cilostazol 200 mg versus pentoxifylline 1200 mg
one RCT of cilostazol 200 mg (with or without supervised exercise) versus
usual care (with or without supervised exercise)
four RCTs of naftidrofuryl oxalate 600 mg versus placebo
one RCT of naftidrofuryl oxalate 300 mg versus placebo
nine RCTs of pentoxifylline 1200 mg versus placebo
three RCTs of inositol nicotinate 4 g versus placebo.
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Overview – Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease
Three of the trials (comparing cilostazol with placebo or pentoxifylline) have
not been published (to date) as trial reports The Assessment Group obtained
information about these trials from the three Cochrane reviews of cilostazol
and from the manufacturer’s submission. Additional information on the
naftidrofuryl oxalate trials was obtained from the Cochrane review of
naftidrofuryl oxalate.
Cilostazol
Eleven RCTs in 11 publications (n = 1435, n = 106, n = 262, n = 466, n = 345,
n = 247, n = 520, n = 239, n = 81, n = 189, n = 142) comparing cilostazol with
placebo or pentoxifylline met the inclusion criteria for the Assessment’s
systematic review. Eight RCTs compared cilostazol (200 mg) with placebo
and three compared cilostazol with pentoxifylline (1200 mg) and placebo. The
treatment duration of the RCTs ranged from 12 weeks to 24 weeks; 6 had a
treatment duration of 24 weeks, one of 16 weeks and 3 of 12 weeks. The
outcomes included in these trials were maximum walking distance, pain-free
walking distance, ABPI, cardiovascular events, mortality, adverse events and
health related quality of life. The baseline age of the participants receiving
cilostazol ranged from 63-67 years of age. Only one out of the eleven RCTs
recruited patients from the UK (n = 106). For further details of these trials see
pages 141–180 of the assessment report.
One RCT in one publication (n = 34) met the inclusion criteria for this review.
In this RCT (Hobbs et al 2007) cilostazol 200 mg (with or without supervised
exercise) was compared with usual care (with or without supervised exercise).
The treatment duration was 24 weeks, the outcomes included were maximum
and pain-free walking distance. The baseline age of the participants receiving
cilostazol was 58 years of age. The trial recruited 38 patients from the UK. For
further details of this trial see pages 229 – 231 of the assessment report.
Naftidrofuryl oxalate
Five RCTs in five publications (n = 74, n = 196, n = 118, n = 104, n = 50) met
the inclusion criteria for the Assessment’s Group review. Four RCTs
compared naftidrofuryl oxalate 600 mg with placebo and one compared
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Overview – Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease
age of the participants receiving inositol nicotinate ranged from 61-68 years of
age. All RCTs recruited UK patients (n = 120, n = 80, n = 123). For further
details of these trials see pages 219–228 of the assessment report.
Quality assessment
The Assessment Group considered the quality of the trials to be generally
good: treatment groups within trials were comparable, blinding was
maintained and trials presented intention-to-treat analyses. For further details
of the Assessment Group’s quality assessment of the trials see pages 36– 38
of the assessment report.
The Assessment Group stated that the results of these trials are generalisable
across all patients in the UK who have stable (at least for the past 3 months)
and symptomatic intermittent claudication, secondary to peripheral arterial
disease, whose symptoms continue despite a period of conventional
management. However, there might be a subgroup of people with more
severe intermittent claudication in which treatment with vasoactive drugs
might prevent the need for angioplasty.
A brief summary of the results of the systematic review is given below. The
Assessment Group provided a narrative synthesis of the treatment effect for
all outcomes and a network meta-analysis was also undertaken for mean
walking distance and pain free walking distance.
Results of the clinical effectiveness review
Maximum walking distance is a measure of how far a person can walk before
symptoms of intermittent claudication prevent them from walking. Pain-free
walking distance is a measure of the distance walked before a person starts
experiencing pain due to intermittent claudication. The European Medicines
Agency (EMA) recommends that treadmill tests should be performed to
assess claudication distances. The EMA specifies two internationally
recognised treadmill protocols; constant workload treadmill protocol and the
graded test treadmill protocol. The constant workload treadmill protocol
involves setting the treadmill a fixed slope at a fixed speed. The graded
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Overview – Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease
treadmill protocol involves setting the treadmill at a fixed speed with the slope
increased by a pre-set amount at regular intervals.
Maximum walking distance
Ten of the eleven trials of cilostazol 200 mg compared with placebo reported
this outcome. Seven out of the ten trials showed a statistically significant
improvement in maximum walking distance for the cilostazol group compared
with the placebo group. Table 1 presents results from published trial reports
for cilostazol compared with placebo.
Table 1 Cilostazol 200 mg versus placebo (maximum walking distance)
Trial Number of participants Treadmill protocol Results – change in maximum walking distance O'Donnell et al 2009 ( weeks) Cilostazol = 51. Placebo = 55. Constant Cilostazol = 161.7% mean improvement. Placebo = 79% mean improvement. p = 0.048. Strandness et al 2002 (24 weeks) Cilostazol = 133. Placebo = 129. Constant Cilostazol = 76.2 m mean improvement. Placebo = 21.1 m mean improvement. p = 0.0003. Dawson et al 2000 ( weeks) Cilostazol = 227. Placebo = 239. Graded Cilostazol = 107 m (SD 158 m) mean improvement. Placebo = 65 m (SD 135 m) improvement. p = 0.0005. Beebe et al 1999 (24 weeks) Cilostazol = 175. Placebo = 170. Constant Cilostazol = 129.1 m mean improvement. Placebo = 26.8 m mean improvement. p < 0.001. Money et al 1998 (16 weeks) Cilostazol = 119. Placebo = 120. Graded Cilostazol = 96.4 m mean improvement. Placebo = 31.4 m mean improvement. p < 0.05. Dawson et al 1998 ( weeks) Cilostazol = 54. Placebo = 27. Constant Cilostazol = 30.5% improvement. Placebo = −9.3% change (worsening). p < 0.01. Elam et al 1998 (12 weeks) Cilostazol = 95. Placebo = 94. Graded Cilostazol = 72.7 m mean improvement. Placebo = 25.8 m mean improvement. p = 0.004. SD = standard deviation.
The Assessment Group stated that using different treadmill protocols might
explain the heterogeneity observed in the trials. The three trials that reported
a graded treadmill protocol reported a statistically significant improvement in
maximum walking distance in the cilostazol groups compared with placebo.
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Overview – Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease
Table 3 Cilostazol 200 mg versus usual care with or without supervised
exercise (maximum walking distance)
Trial Number of participants Treadmill protocol Results – change in maximum walking distance Hobbs et al 2007 (24 weeks) Cilostazol = 16 ( with exercise, 9 without exercise) Usual care = 18 ( with exercise, 9 without exercise. Constant Cilostazol mean ratio with exercise = 2. (SD 1.39) improvement. Cilostazol mean ratio without exercise = 1.69 (SD 0.59) improvement. Usual care mean ratio with exercise = 1. (SD 0.80) improvement. Usual care mean ratio without exercise = 1.09 (SD 0.34) improvement. Difference in effect = 1.64; p = 0.005. SD = standard deviation.
Two trials of naftidrofuryl oxalate 600 mg compared with placebo (table 4)
included the outcome of maximum walking distance. One of the trials showed
a statistically significant improvement in maximum walking distance for
naftidrofuryl oxalate compared with placebo (p< 0.001).
Table 4 Naftidrofuryl 600 mg versus placebo (maximum walking
distance)
Trial Number of participants Treadmill protocol Results – change in maximum walking distance Kieffer et al 2001 ( 24 weeks) Naftidrofuryl = 98 Placebo = 98 Constant Naftidrofuryl = 158.7 m mean improvement Placebo = 28.1 m mean improvement p<0. Trubestein et al 1984 (12 weeks) Naftidrofuryl = 54 Placebo = 50 Constant Naftidrofuryl = 122 m mean improvement Placebo = 90 m mean improvement p = not significant
The Assessment Group stated that this difference might be due to the
different length of follow-up; 24 weeks in one study and 12 weeks in the other.
Both trials employed the same workload treadmill protocol, had similar study
designs and there was very little difference between the two trials in baseline
maximum walking distance.
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Overview – Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease
Eight trials of pentoxifylline 1200 mg reported the outcome of maximum
walking distance. Two of the eight trials showed a statistically significant
improvement in maximum walking distance for the pentoxifylline group
compared with placebo. Table 5 presents the results from published trial
reports for pentoxifylline compared with placebo.
Table 5 Pentoxifylline 1200 mg versus placebo (maximum walking
distance)
Trial Number of participants Treadmill protocol Results – change in maximum walking distance Creager et al 2008 (2 4 weeks) Pentoxifylline = 86. Placebo = 84. Graded Pentoxifylline = 13.90% improvement. Placebo = 3.30% improvement. p = 0.039. Dawson et al 2000 (24 weeks) Pentoxifylline = 232 Placebo = 239 Graded Pentoxifylline = 64 m mean improvement. Placebo = 65 m mean improvement. p = 0.82. Lindgarde et al 1989 (24 weeks) Pentoxifylline = 76 Placebo = 74 Constant Pentoxifylline = geometric mean 50% improvement (SE 9). Placebo = geometric mean 29% improvement (SE 8). p = 0.094. Porter and Bauer 1982 (24 weeks) Pentoxifylline = 67 Placebo = 61 Constant Pentoxifylline = geometric mean 33% improvement (SE 8). Placebo = geometric mean 20% improvement (SE 7). 2 - sided p = 0.316; 1 - sided p = 0.049. Gallus et al 1985 (8 weeks) Pentoxifylline = 25 Placebo = 23 Constant Pentoxifylline = geometric mean 23% improvement Placebo = geometric mean 17% improvement Ratio of percentage change from baseline (pentoxifylline/placebo) 1. (95% CI 0.81 to 1.36) p = not significant Di Perri and Guerini 1983 (8 weeks) Pentoxifylline = 12 Placebo = 12 No treadmill – horizontal ground Pentoxifylline = 136 m mean improvement Placebo = 6 m mean improvement p < 0. SE = standard error.
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Overview – Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease
The Assessment Group stated that the rationale for transforming the data to
the logarithm scale was to produce a scale on which the treatment effects
could be assumed to be linear.
The random effects meta-analysis of the change from baseline in log walking
distance showed that treatment with naftidrofuryl had the greatest increase
(60.3%) compared with placebo, followed by cilostazol (24.6%) and
pentoxifylline (10.6%). The 95% credible intervals for naftidrofuryl oxalate and
cilostazol compared with placebo showed that there was a real increase in the
percentage change from baseline walking distance, although there was some
uncertainty as to the true effect. For further details on the 95% credible
intervals see table 23 on page 49 of the assessment report. The Assessment
Group stated that variation between studies was moderate, suggesting that
the treatment effect varied depending on the characteristics of the study. For
further information on the meta-analysis see pages 48–51 of the assessment
report.
Pain free walking distance
Ten trials of cilostazol 200 mg reported this outcome. Five trials showed a
statistically significant improvement in pain-free walking distance for the
cilostazol group compared with the placebo group. Table 7 presents results
from published trial reports for cilostazol compared with placebo.
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Overview – Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease
Table 7 Cilostazol 200 mg versus placebo (pain free walking distance)
Trial Number of participants Treadmill protocol Results – change in pain-free walking distance O'Donnell et al 2009 (24 weeks) Cilostazol = 51. Placebo = 55. Constant Cilostazol = 67% improvement. Placebo = 51.6% improvement. p = 0.63. Strandness et al 2002 (24 weeks) Cilostazol = 133. Placebo = 129. Constant 22% (favours cilostazol). Dawson et al 2000 (24 weeks) Cilostazol = 227. Placebo = 239. Graded Cilostazol = 94 m (SD 127) mean. Placebo = 57 m (SD 93) mean. p = 0.0001. Beebe et al 1999 (24 weeks) Cilostazol = 175. Placebo = 170. Constant Cilostazol = 67.5 m (59%) mean improvement. Placebo = 23.1 m (20%) mean improvement. p < 0.001. Money et al 1998 (16 weeks) Cilostazol = 119. Placebo = 120. Graded p < 0.05. Dawson et al 1998 (12 weeks) Cilostazol = 54. Placebo = 27. Constant Cilostazol = 31.7% improvement. Placebo = −2.5% change (worsening). p<0.01. SD = standard deviation
Of the trials that used the constant treadmill protocol, three out of seven
showed that cilostazol statistically significantly improved pain-free walking
distance compared with placebo. The Assessment Group stated that the
length of follow-up and the sample size cannot explain the differences
between the significance and non-significance of the results reported in the
trials that used the constant workload protocol. In the trials using the graded
treadmill protocol, two out of three trials showed a statistically significant
improvement in the pain-free walking distance outcome in the cilostazol group
compared with the placebo group.
Three trials of cilostazol compared with pentoxifylline reported the outcome of
pain-free walking distance. Only one trial found a statistically significant
improvement in pain-free walking distance for the cilostazol group compared
with the pentoxifylline group. Table 8 presents results from published trial
reports for cilostazol compared with pentoxifylline.
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Overview – Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease
Table 10 Naftidrofuryl 600 mg versus placebo (pain-free walking
distance)
Trial Number of participants Treadmill protocol Results – change in pain-free walking distance Spengel et al 2002 (24 weeks) Naftidrofuryl = 382. Placebo = 372. Not treadmill – patient estimate only Naftidrofuryl = 204 m (SD 433) mean. Placebo = 51 m (SD 455) mean. p < 0.001. Kieffer et al 2001 (24 weeks) Naftidrofuryl = 98. Placebo = 98. Constant Naftidrofuryl = 158.2 m mean. Placebo = 29.9 m mean. p < 0. Adhoute et al 1986 (24 weeks) Naftidrofuryl = 64. Placebo = 54. Constant Naftidrofuryl = 201.4 1 m mean. Placebo = 98.03 m mean. p < 0.02. Trubestein et al 1984 (12 weeks) Naftidrofuryl = 54. Placebo = 50. Constant Naftidrofuryl = 93 m mean. Placebo = 36 m mean. p < 0.02.
Seven trials that compared pentoxifylline 1200 mg with placebo reported the
outcome of pain-free walking distance. Only two trials showed a statistically
significant improvement in pain-free walking distance in the pentoxifylline
group when compared with the placebo group. Table 11 presents results from
published trial reports for pentoxifylline compared with placebo.
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Overview – Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease
Table 11 Pentoxifylline 1200 mg versus placebo (pain-free walking
distance)
Trial Number of participants Treadmill protocol Results – change in pain-free walking distance Creager et al 2008 (24 weeks) Pentoxifylline = 86. Placebo = 84. Graded Pentoxifylline = 34.30%. Placebo = 21.20%. p = not significant. Dawson et al 2000 (24 weeks) Pentoxifylline = 232. Placebo = 239. Graded Pentoxifylline = 74 m (SD 106) mean. Placebo = 57 m (SD 93) mean. p= 0.07. Lindgarde et al 1989 (24 weeks) Pentoxifylline = 76. Placebo = 74. Constant Pentoxifylline = geometric mean 80% improvement (SE 12). Placebo = geometric mean 60% improvement (SE 11). p = 0.268. Porter et al 1982 (24 weeks) Pentoxifylline = 67. Placebo = 61. Constant Pentoxifylline = 47% (SE 10) by geometric mean. Placebo = 26% (SE 9) by geometric mean. 2 - sided p = 0.042, 1-sided p = 0.01. Gallus et al 1985 (8 weeks) Pentoxifylline = 25. Placebo = 23. Constant Pentoxifylline = 55% improvement by geometric mean. Placebo = 26% improvement by geometric mean. Ratio of percentage change from baseline (pentoxifylline/placebo) 1. (95% CI 0.86 to 1.77) p < 0.3. SD = standard deviation. SE = standard error.
Pain-free walking distance network meta-analysis
The Assessment Group conducted a network meta-analysis including the
same trials as in the network of evidence used for the meta-analysis of
maximum walking distance. The random effects meta-analysis of the change
from baseline in log walking distance showed that treatment with naftidrofuryl
compared with placebo had the greatest effect (64.2%) followed by cilostazol
(13.4%) and pentoxifylline (9.2%). The 95% credible interval suggested that
treatment with naftidrofuryl and cilostazol compared with placebo resulted in
real increases in the percentage change from baseline pain-free walking
distance although there was some uncertainty as to the true effect. For further
details on the 95% credible intervals see table 30 on page 58 of the
assessment report. The Assessment Group stated that variation between
studies was moderate, suggesting that the treatment effect varied depending
