[Topical haemostatic agents in neurosurgery].

Haemostasis is of fundamental significance in neurosurgery, and insufficient control of bleeding is associated with morbidity and mortality. Topical haemostatic agents play an important role, as the characteristics of neuronal tissue limit the use of classical surgical haemostasis techniques. Appropriate choice of agent depends on the location and type of bleeding, but also on knowledge of the products' mechanisms of action, indications, price and accessibility. Biological products are superior to the mechanical in efficacy but require more preparation and are significantly more cost-intensive.

Comparison of rehospitalization rates and associated costs among patients with schizophrenia receiving paliperidone palmitate or oral antipsychotics.

PURPOSE: Comparative data on rehospitalization patterns and associated institutional costs after inpatient treatment with paliperidone palmitate or oral antipsychotic therapy are reported. METHODS: A retrospective cohort study was conducted using discharge and billing records from a large hospital database. Selected clinical and cost outcomes were compared in a cohort of adult patients who received the long-acting antipsychotic paliperidone palmitate during a schizophrenia-related index hospital stay and a cohort of patients who received oral antipsychotic therapy during their index admission. Inverse probability-of-treatment weights based on propensity scores were used to reduce confounding. Rates of all-cause and schizophrenia-related rehospitalization and emergency room (ER) use in the two cohorts over periods of up to 12 months were analyzed using a multivariate Cox proportional hazard model. Institutional costs for the evaluated postdischarge events were compared via multivariate linear regression analysis. RESULTS: In the first 12 months after index hospital discharge, the risk of all-cause rehospitalization and ER use was significantly lower in the paliperidone palmitate cohort than in the oral antipsychotic cohort (hazard ratio, 0.61; 95% confidence interval [CI], 0.59-0.63; p < 0.0001); institutional costs during the first 6 months after discharge were significantly lower in the paliperidone palmitate cohort than in the comparator group (adjusted mean monthly cost difference -$404; 95% CI, -$781 to -$148; p < 0.0001). CONCLUSION: The use of paliperidone palmitate therapy during patients' index hospital admission for schizophrenia was associated with a reduced risk of hospital readmission or ER use and lower postdischarge institutional costs.

Cost-effectiveness of aripiprazole once-monthly compared with paliperidone palmitate once-monthly injectable for the treatment of schizophrenia in the United States.

OBJECTIVE: To develop a decision-analytic model to estimate the cost-effectiveness of initiating maintenance treatment with aripiprazole once-monthly (AOM) vs paliperidone long-acting injectable (PLAI) once-monthly among patients with schizophrenia in the US. METHODS: A decision-analytic model was developed to evaluate a hypothetical cohort of patients initiating maintenance treatment with AOM or PLAI. Rates of relapse, adverse events (AEs), and direct medical costs were estimated for 1 year. Patients either remained on initial treatment or discontinued treatment due to lack of efficacy, AEs, or other reasons, including non-adherence. Data from placebo-controlled pivotal trials and product prescribing information (PI) were used to estimate treatment efficacy and AEs. Analyses were performed assuming dosing of clinical trials, real-world practice, PIs, and highest therapeutic dose available, because of variation in practice settings. The main outcome of interest was incremental cost per schizophrenia hospitalization averted with AOM vs PLAI. RESULTS: Based on placebo-controlled pivotal trials' dosing, AOM improved clinical outcomes by reducing schizophrenia relapses vs PLAI (0.181 vs 0.277 per person per year [pppy]) at an additional cost of US$1276 pppy, resulting in an incremental cost-effectiveness ratio (ICER) of US$13,280/relapse averted. When PI dosing was assumed, this ICER increased to US$19,968/relapse averted. When real-world dosing and highest available dosing were assumed, AOM was associated with fewer relapses and lower overall treatment costs vs PLAI. CONCLUSIONS: AOM consistently provided favorable clinical benefits. Under various dosing scenarios, AOM results indicated fewer relapses at lower overall costs or a reasonable cost-effectiveness threshold (i.e., less than the cost of a hospitalization relapse) vs PLAI. Given the heterogeneous nature of schizophrenia and variability in treatment response, health plans may consider open access for treatments like AOM. Since model inputs were based on data from separate placebo-controlled trials, generalization of results to the real-world setting is limited.

Pharmacoeconomics of depot antipsychotics for treating chronic schizophrenia in Sweden.

AIMS: To determine the cost-effectiveness of long-acting injectable (LAI) antipsychotics for chronic schizophrenia in Sweden. METHODS: A 1-year decision tree was developed for Sweden using published data and expert opinion. Five treatment strategies lasting 1 year were compared: paliperidone palmitate (PP-LAI), olanzapine pamoate (OLZ-LAI), risperidone (RIS-LAI), haloperidol decanoate (HAL-LAI) and olanzapine tablets (oral-OLZ). Patients intolerant/failing drugs switched to another depot; subsequent failures received clozapine. Resources and employment time lost (indirect costs) were costed in 2011 Swedish kroner (SEK), from standard government lists. The model calculated the average cost/patient and quality-adjusted life-years (QALYs), which were combined into incremental cost-effectiveness ratios. Multivariate and 1-way sensitivity analyses tested model stability. RESULTS: PP-LAI followed by OLZ-LAI had the lowest cost/patient (189,696 SEK) and highest QALYs (0.817), dominating in the base case. OLZ-LAI followed by PP-LAI cost 229,775 SEK (0.812 QALY), RIS-LAI followed by HAL-LAI cost 221,062 SEK (0.804 QALY), HAL-LAI followed by oral-OLZ cost 243,411 SEK (0.776 QALY), and oral-OLZ followed by HAL-LAI cost 249,422 SEK (0.773 QALY). The greatest proportions of costs (52.5-83.8%) were for institutional care; indirect costs were minor (2.4-3.8%). RESULTS were sensitive to adherence and hospitalization rates, but not drug cost. PP-LAI followed by OLZ-LAI dominated OLZ-LAI followed by PP-LAI in 59.4% of simulations, RIS-LAI followed by HAL-LAI in 65.8%, HAL-LAI followed by oral-OLZ in 94.0% and oral-OLZ followed by HAL-LAI in 95.9%; PP-LAI followed by OLZ-LAI was dominated in 1.1% of the 40,000 iterations. CONCLUSION: PP-LAI followed by OLZ-LAI was cost-effective in Sweden for chronic schizophrenia and cost-saving overall to the healthcare system.

Validation of an economic model of paliperidone palmitate for chronic schizophrenia.

OBJECTIVE: Model validation is important, but seldom applied in chronic schizophrenia. Validation consists of verifying the model itself for face validity (i.e., structure and inputs), cross-validation with other models assessing the same issue, and comparison with real-life outcomes. The primary purpose was to cross-validate a recent pharmacoeconomic model comparing long-acting injectable (LAI) antipsychotics for treating chronic schizophrenia in Sweden. The secondary purpose was to provide external validation. METHODS: The model of interest was a decision tree analysis with a 1-year time horizon with costs in 2011 Swedish kroner. Drugs analyzed included paliperidone palmitate (PP-LAI), olanzapine pamoate (OLZ-LAI), risperidone (RIS-LAI), haloperidol (HAL-LAI), and oral olanzapine (oral-OLZ). Embase and Medline were searched from 1990-2012 for models examining LAIs. Articles were retrieved, with data extracted for all drugs compared including: expected costs, rates of hospitalization, proportion of time not in relapse, and associated QALYs. Outcomes from the model of interest were compared with those from other articles; costs were projected to 2012 using the consumer price index. RESULTS: Twenty-six studies were used for validation; 14 of them provided evidence for cross-validation, 13 for external validation, and four for cost. In cross-validation, cost estimates varied -1.8% (range: -12.4-20.1%), hospitalizations 5.2% (-12.1-3.1%), stable disease 2.5% (-5.6-1.5%), QALYs 9.0% (4.3% after removing outliers). All estimates of clinical outcomes were within 15%. In external validation, hospitalization rates varied by 6.3% (-0.7-11.3%). The research was limited by data availability and validity of the original results. CONCLUSION: Other models validated the outputs of our model very well.

Cost effectiveness of paliperidone palmitate for the treatment of schizophrenia in Germany.

BACKGROUND: Treatment with antipsychotic medication is an important element of relapse prevention in the management of schizophrenia, and can reduce inpatient stays. Recently, the long-acting atypical antipsychotic paliperidone long-acting injectable (PLAI), a once-monthly LAI antipsychotic, was approved for treatment of schizophrenia in Germany. OBJECTIVE: To estimate, based on a previously published model, the cost effectiveness of PLAI compared with other common antipsychotic treatment strategies in patients diagnosed with schizophrenia in Germany. METHODS: A Markov decision analytic model was adapted to the German healthcare system. The model considers the cost effectiveness for PLAI as a maintenance treatment for patients with schizophrenia from the payer perspective. The patients transition between eight health states on a monthly basis over a 5-year time horizon. As therapeutic strategies, PLAI, quetiapine, risperidone long-acting injections (RLAI), oral olanzapine, oral risperidone, zuclopenthixol decanoate, olanzapine long-acting injections (OLAI), oral typical and oral atypical were compared. Probability of relapse, level of adherence, side effects and treatment discontinuation were derived from the Swedish original model. Input factors regarding resource use and costs were estimated and adjusted for the German healthcare system. A probabilistic sensitivity analyses (PSA) using cost-effectiveness scatter plots was performed to visualize the robustness of the results. RESULTS: In base-case scenario, PLAI is superior to RLAI in gained quality-adjusted life-years (QALYs) and avoided relapses. Relative to all other treatment strategies, PLAI is more effective with regard to gained QALYs and avoided relapses but results in higher treatment costs over a 5-year horizon in base-case scenario. The results were tested in PSA. If a cost-effectiveness threshold of 30,000 is assumed, for example, PLAI can be considered to be cost effective compared with RLAI in about 92.5 % of cases regarding gained QALYs, and in 78.6 % of cases regarding avoided relapse. Compared with OLAI, in about 94.4 % of cases regarding gained QALYs and in 99.9 % of cases regarding avoided relapse, cost effectiveness can be considered. Comparing PLAI and zuclopenthixol decanoate, cost effectiveness can be assumed in about 90.4 % of cases regarding gained QALYs, and in all cases regarding avoided relapse. CONCLUSIONS: PLAI dominates RLAI and compared with the other treatment strategies PLAI has shown to be more effective but results in higher costs in base-case scenario.

Economic and clinical comparison of atypical depot antipsychotic drugs for treatment of chronic schizophrenia in the Czech Republic.

PURPOSE: The Czech Republic is faced with making choices between pharmaceutical products, including depot injectable antipsychotics. A pharmacoeconomic analysis was conducted to determine the cost-effectiveness of atypical depots. METHODS: An existing 1-year decision-analytic framework was adapted to model drug use in this healthcare system. The average direct costs to the General Insurance Company of the Czech Republic of using paliperidone palmitate (Xeplion®), risperidone (Risperdal Consta®), and olanzapine pamoate (Zypadhera®) were determined. Literature-derived clinical rates populated the model, with costs adjusted to 2012 Euros using the consumer price index. Outcomes included quality-adjusted life-years (QALYs), days in remission, and proportions hospitalized or visiting emergency rooms. One-way sensitivity analyses were calculated for all important inputs. A multivariate probability analysis was used to examine the stability of results using 10,000 iterations of simulated input over reasonable ranges of all included variables. RESULTS: Expected average costs/per patient treated were €5377 for PP-LAI, €6118 for RIS-LAI, and €6537 for OLZ-LAI. Respective QALYs were 0.817, 0.809, and 0.811; ER visits were 0.127, 0.134, and 0.141; hospitalizations were 0.252, 0.298, and 0.289. Results were generally robust in sensitivity analyses. PP-LAI dominated RIS-LAI and OLZ-LAI in 90.2% and 92.1% of simulations, respectively. Results were insensitive to drug prices but sensitive to adherence and hospitalization rates. CONCLUSIONS: PP-LAI dominated the other two drugs, as it had a lower overall cost and superior clinical outcomes, making it the preferred choice. Using PP-LAI in place of RIS-LAI for chronic relapsing schizophrenia would reduce the overall costs of care for the healthcare system.

Cost-effectiveness analysis of atypical long-acting antipsychotics for treating chronic schizophrenia in Finland.

OBJECTIVE: In Finland, regional rates of schizophrenia exceed those in most countries, impacting the healthcare burden. This study determined the cost-effectiveness of long-acting antipsychotic (LAI) drugs paliperidone palmitate (PP-LAI), olanzapine pamoate (OLZ-LAI), and risperidone (RIS-LAI) for chronic schizophrenia. METHOD: This study adapted a decision tree analysis from Norway for the Finnish National Health Service. Country-specific data were sought from the literature and public documents, guided by clinical experts. Costs of health services and products were retrieved from literature sources and current price lists. This simulation study estimated average 1-year costs for treating patients with each LAI, average remission days, rates of hospitalization and emergency room visits and quality-adjusted life-years (QALY). RESULTS: PP-LAI was dominant. Its estimated annual average cost was €10,380/patient and was associated with 0.817 QALY; OLZ-LAI cost €12,145 with 0.810 QALY; RIS-LAI cost €12,074 with 0.809 QALY. PP-LAI had the lowest rates of hospitalization, emergency room visits, and relapse days. This analysis was robust against most variations in input values except adherence rates. PP-LAI was dominant over OLZ-LAI and RIS-LAI in 77.8% and 85.9% of simulations, respectively. Limitations include the 1-year time horizon (as opposed to lifetime costs), omission of the costs of adverse events, and the assumption of universal accessibility. CONCLUSION: In Finland, PP-LAI dominated the other LAIs as it was associated with a lower cost and better clinical outcomes.

Cost effectiveness of paliperidone palmitate versus risperidone long-acting injectable and olanzapine pamoate for the treatment of patients with schizophrenia in Sweden.

OBJECTIVE: To model the cost effectiveness of paliperidone palmitate (paliperidone long-acting injectable; PLAI), a new once-monthly long-acting antipsychotic therapy, compared with risperidone long-acting injectable (RLAI) and olanzapine pamoate (OLAI), in multi-episode patients (two or more relapses) with schizophrenia in Sweden. METHODS: A Markov decision analytic model was developed to simulate the history of a cohort of multi-episode patients transitioning through different health states on a monthly basis over a 5-year time horizon from the perspective of the Swedish healthcare system. Therapeutic strategies consisted of starting treatment with RLAI (mean dose 37.5 mg every 2 weeks), PLAI (mean dose 75 mg equivalent (eq.) every month) or OLAI (150 mg every 2 weeks or 300 mg every 4 weeks). Probability of relapse, level of adherence, side-effects (extrapyramidal symptoms, tardive dyskinesia, weight gain and diabetes) and treatment discontinuation (switch) were derived from long-term observational data when feasible. Incremental cost-effectiveness outcomes, discounted at 3% annually, included cost per quality-adjusted life-year (QALY) and cost per relapse avoided (expressed in 2009 Swedish Krona SEK). RESULTS: Relative to RLAI and OLAI, PLAI is economically dominant: more effective (additional QALYs, less relapses) and less costly treatment option over a 5-year time horizon. The results were robust when tested in sensitivity analysis. LIMITATIONS: The impact of once-monthly treatment on adherence levels is not yet known, and not all variables that could impact on real-world outcomes and costs were included in this model. CONCLUSION: PLAI was cost saving from a Swedish payer perspective compared with RLAI and OLAI in the long-term treatment of multi-episode (two or more relapses) schizophrenia patients.

The threshold rate of oral atypical anti-psychotic adherence at which paliperidone palmitate is cost saving.

OBJECTIVE: To identify, estimate, and compare 'real world' costs and outcomes associated with paliperidone palmitate compared with branded oral atypical anti-psychotics, and to estimate the threshold rate of oral atypical adherence at which paliperidone palmitate is cost saving. METHODS: Decision analytic modeling techniques developed by Glazer and Ereshefsky have previously been used to estimate the cost-effectiveness of depot haloperidol, LAI risperidone, and, more recently, LAI olanzapine. This study used those same techniques, along with updated comparative published clinical data, to evaluate paliperidone palmitate. Adherence rates were based on strict Medication Event Monitoring System (MEMS) criteria. The evaluation was conducted from the perspective of US healthcare payers. RESULTS: Paliperidone palmitate patients had fewer mean annual days of relapse (8.7 days; 6.0 requiring hospitalization, 2.7 not requiring hospitalization vs 17.8 days; 12.4 requiring hospitalization, 5.4 not requiring hospitalization), and lower annual total cost ($20,995) compared to oral atypicals (mean $22,481). Because paliperidone palmitate was both more effective and less costly, it is considered economically dominant. Paliperidone palmitate saved costs when the rate of adherence of oral atypical anti-psychotics was below 44.9% using strict MEMS criteria. Sensitivity analyses showed results were robust to changes in parameter values. For patients receiving 156 mg paliperidone palmitate, the annual incremental cost was $1216 per patient (ICER = $191 per day of relapse averted). Inclusion of generic risperidone (market share 18.6%) also resulted in net incremental cost for paliperidone palmitate ($120; ICER = $13). Limitations of this evaluation include use of simplifying assumptions, data from multiple sources, and generalizability of results. CONCLUSIONS: Although uptake of LAIs in the US has not been as rapid as elsewhere, many thought leaders emphasize their importance in optimizing outcomes in patients with adherence problems. The findings of this analysis support the cost-effectiveness of paliperidone palmitate in these patients.

Paliperidone palmitate - review of the efficacy, safety and cost of a new second-generation depot antipsychotic medication.

OBJECTIVE: To describe the efficacy, safety and cost of paliperidone palmitate, a depot antipsychotic medication recently approved for the treatment of schizophrenia. DATA SOURCES: A literature search was conducted by querying the websites http://www.pubmed.gov, http://www.fda.gov, http://www.accessdata.fda.gov/scripts/cder/drugsatfda and http://www.clinicaltrials.gov for the search term 'paliperidone palmitate'. Cost information was obtained from the pharmaceutical vendor servicing a local state-operated psychiatric facility. STUDY SELECTION: All available reports of studies were identified. Product labelling provided additional information. DATA EXTRACTION: Descriptions of the principal results and calculation of the number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the study reports and synopses. Additional safety outcomes subject to NNH analysis were obtained from product labelling. DATA SYNTHESIS: Paliperidone palmitate is a newly available depot formulation of paliperidone (the 9-OH metabolite of risperidone). Upon injection into the deltoid or gluteal muscle, the release of the drug starts as early as day 1, reaches maximum plasma concentrations at 13 days and lasts for as long as 126 days. Maximum concentration following deltoid injection is approximately 28% higher compared with injection into the gluteal muscle, and thus paliperidone palmitate requires initiation by two initial deltoid injections spread 1 week apart to achieve therapeutic concentrations rapidly. Subsequent injections are at 4-week intervals. Acute efficacy was evidenced by four short-term double-blind, randomised, placebo-controlled, fixed-dose studies of acutely relapsed adult inpatients who met DSM-IV criteria for schizophrenia. NNT for a 30% or greater decrease in the Positive and Negative Syndrome Scale total score compared with placebo was consistently lower for the higher dose strengths of 156 and 234 mg, suggesting a therapeutic dose-response. Treatment with paliperidone palmitate at doses between 39 and 156 mg significantly delayed the time to recurrence of symptoms of schizophrenia after 24 weeks of maintained symptom stability. The NNT vs. placebo to avoid a recurrence of symptoms was 5 (95% CI 4-7). Overall, paliperidone palmitate was reasonably well tolerated, with low rates of extrapyramidal symptoms or body weight gain; however, these may be more common at higher doses. Injection site reactions occurred at a rate ranging from 4% to 10%, depending on the dose regimen, compared with 2% for the pooled placebo arms. The acquisition cost of a maintenance dose of paliperidone palmitate calculated on a per day basis is similar to that for risperidone microspheres, but about double the cost for oral paliperidone and approximately 19 times the cost of oral generic risperidone. CONCLUSIONS: Paliperidone palmitate is efficacious for the acute and maintenance treatment of schizophrenia and is reasonably well tolerated. It offers several advantages over other available second-generation depot antipsychotics: it comes in prefilled syringes in a number of different dosage strengths; it does not require refrigeration; it does not require supplementation with oral antipsychotics; it can be administered once monthly; it can be administered with a very small bore needle; the injection volume is small; the injection site can be either the deltoid or gluteal muscles; it does not require an additional precautionary observation period after the injection. For patients for whom oral risperidone or paliperidone is otherwise effective, paliperidone palmitate offers a guaranteed delivery system that enhances adherence. However, the high acquisition cost of paliperidone palmitate will likely be an important obstacle to its routine use.

Studies on the kinetics of Isopropyl Palmitate synthesis in packed bed bioreactor using immobilized lipase.

The objective of this research was to study the kinetics of synthesis of a commercially important ester - Isopropyl Palmitate (IPP) using immobilized lipase (Lipozyme IM). It was studied in a packed bed differential reactor. In order to establish the kinetics of the reaction, parameters such as linear velocity of the fluid through the reactor, particle size, substrate concentration, substrate molar ratio, temperature and water activity were studied. Operational and storage stability of the enzyme were also assessed. The reaction followed Michaelis-Menton kinetics as observed from the relationship of initial rate of the reaction as a function of substrate concentration. It was found that the optimum substrate concentration was 0.15M palmitic acid and isopropyl alcohol in 1:1 stoichiometric ratio. Inhibition by excess of isopropyl alcohol has been identified. The optimum temperature for the esterification reaction was found to be around 50 degrees C. The activation energy of this process was determined to be 43.67 kJ/mol. The optimum water content was 0.50%. The reaction rates were measured in the absence of any significant external diffusional limitations. Since internal diffusional limitations could not be eliminated, the kinetics observed is only apparent.