Cost effectiveness of cilostazol compared with naftidrofuryl and pentoxifylline in the treatment of intermittent claudication in the UK

OBJECTIVE: To estimate the cost effectiveness of cilostazol (Pletal) compared to naftidrofuryl and pentoxifylline (Trental) in the treatment of intermittent claudication in the UK. DESIGN AND SETTING: This was a modelling study on the management of patients with intermittent claudication who are 40 years of age or above and have at least six months history of symptomatic intermittent claudication, secondary to lower extremity arterial occlusive disease. The study was performed from the perspective of the UK's National Health Service (NHS). METHODS: Clinical outcomes attributable to managing intermittent claudication were obtained from the published literature and resource utilisation estimates were derived from a panel of vascular surgeons. Using decision analytical techniques, a decision model was constructed depicting the management of intermittent claudication with cilostazol, naftidrofuryl and pentoxifylline over 24 weeks in the UK. The model was used to estimate the cost effectiveness (at 2002/2003 prices) of cilostazol relative to the other treatments. MAIN OUTCOME MEASURES AND RESULTS: Starting treatment with cilostazol instead of naftidrofuryl is expected to increase the percentage improvement in maximal walking distance by 32% (from 57% to 75%) for a 12% increase in NHS costs (from 801 pounds sterling to 895 pounds sterling). Treatment with cilostazol instead of pentoxifylline is expected to increase the percentage improvement in maximal walking distance by 67% (from 45% to 75%) and reduce NHS costs by 2% (from 917 pounds sterling to 895 pounds sterling). Treatment with naftidrofuryl instead of pentoxifylline is expected to increase the percentage improvement in maximal walking distance by 27% (from 45% to 57%) and decrease NHS costs by 14% (from 917 pounds sterling to 801 pounds sterling). CONCLUSION: Within the limitations of our model, starting treatment with cilostazol is expected to be a clinically more effective strategy for improving maximal walking distance at 24 weeks than starting treatment with naftidrofuryl or pentoxifylline and potentially the most cost effective strategy. Moreover, the acquisition cost of a drug should not be used as an indication of the cost effectiveness of a given method of care.     

Cilostazol

Cilostazol is an antiplatelet agent with vasodilating properties that has been used in the treatment of patients with peripheral ischaemia such as intermittent claudication. The drug inhibits platelet aggregation induced by ADP, collagen and arachidonic acid. Unlike aspirin (acetylsalicylic acid), cilostazol inhibits both primary and secondary aggregation. It also acts as a vascular vasodilator by inhibiting calcium-induced contractions while having no direct effect on contractile proteins. In double-blind randomised trials, patients with intermittent claudication receiving cilostazol showed significant improvements versus placebo in terms of time to initial pain and maximal walking or absolute claudication distance; these findings were confirmed by cilostazol patients' positive responses on subscales measuring physical functioning and quality of life. In a 24-week randomised double-blind trial in patients with intermittent claudication, cilostazol 100mg twice daily produced significant improvements in pain-free and maximum walking distances, compared with pentoxifylline (oxpentifylline) 400mg 3 times daily and placebo. Cilostazol has been well tolerated, with the most common adverse events being headache, diarrhoea, abnormal stools and dizziness.     

Health economic impact of olopatadine compared to branded and generic sodium cromoglycate in the treatment of seasonal allergic conjunctivitis in the UK

ABSTRACT

Objective: This study estimated the health economic impact of olopatadine (Opatanol^*) compared to branded cromoglycate (Opticrom^?) and generic sodium cromoglycate in the treatment of seasonal allergic conjunctivitis (SAC) in the UK.

Design and setting: This was a modelling study performed from the perspective of the UK's National Health Service (NHS).

Methods: A decision model was constructed depicting the management of SAC sufferers who are 4 years of age or above over a typical allergy season of 4 months and considers the decision by a GP to initially treat a patient with olopatadine, branded or generic cromoglycate. The analysis assumed both drugs to be equally effective. Consequently, a cost-minimisation analysis was performed to identify the least costly alternative.

Main outcome measures and results: Starting treatment with olopatadine is expected to lead to a healthcare cost of £92 (95% CI: £46; £150) over 4 months compared to £109 (95% CI: £65; £166) with branded cromoglycate and £95 (95% CI: £51; £152) with generic cromoglycate, resulting in a 16% and 3% reduction in healthcare costs respectively over 4 months of treatment. This cost-difference is primarily due to fewer GP visits among olopatadine-treated patients.

Conclusion: Use of olopatadine instead of branded or generic cromoglycate affords an economic benefit to the NHS. Hence, within the limitations of the model, olopatadine is the preferred first-line treatment for use in SAC sufferers, since it is expected to lead to fewer GP visits, thereby releasing healthcare resources for alternative use.     

Oral vasoactive medication in intermittent claudication: utile or futile?

Objective: To evaluate the role of orally administered vasoactive medication in the management of intermittent claudication. Setting: We limited our study to the products on the market in Belgium: cinnarizine, cyclandelate, isoxsuprine, naftidrofuryl, pentoxifylline, xanthinol nicotinate and buflomedil. Data sources: We conducted a systematic literature search involving Medline, International Pharmaceutical Abstracts, the Cochrane Library, direct contact with marketing companies and key authors, snowballing and Science Citation Index search. We looked for randomised placebo-controlled trials (RCTs) in patients with Fontaine stage II, in which pain-free and/or maximal walking distance were measured using a standardised exercise test. For isoxsuprine and xanthinol nicotinate, no trials conforming to these criteria were found. Thirty-six trials on cinnarizine, cyclandelate, buflomedil, naftidrofuryl and pentoxifylline met our inclusion criteria. Study selection: After quality assessment, 26 trials were excluded, mainly because of short trial duration (less than 12 weeks), small sample size (less than 30 patients) and/or failure to report details on variability (standard deviation or confidence limits). For cinnarizine and cyclandelate, none of the three selected RCTs was included. Data extraction: For buflomedil, of six published RCTs, two were included after quality assessment, each showing a marginally positive effect of buflomedil versus placebo. For naftidrofuryl, nine RCTs were selected; six were included of which five showed a significant positive result. The likelihood of publication bias and the heterogeneity of the results within and between trials precluded a meta-analysis. For pentoxifylline, of the 18 selected RCTs, only two could be included, both with inconclusive results. Conclusion: A national consensus conference, based on this review, concluded that health resources should be allocated to prevention and rehabilitation of intermittent claudication rather than to reimbursement of these products with doubtful efficacy. Received: 11 November 1999 / Accepted in revised form: 10 February 2000     

Naftidrofuryl: a review of its use in the treatment of intermittent claudication

Naftidrofuryl (Praxilene) is a vasodilator that has been used in the treatment of intermittent claudication for >30 years in Europe to improve walking distance and provide symptomatic relief. However, earlier trials had inconsistencies in design and the clinical relevance of the treatment effect has been controversial. Recent randomised, double-blind, placebo-controlled trials, however, have generally been conducted in accordance with updated methodology guidelines. In these studies, naftidrofuryl 200mg three times daily improved pain-free and maximal walking distances and health-related quality of life by a significantly greater extent than placebo in patients with intermittent claudication. The magnitude of these effects appears to support claims that the effects of naftidrofuryl are clinically relevant in these patients.     

Cilostazol Treatment of Claudication in Diabetic Patients

Summary

Objective: To compare the efficacy and safety of cilostazol in diabetic and non-diabetic patients from eight (six placebo- and two active-controlled) randomised, double-blind phase III trials.

Design: We only included patients from the trial data set receiving cilostazol 100?mg twice daily (216 diabetic/599 non-diabetic) or placebo (220/616). Efficacy was measured by absolute claudication distance (ACD), using standard treadmill exercise protocols.

Results: Among diabetic and non-diabetic patients, cilostazol was superior to placebo (estimated treatment effect 1.15, 95% confidence interval, 1.05-1.25, p?=?0.001; and 1.24,1.18-1.31, p?<?0.0001, respectively). There was no statistical difference in response between diabetic and non-diabetic subjects. In the efficacy analysis, cilostazol-treated diabetic subjects with the lowest baseline ACD (but not those with greater baseline ACD) walked approximately 34% farther than at baseline,

whereas their non-diabetic counterparts walked 23% farther. There was no significant difference in the adverse event profile of the diabetic and non-diabetic patients on cilostazol. No excess haemorrhagic events occurred in cilostazol-treated diabetic patients. Trial duration varied from 12 to 24 weeks.

Conclusions: Diabetic and non-diabetic patients with intermittent claudication respond favourably to cilostazol, with no significant difference in their overall response. Diabetic individuals with the most severe claudication respond better than those less affected, but the response of non-diabetic patients increases as baseline ACD increases. Adverse event incidence was comparable in the two populations, although diabetic patients might be expected to experience greater morbidity. Cilostazol is a safe and effective treatment for claudication in diabetic and non-diabetic populations.     

Cost-utility of levonorgestrel intrauterine system compared with hysterectomy and second generation endometrial ablative techniques in managing patients with menorrhagia in the UK

ABSTRACT

Objective: To estimate the cost-utility of levonorgestrel intrauterine system (LNG-IUS; Mirena) compared to second generation endometrial ablative techniques [i.e. microwave endometrial ablation (MEA) and thermal balloon endometrial ablation (TBEA)] and hysterectomy in the UK.

Methods: Clinical and utility data from a 5-year randomised controlled trial comparing LNG-IUS with hysterectomy were combined with further data from published studies to construct a state-transition (Markov) model. The model depicted the movement of patients between health states over 5 years following treatment for menorrhagia. The model was used to estimate the cost-utility of LNG-IUS followed by ablation (L-A); LNG-IUS followed by hysterectomy (L-H); immediate ablation (MEA or TBEA) and immediate hysterectomy in the UK at 2004/2005 prices, from the perspective of the UK's National Health Service (NHS).

Main outcome measures and results: The expected 5-yearly cost of treating menorrhagia with L-A, L-H, TBEA, MEA and hysterectomy was estimated to be £828, £1355, £1679, £1812 and £2983 per patient respectively and the expected level of health gain to be 4.14, 4.12, 4.13, 4.13 and 4.01 QALYs per patient respectively. LNG-IUS followed by ablation dominated all the alternative treatments. Hysterectomy was dominated by the alternative treatments. Sensitivity analysis found the model to be sensitive to the quality of life data used.

Conclusion: Within the model's limitations, LNG-IUS followed by ablation appears to offer the NHS a cost-effective treatment for menorrhagia, when compared to immediate surgery, affording the NHS a less expensive treatment modality without detrimental effects on resulting health gain.     

Drug treatment of intermittent claudication

The US FDA has approved two drugs for the management of intermittent claudication: pentoxifylline and cilostazol. The mechanism of action that provides symptom relief with pentoxifylline is poorly understood but is thought to involve red blood cell deformability as well as a reduction in fibrinogen concentration, platelet adhesiveness and whole blood viscosity. The recommended dose of pentoxifylline is 400 mg three times daily with meals. Cilostazol is a potent, reversible, phosphodiesterase III inhibitor. The inhibition of phosphodiesterase allows for the increased availability of cyclic adenosine monophosphate (cAMP). cAMP mediates many agonist-induced platelet inhibitory, vasodilatory and vascular antiproliferative responses. Cilostazol, at a dose of 100 mg twice daily, is recommended to be taken 30 minutes before or 2 hours after breakfast and dinner. In addition to pentoxifylline and cilostazol, clinical trials indicate many other drugs may relieve the symptoms of intermittent claudication. Ginkgo biloba, available as an over-the-counter extract, provides symptom relief comparable to pentoxifylline. Two European agents, naftidrofuryl and buflomedil, also have efficacy that is reported to be similar to pentoxifylline. Policosanol is a mixture of fatty alcohols derived from honeybee wax which, according to very limited data, reduces symptoms of claudication. Amino acids, certain peptides and prostaglandins may have a therapeutic role. Finally, novel approaches including angiogenesis mediated by growth factors, are currently under investigation.     

Cost-effectiveness of macrogol 4000 compared to lactulose in the treatment of chronic functional constipation in the UK

ABSTRACT

Objective: To estimate the cost-effectiveness of macrogol 4000 compared to lactulose in the treatment of chronic functional constipation, from the perspective of the National Health Service (NHS) in the UK.

Methods: A decision model depicting the management of chronic functional constipation was constructed using clinical outcomes and resource use values derived from patients suffering from chronic functional constipation in The Health Improvement Network (THIN) Database. The model was used to estimate the cost-effectiveness of a general practitioner (GP) prescribing macrogol 4000 relative to lactulose to treat adults ≥18 years of age suffering from chronic functional constipation.

Results: Forty-two per cent (95% confidence interval [CI]: 38%; 46%) of macrogol 4000-treated patients are expected to be successfully treated within 3 months after starting treatment, compared to 31% (95% CI: 27%; 37%) of lactulose-treated patients. Patients' health status at 3 months was estimated to be 0.213 (95% CI: 0.200; 0.223) and 0.210 (95% CI: 0.197; 0.220) quality-adjusted life years (QALYs) in the macrogol 4000 and lactulose groups, respectively. The total 3-monthly NHS cost of treating patients with macrogol 4000 or lactulose was estimated to be £115 (95% CI: £98; £132) and £102 (95% CI: £86; £119), respectively. Hence, the cost per QALY gained with macrogol 4000 was estimated to be £4333.

Conclusion: Within the limitations of the model, treatment with macrogol 4000 relative to lactulose is expected to increase the probability of being successfully treated by 35% at 3 months (p < 0.0001), although this yields only a 1% improvement in health gain. Nevertheless, macrogol 4000 affords a cost-effective addition to the range of laxatives available for this potentially resource-intensive condition, since it is clinically more effective than lactulose and the cost-effective strategy from the perspective of the NHS.     

Pharmacological approaches to the treatment of intermittent claudication.

Intermittent claudication is a common condition of the elderly, occurring in 3 to 20% of individuals over the age of 65 years. Although local disease is usually benign, life expectancy in patients with intermittent claudication is reduced by approximately 10 years due to associated cardiovascular mortality. Several classes of drugs have been used in intermittent claudication, but clinical studies evaluating their efficacy leave much to be desired. Pentoxifylline (oxpentifylline), a rheological agent, and naftidrofuryl, an enhancer of aerobic metabolism, are the 2 most widely investigated and utilised drugs. The combined results of 10 placebo-controlled studies with pentoxifylline and 4 with naftidrofuryl estimate increases in claudication distances of 51 and 42%, respectively. However, due to publication bias, these figures are probably overestimates of the true benefit from treatment with these drugs. It is likely that any benefit from pentoxifylline or naftidrofuryl is small and of little clinical importance. The suggestion that naftidrofuryl has greater efficacy in older patients remains unproven. Other classes of drugs including vasodilators, antiplatelet drugs, anticoagulants and prostaglandins have not been shown to be effective. Only 2 approaches to the management of intermittent claudication have been shown convincingly to be of benefit: stopping smoking and exercising regularly.     

Modelling the cost-utility of bio‑electric stimulation therapy compared to standard care in the treatment of elderly patients with chronic non-healing wounds in the UK

ABSTRACT

Objective: To estimate the cost-utility of bio-electric stimulation therapy (Posifect^*) compared to standard care in elderly patients with chronic, non-healing wounds of > 6 months duration, from the perspective of the National Health Service (NHS) in the UK.

Methods: Clinical and resource use data from a 16 week clinical evaluation of bio-electric stimulation therapy among patients who had recalcitrant wounds were combined with utility data obtained from a standard gamble analysis to construct a 16 week Markov model. The model considers the decision by a clinician to continue with a patient's previous care plan or treat with bio-electric stimulation therapy. Unit resource costs at 2005/2006 prices were applied to the resource utilisation estimates within the model, enabling the cost-utility of bio-electric stimulation therapy compared to standard care to be estimated. The acquisition cost of Posifect had not been decided at the time of performing this study. Hence, the base case analysis used a cost of £50 per dressing.

Results: 33% of all wounds are expected to heal within 16 weeks after the start of bio-electric stimulation therapy. Consequently, using bio-electric stimulation therapy is expected to lead to a 51% decrease in the number of domiciliary clinician visits, from 4.7 to 2.3 per week. The model also showed that using bio-electric stimulation therapy instead of patients’ standard care is expected to reduce the NHS cost of managing them by 16% from £2287 (95% CI: £1838; £2735) to £1921 (95% CI: £1609; £2233) and result in a health gain of 0.023 QALYs over 16 weeks. Hence, bio-electric stimulation therapy was found to be a dominant treatment. Sensitivity analyses demonstrated that the cost-utility of using bio-electric stimulation therapy relative to standard care is very sensitive to the acquisition cost of the therapy, the acquisition cost of patients’ drugs and the number of clinician visits and less sensitive to utility values and the acquisition cost of other dressings.

Conclusion: Within the limitations of the model, bio-electric stimulation therapy is expected to afford the NHS a cost-effective dressing compared to standard care in the management of chronic non-healing wounds of > 6 months duration. Bio-electric stimulation therapy's acquisition cost is expected to be offset by a reduction in the requirement for domiciliary clinician visits, leading to a release of NHS resources for use elsewhere in the system, thereby generating an increase in NHS efficiency.     

Cilostazol and atherogenic dyslipidemia: a clinically relevant effect?

Introduction: Cilostazol is a reversible, selective inhibitor of PDE3A able to significantly improve walking distance in patients with intermittent claudication. However, beyond its antiplatelet and vasodilator properties, cilostazol seems to have significant effects on atherogenic dyslipidemia.

Areas covered: The effects of cilostazol on plasma lipids, lipoproteins, apolipoproteins and postprandial lipemia are reviewed. A literature search (using Medline and Scopus) was performed up to 24 October 2010. The authors also manually reviewed the references of selected articles for any pertinent material.

Expert opinion: Cilostazol is able to significantly lower plasma triglyceride levels, with a concomitant increase in high-density lipoprotein (HDL) cholesterol concentrations. Additional effects on pro-atherogenic lipoproteins and apolipoproteins include those on remnant-like particles, HDL subclasses, apolipoprotein B and postprandial lipemia. Cilostazol can improve the pro-atherogenic lipid profile in patients with peripheral arterial disease or type 2 diabetes. Further studies are needed to establish whether cilostazol treatment exerts clinically relevant effects on atherogenic dyslipidemia in high-risk patients.     

Pharmacological management of intermittent claudication: a meta-analysis of randomised trials

Intermittent claudication, a symptom of atherosclerosis in the large vessels of the lower limbs, greatly affects patient mobility and quality of life. Medical therapy for a moderate form of this condition includes vasodilators, antiplatelet agents and alternative treatments such as ginkgo biloba.A meta-analysis of results from 52 trials (including 5088 patients) was conducted for all current medical therapies for intermittent claudication. After 24 weeks, some of the medical therapies were found to be more effective than placebo for the primary end-points of either pain-free walking distance or maximum walking distance. Vasodilators presented the best results in walking distance. Pentoxifylline offered better results than naftidrofuryl, although the treatment benefit, measured in additional metres walked with treatment than without, was modest. Antiplatelets, ginkgo biloba and levocarnitine were slightly more effective than placebo, although the treatment benefit was of limited clinical importance. On average, patients walked 60m further with therapy than without, and only about half of that added distance was pain-free. Very little consistent information was available for other clinical end-points, such as overall mortality and adverse effects. These data suggest that some of the medical therapy, pentoxifylline in particular, can only modestly increase functional status in patients with moderate intermittent claudication. There is a need for uniformity in research design and reporting of trials. A future trial comparing medical therapy with physical therapy is indicated.     

Costs and consequences of using pamidronate compared with zoledronic acid in the management of breast cancer patients in the UK

ABSTRACT

Objective: To estimate the costs and consequences of using pamidronate compared to zoledronic acid in the prophylactic management of skeletal morbidity among breast cancer patients in the UK.

Design and setting: This was a modelling study performed from the perspective of the UK's National Health Service (NHS).

Methods: Published clinical outcomes from a comparative study were combined with resource utilisation estimates derived from a panel of clinicians. This enabled the construction of a decision model depicting the management of patients with breast cancer receiving antineoplastic therapy who are 18 years of age or above and who have at least one bone metastasis (lytic or mixed). There are no significant differences in outcome between using pamidronate and zoledronic acid in breast cancer patients. Therefore, a cost minimisation analysis was performed to identify the treatment strategy that achieves the same outcome for least cost. The expected time attributable to a pamidronate and zoledronic acid infusion was also estimated.

Main outcome measures and results: Starting treatment with pamidronate among patients receiving chemotherapy is expected to lead to a healthcare cost of £6046 over 12 months compared to £6981 with zoledronic acid. In comparison, for patients receiving hormonal therapy, starting treatment with pamidronate is expected to lead to a healthcare cost of £5401 over 12 months compared to £6043 with zoledronic acid. This cost difference is primarily due to the lower acquisition cost of pamidronate and fewer tests among pamidronate-treated patients. Accordingly, pamidronate affords a less expensive management modality. Multivariate analysis showed the expected time attributable to a pamidronate infusion to be 110 to 277 minutes compared with 136 to 296 minutes for a zoledronic acid infusion.

Conclusion: Use of pamidronate instead of zoledronic acid affords an economic benefit to the NHS. Moreover, published clinical trials show no statistical difference between pamidronate and zoledronic acid at 1 year. Hence, within the limitations of our model and the published evidence, pamidronate is the preferred first-line intravenous bisphosphonate for use in breast cancer patients receiving antineoplastic therapy who are 18 years of age or above and who have at least one bone metastasis (lytic or mixed).     

Multi-centre general practitioner trial of isoxsuprine in peripheral vascular disease

Summary

The results of a multi-centre general practitioner trial of isoxsuprine in peripheral vascular disease suggest that continuous treatment with isoxsuprine increases the walking distance of patients with intermittent claudication and improves subjective symptoms. One hundred and forty-nine patients completed the 4-month trial.

A survey of this type of peripheral vascular disease has shown that claudication is a far more frequent symptom than trophic skin lesion. The results of the trial show that where no improvement of claudication distance occurs, then no improvement in subjective symptoms can be expected.     

Clinical and economic impact of using macrogol 3350 plus electrolytes in an outpatient setting compared to enemas and suppositories and manual evacuation to treat paediatric faecal impaction based on actual clinical practice in England and Wales

ABSTRACT

Objective: To estimate the clinical and economic impact of using macrogol 3350 plus electrolytes (macrogol 3350; Movicol; Movicol Paediatric Plain) in an outpatient setting compared to enemas and suppositories and manual evacuation to treat paediatric faecal impaction.

Methods: A chart review was undertaken to extract clinical outcomes and resource use from the case notes of a cohort of children aged 2–11 years with faecal impaction who initially received either macrogol 3350 (in an outpatient setting) or enemas and suppositories or manual evacuation for initial disimpaction. Five centres across England and Wales participated in the study. These data were used to inform a decision model which depicted the management of children during the disimpaction phase and for a period of 12 weeks following initial disimpaction. Unit resource costs at 2005/2006 prices were applied to the resource utilisation estimates within the model, enabling the incremental costs and consequences of using macrogol 3350 in an outpatient setting, compared to the other treatments, to be estimated.

Results: 112 patients treated with macrogol 3350, 101 who received enemas and suppositories and 11 who underwent a manual evacuation were eligible for analysis. Ninety-seven per cent of children treated with macrogol 3350 were successfully disimpacted within 5 days, compared to 73% of those who received enemas and suppositories and 89% of those who underwent a manual evacuation (?p < 0.001). There were no significant differences in reported adverse events between the different treatments for disimpaction, with the exception of vomiting which was significantly higher among those who underwent a manual evacuation (18% versus 2% with the other treatments; p < 0.01). There were no significant differences in the number of clinician outpatient visits between treatments. However, macrogol 3350-treated patients had significantly fewer hospital admissions than those who received the other interventions (0.1 versus 1.4 and 1.0 for enemas and suppositories and manual evacuation respectively; p < 0.05) and occupied fewer bed days. The total NHS cost of disimpaction and subsequent maintenance of children initially treated with macrogol 3350 was estimated to be £694 (95% CI: £496; £892). This compared with £2759 (95% CI: £1266; £4252) and £2333 (95% CI: £1609; £3058) for those who initially received enemas and suppositories or underwent a manual evacuation, respectively. Hence, using macrogol 3350 instead of enemas and suppositories and manual evacuation to disimpact the whole annual cohort of faecally impacted children aged 2–11 years in England could potentially reduce annual NHS expenditure on this condition by 59% (£5 million) and reduce the annual number of paediatric hospital admissions for this condition by 92% (4330).

Conclusion: Within the limitations of our model, macrogol 3350 affords the NHS a clinically effective and cost-effective treatment for the disimpaction of children suffering from faecal impaction compared to enemas and suppositories or a manual evacuation, and has the potential to release healthcare resources for alternative use within the system.     

Economic evaluation of etoricoxib versus non-selective NSAIDs in the treatment of ankylosing spondylitis in the UK

ABSTRACT

Objectives: To evaluate the cost-effectiveness of etoricoxib, a cyclooxygenase (COX)‐2 selective inhibitor, versus non-selective nonsteroidal anti-inflammatory drugs (nsNSAIDs) in the treatment of ankylosing spondylitis (AS).

Methods: The cost-effectiveness of etoricoxib versus nsNSAIDs was evaluated from the UK National Health Service (NHS) and society perspective with a decision-analytic model. Patients stayed on initial therapy throughout 52 weeks unless they experienced an adverse event (AE) or lacked efficacy, in which case they switched to another nsNSAID or a tumor necrosis factor alpha antagonist. Efficacy data were obtained from a 1‐year etoricoxib clinical trial in AS. Bath AS Functional Index (BASFI) data were translated into Quality Adjusted Life Year (QALY) weights using a published data on the relation between BASFI and Short-form (SF) 36 Quality of life scores, as well as the relation between SF‐36 and utility. Safety data were based on meta-analyses of etoricoxib trials. Information on treatment pathways, resource consumption, and absenteeism from work was obtained from literature and experts. Model outcomes included QALYs, perforations, ulcers, or bleeds, cardiovascular events, and costs.

Results: Etoricoxib was cost-effective compared to nsNSAIDs in terms of cost per QALY saved (£5611). Probabilistic sensitivity analysis found a 77% probability of the incremental cost per QALY saved being within a threshold for cost-effectiveness of £20?000. The expected direct costs over the 52-week period were £1.23 (95% uncertainty distribution £1.10; £1.39) and £1.13 per day (£0.78; £1.55) for patients starting with etoricoxib and nsNSAIDs, respectively. When costs related to absenteeism were taken into account, the cost per QALY saved was £281.

Conclusions: Given the underlying assumptions and data used, this economic evaluation demonstrated that, compared to nsNSAIDs, etoricoxib is a cost-effective therapy for AS patients in the UK.     

Controlled clinical trial on the efficacy and safety of oral sulodexide in patients with peripheral occlusive arterial disease

Summary

One hundred and seven adult outpatients with Leriche stage II peripheral occlusive arterial disease took part in this open, controlled trial. Patients were randomly treated over a six-month period either with sulodexide capsules containing 250 lipoproteinlipase releasing units (LRU. two capsules twice daily for 176 days on average: 56 patients), or with pentoxifylline 400?mg tablets (one tablet three times a day for 180 days on average: 51 patients). The incidences of diabetes, hyperlipoproteinaemias. smoking habit and other risk factors were the same in the two groups.

The drugs' efficacies were evaluated by monitoring, at the start of treatment and every month during it, the Winsor Index and the walking distance, both prior to (initial claudication distance — IDC) and after (absolute claudication distance — ACD) the symptom's onset. Compliance with treatment and occurrence of adverse events were constantly monitored: systemic tolerability was evaluated through the use of routine haemutological and haematochemical tests.

Both treatments brought about a progressive increa. Se in the claudication-free walking distance, statistically signiificant versus haselitie from the second month (ACD, sulodexide group) and third month (ACD and ICD, pentoxifylline and sulodexide groups).

At the end of treatment. the absolute increase of ACD was significantly greater in sulodexide-treated patients (p < 0.01) with respect to the pentoxifylline-treated group. In both groups the Doppler test evidenced a good improvement in local arterial haemodynamics.

In the sulodexide group, 3.6% of patients developed nausea, dyspepsia and other minor gastrointestinal phenomena In the pentoxifylline group 17.6% of patients complained of gastroenteric disorders (nausea. vomiting, dyspepsia), or of headache and dizziness. In one patient of this latter group insomnia was also present. Systemic tolerance of both drugs was con.sistently good.     

Treatment of intermittent claudication with pentoxifylline and cilostazol.

The pathophysiology of intermittent claudication (IC) and the role of pentoxifylline and cilostazol for treating IC are discussed. IC, a result of inadequate blood flow to the musculature, is the primary symptom of occlusive peripheral vascular disease (PVD). Patients with IC often have a decreased quality of life because of mobility limitations. PVD is a sign of generalized atherosclerosis and increases the risk of cardiac morbidity and mortality. Smoking, hypertension, diabetes mellitus, and increasing age may hasten the progression of PVD. Strategies for treating IC are aimed at improving symptoms and reducing the progression of atherosclerosis and include risk-factor modification, exercise, and antiplatelet therapy. Cilostazol and pentoxifylline are the only two drugs with FDA-approved labeling for use in treating IC. Both drugs have been shown to increase pain-free walking time and total distance walked, although there is some conflicting evidence for pentoxifylline. Cilostazol and pentoxi-fylline are fairly well tolerated; the most common adverse effects involve the gastrointestinal tract and central nervous system. Inhibitors of cytochrome P-450 isoenzymes 3A4 and 2C19 should be used cautiously in patients taking cilostazol, and this drug is contraindicated in patients with congestive heart failure. Cilostazol is more costly than pentoxifylline. Initiation of therapy with either pentoxifylline or cilostazol may be reasonable if risk-factor modifications, lifestyle changes, and antiplatelet therapy are not effective. The mainstays of therapy for IC are risk-factor modification, exercise, and antiplatelet therapy. If these prove inadequate, treatment with pentoxifylline or cilostazol may be reasonable.     

Cilostazol (pletal): a dual inhibitor of cyclic nucleotide phosphodiesterase type 3 and adenosine uptake

Cilostazol (Pletal), a quinolinone derivative, has been approved in the U.S. for the treatment of symptoms of intermittent claudication (IC) since 1999 and for related indications since 1988 in Japan and other Asian countries. The vasodilatory and antiplatelet actions of cilostazol are due mainly to the inhibition of phosphodiesterase 3 (PDE3) and subsequent elevation of intracellular cAMP levels. Recent preclinical studies have demonstrated that cilostazol also possesses the ability to inhibit adenosine uptake, a property that may distinguish it from other PDE3 inhibitors, such as milrinone. Elevation of interstitial and circulating adenosine levels by cilostazol has been found to potentiate the cAMP-elevating effect of PDE3 inhibition in platelets and smooth muscle, thereby augmenting antiplatelet and vasodilatory effects of the drug. In contrast, elevation of interstitial adenosine by cilostazol in the heart has been shown to reduce increases in cAMP caused by the PDE3-inhibitory action of cilostazol, thus attenuating the cardiotonic effects. Cilostazol has also been reported to inhibit smooth muscle cell proliferation in vitro and has been demonstrated in a clinical study to favorably alter plasma lipids: to decrease triglyceride and to increase HDL-cholesterol levels. One, or a combination of several of these effects may contribute to the clinical benefits and safety of this drug in IC and other disease conditions secondary to atherosclerosis. In eight double-blind randomized placebo-controlled trials, cilostazol significantly increased maximal walking distance, or absolute claudication distance on a treadmill. In addition, cilostazol improved quality of life indices as assessed by patient questionnaire. One large randomized, double-blinded, placebo-controlled, multicenter competitor trial demonstrated the superiority of cilostazol over pentoxifylline, the only other drug approved for IC. Cilostazol has been generally well-tolerated, with the most common adverse events being headache, diarrhea, abnormal stools and dizziness. Studies involving off-label use of cilostazol for prevention of coronary thrombosis/restenosis and stroke recurrence have also recently been reported.