1 Appraisal Committee's preliminary recommendations

1.1 Naftidrofuryl oxalate is recommended as an option for the treatment of intermittent claudication in people with peripheral arterial disease for whom vasodilator therapy is considered clinically appropriate. Treatment with naftidrofuryl oxalate should be started with the least costly licensed preparation.

1.2 Cilostazol, pentoxifylline and inositol nicotinate are not recommended for the treatment of intermittent claudication in people with peripheral arterial disease.

2 Clinical need and practice

2.1 Peripheral arterial disease, also known as peripheral vascular disease, is a condition in which there is blockage or narrowing of the arteries that carry blood to the legs and arms. The main cause of peripheral arterial disease is atherosclerosis.

2.2 The Fontaine classification scheme is used to define four different stages of peripheral arterial disease. Peripheral arterial disease can be asymptomatic (Fontaine classification I) or symptomatic (Fontaine classification II–IV). The most common symptom of peripheral arterial disease 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. Two further stages exist: pain in the extremities at rest (ischaemic rest pain, Fontaine classification III) and necrosis and gangrene (Fontaine classification IV).

2.3 The pain associated with intermittent claudication occurs because of a lack of oxygen in the leg muscles owing to of the impaired blood supply. Rest normalises blood flow and relieves the pain. Intermittent claudication is most commonly associated with disease in the femoropopliteal segment of the arterial circulation. Peripheral arterial disease can also be present at the aorto-iliac level causing pain in the thigh, hip or buttock. Peripheral arterial disease can also cause foot pain. Around 20% of people aged 55–75 years have evidence of peripheral arterial disease in the legs and a quarter of these have symptoms.

2.4 The major risk factors for peripheral arterial disease are smoking, diabetes mellitus and pre-existing cardiovascular disease. Other factors include increasing age, male sex, ethnicity, hypertension, hypercholesterolaemia, renal insufficiency and sedentary lifestyle.

2.5 Intermittent claudication has a detrimental effect on people’s quality of life because of their restricted mobility. People with peripheral arterial disease, and specifically 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 people with asymptomatic peripheral arterial disease.

2.6 The diagnosis of intermittent claudication includes a clinical history that assesses the presence and character of the pain. A clinician may also measure a patient’s ankle-brachial pressure index, that is, the ratio of the blood pressure in the lower leg to the blood pressure in the arm at rest. A value of 0.9 indicates disease, and high values (that is, greater than 1.3) may reflect arterial stiffening associated with disease.

2.7 Evaluating the presence and progression of disease takes into account symptoms and signs (for example, the development of ischaemic ulcerations). As an objective measure, walking on a treadmill, either at a fixed speed and slope, or a fixed speed and increasing slope, determines how far a patient can walk before developing claudication pain and how far a patient can walk with pain before having to stop.

2.8 A number of interventions are used to manage intermittent claudication. Stopping smoking and increasing exercise can help to reduce symptoms of claudication. People are more likely to benefit from supervised exercise programmes than from unsupervised exercise. Vasoactive drugs including cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate have marketing authorisations for the symptomatic relief of intermittent claudication and are considered in this appraisal. Angioplasty (that is, mechanical widening of the blood vessel) or other revascularisation (for example, arterial bypass) may be undertaken for people whose symptoms continue despite treatment. To reduce the risk of a heart attack or stroke, interventions include helping patients stop smoking, lowering cholesterol, controlling blood pressure, offering aspirin, and, in people with diabetes, controlling glycaemia.

3 The technologies

3.1 Cilostazol (Pletal, Otsuka Pharmaceuticals) is an oral phosphodiesterase III inhibitor. Cilostazol is a direct arterial vasodilator and it also inhibits platelet aggregation. 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. 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 and pregnancy. Cilostazol is also contraindicated in people with any known predisposition to bleeding or with any history of ventricular tachycardia, ventricular fibrillation or multifocal ventricular ectopic beats. For full details of side effects and contraindications see the summaries of product characteristics.

3.2 Cilostazol is available as a 50 and 100 mg tablet at a cost of £35.31 for a 56-tablet pack (excluding VAT; ‘British national formulary’ [BNF] edition 60). The recommended dose is 100 mg twice daily. Therefore, the average monthly cost is £38.26 assuming a tablet of 100mg tablet. Costs may vary in different settings because of negotiated procurement discounts.

3.3 Naftidrofuryl oxalate (Praxilene, Merk Serono) is an oral peripheral vasodilator that selectively blocks vascular and platelet 5‑hydroxytryptamine 2 (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.

3.4 Naftidrofuryl oxalate is available as a branded preparation of 100 mg capsules at a cost of £8.10 for an 84-capsule pack (excluding VAT; BNF edition 60). Generic preparations are also available at a cost of £5.30 for a 100 mg 84-capsule pack (excluding VAT; BNF edition 60). The recommended dose is one or two 100 mg capsules three times daily. Therefore, for the branded preparation the average monthly cost is £8.80 assuming three 100 mg capsules daily or £17.89 assuming six 100 mg capsules daily. For the generic preparation the average monthly cost is £4.90 for three 100 mg capsules daily or £9.79 assuming six 100 mg capsules daily. Costs may vary in different settings because of negotiated procurement discounts.

3.5 Pentoxifylline (Trental 400, Sanofi-Aventis) is an oral peripheral vasodilator 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.

3.6 Pentoxifylline is available as a 400 mg tablet at a cost of £19.68 for a 90-tablet pack (excluding VAT; BNF edition 60). The recommended dose is one tablet three times daily. Therefore, the average monthly cost is £19.90. However, the summary of product characteristics states that two tablets daily may prove sufficient in some patients, particularly for maintenance therapy. Costs may vary in different settings because of negotiated procurement discounts.

3.7 Inositol nicotinate (Hepoxal, Genus Pharmaceuticals) is an oral peripheral vasodilator that slows 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 stroke. For full details of side effects and contraindications see the summaries of product characteristics.

3.8 Inositol nicotinate is available as a 500 mg tablet at a cost of £30.76 for a 100-tablet pack. It is also available as a 750 mg tablet at a cost of £51.03 for a 112-tablet pack (excluding VAT; BNF edition 60). The recommended dose is 3 g daily (that is, two tablets three times a day), increased to 4 g daily if necessary. The average monthly cost, assuming two 500 mg tablets three times a day, is £56.14. Costs may vary in different settings because of negotiated procurement discounts.

4 Evidence and interpretation

The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).

4.1 Clinical effectiveness

4.1.1 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 peripheral arterial disease whose symptoms continue despite conventional management. The Assessment Group identified 26 randomised controlled trials, including placebo-controlled trials, for all four of the vasoactive drugs. The only head-to head comparison was between cilostazol and pentoxifylline. The Assessment Group stated that quality of the trials was generally good: treatment groups within trials were comparable, blinding was maintained and trials presented intention-to-treat analyses.

Cilostazol: Maximum walking distance

4.1.2 The Assessment Group identified 11 randomised controlled trials of cilostazol 200 mg compared with placebo. In addition, three randomised controlled trials of cilostazol 200 mg compared with pentoxifylline 1200 mg and one randomised controlled trial of cilostazol 200 mg (with or without supervised exercise) compared with usual care (with or without supervised exercise) were identified. The duration of treatment of the randomised controlled trials 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 the trials were maximum walking distance (before having to stop because of pain), pain-free walking distance (before developing claudication pain), ankle brachial pressure index, cardiovascular events, mortality, adverse events and health-related quality of life. The mean baseline age of the participants across the trials ranged from 63 to 67 years. The number of participants in the trials ranged from 81 to 1435. Two out of the 11 randomised controlled trials recruited patients from the UK (n = 38,106).

4.1.3 Of the 11 trials of cilostazol 200 mg compared with placebo, ten reported the outcome of maximum walking distance. Seven out of the ten trials showed a statistically significant improvement in maximum walking distance with cilostazol compared with placebo. Two of the studies reported mean improvement in percentages. One of these reported 161.7% mean improvement for the cilostazol group compared with 79% mean improvement for the placebo group. The other reported a 30.5% improvement for the cilostazol group and a 9.3% worsening for the placebo group. The other studies reported mean improvement in metres. The individual results for the cilostazol groups compared with placebo were: 76.2 metres versus 21.1 metres, 107 metres versus 65 metres, 129.1 metres versus 26.8 metres, 96.4 metres versus 31.4 metres and 72.7 metres versus 25.8 metres. Three trials that compared cilostazol with pentoxifylline reported the outcome of maximum walking distance. Only one of these trials found a statistically significant improvement in maximum walking distance for cilostazol compared with pentoxifylline (mean maximum walking distance improved by 107 metres with cilostazol compared with  64 metres with pentoxifylline [p = 0.0002]). The other two studies showed no significant difference between cilostazol and pentoxifylline. One trial compared cilostazol (with or without supervised exercise) with usual care (with or without supervised exercise). The results of this trial showed that all treatment groups improved, but that greater improvement occurred when cilostazol was added to supervised exercise (mean ratio – change in maximum walking distance: cilostazol plus exercise 2.58, cilostazol without exercise 1.69, usual care plus exercise 1.45, usual care without exercise 1.09, p = 0.005).

Cilostazol: Pain-free walking distance

4.1.4 For cilostazol 200 mg compared with placebo, 10 trials reported the outcome of pain-free walking distance. Of these, five trials showed a statistically significant improvement in pain-free walking distance with cilostazol compared with placebo. In two of the trials, the mean difference in metres was reported. The results were 94 metres versus 57 metres and 68 metres versus 23 metres for cilostazol compared with placebo respectively. One trial reported results in percentages: which showed, a 31.7% improvement with cilostazol compared with a 2.5% worsening for those randomised to the placebo group. One trial reported a p value only (p < 0.05) and another one showed a net improvement of 22% between groups comparison favouring cilostazol.

4.1.5 Three trials of cilostazol compared with pentoxifylline reported the outcome of pain-free walking distance, of which one found a statistically significant improvement for the group randomised to cilostazol compared with pentoxifylline (mean pain-free walking distance improved by 94 metres for those patients in the cilostazol group compared with 74 metres for those in the pentoxifylline group [p = 0.02]).The results of the one trial comparing cilostazol (with or without supervised exercise) with usual care (with or without supervised exercise) showed an improvement in pain-free walking distance for all four treatment groups (that is, cilostazol with supervised exercise, cilostazol without supervised exercise, usual care with supervised exercise and usual care without supervised exercise), but there was no statistically significant effect of cilostazol when added to supervised exercise or usual care (mean ratio – change in maximum walking distance: cilostazol plus supervised exercise 3.84, cilostazol without supervise exercise 3.34, usual care plus supervised exercise 2.22, usual care without supervised exercise 1.23).

Naftidrofuryl oxalate: Maximum walking distance and pain-free walking distance

4.1.6 The Assessment Group identified four randomised controlled trials of naftidrofuryl oxalate 600 mg compared with placebo and one randomised controlled trial of naftidrofuryl oxalate 300 mg compared with placebo. The duration of treatment of the trials ranged from 12 weeks to 24 weeks; three were 24 weeks long and two were 12 weeks long. The outcomes included in these studies were maximum walking distance, pain-free walking distance, ankle brachial pressure index, cardiovascular events, mortality, adverse events and health related quality of life. The mean baseline age of the participants receiving naftidrofuryl oxalate in three of the trials ranged from 58 to 67 years. Baseline age of participants in the remaining trials was not reported in the assessment report. The number of participants in the trials ranged from 50 to 754 .Only one randomised controlled trial recruited UK patients (n = 50).

4.1.7 Two trials of naftidrofuryl oxalate 600 mg compared with placebo 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). In this trial, the maximum walking distance of patients randomised to naftidrofuryl oxalate was improved by 158.7 metres compared with 28.1 metres for placebo. For the outcome of pain-free walking distance, five trials that compared of naftidrofuryl oxalate with placebo reported this outcome. Four of the trials showed a statistically significant improvement in pain-free walking distance with naftidrofuryl oxalate compared with placebo (mean difference in metres were 204.0, 158.2, 201.4 and 93.0 for those in the naftidrofuryl oxalate groups compared with 51.0, 29.9, 98.0 and 36.0 for those in the placebo group respectively). 

Pentoxifylline: Maximum walking distance and pain-free walking distance

4.1.8 The Assessment Group identified nine randomised controlled trials of pentoxifylline 1200 mg compared with placebo. The treatment durations ranged from 8 weeks to 52 weeks (one had a treatment duration of 52 weeks, six of 24 weeks, and two of 8 weeks. The outcomes included in these trials were maximum walking distance, pain-free walking distance, ankle brachial pressure index, cardiovascular events (and cardiovascular events leading to withdrawal), mortality, adverse events and health related quality of life. The mean baseline age of the participants receiving pentoxifylline ranged from 59 to 68 years. The number of participants in the trials ranged from 24 to 524. None of the nine randomised controlled trials recruited patients from the UK.

4.1.9 Eight out of the nine 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. One of these trials reported a 13.9% improvement for those in the pentoxifylline group compared with 3.3% improvement for those in the placebo group. The other trial reported a mean difference improvement of 136 metres for those in the pentoxifylline group compared with 6 metres for those in the placebo group.

4.1.10 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 with pentoxifylline compared with placebo. One of these reported a mean difference improvement of 74 metres with pentoxifylline compared with 57 metres with placebo (p = 0.07). The other trial reported a 47% improvement by geometric mean for the pentoxifylline group compared with 26% for the placebo group (2-sided p = 0.042).

Inositol nicotinate: Maximum walking distance

4.1.11 The Assessment Group identified three randomised controlled trials of inositol nicotinate 4 g compared with placebo. The treatment duration in each of the trials was 12 weeks. The outcomes included in these studies were pain-free walking paces, maximum walking distance, ankle brachial pressure index, time to claudication, cardiovascular events, mortality and adverse events. The mean baseline age of the participants receiving inositol nicotinate ranged from 61 to 68 years. The number of participants in the trials ranged from 80 to 123. One reported the outcome of maximum walking distance. The results of this trial showed no statistically significant differences between the groups given inositol nicotinate and placebo. None of the three trials reported pain-free walking distance.

Assessment Group meta-analyses

4.1.12 The Assessment Group conducted a meta-analysis of the data for maximum walking distance for cilostazol relative to placebo, reanalysing results from a previous Cochrane review. A random effects meta-analysis of the change in walking distance from baseline showed that treatment with cilostazol compared with placebo resulted in an increase of 52.27 metres (95% credible interval (interval estimate based on Bayesian techniques) 24.93 to 86.57).

4.1.13 The Assessment Group undertook a network meta-analysis of the data for maximum walking distance for the overall comparison of treatment options. The objective of the meta-analysis was to estimate the effect of treatment for each drug in comparison with placebo, and, if possible, compared with each other. This consisted of an analysis of the change from baseline to end of study in log mean maximum walking distance (log metre) from ten out of the 26 trials (leading to 16 comparisons) that the Assessment Group had indentified for cilostazol, naftidrofuryl oxalate and pentoxifylline. Reasons for excluding studies included that studies were less than 24 weeks in duration, lacked endpoints (for example, maximum walking distance or pain free walking distance), did not report results, used inappropriately low drug dosages, or were secondary analyses. The Assessment Group stated that inositol nicotinate was not included in the meta-analysis because of the lack of 24-week data. The network of evidence consisted of seven two-arm, and three three-arm, 24 week trials. The Assessment Group transformed the data on maximum walking distance to the logarithm scale to produce a scale on which the treatment effects could be assumed to be linear.

4.1.14 The random effects meta-analysis of the change from baseline to end of study in log mean maximum walking distance showed that the greatest increase compared with placebo was for naftidrofuryl (60.3%), followed by cilostazol (24.6%) and pentoxifylline (10.6%). The 95% credible intervals for naftidrofuryl oxalate and cilostazol suggested that there was an increase in the percentage change from baseline walking distance when compared with placebo, although there was some uncertainty about the true effect. Variation between studies was moderate, suggesting that the treatment effect varied depending on the characteristics of the study.

4.1.15 The Assessment Group also undertook a network meta-analysis of the data for pain-free walking distance for the overall comparison of treatment options. This included the same trials as the meta-analysis of maximum walking distance. The random effects meta-analysis of the change from baseline in log pain-free walking distance showed that treatment with naftidrofuryl oxalate 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 oxalate and cilostazol compared with placebo resulted in increases in the percentage change from baseline pain-free walking distance, although there was some uncertainty about the true effect. Variation between studies was moderate, suggesting that the treatment effect varied depending on the characteristics of the study.

Adverse events

4.1.16 The reporting of adverse event data varied across the trials. A number of trials reported only adverse events that led to discontinuation of the drug or had unclear clinical criteria for adverse events. Only two trials that reported adverse events had follow-up of over 24 weeks. These factors meant the Assessment Group could not undertake a meta-analysis of adverse events. 

4.1.17 Of the 26 trials included in the Assessment Group’s systematic review, 18 reported on deaths (nine comparing cilostazol with placebo, two comparing cilostazol with pentoxifylline, one comparing naftidrofuryl oxalate with placebo, five comparing pentoxifylline with placebo and one comparing inositol with placebo). Follow-up was relatively short and no significant differences in mortality rates were reported between treatment groups.

4.1.18 Cardiovascular events were reported in 18 of the 26 trials identified by the Assessment Group (eight comparing cilostazol with placebo which were included in a published analysis of adverse events, one comparing naftidrofuryl oxalate with placebo, six comparing pentoxifylline with placebo, and three comparing inositol nicotinate with placebo). No significant differences in cardiovascular events were observed between treatment groups.

4.1.19 With respect to other adverse events, eight of the trials comparing cilostazol with placebo were included in a published analysis of adverse events. The results showed a higher frequency of headaches, diarrhoea, peripheral oedema and palpitations in the cilostazol groups than in the placebo groups. In three trials that compared cilostazol with pentoxifylline similar rates of serious adverse events and adverse events were reported in both treatment groups.

4.1.20 In the studies that compared pentoxifylline with placebo, similar rates of adverse and serious adverse events were reported in both groups. Non-serious adverse events were mostly headaches or gastro-intestinal complaints.

4.1.21 In the studies that compared 600 mg or 300 mg of naftidrofuryl oxalate with placebo the rates of adverse events and serious adverse events were similar between treatment groups.

4.1.22 Four trials that compared inositol nicotinate with placebo reported only adverse events that led to withdrawal from trials, and these were similar between treatment groups and mostly related to difficulty swallowing or gastrointestinal problems.

4.2 Cost effectiveness

4.2.1 None of the manufacturers submitted cost-effectiveness evidence.

4.2.2 The Assessment Group developed a de novo Markov economic model to estimate the cost effectiveness of the vasoactive drugs cilostazol, naftidrofuryl oxalate and, pentoxifylline compared with each other and with no vasoactive drugs. The Assessment Group stated that it excluded inositol nicotinate from the main analysis because it had not been possible to include it in the meta-analyses of maximum walking distance and pain-free walking distance. Instead, the cost effectiveness of inositol nicotinate was assessed in a threshold analysis to determine how effective (in terms of quality-adjusted life years [QALYs]) inositol nicotinate would have to be to consider it a cost-effective use of NHS resources.

4.2.3 The model had three distinct health states: vasoactive drug treatment (in which patients received one of the four drugs under evaluation), no vasoactive drug treatment (in which patients received none of the four drugs or had received the drug but had discontinued it) and death. The Assessment Group did not include progression of disease in the economic model because the drugs under evaluation are for symptom relief and not assumed to have an effect on disease progression or cardiovascular events. The model assumed that treatment with vasoactive drugs improved quality of life. The model assumed that a person could stop drug treatment because of adverse events, deaths or of other reasons of non-adherence. The model assumed no further benefit once drug treatment was stopped. The model had a cycle of 1 week and a lifetime horizon.

4.2.4 The population included in the economic model comprised people with peripheral arterial disease, whose intermittent claudication had been stable for at least 3 months and whose symptoms continue despite conventional management (such as smoking cessation and exercise). The Assessment Group chose 66 years as the average age of patients with intermittent claudication (based on one of the trials comparing cilostazol with placebo which had the longest follow-up period and the largest sample size of all randomised controlled trials included in the Assessment Group’s systematic review. The economic model did not distinguish between people followed in primary or secondary care. An exploratory subgroup analysis was presented for people who have more severe intermittent claudication who might have angioplasty after stopping one of the vasoactive drugs.

4.2.5 Only two randomised controlled trials (both for cilostazol) included in the Assessment Group’s systematic review provided quality of life data from SF-36. The Assessment Group converted these to utility values using a published algorithm. The Assessment Group requested patient-level or summary SF-36 data from the authors of both trials in which the SF-36 questionnaire was used. The Assessment Group aimed to use the data to determine a relationship between the change in mean walking distance and the change in SF-36 to the change in utility scores, which it could then use to estimate the utility gain for each of the four vasoactive drugs. The authors of one trial comparing cilostazol with no vasoactive treatment provided a complete set of patient-level data (n = 106) for mean walking distance and SF-36 scores.

4.2.6 The Assessment Group used a published SF-36 conversion algorithm to estimate the utility values at week 0 and 24. The patient-level data were used to test for a correlation between the change in maximum walking distance and the change in utility values from week 0 to week 24. The Assessment Group then used a linear regression model to estimate the absolute changes in utility values from the absolute change in the maximum walking distance on the logarithm scale during the period of the randomised controlled trial. A regression model was applied to all four treatments and to no vasoactive treatment to estimate the absolute changes in utility values given a certain change in mean walking distance from week 0 to week 24. The Assessment Group also estimated a mean baseline (that is, at week 0) utility value of 0.4838 using the patient-level data.

4.2.7 The Assessment Group applied utility estimates by age for the general population (that is, for people without intermittent claudication) from a published algorithm. The Assessment Group then adjusted these age-related utility values for the general population downwards to account for the lower average utility associated with intermittent claudication. The Assessment Group estimated that at 24 weeks the mean utility of a person who had not been treated with a vasoactive drug was 0.4873, compared with values of 0.4973 for cilostazol, 0.5088 for naftidrofuryl oxalate and 0.4919 for pentoxifylline.

4.2.8 The Assessment Group assumed that mortality rates did not differ whether a patient received treatment or not, or by which treatment a patient received because vasoactive treatment provides only symptomatic relief and is unlikely to affect the progression of peripheral vascular or other cardiovascular disease. The Assessment Group obtained the death rates in the general population from the life tables for England and Wales (Office for National Statistics, 2008). The mortality of the general population was multiplied by the relative risk of mortality for patients with intermittent claudication (1.6) based on a study of the risk of mortality and cardiovascular disease associated with low ankle-brachial pressure index

4.2.9 The costs of the drugs were based on the drug tariff of October 2010. If there is more than one licensed dose available, the cost was based on the doses used with the trials included in the Assessment Group’s systematic review. In the base case, the model used the cost of generic naftidrofuryl oxalate, but the Assessment Group explored the impact on the incremental cost-effectiveness ratio (ICER) of using the price of the branded preparation in sensitivity analyses. The Assessment Group assumed that no difference existed in the costs of diagnosis and frequency of follow-up visits between treatment with or without the vasoactive drugs.

4.2.10 The base-case results suggested that naftidrofuryl oxalate has the lowest additional cost (£298) compared with no vasoactive drug and cilostazol has the highest additional cost (£964). The additional cost of pentoxifylline was £493. Naftidrofuryl oxalate was estimated to increase QALYs by 0.049 compared with no vasoactive drug. Pentoxifylline was estimated to have the smallest QALY gains (0.009) compared with no vasoactive drug. Cilostazol increased QALYs by 0.019 compared with no vasoactive drug. Overall, the results showed that both pentoxifylline and cilostazol are dominated by naftidrofuryl oxalate, which has higher total QALYs and lower additional costs. The ICERs for cilostazol, naftidrofuryl oxalate, and pentoxifylline compared with no vasoactive drug were estimated to be £50,737, £6070 and £54,777 per QALY gained respectively.

4.2.11 The Assessment Group undertook a number of one-way sensitivity analyses. These were: assuming that the utility value remains the same as when on the drug if the drug is stopped after 24 weeks; alternative baseline utility values; alternative cost for naftidrofuryl oxalate (use of the price of the branded preparation); shorter time horizon; alternative starting age (55 years); alternative long-term discontinuation rates; and angioplasty procedures for patients stopping vasoactive treatment within 24 weeks. The results of the sensitivity analyses indicated that the ICERs of naftidrofuryl oxalate were relatively insensitive to different baseline utility values, alternative starting ages, and alternative long term discontinuation rates. However, the ICER of naftidrofuryl oxalate decreased to £1538 per QALY gain when the effectiveness associated with the vasoactive drugs was assumed to continue over a patient’s lifetime when they stop the drug after 24 weeks. In all of these sensitivity analyses, both cilostazol and pentoxifylline are dominated or extendedly dominated. The Assessment Group undertook an exploratory subgroup analysis in which it was assumed that patients would receive angioplasty when stopping vasoactive treatment within 24 weeks. This analysis showed that if the utility value associated with angioplasty was higher than the utility value associated with naftidrofuryl oxalate, the ICERs of no vasoactive drugs compared with naftidrofuryl oxalate were less than £20,000 per QALY gained. .Cilostazol and pentoxifylline were either dominated by naftidrofuryl oxalate or by no vasoactive drug. The Assessment Group also explored the impact on the incremental cost-effectiveness ratio (ICER) of using the price of the branded preparation of naftidrofuryl oxalate in a sensitivity analysis which increased the ICER to £11,060 per QALY gained. In all of the sensitivity analyses performed by the Assessment Group, both cilostazol and pentoxifylline were dominated or extendedly dominated by naftidrofuryl oxalate.

4.2.12 The Assessment Group provided threshold analyses that estimated the number of QALYs each drug would have to generate to result in ICERs below £20,000 and £30,000 per QALY gained. These analyses showed that naftidrofuryl oxalate needed the smallest QALY gains compared with no vasoactive treatment: QALY gains of 0.015 and 0.010 were needed for the ICERs to be below £20,000 and £30,000 per QALY gained respectively. For pentoxifylline QALY gains of 0.025 and 0.016 were needed for the ICERs to be below £20,000 and £30,000 per QALY gained respectively. For cilostazol QALY gains of 0.048 and 0.032 were needed for the ICERs to be below £20,000 and £30,000 per QALY gained respectively). For Inositol nicotinate QALY gains 0.085 and 0.056 were needed for the ICERs to be below £20,000 and £30,000 per QALY gained respectively.

4.3 Consideration of the evidence

4.3.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate having considered evidence on the nature of intermittent claudication in people with peripheral arterial disease and the value placed on the benefits of these vasoactive drugs by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.3.2 The Committee discussed the current clinical management for intermittent claudication in people with peripheral arterial disease. It heard that it is common practice for a specialist vascular clinic to diagnose patients with intermittent claudication before drug treatment to relieve symptoms is started. The Committee heard that diagnosis and treatment with vasoactive drugs can take place in primary care. The Committee heard from the clinical specialists that vasoactive therapy was an important part of treatment for intermittent claudication, but is just one part of a wider programme of management involving both pharmacological (for example, antiplatelet and statin therapy to prevent myocardial infarction and stroke) and non-pharmacological treatment including changes in life style (for example, smoking cessation), exercise programmes, and revascularisation (for example, angioplasty). The clinical specialists highlighted the importance of lifestyle changes and exercise programmes, in particular supervised programmes in the clinical management of the condition. The clinical specialists also noted that few patients in the NHS had access to these supervised programmes in England and Wales. The clinical specialists emphasised that vasoactive drugs relieve symptoms and do not delay progression of peripheral arterial disease or lower the incidence of myocardial infarction and stroke. In addition, the clinical specialists explained that prescribing of vasoactive therapies varies across clinical practice, but that cilostazol and naftidrofuryl oxalate were more commonly prescribed than pentoxifylline and inositol nicotinate. The Committee was aware that a NICE clinical guideline on ‘Lower limb peripheral arterial disease: diagnosis and management’ is being developed to address the variation in clinical practice.

4.3.3 The clinical specialists said that most clinicians offer vasodilator therapy only to those patients for whom angioplasty is considered an inappropriate treatment or in whom angioplasty has failed, although some offer vasodilator therapy before assessing whether angioplasty would be appropriate. The clinical specialists also noted that vasoactive drugs would be offered to patients who do not have easy access to a supervised exercise programme or for whom a trial of supervised exercise of 8–16 weeks did not improve the symptoms of claudication.

4.3.4 The Committee considered groups of patients in whom the clinical pathway might differ, and heard from the clinical specialists that patients with diabetes might be less likely to have atherosclerotic disease that could be treated with angioplasty. The Committee heard that patients with diabetes were more likely to have intermittent claudication than people without diabetes, but that a person with diabetes was more likely to have peripheral arterial disease without symptoms of pain. Given the evidence, the Committee accepted that there was no group of patients in which the clinical pathway might differ.

4.3.5 The Committee discussed the clinical need of people with intermittent claudication. It was aware that severe pain on physical exertion has a large impact on the quality of life, resulting largely from restricted mobility. This may lead to loss of independence, limited social life and decreased participation in recreation and work activities. The Committee concluded that intermittent claudication negatively affects quality of life.

4.3.6 The Committee considered the evidence for the clinical effectiveness of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate presented by the Assessment Group. The Committee noted that the trials reported a number of endpoints measuring efficacy including maximum walking distance, pain-free walking distance and the ankle brachial pressure index. The Committee heard from the clinical specialists that neither the ankle brachial pressure index nor pain-free walking distance were clinically relevant outcome measures. The ankle brachial pressure index is used in clinical practice only as a diagnostic tool for peripheral arterial disease and that a patient was unlikely to be offered treadmill testing in the course of routine clinical practice. In addition, assessing maximum walking distance can be difficult to interpret without using the fixed-speed treadmill because patients usually adjust the speed of their walking to avoid pain and to maximise walking distance. The Committee agreed that it was appropriate to focus on the Assessment Group’s analyses of maximum walking distance.

4.3.7 The Committee considered the differences in clinical effectiveness between cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate from the maximum walking distances reported in the randomised controlled trials. It noted that the majority of the trials compared the four drugs with placebo and that the only head-to-head comparison was that of cilostazol compared with pentoxifylline. The Committee was aware that the size of the treatment effect reported in the trials for each of the drugs varied. The Committee heard from the clinical specialists that a clinically significant improvement in maximum walking distance approximated 50 meters, or, in relative terms, a 100% increase. The Committee also noted that in the trials, patients randomised to both treatment and placebo groups tended to improve. However, the Committee recognised that the evidence for cilostazol and naftidrofuryl oxalate showed that there was a clinically significant improvement in maximum walking distance compared with the placebo groups.

4.3.8 The Committee discussed the Assessment Group’s network meta-analysis that estimated the change from baseline in log maximum walking distance. It was aware that the Assessment Group had excluded trials of inositol nicotinate because the trials had follow-up periods of only 12 weeks and it considered the data reported in the trials to be unsuitable (there was no information on change in percentage change from baseline) for inclusion in the meta-analysis. The Committee noted from the meta-analysis that treatment with naftidrofuryl oxalate had the greatest effect relative to placebo, that is, a 60% increase from baseline walking distance, followed by cilostazol (25%) and pentoxifylline (11%). Given these results, the Committee considered whether it would be appropriate to infer a difference in the clinical effectiveness of the drugs. The Committee noted the wide credible intervals around the estimates of effectiveness, indicating a high degree of uncertainty. The Committee discussed the duration of follow-up of the trials, the heterogeneity of the studies, and the generalisability of the studies to the population in England and Wales. For example, the Committee heard that, in general, the trials did not differentiate between patients who did or did not have previous exercise therapy. The Committee also discussed the single trial of naftidrofuryl oxalate included in the meta-analysis. The Committee considered that the above-listed issues contributed to uncertainty in the results of the meta-analysis. 

4.3.9 The Committee discussed the duration of follow-up of the trials included in the network meta-analysis. The Committee noted that the trials had a follow-up of 24 weeks, which it understood to be relatively short-term compared with clinical practice, in which patients could take vasoactive drugs indefinitely. The Committee heard that trials in which an effect was seen at 24 weeks generally had also showed an effect at 12 weeks. The Committee heard from the clinical specialists that in current clinical practice clinicians stop vasoactive therapy if there is not an adequate response to treatment after 12 weeks. The Committee also heard from the Assessment Group that the trials of inositol nicotinate excluded from the meta-analysis were excluded for reasons other than their duration (for example, they did not include data on maximum walking distance or were reported in a way that did not allow comparison of results across studies). The Committee heard that there is no agreement about the magnitude of improvement in walking distance needed to define an adequate response to vasoactive therapy. The Committee considered whether the impact of the vasoactive drugs on walking distance was likely to be sustained in the long term. However, the clinical specialists did not expect that if effective treatment was stopped for a reason other than inadequate response that a patient would continue to experience relief of symptoms. The Committee accepted that the duration of follow-up of the trials did not lead to uncertainty around the size of effect.

4.3.10 The Committee then considered the heterogeneity of the results of the trials included in the network meta-analysis. The Committee considered whether this could lead to bias in the analyses of the comparative clinical effectiveness of cilostazol, naftidrofuryl oxalate and pentoxifylline. The Committee heard from the Assessment Group that the eligibility criteria and baseline characteristics of patients recruited were similar across the trials. However, the heterogeneity was a result of the changes in standard clinical practice over time, which is reflected in the fact that the publication dates of the included trials spanned 20 years (from 1989 to 2009). The Committee noted that the point estimates for maximum walking distance for cilostazol, naftidrofuryl oxalate and pentoxifylline compared with placebo obtained from the meta-analysis were similar to those obtained from the direct estimates from the randomised clinical trials, but were associated with narrower credible intervals, indicating a greater degree of certainty about the effectiveness point estimates. The Committee accepted that the heterogeneity in the results could lead to bias in the estimated effectiveness of these drugs, but was persuaded that the relative benefits in terms of improvement in maximum walking was plausible given the empirical data.

4.3.11 The Committee noted that only one out of five trials of naftidrofuryl oxalate compared with placebo identified by the Assessment Group was included in the meta-analysis, and in particular that the Assessment Group had excluded the largest trial, which included over 700 participants. The Assessment Group highlighted that the excluded trials including the largest trial with 700 participants, did not include data on maximum walking distance or that data on maximum walking distance was not comparable across studies. The Committee accepted the rationale for only including one trial of naftidrofuryl oxalate in the meta-analysis.

4.3.12 The Committee discussed the adverse events seen in the trials of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate. It noted that the data from the trials suggested that non-serious adverse events (such as headaches and gastrointestinal complaints) and serious adverse events (such as cardiovascular events and death) did not differ between the groups given vasoactive drugs compared with placebo. The Committee appreciated that the trials were not designed to address mortality, and, in any event, were too short or too small to detect a difference if one existed. The Committee also noted that the clinical specialists did not have concerns about the long-term safety of the vasoactive drugs. The Committee concluded that based on the currently available information, there were no major concerns regarding the adverse effects of vasodilator drugs.

4.3.13 The Committee concluded that based on the Assessment Group’s network meta-analysis, cilostazol, naftidrofuryl oxalate and pentoxifylline improved maximum walking distance compared with placebo. In addition the Committee concluded that naftidrofuryl oxalate had been demonstrated to be more effective than cilostazol and pentoxifylline. Because the meta-analysis did not include any information on the clinical effectiveness of inositol nicotinate, the Committee concluded that it was unable to assess the efficacy of inositol nicotinate compared with cilostazol, naftidrofuryl oxalate and pentoxifylline.

4.3.14 The Committee examined the economic modelling developed for the appraisal and agreed that the Assessment Group’s economic evaluation was of good quality. Because the drugs did not affect the risk of fatal cardiovascular disease, the Committee recognised that the QALYs in the model were driven by the utility gain from increased mobility rather than from any survival benefit. The Committee noted that the utility values used in the model were derived from a regression model using the change of maximum walking distance and SF-36 data, based on patient-level data from a trial of cilostazol compared with placebo. The Committee noted that the order of the utility values were consistent with the order of effectiveness of the vasoactive drugs as shown in the meta-analysis. The Committee recognised the limited published evidence for quality of life associated with these drugs, and agreed that the approach used by the Assessment Group to obtain utility values for the economic model was acceptable.

4.3.15 The Committee considered the ICERs derived from the Assessment Group’s economic model of £50,700, £6070, £11,060 and £54,800 per QALY gained for cilostazol, generic naftidrofuryl oxalate, branded naftidrofuryl oxalate and pentoxifylline, respectively, when each was compared with placebo. The Committee was aware that naftidrofuryl oxalate was associated with the largest QALY gain and the lowest cost thereby dominating cilostazol and pentoxifylline. The Committee recognised that there was uncertainty associated with the ICER for naftidrofuryl oxalate because the data for naftidrofuryl oxalate included in the model were derived from only one trial. However, the Committee agreed that the uncertainty associated with the ICERs for naftidrofuryl oxalate could be tolerated because the ICERs were low. It therefore concluded that naftidrofuryl oxalate could be recommended as a cost-effective use of NHS resources for people for whom vasodilator therapy is considered clinically appropriate and that treatment with naftidrofuryl oxalate should be started with the least costly licensed preparation. The Committee agreed that cilostazol and pentoxifylline could not be considered appropriate treatment options because naftidrofuryl oxalate dominates cilostazol and pentoxifylline, and even compared with placebo the ICERs for cilostazol and pentoxifylline exceeded those normally considered to be an acceptable use of NHS resources. The Committee concluded that cilostazol and pentoxifylline could not be recommended as a cost-effective use of NHS resources.  

4.3.16 The Committee considered the Assessment Group’s threshold analysis that assessed the cost effectiveness of inositol nicotinate. The Committee noted that the estimated QALY gains needed for inositol nicotinate compared with placebo to be below £20,000 or £30,000 per QALY gained were 0.085 or 0.056 respectively. The Committee was aware that these QALY gains were much higher than the QALY gains actually calculated for naftidrofuryl oxalate (0.015 and 0.010 respectively). The Committee therefore inferred that in order to achieve the QALY gains necessary for inositol nicotinate to be considered cost effective, it would have to demonstrate considerably greater impacts on quality of life resulting from improvements in maximum walking distance than those demonstrated for the other vasoactive drugs. The Committee agreed that this assumption was not plausible because the only trial in the Assessment Group’s systematic review that reported maximum walking distance for inositol nicotinate did not show an improvement in maximum walking distance as great as that for placebo. The Committee therefore concluded that inositol nicotinate could not be recommended as a cost-effective use of NHS resources.

4.3.17 The Committee considered whether its preliminary recommendations were associated with any issues related to equality legislation and the requirement for fairness. The Committee noted that no issues had been highlighted during the scoping exercise or during the course of the appraisal. The Committee was aware that the prevalence of peripheral arterial disease differs by ethnic groups, but concluded that the preliminary recommendations do not affect access to the technology for any specific groups.

Summary of Appraisal Committee's key conclusions

TA22/8	Appraisal title:		Section
Key conclusion
Naftidrofuryl oxalate is recommended as an option for the treatment of intermittent claudication in people with peripheral arterial disease for whom vasodilator therapy is considered clinically appropriate. The Committee concluded that there was uncertainty about the ICERs because the model included data from only one clinical trial of naftidrofuryl oxalate, but that this uncertainty could be tolerated in light of an ICER of £6070 per QALY gained for the generic preparation of naftidrofuryl oxalate. Cilostazol, pentoxifylline and inositol nicotinate are not recommended for the treatment of intermittent claudication in people with peripheral arterial disease. This is because naftidrofuryl oxalate dominates cilostazol and pentoxifylline, and even compared with placebo the ICERs for cilostazol and pentoxifylline were £50,740 and £54,800 per QALY gained respectively and exceeded than those normally considered to be an acceptable use of NHS resources.
Current practice
Clinical need of patients, including the availability of alternative treatments		The Committee was aware that severe pain on physical exertion has a large impact on the quality of life from a person’s restricted mobility as experienced by people with intermittent claudication. This may lead to loss of independence, limited social life and decreased participation in recreation and work activities. The Committee concluded that intermittent claudication negatively affects quality of life.	4.3.5
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate are vasodilator drugs and have marketing authorisations for the symptomatic relief of intermittent claudication. No specific claims of innovation have been made.	2.8
What is the position of the treatment in the pathway of care for the condition?		The Committee heard from the clinical specialists that vasoactive therapy was an important part of treatment for intermittent claudication, but is just one part of a wider programme of management involving both pharmacological (for example, antiplatelet and statin therapy to prevent myocardial infarction and stroke) and non-pharmacological treatment including changes in life style (for example, smoking cessation), exercise programmes, and revascularisation (for example, angioplasty). The clinical specialists emphasised that vasoactive drugs relieve symptoms and do not delay progression of peripheral arterial disease or lower the incidence of myocardial infarction and stroke. The clinical specialists said that most clinicians offer vasodilator therapy only to those patients for whom angioplasty is considered an inappropriate treatment or in whom angioplasty has failed, although some offer vasodilator therapy before assessing whether angioplasty would be appropriate. An ongoing NICE clinical guideline on ‘Lower limb peripheral arterial disease: diagnosis and management’ is under development.	4.3.2 4.3.3
Adverse effects		The Committee noted that the data from the trials suggested that non-serious adverse (such as headaches and gastrointestinal complaints) and serious adverse events (including cardiovascular events and death) did not differ between the groups given vasoactive drugs compared with placebo. The Committee concluded that based on the currently available information, there were no major concerns regarding the adverse effects of vasodilator drugs.	4.3.12
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The identified trials reported a number of endpoints measuring efficacy including maximum walking distance, pain-free walking distance the ankle brachial pressure index. The Committee agreed that it was appropriate to focus on the Assessment Group’s analyses of maximum walking distance. The majority of the trials compared the four drugs with placebo and that the only head-to-head comparison was that of cilostazol compared with pentoxifylline. The Assessment Group undertook a network meta-analysis that estimated the change from baseline in log walking distance. The network meta-analysis excluded trials of inositol nicotinate.	4.3.6 4.3.7 4.3.8
Relevance to general clinical practice in the NHS		The Committee did not consider the generalisability of the trials to the population in England and Wales as an issue.
Uncertainties generated by the evidence		The Committee noted that the wide credible intervals (from the network meta-analysis of maximum walking distance) around the estimates of effectiveness, indicating a high degree of uncertainty. The Committee discussed the duration of follow-up of the trials, the generalisability of the trials to the population in England and Wales, the heterogeneity of the studies, and the number of trials of naftidrofuryl oxalate. The Committee considered the above-listed issues contributed to uncertainty in the results of the meta-analysis The Committee accepted that the duration of follow-up of the trials did not lead to uncertainty around the size of effect. The Committee accepted that the heterogeneity in the results could lead to bias in the estimated effectiveness of these drugs, but was persuaded that the relative benefits in terms of improvement in maximum walking was plausible given the empirical data. The Assessment Group highlighted that the excluded trials of naftidrofuryl oxalate including the largest trial with 700 participants, did not include data on maximum walking distance or that data on maximum walking distance was not comparable across studies. The Committee accepted the rationale for only including one trial of naftidrofuryl oxalate in the meta-analysis.	4.3.8 4.3.9 4.3.10 4.3.11
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		The Committee considered groups of patients in whom the clinical pathway might differ, and heard from the clinical specialists that patients with diabetes might be less likely to have atherosclerotic disease that could be treated with angioplasty. The Committee accepted that there was no group of patients in which the clinical pathway might differ.	4.3.4
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The Committee considered the differences in clinical effectiveness between cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate from the maximum walking distances reported in the randomised controlled trials. The Committee was aware that the size of the treatment effect reported in the trials for each of the drugs varied. However, the Committee recognised that the evidence for cilostazol and naftidrofuryl oxalate showed that there was a clinically significant improvement in maximum walking distance compared with the placebo groups. The Committee noted from the meta-analysis that treatment with naftidrofuryl oxalate had the greatest effect relative to placebo, that is, a 60% increase from baseline walking distance, followed by cilostazol (25%) and pentoxifylline (11%). The Committee noted that the wide credible intervals around the estimates of effectiveness, indicating a high degree of uncertainty. Because the meta-analysis did not include any information on the clinical effectiveness of inositol nicotinate, the Committee concluded that it was unable to assess the comparative efficacy of inositol nicotinate compared with cilostazol, naftidrofuryl oxalate and pentoxifylline.	4.3.7 4.3.8 4.3.13
Evidence for cost effectiveness
Availability and nature of evidence		The Committee agreed that the Assessment Group’s economic evaluation was of good quality.	4.3.14
Uncertainties around and plausibility of assumptions and inputs in the economic model		Because the drugs did not affect the risk of fatal cardiovascular disease, the Committee recognised that the QALYs in the model were driven by the utility gain from increased mobility rather than from any survival benefit. The Committee noted that the utility values used in the model were derived from a regression model using the change of maximum walking distance and SF-36 data, based on patient-level data from a trial of cilostazol compared with placebo. The Committee noted that the order of the utility values were consistent with the order of effectiveness of the vasoactive drugs as shown in the meta-analysis. The Committee recognised the limited published evidence for quality of life associated with these drugs, and agreed that the approach used by the Assessment Group to obtain utility values for the economic model was acceptable.	4.3.14
Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?		Because the drugs did not affect the risk of fatal cardiovascular disease, the Committee recognised that the QALYs in the model were driven by the utility gain from increased mobility rather than from any survival benefit. The Committee recognised the limited published evidence for quality of life associated with these drugs, and agreed that the approach used by the Assessment Group to obtain utility values for the economic model was acceptable.	4.3.14
Are there specific groups of people for whom the technology is particularly cost effective?		Not applicable.
What are the key drivers of cost effectiveness?		No other key drivers were identified apart from the differences between treatment costs and utility values related to the differences in the walking distance.
Most likely cost-effectiveness estimate (given as an ICER)		The Committee noted the ICERs of £50,740, £6070 and £54,800 per QALY gained for cilostazol, naftidrofuryl oxalate and pentoxifylline respectively and that both cilostazol and pentoxifylline were dominated by naftidrofuryl oxalate. The Committee therefore concluded that naftidrofuryl oxalate could be recommended as a cost-effective use of NHS resources and that treatment with naftidrofuryl oxalate should be started with the least costly licensed preparation. The Committee agreed that cilostazol and pentoxifylline could not be considered appropriate treatment options because naftidrofuryl oxalate dominates cilostazol and pentoxifylline, and even compared with placebo the ICERs for cilostazol and pentoxifylline exceeded those normally considered to be an acceptable use of NHS resources. The Committee concluded that cilostazol and pentoxifylline could not be recommended as a cost-effective use of NHS resources.  The Committee considered the Assessment Group’s threshold analysis that assessed the cost effectiveness of inositol nicotinate. The Committee noted that the estimated QALY gains needed for inositol nicotinate compared with placebo to be below £20,000 or £30,000 per QALY gained were 0.085 or 0.056 respectively. The Committee agreed that this assumption was not plausible because the only trial in the assessment Group’s systematic review that reported maximum walking distance for inositol nicotinate did not show an improvement in maximum walking distance as great as that for placebo. The Committee therefore concluded that inositol nicotinate could not be recommended as a cost-effective use of NHS resources.	4.3.15 4.3.15 4.3.16
Additional factors taken into account
Patient access schemes (PPRS)		Not applicable.
End-of-life considerations		Not applicable.
Equalities considerations and social value judgements		The Committee noted that no issues had been highlighted during the scoping exercise or during the course of the appraisal. The Committee was aware that the prevalence of peripheral arterial disease differs by ethnic groups, but concluded that the preliminary recommendations do not affect access to the technology for any specific groups.	4.3.17

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS in England and Wales on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must usually provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. When there is no NICE technology appraisal guidance on a drug, treatment or other technology, decisions on funding should be made locally.

5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website.

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6 Proposed recommendations for further research

6.1 A trial comparing the long term effectiveness (beyond 24 weeks) of cilostazol, naftidrofuryl oxalate and placebo would be beneficial, which should collect utility data as well as walking distance outcomes.

7 Related NICE guidance

Published

• Clopidogrel and modified-release dipyridamole in the prevention of occlusive vascular events: review of NICE technology appraisal guidance 90. NICE technology appraisal guidance 210 (2010). Available from www.nice.org.uk/guidance/TA210

Under development

NICE is developing the following guidance (details available from www.nice.org.uk):

• Diagnosis and management of lower limb peripheral arterial disease in adults. NICE clinical guideline (publication expected October 2012).

8 Proposed date for review of guidance

8.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in May 2014. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Amanda Adler
Chair, Appraisal Committee
January 2011

Appendix A: Appraisal Committee members, guideline representatives and NICE project team

A Appraisal Committee members

The Appraisal Committee is one of NICE's standing advisory committees. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice chair. Each branch considers its own list of technologies, and ongoing topics are not moved between the branches.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr Amanda Adler (Chair)
Consultant Physician, Addenbrooke's Hospital

Professor Keith Abrams
Professor of Medical Statistics, University of Leicester

Dr Ray Armstrong
Consultant Rheumatologist, Southampton General Hospital

Dr Michael Boscoe
Consultant Cardiothoracic Anaesthetist, Royal Brompton and Harefield NHS Foundation Trust

Mrs Eleanor Grey
Lay member

Mr Sanjay Gupta
YPD Service Case Manager, Southwark Health and Social Care, Southwark PCT

Dr Neil Iosson
General Practitioner

Mr Terence Lewis
Lay Member

Dr Ruairidh Milne

Director of Strategy and Development and Director for Public Health Research at the NIHR Evaluation, Trials and Studies Coordinating Centre at the University of Southampton

Dr Rubin Minhas
General Practitioner and Clinical Director, BMJ Evidence Centre

Dr Sanjeev Patel
Consultant Physician & Senior Lecturer in Rheumatology, St Helier University Hospital

Dr John Pounsford
Consultant Physician, Frenchay Hospital, Bristol

Dr Casey Quinn
Lecturer in Health Economics, Division of Primary Care, University of Nottingham

Mr Alun Roebuck
Consultant Nurse in Critical and Acute Care, United Lincolnshire NHS Trust

Dr Florian Alexander Ruths
Consultant Psychiatrist & Cognitive Therapist at the Maudsley Hospital, London

Mr Navin Sewak
Primary Care Pharmacist, NHS Hammersmith and Fulham

Mr Roderick Smith
Finance Director, West Kent Primary Care Trust

Mr Cliff Snelling
Lay Member

Professor Ken Stein (Vice Chair)
Professor of Public Health, Peninsula Technology Assessment Group (PenTAG), University of Exeter

Professor Andrew Stevens
Professor of Public Health, Department of Public Health and Epidemiology, University of Birmingham

Dr Rod Taylor
Professor in Health Services Research, Peninsula Medical School, Universities of Exeter and Plymouth

Mr Tom Wilson
Director of Contracting & Performance, NHS Tameside & Glossop

B Guideline representatives

The following individuals, representing the Guideline Development Group responsible for developing NICE’s clinical guideline related to this topic, were invited to attend the meeting.

• Professor Jonathan Michaels, Professor of Vascular Surgery, University of Sheffield

C NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Panagiota Vrouchou
Technical Lead

Nicola Hay
Technical Adviser

Jeremy Powell
Project Manager

Appendix B: Sources of evidence considered by the Committee

A The assessment report for this appraisal was prepared by the School of Health & Related Research Sheffield:

• Squires H, Simpson E, Meng Y et al, Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease, October 2010

B The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, assessment report and the appraisal consultation document (ACD). Organisations listed in I and II were also invited to make written submissions and have the opportunity to appeal against the final appraisal determination.

I Manufacturers/sponsors:

• Otsuka

II Professional/specialist and patient/carer groups:

• British Cardiovascular Intervention Society (BCIS)
• British Heart Foundation
• Royal College of Nursing
• Royal College of Physicians

III Other consultees:

• Department of Health
• NHS Luton
• NHS Salford
• Welsh Assembly Government

IV Commentator organisations (without the right of appeal):

• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• Medicines and Healthcare products Regulatory Agency
• NHS Quality Improvement Scotland

C The following individual was selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They participated in the Appraisal Committee discussions and provided evidence to inform the Appraisal Committee’s deliberations. They gave their expert personal view on cilostazol, naftidrofyryl oxalate, pentoxifylline and inositol nicotinate by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD.

• Mr Constantinos Kyriakides, Consultant Vascular Surgeon, Barts and The London NHS Trust, nominated by Otsuka Pharmaceuticals – clinical specialist

D  Representatives from the following manufacturers/sponsors attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• Otsuka