Cost effectiveness of riluzole in amyotrophic lateral sclerosis. Italian Cooperative Group for the Study of Meta-Analysis and the Osservatorio SIFO sui Farmaci.

OBJECTIVE: In patients with amyotrophic lateral sclerosis, long term treatment with riluzole has been reported to improve survival or tracheostomy-free survival in comparison with placebo. We conducted a pharmacoeconomic analysis for estimating the cost per life-year gained using this drug. DESIGN: This study was an incremental cost-effectiveness lifetime analysis. SETTING: The clinical material was derived from 2 placebo-controlled randomised controlled trials comparing riluzole versus usual care without riluzole, which were identified through a literature search based on the IOWA and the Medline systems. PATIENTS AND INTERVENTIONS: The study included 633 patients with amyotrophic lateral sclerosis. Patient-level information was retrieved from 313 patients treated with riluzole and 320 patients assigned to placebo. Survival after randomisation was compared between the 2 groups using standard statistics (log-rank test and Cox analysis), whereas the lifetime survival gain was estimated using Gompertz extrapolation. Cost data relative to the expenditure for healthcare resources were obtained from published information (using the US average wholesale price for the acquisition cost of riluzole). Sensitivity testing assessed the impact of different cost-of-illness assumptions for treated and untreated patients. MAIN OUTCOME MEASURES AND RESULTS: Our primary analysis showed that treatment with riluzole significantly prolonged survival [death risk = 0.77; 95% confidence interval (CI): 0.62 to 0.96; p = 0.022]. The lifetime survival gain (including 3% annual discounting) was, on average, 2.3 months per patient, while the incremental cost was around $US12,000 per patient. Hence, the cost-effectiveness ratio of riluzole versus usual care without riluzole was $US62,609 per life-year gained (discounted dollars per discounted years; 95% CI: $US13,458 to $US205,714). The sensitivity analysis, considering different values of national cost for riluzole, suggested an interval for this parameter ranging from $US45,048 to $US62,609. CONCLUSIONS: Our study indicates that in patients with amyotrophic lateral sclerosis, riluzole has an unfavourable cost-effectiveness ratio or, at best, a borderline pharmacoeconomic profile.

Treatments for newly diagnosed multiple myeloma: analysis of survival data and cost-effectiveness evaluation.

The main therapeutic options currently available to induce remission in newly diagnosed cases of multiple myeloma include: i) melphalan at conventional doses without concurrent administration of interferon; ii) melphalan at conventional dose combined with interferon; iii) autologous bone marrow transplantation (ABMT). We conducted an analysis of the survival data reported in five large-scale published clinical trials and we evaluated the cost-effectiveness ratio. We determined the mean lifetime survival (MLS) for each treatment group using the Gompertz model. The cost data of patients given ABMT or standard chemotherapy were estimated from published information. The values of MLS were 3.47 years per patient for melphalan at conventional doses without interferon, 3.74 years for melphalan at conventional doses combined with interferon, and 7.28 years for ABMT. As compared with conventional melphalan treatment, ABMT yielded a significantly better survival. Survival after melphalan combined with interferon was not significantly different from that following melphalan alone. Using melphalan at conventional doses without interferon as reference term, the marginal cost-effectiveness ratio of ABMT was of about $26,000 per life year gained. For the induction treatment in patients with newly diagnosed myeloma, ABMT seems to be more effective and more cost-effective than the standard treatment with melphalan at conventional doses.

Adjunctive lamotrigine therapy in patients with refractory seizures: a lifetime cost-utility analysis.

OBJECTIVE: Lamotrigine as add-on treatment (500 mg per day) is effective in patients with refractory epilepsy, but its high cost requires a pharmacoeconomic analysis. We conducted a retrospective lifetime cost utility study in which clinical data were derived from a recent placebo-controlled clinical trial, cost-of-illness data were drawn from a previous ad-hoc study, and quality-of-life values were obtained by prospectively interviewing a separate group of 81 patients referred to our institution with epilepsy. RESULTS: Our analysis showed that chronic lamotrigine treatment implies an incremental lifetime cost of about $1,600,000 for every 100 patients. Incremental lifetime utility was around 40 quality-adjusted life-years (QALYs) for every 100 patients. On the basis of these data, adjunctive lamotrigine was estimated to cost approximately $41,000 per QALY gained. Sensitivity testing suggested a range of $25,000-$85,000 per QALY gained. CONCLUSION: Adjunctive lamotrigine (500 mg per day) in refractory epilepsy seems to have a worse pharmacoeconomic profile than many pharmacological treatments commonly used in areas other than epilepsy. Further data are needed to determine if lamotrigine can be equally effective at lower (and less costly) daily doses which could markedly improve its pharmacoeconomic characteristics.

Treatments for newly diagnosed advanced ovarian cancer: analysis of survival data and cost-effectiveness evaluation.

The main therapeutic options currently available for patients with newly diagnosed advanced ovarian cancer include: (i) cisplatin-based chemotherapy at conventional doses without paclitaxel, (ii) paclitaxel+cisplatin at conventional doses and (iii) high-dose chemotherapy with autologous hematopoietic rescue. After conducting a literature search to identify large-scale clinical trials based on these three therapeutic modalities, we carried out an analysis of the survival data and evaluated the cost-effectiveness ratio where appropriate. Cost data were obtained from published information. Effectiveness was estimated by determining the values of mean lifetime survival (MLS). Our analysis included a total of 15 clinical trials. The values of MLS were 3.05 years per patient for cisplatin-based chemotherapy at conventional doses without paclitaxel (1931 patients), 2.95 years per patient for chemotherapy with paclitaxel+cisplatin at conventional doses (184 patients) and 5.76 years per patient for high-dose chemotherapy with autologous hematopoietic rescue (53 patients). As compared with cisplatin-based chemotherapy without paclitaxel, high-dose treatments with hematopoietic rescue yielded a significantly better survival. Using cisplatin-based chemotherapy as a reference term, the incremental cost-effectiveness ratio for high-dose treatments was $25641 per life year gained (discounted dollars per discounted life year gained). Sensitivity testing suggested that the ratio remained below $50000 under most circumstances. We conclude that in the treatment of patients with advanced ovarian cancer, high-dose chemotherapy with hematopoietic rescue seems to be more effective and more cost-effective than standard treatments with cisplatin-based regimens at conventional doses.

A retrospective cost-effectiveness analysis of interferon as adjuvant therapy in high-risk resected cutaneous melanoma.

To assess the cost per life year gained of alpha interferon (IFN) as adjuvant therapy for patients with high-risk resected melanoma, we conducted a retrospective, incremental cost-effectiveness analysis on clinical data from a previously published ECOG trial [9]. The Gompertz model was used to estimate the total lifetime values of patient-years of subjects receiving IFN in comparison with subjects given no adjuvant treatment. The ECOG trial involved 143 patients treated with high-dose IFN and 137 given no adjuvant treatment. Estimated drug expenditures were based on the assumption of a cost of $109.25 per 10 MU of IFN. Our analysis of the ECOG results showed that the adjuvant treatment of 100 subjects with high-dose IFN improved survival expectancy by 133.6 discounted life years or 308 undiscounted life years. The use of IFN (compared with no adjuvant treatment) implied an incremental cost of $16,467 per discounted life year saved (95% CI of $4752-50,000) or $7143 per undiscounted life year saved (95% CI of $3226-33,846). Sensitivity testing, in which variations were introduced in the main factors influencing cost and effectiveness, showed that this value always remained below $50,000. Our pharmacoeconomic analysis indicates that adjuvant treatment with high-dose IFN in patients with high-risk resected melanoma implies a favourable cost-effectiveness ratio. Because two other studies showed no significant survival benefit in patients receiving adjuvant IFN at lower values of total dose per patient, the controversy remains and confirmation data are needed for the ECOG trial's results. If these clinical results are confirmed, our analysis shows that the dosage of IFN given in this trial has a favourable pharmacoeconomic profile.

Adjuvant cyclophosphamide, methotrexate and fluorouracil for node-positive breast cancer: a lifetime cost-utility analysis based on a modified Q-TWIST method.

The Q-TWIST (time spent without symptoms and toxicity) method [1-4] and the Gompertz extrapolation method [5-11] are two techniques that have been proposed for evaluating survival in cancer patients. The mathematical basis of the Q-TWIST method relies on estimating the area under the survival curve and partitioning its value into three components with different levels of quality of life (presence of toxicity, presence of symptoms, absence of symptoms and toxicity). The Gompertz approach utilises a curve-fitting procedure to extrapolate the survival curves to infinity. A recent report [12] has described a combined application of the Q-TWIST method and the Gompertz approach ("extrapolated Q-TWIST" method), which allows one to conduct a cost-utility analysis with the calculation of the cost per QALY (quality-adjusted life year) gained. In this paper, we describe a reappraisal of an earlier cost-effectiveness study [7] by application of this extrapolated Q-TWIST method [12]. Our cost-effectiveness study [7] evaluated the pharmacoeconomic profile of adjuvant cyclophosphamide, methotrexate and fluorouracil (CMF) in patients with node-positive breast cancer [13] and utilised a Gompertz analysis to estimate lifetime overall survival (OS), which was 862 and 756 discounted years per 100 patients in the CMF and the control groups, respectively. In applying the extrapolated Q-TWIST method to this data set, a second Gompertz analysis is carried out on the disease-free survival (DFS) curve of the two patient groups. Lifetime DFS of Bonadonna's patients can thus be estimated as 741 years in the CMF group and 572 years in the controls (discounted values normalised to 100 patients). Figure 1 shows the two curves of OS and DFS for the CMF group and the partition of the area under the OS curve into its three components. To introduce an assessment of quality of life into these data, the Q-TWIST method partitions the value of OS into the three components called TWIST (absence of symptoms and toxicity), TOX (time spent with toxicity) and REL (survival after relapse). Hence, OS = TWIST + REL + TOX, where REL = OS - DFS. In the control group, TOX = O and TWIST = DFS because no treatment-related toxicity is present.

Cost-effectiveness of neoadjuvant multimodal therapy in patients with esophageal adenocarcinoma.

We conducted an incremental cost-effectiveness analysis to evaluate an adjuvant multimodal therapy (chemotherapy + radiotherapy) in patients with esophageal adenocarcinoma undergoing surgery. We utilized the clinical data of a published controlled trial comparing preoperative chemotherapy + radiotherapy versus surgery alone. Information on costs was derived from local data and verified against reported values. Multimodal treatment was found to improve life expectancy by 196.9 discounted years every 100 subjects (survival gain of about 2 years per patient). Costs of this neoadjuvant therapy were estimated as $780,010 per 100 patients. Our cost-effectiveness analysis showed that the cost per life year gained was $3,961 for the multimodal therapy in comparison with surgery alone. The pharmacoeconomic profile of this therapeutic modality compares favorably with previous economic data calculated for other types of health care intervention.

Advanced HIV infection treated with zidovudine monotherapy: lifetime values of absolute cost-effectiveness as a pharmacoeconomic reference for future studies evaluating antiretroviral combination treatments. The Osservatorio SIFO sui Farmaci.

OBJECTIVE: This study was undertaken to evaluate the cost and the effectiveness of zidovudine monotherapy in patients with advanced HIV infection and to derive preliminary data on the cost-effectiveness of the triple treatment with saquinavir plus zalcitabine plus zidovudine compared with zidovudine alone. DESIGN: We used a combined method of survival analysis utilizing both the quality-adjusted time without symptoms or toxicity (Q-TWIST) method and the Gompertz approach. This combined method was applied to assess the absolute cost-effectiveness and cost-utility ratios of zidovudine monotherapy and to perform a preliminary incremental cost-effectiveness comparison of saquinavir plus zalcitabine plus zidovudine versus zidovudine alone. The clinical material used in our study was derived from two reports on the treatment of advanced HIV infection. Data of lifetime costs of HIV infection were obtained from published information. RESULTS: In patients with advanced HIV infection treated with zidovudine monotherapy, lifetime survival was 252.1 discounted person-years per 100 patients. Using an average lifetime cost of $93,000 (discounted) per individual, the absolute ratio of cost-effectiveness for zidovudine monotherapy was $36,980 per life-year, while the absolute cost-utility ratio was $47,112 per quality-adjusted life-year. In the comparative analysis of saquinavir plus zalcitabine plus zidovudine versus zidovudine alone, our calculations showed that the administration of the triple treatment can have an "average" cost-effectiveness, provided that mean lifetime survival per patient (discounted) is improved to at least 3.68 years (with an average survival gain of at least 14 mo per patient). CONCLUSIONS: The values of absolute cost-effectiveness and cost-utility ratios for zidovudine monotherapy are a useful reference point for further pharmacoeconomic studies in the area of antiretroviral drugs.

Pharmacoeconomic profile of paclitaxel as a first-line treatment for patients with advanced ovarian carcinoma. A lifetime cost-effectiveness analysis.

BACKGROUND: Analysis of published survival curves has recently been proposed as a method for conducting incremental cost-effectiveness analysis in which two treatments are compared with each other in terms of cost per year of life gained. In patients with advanced ovarian carcinoma, the combination of paclitaxel and cisplatin has been reported to improve survival more significantly than standard therapy with cyclophosphamide and cisplatin. However, the high cost of paclitaxel indicates a need for an evaluation of the pharmacoeconomic profile of these treatments. METHODS: The authors conducted an incremental cost-effectiveness analysis to assess the paclitaxel-based regimen in terms of cost per year of life gained. The analysis utilized data from a published controlled long term trial involving 184 patients treated with paclitaxel and cisplatin and 202 patients treated with cyclophosphamide and cisplatin. Gompertz' law was employed to obtain the lifetime estimate of the years gained by patients given the first treatment in comparison with patients given the second. RESULTS: The paclitaxel-based treatment was found to improve life expectancy by 46 years for every 100 patients. Costs of chemotherapy were higher in the paclitaxel group than in the standard-therapy group (the cost difference was $901,723 for every 100 patients; costs for treating febrile neutropenia induced by chemotherapy were taken into account). On the basis of these data of cost and effectiveness, the administration of paclitaxel and cisplatin was found to imply a cost per year of life gained of $19,603 more than standard chemotherapy. CONCLUSIONS: The pharmacoeconomic profile of paclitaxel compares favorably with economic data previously calculated for other types of pharmacologic treatment.

Cost-effectiveness of adjuvant chemotherapy with cyclophosphamide+methotrexate+fluorouracil in patients with node-positive breast cancer.

BACKGROUND: The analysis of published survival curves can be used as the basis for incremental cost-effectiveness analyses in which two treatments are compared with each other in terms of cost per life year saved. In patients with node-positive breast cancer adjuvant chemotherapy with cyclophosphamide+ methotrexate+fluorouracil has been reported to improve survival in comparison with patients who are not given this treatment. METHODS: To assess the pharmacoeconomic profile of this adjuvant chemotherapeutic regimen in terms of cost per life-year gained, we conducted an incremental cost-effectiveness analysis in which the Gompertz model was used to calculate the lifetime estimate of the patient-years gained by treated subjects compared to controls. RESULTS: Using data from a published, controlled long-term trial involving 207 patients treated with cyclophosphamide+methotrexate+fluorouracil and 179 controls, we estimated that this adjuvant chemotherapy improved life expectancy by 357 patient-years per 100 subjects. Direct costs, which were almost exclusively related to the administration of chemotherapy, were estimated to be US $159,516 per 100 patients. On the basis of these data, adjuvant chemotherapy was found to imply an incremental cost of US $447 per life-year saved. CONCLUSIONS: The cost-effectiveness ratio of adjuvant chemotherapy with cyclophosphamide+methotrexate+fluorouracil in patients with node-positive breast cancer seems to be particularly favourable in comparison with estimates of cost per life-year saved previously calculated for other types of pharmacological intervention.

Effects of idrapril calcium on tissue angiotensin-converting enzyme in rats.

Tissue angiotensin-converting enzyme (ACE) inhibition was measured in rats after single intravenous (i.v.) and oral (p.o.) doses of idrapril calcium, and the correlation between peak inhibition and tissue concentration of the drug was investigated. Five minutes after idrapril calcium (3 mg/kg i.v. as free acid), ACE in the examined tissues (serum, lungs, kidneys, heart, aorta, adrenals, testes, and brain) showed > 50% inhibition, always associated with measurable amounts of idrapril. After 90 min, ACE activity was still inhibited only in serum, lungs, kidneys, and aorta, recovering to basal values by 8 h in all samples but serum. Oral idrapril calcium (30 mg/kg) produced > 50% peak ACE inhibition in serum, lungs, and kidneys, in which measurable levels of the drug were detected, and in the aorta, where idrapril was not detected. Other tissues showed neither marked inhibition nor measurable drug levels. Kinetics of ACE inhibition in affected tissue mirrored those observed after intravenous administration. Idrapril, despite its hydrophilic nature, is able to reach extravascular tissues and to inhibit local ACE. However, in no tissue did the effect on ACE last longer than in serum and the hypothesis of a peculiar role of tissue RAS in determining the hypotensive activity of idrapril calcium is not supported in rats.