Gastrointestinal and renal side effects of bisphosphonates: differentiating between no proof of difference and proof of no difference.

BACKGROUND: This study was aimed at comparing the safety of bisphosphonates in women with osteoporosis by application of equivalence testing. METHODS: Gastrointestinal and renal side effects were evaluated based on information published in randomized controlled trials. RESULTS: The data on gastrointestinal side effects (47 trials) indicated that alendronate, risedronate etidronate, and zolendronate have similar rates of the adverse effects; application of Bayesian network meta-analysis showed that equivalence was demonstrated according to margins around ±10%. The data on renal safety were more sparse and suffered from the use of different outcome measures; hence, a single trial could be evaluated. This trial showed a similar effect of alendronate and risedronate on renal function at 12 months; equivalence was based on differences between the two agents in renal function with margins of less than ±10.4 ml/min. CONCLUSION: Our study provided quantitative information to determine to what extent bisphosphonates can be considered equivalent in terms of gastrointestinal and renal side effects.

A uniform procedure for reimbursing the off-label use of antineoplastic drugs according to the value-for-money approach.

National healthcare systems as well as local institutions generally reimburse numerous off-label uses of anticancer drugs, but an explicit framework for managing these payments is still lacking. As in the case of on-label uses, an optimal management of off-label uses should be aimed at a direct proportionality between cost and clinical benefit. Within this framework, assessing the incremental cost/effectiveness ratio becomes mandatory, and measuring the magnitude of the clinical benefit (e.g. gain in overall survival or progression-free survival) is essential.This paper discusses how the standard principles of cost-effectiveness and value-for-money can be applied to manage the reimbursement of off-label treatments in oncology. It also describes a detailed operational scheme to appropriately implement this aim. Two separate approaches are considered: a) a trial-based approach, which is designed for situations where enough information is available from clinical studies about the expected effectiveness of the off-label treatment; b) an individualized payment-by-results approach, which is designed for situations in which adequate information on effectiveness is lacking; this latter approach requires that each patient receiving off-label treatment is followed-up to determine individual outcomes and tailor the extent of payment to individual results.Some examples of application of both approaches are presented in detail, which have been extracted from a list of 184 off-label indications approved in 2010 by the Region of tuscany in italy. these examples support the feasibility of the two methods proposed.In conclusion, the scheme described in this paper represents an operational solution to an unsettled problem in the area of oncology drugs.

Dropout rates with olanzapine or risperidone: a multi-centre observational study.

OBJECTIVE: In patients with schizophrenia, risperidone and olanzapine are the two most commonly used atypical anti-psychotics. A recent meta-analysis based on randomized trials suggests that, in the long term, olanzapine can have a lower frequency of treatment discontinuation (or dropout) in comparison with risperidone. To better test this hypothesis, our observational study was aimed at assessing whether or not this advantage of olanzapine versus risperidone could be confirmed in a patient series examined in an observational setting. METHODS: Our study was based on a retrospective multi-centre observational design. We collected the following information from each patient: demographic characteristics; current anti-psychotic treatment (olanzapine or risperidone, under the condition of a stable therapy over months -1 to -4); cumulative dose of the drug; previous anti-psychotic treatment (during months -5, -6, -7 and/or, when available, also before month -7); daily dose and treatment duration. Our primary analysis traced back the patient's history from the date of enrollment retrospectively up to month -7. The secondary analysis followed-up the patient's history prior to month -7, thus extending this retrospective recording as long as possible (depending on what information was actually available for individual patients). RESULTS: The patients were enrolled from 31 institutions. In our primary analysis (months -1 to -7), a total of 144 patients were included; in this subgroup treated with olanzapine or risperidone as initial drug ( n=94), we observed 4 of 54 switches from olanzapine to risperidone and 11 of 40 switches from risperidone to olanzapine ( P=0.01). A total of 454 patients were enrolled in our secondary analysis (from month -1 up to month -73); the same comparison showed 9 of 236 switches from olanzapine to risperidone and 17 of 150 switches from risperidone to olanzapine ( P=0.004). CONCLUSION: Our analysis confirms the results of a recent meta-analysis and shows that olanzapine might imply a lower risk of dropout than risperidone.

Quality of life and utility in patients with non-small cell lung cancer. Quality-of-life Study Group of the Master 2 Project in Pharmacoeconomics.

BACKGROUND: Although several studies have determined quality of life in patients with lung cancer, there is still little information about the use of generic questionnaires [e.g. the 36-item Short Form health survey (SF-36)] and utility questionnaires [e.g. the EuroQOL instrument (EQ-5D)] in this disease. OBJECTIVES: To (i) measure quality of life and utility in patients with non-small cell lung cancer (NSCLC) using the SF-36 and the EuroQOL questionnaires; (ii) to evaluate the impact of some clinical variables on quality of life and utility; (iii) to assess the correlation between the measurements produced by the 2 questionnaires. STUDY DESIGN: Cross-sectional study. PARTICIPANTS: 95 patients from 15 Italian hospitals with NSCLC (93% male, mean age 62 years) completed both questionnaires. RESULTS: The mean scores for the 8 domains of the SF-36 ranged from 20.8 (physical role) to 63.0 (social functioning). The mean physical and mental summed scores of the SF-36 were 36.8 [standard deviation (SD) 9.8] and 43.0 (SD 11.5), respectively. The EuroQOL mean score was 0.58 (SD 0.32) in the self-classifier (SC) version and 0.58 (SD 0.20) in the visual analogue scale (VAS) version. Among the clinical variables that affected quality of life and utility, the presence of metastasis had the greatest impact: patients with metastasis had statistically significantly lower scores for 2 domains of the SF-36 (physical functioning, p = 0.009; bodily pain, p = 0.016), for the physical component summed score of the SF-36 (p = 0.015) and for both utility estimates (EuroQOL-SC, p = 0.027; EuroQOL-VAS, p = 0.038) than patients without metastasis. Both the SC and VAS EuroQOL scores showed a statistically significant correlation with each of the 8 domains of the SF-36. The scores for both the SF-36 and the EuroQOL in patients with NSCLC were considerably worse (relative differences ranging from -8 to -73%) than the corresponding values (normative data) previously reported for healthy individuals. CONCLUSIONS: Our study quantified the degree to which quality of life is impaired in patients with NSCLC, showed that the presence of metastasis had an important role, and indicated a strong correlation between the measurements produced by the 2 questionnaires. The EuroQOL measurements obtained from these patients will aid evaluation of the cost-utility ratio for NSCLC therapies.

Multivariate analysis of factors influencing quality of life and utility in patients with haemophilia.

BACKGROUND AND OBJECTIVES: Although several studies have determined quality of life (QOL) in patients with hemophilia, generic questionnaires have rarely been used. The objectives of our study were; 1) to measure QOL and utility in patients with hemophilia using the Short Form 36 (SF-36) and the EuroQOL questionnaires; 2) to evaluate the influence of some clinical variables on QOL and utility; 3) to assess the correlation between the two questionnaires. DESIGN AND METHODS: All consecutive patients with hemophilia were asked to complete the SF-36 and the EuroQOL questionnaires. The following information was recorded from each patient: age, type of hemophilia, severity of disease, HCV and HIV infection, number of bleeding episodes and cumulative dose of coagulation factors over the previous year. These items were entered into a multivariate analysis to assess their effect on QOL. Correlation analyses were conducted to evaluate the relationship between the EuroQOL and SF-36. RESULTS: Fifty-six patients completed the SF-36 and the EuroQOL questionnaires. The mean scores of the SF-36 ranged from 55.2 (general health) to 74.7 (social functioning). The EuroQOLself-classifier and the EuroQOLvas showed a mean score of 0.67 (SD=0.26) and 0.66 (SD=0.17), respectively. Among the clinical variables, age significantly influenced both the EuroQOL and the SF-36 scores. The EuroQOL indices showed a statistically significant correlation with each dimension of the SF-36. INTERPRETATION AND CONCLUSIONS: Our study quantified the degree to which QOL is impaired in patients with hemophilia by using both a generic questionnaire and a utility-based approach.

Survival in patients with intermediate or high grade non-Hodgkin's lymphoma: meta-analysis of randomized studies comparing third generation regimens with CHOP.

In patients with intermediate or high grade non-Hodgkin lymphoma (NHL), third generation chemotherapy regimens have been introduced to improve survival in comparison with the standard CHOP regimen. However, most studies have found no difference between these two treatments. We conducted a meta-analysis to assess the effectiveness of third generation regimens as compared with CHOP. Our study included the randomized controlled trials published in English from 1970 to 1999. After a Medline search, 5 trials were found to meet our inclusion criteria. A total of 1982 patients, that were enrolled in these trials, were included in the survival meta-analysis. Our methodology retrieved patient-level information from all of these subjects; survival up to 9 years after randomization was compared between the two treatment options. The results of our meta-analysis showed that, in comparison with CHOP, third generation chemotherapy did not prolong survival at levels of statistical significance (chi-square by log-rank test = 1.44, P = 0.23). The relative death risk for third generation regimens vs. CHOP was 0.92 (95%CI: 0.80 to 1.06;P = 0.26). We conclude that, on the basis of our meta-analysis, third generation regimens do not confer any survival benefit to patients with intermediate or high grade NHL as compared with CHOP.

Survival in patients with metastatic breast cancer: analysis of randomized studies comparing oral aromatase inhibitors versus megestrol.

In patients with metastatic breast cancer, second-line therapy with aromatase inhibitors can improve survival in comparison with megestrol. We conducted a meta-analysis to assess the effectiveness of aromatase inhibitors versus megestrol. After a Medline search, three trials (evaluating letrozole, anastrozole or exemestane versus megestrol) were included in the survival meta-analysis. Our methodology retrieved patient-level information on survival. In comparison with megestrol, aromatase inhibitors prolonged survival at levels of statistical significance (relative death risk for oral aromatase inhibitors=0.79, 95% confidence interval 0.69-0.91; p=0.0011). A lifetime analysis of the pooled survival curves of aromatase inhibitors versus megestrol found a mean survival gain of 4.1 months per patient. Aromatase inhibitors confer a significant survival benefit to patients with metastatic breast cancer as compared with megestrol. A preliminary calculation of the cost per life year gained shows that the pharmacoeconomic profile of these drugs is favorable.

Bleeding and pneumonia in intensive care patients given ranitidine and sucralfate for prevention of stress ulcer: meta-analysis of randomised controlled trials.

OBJECTIVES: To determine the effectiveness of ranitidine and sucralfate in the prevention of stress ulcer in critical patients and to assess if these treatments affect the risk of nosocomial pneumonia. DESIGN: Published studies retrieved through Medline and other databases. Five meta-analyses evaluated effectiveness in terms of bleeding rates (A: ranitidine v placebo; B: sucralfate v placebo) and infectious complications in terms of incidence of nosocomial pneumonia (C: ranitidine v placebo; D: sucralfate v placebo; E: ranitidine v sucralfate). Trial quality was determined with an empirical ad hoc procedure. MAIN OUTCOME MEASURES: Rates of clinically important gastrointestinal bleeding and nosocomial pneumonia (compared between the two study arms and expressed with odds ratios specific for individual studies and meta-analytic summary odds ratios). RESULTS: Meta-analysis A (five studies) comprised 398 patients; meta-analysis C (three studies) comprised 311 patients; meta-analysis D (two studies) comprised 226 patients: and meta-analysis E (eight studies) comprised 1825 patients. Meta-analysis B was not carried out as the literature search selected only one clinical trial. In meta-analysis A ranitidine was found to have the same effectiveness as placebo (odds ratio of bleeding 0.72, 95% confidence interval 0.30 to 1.70, P=0.46). In placebo controlled studies (meta-analyses C and D) ranitidine and sucralfate had no influence on the incidence of nosocomial pneumonia. In comparison with sucralfate, ranitidine significantly increased the incidence of nosocomial pneumonia (meta-analysis E: 1.35, 1.07 to 1.70, P=0.012). The mean quality score in the four analyses (on a 0 to 10 scale) ranged from 5.6 in meta-analysis E to 6.6 in meta-analysis A. CONCLUSIONS: Ranitidine is ineffective in the prevention of gastrointestinal bleeding in patients in intensive care and might increase the risk of pneumonia. Studies on sucralfate do not provide conclusive results. These findings are based on small numbers of patients, and firm conclusions cannot presently be proposed.