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Comparing Medications for Intermittent Claudication in Peripheral Arterial Disease, Study notes of Marketing

A summary of the evidence and views submitted by consultants and the Assessment Group regarding the use of Cilostazol, Naftidrofuryl Oxalate, Pentoxifylline and Inositol Nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease. information on clinical effectiveness, cost-effectiveness, and health-related quality of life evidence for these drugs.

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CONFIDENTIAL
National Institute for Health and Clinical Excellence Page 1 of 38
Overview Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of
intermittent claudication in people with peripheral arterial disease
Issue date: December 2010
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 IIIV). 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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National Institute for Health and Clinical Excellence Page 1 of 38

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

National Institute for Health and Clinical Excellence Page 2 of 38

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

National Institute for Health and Clinical Excellence Page 4 of 38

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

National Institute for Health and Clinical Excellence Page 5 of 38

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.

National Institute for Health and Clinical Excellence Page 7 of 38

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.

National Institute for Health and Clinical Excellence Page 8 of 38

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

National Institute for Health and Clinical Excellence Page 10 of 38

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

National Institute for Health and Clinical Excellence Page 11 of 38

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.

National Institute for Health and Clinical Excellence Page 13 of 38

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.

National Institute for Health and Clinical Excellence Page 14 of 38

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.

National Institute for Health and Clinical Excellence Page 16 of 38

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.

National Institute for Health and Clinical Excellence Page 17 of 38

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.

National Institute for Health and Clinical Excellence Page 19 of 38

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.

National Institute for Health and Clinical Excellence Page 20 of 38

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