Cost-effectiveness of cilostazol, naftidrofuryl oxalate, and pentoxifylline for the treatment of intermittent claudication in people with peripheral arterial disease.

We assessed the cost-effectiveness of cilostazol, naftidrofuryl oxalate, and pentoxifylline for intermittent claudication due to peripheral arterial disease (PAD) in adults whose symptoms continue despite a period of conventional management. A Markov decision model was developed to assess the lifetime costs and benefits of each vasoactive drug compared to no vasoactive drug and with each other. Regression analysis was undertaken to model the relationship between maximum walking distance and utility. Resource use data were sourced from the literature and sensitivity analyses were undertaken. Naftidrofuryl oxalate is more effective and less costly than cilostazol and pentoxifylline and has an estimated cost per quality-adjusted life year gained of around £6070 compared to no vasoactive drug. The analysis uses effectiveness evidence from a network meta-analysis. In contrast to previous guidelines recommending cilostazol, the analysis suggests that naftidrofuryl oxalate is the only vasoactive drug for PAD which is likely to be cost-effective.

Pentoxifylline use in dermatology.

Pentoxifylline is methylxanthine derivative which is used in microcirculatory disorders as a vasoactive drug. Novel immunomodulatory properties of pentoxifylline have been reported including the down regulation of tumour necrosis factor-α synthesis and other inflammatory cytokines. Studies have shown that pentoxifylline might be efficacious in a wide spectrum of skin diseases. This article focuses on the use of pentoxifylline which is a safe and cheap drug in various dermatological disorders.

A systematic review and economic evaluation of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease.

BACKGROUND: Peripheral arterial disease (PAD) is a condition in which there is blockage or narrowing of the arteries that carry blood to the legs and arms. It is estimated to affect around 4.5% of people aged between 55 and 74 years within the UK. The most common symptom of PAD is intermittent claudication (IC), characterised by pain in the legs on walking that is relieved with rest. OBJECTIVE: To assess the effectiveness and cost-effectiveness of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate, compared with no vasoactive drugs, for IC due to PAD in adults whose symptoms continue despite a period of conventional management. DATA SOURCE: Electronic bibliographic databases were searched during April to June 2010 (MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Conference Proceedings Citation Index, BIOSIS Previews). REVIEW METHODS: Effectiveness outcomes sought were maximal walking distance (MWD), pain-free walking distance (PFWD), ankle-brachial pressure index, cardiovascular events, mortality, adverse events (AEs) and health-related quality of life (HRQoL). A narrative synthesis was provided for all outcomes and a network meta-analysis was undertaken for the walking distance outcomes. A Markov model was developed to assess the relative cost-effectiveness of the interventions from a NHS perspective over a lifetime. The model has three states: vasoactive drug treatment, no vasoactive drug treatment and death. Each 1-week cycle, patients may continue with the drug, discontinue the drug or die. Regression analysis was undertaken to model the relationship between MWD and utility so that a cost per quality-adjusted life-year (QALY) outcome measure could be presented. Univariate and probabilistic sensitivity analyses were undertaken. All costs and outcomes were discounted at 3.5%. RESULTS: Twenty-six randomised controlled trials were identified that met the inclusion criteria for the clinical effectiveness review. There was evidence that walking distance outcomes were significantly improved by both cilostazol and naftidrofuryl oxalate; the 95% credible intervals for the difference from placebo in the logarithm mean change MWD from baseline were 0.108 to 0.337 and 0.181 to 0.762, respectively. It was not possible to include inositol nicotinate within the meta-analysis of MWD and PFWD owing to the lack of 24-month data; however, the shorter-term data did not suggest a significant effect. AEs were minor for all drugs and included headaches and gastrointestinal difficulties. The incidence of serious adverse events (SAEs), including cardiovascular events and mortality, was not increased by the vasoactive drugs compared with placebo; however, most studies had a relatively short follow-up time to address this outcome. HRQoL data were limited. Two studies of limited quality were identified within the review of cost-effectiveness. The de novo model developed suggests that naftidrofuryl oxalate dominates cilostazol and pentoxifylline and has a cost per QALY gained of around £6070 compared with no vasoactive drug. This result is reasonably robust to changes within the key model assumptions. Inositol nicotinate was not included within the main analysis owing to lack of data. However, it is unlikely to be considered to be cost-effective due to its high acquisition cost (£900 vs £100-500 per year for the other drugs). CONCLUSIONS: Naftidrofuryl oxalate and cilostazol both appear to be effective treatments for this patient population, with minimal SAEs. However, naftidrofuryl oxalate is the only treatment that is likely to be considered cost-effective. The long-term effectiveness is uncertain and hence a trial comparing cilostazol, naftidrofuryl oxalate and placebo beyond 24 weeks would be beneficial. Outcomes associated with naftidrofuryl oxalate could also be compared with those associated with supervised exercise programmes and angioplasty.

The use of sulfasalazine and pentoxifylline (low-cost antitumour necrosis factor drugs) as adjuvant therapy for the treatment of pemphigus vulgaris: a comparative study.

BACKGROUND: Pemphigus vulgaris (PV) represents a potentially life-threatening autoimmune blistering disease in which IgG autoantibodies are directed against cell-cell adhesion molecules. Tumour necrosis factor (TNF)-alpha has been suggested to have a possible role in the mechanism underlying acantholysis. OBJECTIVES: This comparative double-blinded study was carried out to estimate the use of both sulfasalazine (SSZ) and pentoxifylline (PTX) (low-cost anti-TNF drugs) as an adjuvant therapy for PV. METHODS: The study included 64 patients with PV: 42 patients received the full treatment regimen (with SSZ and PTX) and 22 patients followed the same regimen except they received placebo instead of PTX and SSZ. Five healthy subjects were included as controls. Serum samples were taken to measure TNF-alpha levels in the control group and before starting treatment in both the patient groups and this was repeated every 2 weeks for 8 weeks; a clinical assessment was made every week for all the patients. RESULTS: The serum level of TNF-alpha was statistically higher in both groups of patients than in the healthy individuals. There was a statistically significant decrease in the serum levels of TNF-alpha in patients in group 1 compared with those in group 2 at 6 and 8 weeks. There was also a significant clinical improvement in patients in group 1 compared with those in group 2. CONCLUSION: The use of PTX and SSZ as adjuvant therapy in the treatment of PV induced a faster and more significant decrease in the serum level of TNF-alpha, and this decrease was associated with rapid clinical improvement.

Health care resources and costs for treating peripheral artery disease in a managed care population: results from analysis of administrative claims data.

OBJECTIVE: Peripheral arterial disease (PAD) is associated with high rates of morbidity and mortality and serves as an important marker for advanced systemic atherosclerosis accompanied by symptomatic or asymptomatic ischemia of the coronary, cerebral, and visceral vasculature. There are little published data on the use of health care resources and costs attributable to PAD. The objectives of this study were to evaluate, from a societal perspective, PAD-related health care resource utilization and to determine the total annualized costs and cost components for patients with PAD, with particular attention to the key outcomes of myocardial infarction (MI), transient ischemic attacks (TIA), stroke, and amputations. METHODS: This study examined medical, hospital and outpatient, and pharmacy claims from a large managed care database with dates of service from January 1, 1999, through August 31, 2003. Patients with PAD were identified from claims using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes (primary or secondary codes), ICD-9-CM procedure codes, current procedural terminology (CPT) codes, or by a pharmacy claim for cilostazol or pentoxifylline. The index date for each patient was the first occurrence of either a medical claim for PAD or a pharmacy claim for 1 of the 2 drugs. Patients were required to be a minimum of 18 years old with continuous plan eligibility. The prevalence of PAD in adults in a managed care setting was also determined, as were annual rates for the key outcomes of MI, TIA, stroke, and amputations. Health care resource utilization and costs were calculated for PAD patients after the index date for a period of at least 12 months per patient for medications, outpatient/physician office visits, laboratory/diagnostic procedures, emergency department visits, and hospitalization. Cost was defined as the allowed charge on each administrative claim, including the amount paid by the insurer plus the amount paid by the health plan members (copay, deductible, and coinsurance). RESULTS: Prior to application of exclusion criteria for patients aged 18 years or older and the minimum period of continuous eligibility, the overall prevalence of PAD was 1.18% of the total managed care organization population.s 6.67 million members. The PAD study cohort consisted of 30,561 patients with a mean age of 70.7 years at index. The most common comorbidities identified in the preindex period for these PAD patients included hypertension (67% of patients); metabolic disorders/hypercholesterolemia (57%); heart disease including cardiomyopathy, dysrhythmias, and heart failure (55%); and ischemic heart disease (47%). Over a mean postindex period of 25.2 months (median 23.4 months), the total mean annualized PAD-related cost was $5,955 per patient per year (PPPY). Hospitalizations accounted for the largest component cost category, averaging $4,442 PPPY or 75% of the total annualized PAD-related cost per PAD patient. PAD-related noncoronary procedures averaged $729 PPPY (12.2% of total annual PAD-related costs), and PAD-related medications (including antihypertensives and lipid-lowering therapy) totaled $610 (10.2% of total annual costs), including $313 PPPY for antihypertensives and $207 for lipid-lowering therapy. For the subgroup of 24,075 newly identified PAD patients, 8,479 (35.2%) were hospitalized during an average 25.2 months of follow-up, with the mean time to first hospitalization of 8.9 months. CONCLUSIONS: Approximately 75% of the total PAD-related patient cost in an average of 25 months of follow-up is contributed by hospital costs, and 35% of patients newly diagnosed with PAD experienced a hospitalization in a mean of 8.9 months after the index diagnosis. Based upon mean annual health and member costs of only $313 PPPY for antihypertensives and $207 for lipid-lowering therapy, drug therapy in PAD patients may be underutilized.

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.

Treatment of severe intermittent claudication with pentoxifylline: a 40-week, controlled, randomized trial.

The efficacy, safety, and cost of pentoxifylline (PXF) in the treatment of severe intermittent claudication were studied comparing PXF and placebo in a randomized 40-week study. A treadmill test was performed at inclusion and at the end of weeks 20 and 40. A progressive training plan and the control of risk factors (with antiplatelet treatment) were used in both groups. Of the 200 included patients, 178 completed the study: 88 in the PXF group and 90 in the placebo group. There were 22 dropouts. The two groups were comparable for age, sex distribution, and for the presence of risk factors and smoking. There was a significant increase in pain-free walking distance (PFWD) in both groups. The absolute and percent increase in PFWD was significantly greater in the PXF group (p<0.05). At 20 weeks, the increase was 360.5% in the PXF vs 252% in the placebo group. At 40 weeks, the increase was 386% in the PXF and 369% in the placebo group (p<0.02). Total walking distance (TWD) increased at 20 weeks (up to 254%) and up to 329% at 40 weeks. In the placebo groups the increase was 158% at 20 weeks and 183% at 40 weeks. The excess increase produced by PXF treatment was 30% at 20 weeks and 38% at 40 weeks (p<0.02). Unwanted effects treatment was well tolerated. No serious drug-related side effects were observed. In summary, between-group analysis favors PXF considering walking distance and costs. Results indicate good efficacy and tolerability.

Treatment of long-distance intermittent claudication with pentoxifylline: a 12-month, randomized trial.

The efficacy, safety, and cost of pentoxifylline (PXF) in long-range (>400 m interval) intermittent claudication was studied comparing PXF and placebo in a 12-month study. A standardized treadmill test was performed at inclusion and at 6 and 12 months. A training plan based on walking was associated with the control of risk factor levels. Of the 194 included patients, 135 completed the study: 75 in the PXF group and 60 in the placebo group. There were 59 dropouts (due to low compliance). The authors observed a 148% increase in total walking distance (TWD) at 6 months with PXF (vs 110% with placebo; p<0.05); at 12 months, the increase was 170% with PXF (vs 131% with placebo; p<0.02). There was a 38% difference at 6 months and 39% at 12 months in favor of PXF. Treatment was well tolerated. In conclusion, PXF improved walking distance significantly better than placebo.

Treatment of venous ulcers with pentoxifylline: a 6-month randomized, double-blind, placebo controlled trial.

The aim of this study was the evaluation of treatment with pentoxifylline in patients with venous ulcers in a 6-month, randomized, controlled trial. Treatment with placebo or pentoxifylline (PXF; 400 mg, 3 times daily) lasted 6 months and was associated to elastic bandaging. The endpoints were the number of limbs with complete healing and the variation in the area of ulceration. A group of 172 patients were included: 82 in the PXF group and 88 in the placebo group; 82 completed the study in the PXF group and 78 in the placebo group. Results. The two groups were comparable for age and sex distribution. The treatment was well tolerated. Complete healing was obtained in 67% of patients in the PXF group and 30.7% in the placebo group (p<0.02). The variations in the average area of ulceration were 86.7% (decrease) in the PXF group and 47% in the placebo group. The cost of treatment increased 21% with PXF but the cost due to non-healing of the ulcer was equivalent to a 44% increase (in comparison with the PXF group). In conclusion PXF is effective and cost-effective in improving ulcer healing in patients with chronic venous hypertension.

Treatment of intermittent claudication with pentoxifylline: a 12-month, randomized trial--walking distance and microcirculation.

The efficacy, safety and cost of pentoxifylline (PXF) in severe intermittent claudication was studied comparing PXF and placebo in a 12-month study. A treadmill test and microcirculatory evaluation with laser Doppler flowmetry were performed at inclusion and at the end of 6 and 12 months. A physical training plan (based on walking) and reduction in risk factor levels plan was used in both groups. Of the 120 included patients, 101 completed the study: 56 in the PXF group and 45 in the placebo group. There were 19 dropouts (due to low compliance). The two groups were comparable for age, sex distribution, walking distance, and the presence of risk factors and smoking. Intention-to-treat analysis indicated a 268% increase in walking distance in the PXF group (vs 198% in the placebo group; p<0.05) at 6 months and an increase of 404% (vs 280% in the placebo group; p<0.02) at 12 months. The absolute and percent increase in pain-free walking distance (PFWD) was greater in the PXF group (p<0.05). Treatment was well tolerated. No serious drug-related side effects were observed. Microcirculatory evaluation indicated an increase in flux (p < 0.05) in the PXF group (not significant in the placebo group); the after-exercise flux (AEF) was increased (p<0.05) in both groups at 6 months but the increase in AEF was greater in the PXF group at 12 month. In conclusion, between-group analysis favors PXF considering walking distance and microcirculatory parameters. Results indicate good efficacy and tolerability.

Pentoxifylline and intermittent claudication: review of clinical trials and cost-effectiveness analyses.

Intermittent claudication (IC) is common in the elderly; the prevalence is approximately 6% in 50- to 60-year-old patients and 10-20% in those over the age of 70. Several risk factors, especially smoking, are associated with increased prevalence. Disease progression results in increasingly debilitating and costly surgical intervention for about 20% of patients. This report reviews findings from some of the clinical studies that demonstrated the efficacy of pentoxifylline, the only U.S.-approved medical therapy for IC. Findings from a recently published cost-effectiveness analysis are presented. IC is difficult to study clinically because pain is both variable and subjective. In two multicenter, randomized, placebo-controlled studies, carefully monitored treadmill testing showed that pentoxifylline-treated patients had significantly improved walking distances even in the presence of a placebo effect. The pentoxifylline effect was pronounced in patients from a clinical target population defined by low baseline resting pressure ratios (< or =0.8) and long disease duration ( > 1 year). To understand the social implications of these findings, treadmill distances were converted to comparable distances on flat ground. Improvements on pentoxifylline therapy translate to walking distances that enable greater daily function. This improvement has significant practical benefit to the quality of life of IC patients. Using Medicare expenditure data, it was found that pentoxifylline therapy reduced average hospital costs per patients by $1,173. Direct medical cost savings of $69 to $3,090 were suggested by sensitivity analyses. In analyses of practical aspects of walking distance as well as cost-effectiveness analyses, pentoxifylline appears to be a highly useful treatment for IC.

Medical cost savings from pentoxifylline therapy in chronic occlusive arterial disease.

This article assesses the direct medical cost savings associated with therapeutic dosages of pentoxifylline therapy compared with lower dosages in treating chronic occlusive arterial disease (COAD). The savings accrue from elimination of invasive diagnostic measures or a number of surgical procedures received by patients with COAD during hospital admissions. Findings are based on a secondary analysis of results presented in a previously published report of a population based historical cohort study. Patients in this study were severely enough afflicted by the disease that most were under the care of vascular specialists and many underwent surgery to restore normal blood flow. Costs are based on charges from Medicare expenditures in 4 US states in 1989. A case-mix adjustment procedure was applied and a sensitivity analysis was conducted on key assumptions and variables in the cost savings model. Pentoxifylline therapy reduced average hospital costs per patient by $US1173 per year (1989 dollars). After further adjustment for the costs of outpatient visits, other related drugs and the drug acquisition cost, an overall saving of $US965 would still be realised with a patient who received the full therapeutic dose of pentoxifylline. Sensitivity analysis suggests total annual direct medical cost savings between $US69 and $US3090 per patient. Hence, under the most plausible assumptions regarding choice of procedures, study design and patient population, and considering the possibility that diagnostic and surgical costs are delayed but not prevented, pentoxifylline therapy substantially reduces direct medical costs.

Serving patient needs while implementing cost effectiveness programs in health care administration.

The rising costs of health care have focused administrators' attentions on controlling expenses rather than patient needs and preferences. This paper describes a method by which administrators can assess possible cost effectiveness of alternative therapies that may be preferable to patients.

Medical care and cost outcomes after pentoxifylline treatment for peripheral arterial disease.

We assessed the medical outcomes and costs associated with the pharmacologic treatment of patients with peripheral arterial disease (PAD) in a population-based historical cohort study of patients enrolled in a health maintenance organization. For up to 2 years, we compared 58 patients who used therapeutic amounts of pentoxifylline with a comparison group of 112 patients who received a minimal subefficacious trial of pentoxifylline. Medical records data were used to assess and control for the severity of PAD and other potentially confounding factors. Continuous use of a therapeutic amount of pentoxifylline during an initial 120-day period significantly reduced the incidence of PAD-related invasive therapeutic and diagnostic procedures in the first year of follow-up (adjusted relative risk, 0.35; 95% confidence interval, 0.12 to 0.99). However, there were no significant differences in the risk of a PAD-related hospitalization or cost of PAD-related care between continuous pentoxifylline users and the comparison group. Pentoxifylline therapy may reduce the risk of vascular surgery while not increasing the total cost of PAD care.