A systematic literature review of cysteamine bitartrate in the treatment of nephropathic cystinosis.

OBJECTIVES: To summarize available clinical evidence for cysteamine bitartrate preparations in the treatment of nephropathic cystinosis as identified through a systematic literature review (SLR). METHODS: We searched MEDLINE, MEDLINE In-Process and Embase using Ovid with a predefined search strategy through 19 January 2016. All publicly available clinical reports on the use of delayed-release (DR) cysteamine bitartrate (Procysbi 1 ) or immediate-release (IR) cysteamine bitartrate (Cystagon 2 ) in patients with cystinosis were included. RESULTS: We identified a total of 103 publications and 10 trial records. Of these, 9 studies describe DR cysteamine bitartrate (n = 267 patients), 42 describe IR cysteamine bitartrate (n = 1,427 patients) and in 53 studies the exact preparation was not specified (n = 906 patients). The vast majority of the studies used a non-randomized study design, with randomized clinical trials (RCTs) being scarce (1 study comparing DR and IR formulation) and case reports (n = 49) being the most common study design representing 47% of the total. CONCLUSION: A substantial evidence base for cysteamine bitartrate in the treatment of nephropathic cystinosis was identified. However, the majority of the evidence was of relatively low quality, with evidence levels of 3 or 4.

Short- and long-term health consequences of sleep disruption.

Sleep plays a vital role in brain function and systemic physiology across many body systems. Problems with sleep are widely prevalent and include deficits in quantity and quality of sleep; sleep problems that impact the continuity of sleep are collectively referred to as sleep disruptions. Numerous factors contribute to sleep disruption, ranging from lifestyle and environmental factors to sleep disorders and other medical conditions. Sleep disruptions have substantial adverse short- and long-term health consequences. A literature search was conducted to provide a nonsystematic review of these health consequences (this review was designed to be nonsystematic to better focus on the topics of interest due to the myriad parameters affected by sleep). Sleep disruption is associated with increased activity of the sympathetic nervous system and hypothalamic-pituitary-adrenal axis, metabolic effects, changes in circadian rhythms, and proinflammatory responses. In otherwise healthy adults, short-term consequences of sleep disruption include increased stress responsivity, somatic pain, reduced quality of life, emotional distress and mood disorders, and cognitive, memory, and performance deficits. For adolescents, psychosocial health, school performance, and risk-taking behaviors are impacted by sleep disruption. Behavioral problems and cognitive functioning are associated with sleep disruption in children. Long-term consequences of sleep disruption in otherwise healthy individuals include hypertension, dyslipidemia, cardiovascular disease, weight-related issues, metabolic syndrome, type 2 diabetes mellitus, and colorectal cancer. All-cause mortality is also increased in men with sleep disturbances. For those with underlying medical conditions, sleep disruption may diminish the health-related quality of life of children and adolescents and may worsen the severity of common gastrointestinal disorders. As a result of the potential consequences of sleep disruption, health care professionals should be cognizant of how managing underlying medical conditions may help to optimize sleep continuity and consider prescribing interventions that minimize sleep disruption.

A comparative study of orphan drug prices in Europe.

Background and Objective: This study assessed price differences by comparing annual treatment costs of similarly available orphan drugs in France, Germany, Italy, Norway, Spain, Sweden, and UK. Methods: Annual treatment costs per drug were calculated using ex-factory prices from IHS POLI and country price databases. The treatment cost in the comparator country was compared to the UK and ratios were analysed. Subanalyses were done on disease areas and UK cost quartiles. Results: 120 orphan drugs were included. Compared to the UK, the average costs were more expensive in France (1.13), Germany (1.11), Italy (1.08), Spain (1.07), and were cheaper in Sweden (0.99) and Norway (0.88). The average ratios offered a restrictive view as ratios were greatly heterogeneous (0.26 to 1.92) which was also seen in the different disease areas. The averaged ratios varied minimally among the cost quartiles which shows that cost differences were similar for the most expensive and least expensive orphan drugs in the UK. Conclusions: Individual orphan drug prices can vary widely across European countries, although on average these differences are relatively minor. This study suggests that in Europe, we may not be able predict which country may have higher or lower prices for orphan drugs.

Do payers value rarity? An analysis of the relationship between disease rarity and orphan drug prices in Europe.

Background and Objective: Orphan drugs have been a highlight of discussions due to their higher prices than non-orphan drugs. There is currently no European consensus on the method of value assessment for orphan drugs. This study assessed the relationship between the prevalence of rare diseases and the annual treatment cost of orphan drugs in France, Germany, Italy, Norway, Spain, Sweden, and UK. Methods: Approved orphan drugs and prevalence data were extracted from the European Medicines Agency website. Annual treatment costs were calculated using ex-factory price. Simple regression was used to analyse the relationship between costs and prevalence. A specific bivariate analysis was performed for the rarest diseases (≤1 per 10,000). Results: 120 drugs were analysed. Prevalence ranged from 0.001 to 5 per 10,000 (mean 1.24, median 1). Annual treatment costs per patient ranged from €755 to €1,051,956 (mean €100,000, median €39,303). Results show a statistically significant inverse correlation between annual treatment cost and disease prevalence in all countries (France: r = -0.370, p = 0.002; Germany: r = -0.365, p = 0.002; Italy: r = -0.340, p = 0.002; Spain: r = -0.316, p = 0.041; UK: r = -0.358, p = 0.0004; Sweden: r = -0.414, p = 0.014; Norway: r = -0.367, p = 0.002). When analysis was focused on the rarest diseases, a stronger correlation exists in all countries (France: r = -0.525, Germany: r = -0.482, Italy: r = -0.497, Spain: r = -0.531, UK: r = -0.436, Sweden: r = -0.455, Norway: r = -0.466; all p < 0.05 except Sweden p = 0.077). Conclusions: This study shows an inverse correlation between annual treatment cost and prevalence with high statistical significance in the studied countries. Although pricing is a complex process where different attributes are assessed, this study supports the idea that payers value rarity in pricing decisions.

Comparison of Inhaled Antibiotics for the Treatment of Chronic Pseudomonas aeruginosa Lung Infection in Patients With Cystic Fibrosis: Systematic Literature Review and Network Meta-analysis.

PURPOSE: In Europe, 4 inhaled antibiotics (tobramycin, colistimethate sodium, aztreonam, and levofloxacin) are currently approved for the treatment of chronic Pseudomonas aeruginosa lung infection in patients with cystic fibrosis (CF). Levofloxacin inhalation solution (LIS) is the most recently approved inhaled antibiotic for adult patients with CF. A systematic literature review and Bayesian network meta-analysis (NMA) was conducted to compare the relative short-term (4 weeks) and long-term (24 weeks) outcomes of these inhaled antibiotics versus LIS. METHODS: A systematic literature search was conducted on February 16, 2016, using EMBASE and Medline via OvidSP. All randomized controlled trials comparing any of the aforementioned inhaled antibiotics with 4 or 24 weeks of follow-up were evaluated. NMA was performed for the following outcomes: relative and absolute percent changes from baseline in forced expiratory volume in 1 second (FEV1%) predicted, change in P aeruginosa sputum density, respiratory symptoms score from the CF questionnaire-revised, hospitalization, additional antibiotics use, and study withdrawal rates. RESULTS: Of the 685 articles identified, 7 unique studies were included in the 4 weeks' NMA and 9 unique studies were included in the 24 weeks' NMA. Aztreonam was predicted to result in the greatest numerically increase in FEV1% predicted at 4 weeks, whereas LIS were predicted to be numerically greater than colistimethate sodium, tobramycin inhaled solution (TIS), and tobramycin inhaled powder (TIP). However, all of the 95% credibility intervals (CrIs) of these comparisons included zero. At 24 weeks, none of the treatments was significantly more effective than LIS. The estimates for the mean change from baseline to 24 weeks in relative FEV1% versus LIS was -0.55 (95% CrI, -3.91 to 2.80) for TIS, -2.36 (95% CrI, -7.32 to 2.63) for aztreonam, -2.95 (95% CrI, -10.44 to 4.51) for TIP, and -9.66 (95% CrI, -15.01 to -4.33) for placebo. Compared with LIS, the odds ratio for hospitalization at 24 weeks was 1.92 (95% CrI, 1.01-3.30) for TIS, 2.25 (95% CrI, 1.01-4.34) for TIP, and 3.16 (95% CrI, 1.53-5.78) for placebo, all statistically worse than LIS. P aeruginosa sputum density scores, additional use of antipseudomonal antibiotics, and study withdrawal rates were comparable among all inhaled antibiotics at all times. IMPLICATIONS: Based on this NMA, the analyses for many of the outcomes did not provide significant evidence to indicate that the other approved inhaled antibiotics were more effective than LIS for the treatment of chronic P aeruginosa lung infection in patients with CF. Study withdrawal rates seemed to be comparable among these inhaled antibiotics.

Systematic review of models used in economic analyses in moderate-to-severe asthma and COPD.

BACKGROUND: Respiratory diseases exert a substantial burden on society, with newer drugs increasingly adding to the burden. Economic models are often used, but seldom reviewed. PURPOSE: To summarize economic models used in economic analyses of drugs treating moderate-to-severe/very severe asthma or chronic obstructive pulmonary disease (COPD). METHODS: This study searched Medline and Embase from inception to the end of February 2015 for cost-effectiveness/utility analyses that examined at least one drug against placebo, another drug, or other standard therapy in asthma or COPD. Two reviewers independently searched and extracted data with differences adjudicated via consensus discussion. Data extracted included model used and its qualities, validation methods, treatments compared, disease severity, analytic perspective, time horizon, data collection (pro- or retrospective), input rates and sources, costs and sources, planned sensitivity analyses, criteria for cost-effectiveness, reported outcomes, and sponsor. RESULTS: This study analyzed 53 articles; 14 (25%) on asthma and 39 (75%) COPD. Markov models were commonly used for both asthma and COPD-related economic evaluations. Relatively few studies validated their model. For asthma-related studies, 10 examined inhaled corticosteroids and nine studied omalizumab. Placebo or standard therapy was the comparison in 11 studies and active drugs in the remainder. CONCLUSIONS: Few studies include validation of their models. Furthermore, controversy concerning some results was uncovered in this study, which needs to be avoided in the future.

Patient preferences in severe COPD and asthma: a comprehensive literature review.

BACKGROUND: Management of chronic incurable diseases such as chronic obstructive pulmonary disease (COPD) and asthma is difficult. Incorporation of patient preferences is widely encouraged. PURPOSE: To summarize original research articles determining patient preference in moderate-to-severe disease. METHODS: Acceptable articles consisted of original research determining preferences for any aspect of care in patients with COPD/asthma. The target population included those with severe disease; however, articles were accepted if they separated outcomes by severity or if the majority had at least moderate-to-severe disease. We also accepted simulation research based on scenarios describing situations involving moderate-to-severe disease that elicited preferences. Two reviewers searched Medline and Embase for articles published from the date of inception of the databases until the end of November 2014, with differences resolved through consensus discussion. Data were tabulated and analyzed descriptively. RESULTS: About 478 articles identified, 448 were rejected and 30 analyzed. There were 25 on COPD and five on asthma. Themes identified as most important in COPD were symptom relief (dyspnea/breathlessness), a positive patient-physician relationship, quality-of-life impairments, and information availability. Patients strongly preferred sponsors' inhalers. At end-of-life, 69% preferred receiving CPR, 70% wanted noninvasive, and 58% invasive mechanical intervention. While patients with asthma preferred treatments that increased symptom-free days, they were willing to trade days without symptoms for a reduction in adverse events and greater convenience. Asthma patients were willing to pay for waking up once and not needing their inhaler over waking up once overnight and needing their inhaler. CONCLUSION: Few studies have examined patient preference in these diseases. More research is needed to fill in knowledge gaps.

Utilities for asthma and COPD according to category of severity: a comprehensive literature review.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are incurable diseases that impact quality-of-life. OBJECTIVE: To summarize original research articles that measured or utilized preference-based utilities or disutilities according to disease severity. METHODS: Medline and Embase were searched from inception until the end of November 2014. Two reviewers independently searched the literature with differences settled through discussion. Data extracted included utility scores as determined in original research categorized according to disease severity as well as disutilities associated with exacerbations or comorbidities. Data were tabulated and analyzed descriptively. RESULTS: In total, 862 articles were identified, 790 were rejected, and 69 analyzed. There were 44 dealing with COPD and 25 with asthma. Average utilities determined by research were 0.828 ± 0.062, 0.765 ± 0.090, 0.711 ± 0.120, and 0.607 ± 0.120 for mild, moderate, severe, and very severe COPD, respectively. Utilities used in economic analyses were 0.866 ± 0.038, 0.770 ± 0.024, 0.739 ± 0.045, and 0.596 ± 0.075, respectively. Disutilities (annual) ranged from 0.002-0.378; major and minor exacerbations had respective disutilities of 0.287 and 0.108. For asthma patients, utilities were for 0.86 ± 0.32, 0.83 ± 0.065, and 0.74 ± 0.029, for mild, moderate, and severe disease, respectively. CONCLUSIONS: Utilities have been summarized according to severity category of asthma and COPD. These values should be useful for researchers undertaking economic analyses of these diseases.

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.

Definitions and drivers of relapse in patients with schizophrenia: a systematic literature review.

Relapse in patients with schizophrenia has devastating repercussions, including worsening symptoms, impaired functioning, cognitive deterioration and reduced quality of life. This progressive decline exacerbates the burden of illness on patients and their families. Relapse prevention is identified as a key therapeutic aim; however, the absence of widely accepted relapse definition criteria considerably hampers achieving this goal. We conducted a literature review in order to investigate the reporting of relapses and the validity of hospitalization as a proxy for relapse in patients with schizophrenia. The primary aim was to assess the range and validity of methods used to define relapse in observational or naturalistic settings. The secondary aim was to capture information on factors that predicted or influenced the risk of relapse. A structured search of the PubMed database identified articles that discussed relapse, and hospitalization as a proxy of relapse, in patients with schizophrenia. National and international guidelines were also reviewed. Of the 150 publications and guidelines identified, 87 defined relapse and 62% of these discussed hospitalization. Where hospitalization was discussed, this was as a proxy for, or a component of, relapse in the majority of cases. However, hospitalization duration and type varied and were not always well defined. Scales were used to define relapse in 53 instances; 10 different scales were used and multiple scales often appeared within the same definition. There were 95 references to factors that may drive relapse, including non-adherence to antipsychotic medication (21/95), stress/depression (11/95) and substance abuse (9/95). Twenty-five publications discussed the potential of antipsychotic therapy to reduce relapse rates-continuous antipsychotic therapy was associated with reduced frequency and duration of hospitalization. Non-pharmacological interventions, such as psychoeducation and cognitive behavioural therapy, were also commonly reported as factors that may reduce relapse. In conclusion, this review identified numerous factors used to define relapse. Hospitalization was the factor most frequently used and represents a useful proxy for relapse when reporting in a naturalistic setting. Several factors were reported to increase the risk of relapse, and observation of these may aid the identification of at-risk patients.

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.

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-Utility Analysis of Depot Atypical Antipsychotics for Chronic Schizophrenia in Croatia.

OBJECTIVES: As a nation with a developing economy, Croatia is faced with making choices between pharmaceutical products, including depot injectable antipsychotics. We conducted a pharmacoeconomic analysis to determine the cost-effectiveness of atypical depots in Croatia. METHODS: A 1-year decision-analytic framework modeled drug use. We determined the average direct cost to the Croatian Institute for Health Insurance of using depot formulations of paliperidone palmitate long-acting injectable (PP-LAI), risperidone LAI (RIS-LAI), or olanzapine LAI (OLZ-LAI). An expert panel plus literature-derived clinical rates populated the core model, along with costs adjusted to 2012 by using the Croatian consumer price index. Clinical outcomes included quality-adjusted life-years, hospitalization rates, emergency room treatment rates, and relapse days. Robustness of results was examined with one-way sensitivity analyses on important inputs; overall, all inputs were varied over 10,000 simulations in a Monte Carlo analysis. RESULTS: Costs (quality-adjusted life-years) per patient were €5061 (0.817) for PP-LAI, €5168 (0.807) for RIS-LAI, and €6410 (0.812) for OLZ-LAI. PP-LAI had the fewest relapse days, emergency room visits, and hospitalizations. Results were sensitive against RIS-LAI with respect to drug costs and adherence rates, but were generally robust overall, dominating OLZ-LAI in 77.3% and RIS-LAI in 56.8% of the simulations. CONCLUSIONS: PP-LAI dominated the other drugs because it had the lowest cost and best clinical outcomes. Compared with depots of olanzapine and risperidone and oral olanzapine, PP-LAI was the cost-effective atypical LAI for treating chronic schizophrenia in Croatia. Using depot paliperidone in place of either olanzapine or risperidone would reduce the overall costs of caring for these patients.

Pharmacoeconomic analysis of paliperidone palmitate versus olanzapine pamoate for chronic schizophrenia in Norway.

OBJECTIVE: Paliperidone palmitate long-acting injection (PP-LAI) has recently been approved for treatment of chronic schizophrenia. Its cost-effectiveness has not been established. The objective was to compare direct costs and outcomes between PP-LAI and olanzapine pamoate (OLZ-LAI) in treating chronic schizophrenia in Norway from the perspective of the government payer. METHODS: We used a decision analytic model over a 1-year time horizon. Clinical inputs were derived from the literature and an expert panel; costs were taken from standard lists, adjusted to 2010 Norwegian kroner (NOK). Discounting was not done. Main outcomes included average cost per patient treated, hospitalisations, emergency room (ER) visits and quality-adjusted life years (QALYs). The pharmacoeconomic outcome was the incremental cost per QALY. Robustness was examined using one-way sensitivity analyses on critical variables and a 5000-iteration probabilistic Monte Carlo sensitivity analysis with all variables included. RESULTS: PP-LAI generated 0.845 QALY at a cost of 151 336 NOK of which 23% was due to drugs; 25% of patients were hospitalised and another 12% required ER visits. OLZ-LAI cost 174 351 NOK (21% due to drugs); patient outcomes included 0.844 QALY, 27% hospitalisations and 14% ER visits. PP-LAI dominated OLZ-LAI in the base case. The analysis was reasonably robust against variations in drug cost but sensitive to small changes in adherence and hospitalisation rates. Overall, PP-LAI was dominant over OLZ-LAI in 54.5% of simulations. Replacing OLZ-LAI with PP-LAI would be cost saving for the Norwegian healthcare system. CONCLUSION: PP-LAI was cost-effective compared with OLZ-LAI in treating patients with chronic schizophrenia in Norway but sensitive to changes in adherence and hospitalisation rates.

An analysis of potentially prolactin-related adverse events and abnormal prolactin values in randomized clinical trials with paliperidone palmitate.

BACKGROUND: Paliperidone palmitate has been associated with serum prolactin elevations in some patients. However, few individuals with elevated prolactin levels (hyperprolactinemia) have symptomatic potentially prolactin-related adverse events (PPR-AEs). OBJECTIVE: To quantify rates of hyperprolactinemia in subjects treated with the newly marketed paliperidone palmitate long-acting injection (PP-LAI) in randomized clinical trials, summarize rates of PPR-AEs in those trials by sex and dose, and determine how many PPR-AEs required treatment. METHODS: Numbers and rates of investigator-reported hyperprolactinemia and PPR-AEs were obtained from the sponsor's clinical trial database and have been included in regulatory filings. Results were tabulated for males, females, and overall, and by dose administered, using descriptive statistics. Those requiring treatment were described as well. RESULTS: There were 3173 subjects (61.4% males) exposed to PP-LAI in 10 clinical trials; 2831 (89.2%) patients had recorded prolactin levels, including 1759 males (90.3% of exposed males) and 1072 females (87.5% of exposed females). Overall, at any time, prolactin levels were elevated for 38.8% of the subjects (39.5% for males and 37.7% for females; p = 0.354 between sexes). However, there was no significant correlation between monthly dose and proportion of subjects with elevated prolactin levels (p = 0.109). There were 115 PPR-AEs in 107 patients (3.4%); 51 (44.3% of PPR-AEs) cases represented asymptomatic hyperprolactinemia. The remaining 64 symptomatic PPR-AEs affected 2.0% of the total number of subjects. Fifteen events in 13 participants (0.41% of patients or 4.7 events/1000 patients) required treatment. CONCLUSIONS: Clinicians should periodically assess patients on paliperidone palmitate for any PPR-AEs and carefully assess the benefits and risks when managing these effects.

Pharmacoeconomic analysis of paliperidone palmitate for treating schizophrenia in Greece.

BACKGROUND: Patients having chronic schizophrenia with frequent relapses and hospitalizations represent a great challenge, both clinically and financially. Risperidone long-acting injection (RIS-LAI) has been the main LAI atypical antipsychotic treatment in Greece. Paliperidone palmitate (PP-LAI) has recently been approved. It is dosed monthly, as opposed to biweekly for RIS-LAI, but such advantages have not yet been analysed in terms of economic evaluation. PURPOSE: To compare costs and outcomes of PP-LAI versus RIS-LAI in Greece. METHODS: A cost-utility analysis was performed using a previously validated decision tree to model clinical pathways and costs over 1 year for stable patients started on either medication. Rates were taken from the literature. A local expert panel provided feedback on treatment patterns. All direct costs incurred by the national healthcare system were obtained from the literature and standard price lists; all were inflated to 2011 costs. Patient outcomes analyzed included average days with stable disease, numbers of hospitalizations, emergency room visits, and quality-adjusted life-years (QALYs). RESULTS: The total annual healthcare cost with PP-LAI was €3529; patients experienced 325 days in remission and 0.840 QALY; 28% were hospitalized and 15% received emergency room treatment. With RIS-LAI, the cost was €3695, patients experienced 318.6 days in remission and 0.815 QALY; 33% were hospitalized and 17% received emergency room treatment. Thus, PP-LAI dominated RIS-LAI. Results were generally robust in sensitivity analyses with PP-LAI dominating in 74.6% of simulations. Results were sensitive to the price of PP-LAI. CONCLUSIONS: PP-LAI appears to be a cost-effective option for treating chronic schizophrenia in Greece compared with RIS-LAI since it results in savings to the health care system along with better patient outcomes.

Blood glucose and subsequent cardiovascular disease: update of a meta-analysis.

BACKGROUND/PURPOSE: A 1999 meta-analysis described the relationship between blood glucose and subsequent cardiovascular events (MI, stroke, cardiovascular mortality). More studies have been published; therefore, we updated and refined estimates of this relationship in people without diabetes. ACCEPTABILITY CRITERIA: We accepted prospective studies that reported screening results for blood glucose levels (either fasting, 2-hour postprandial, 1-hour postprandial, or casual) divided into ≥3 quantiles. Required data within each quantile were numbers exposed plus study duration or person-years at risk, and numbers of cardiovascular outcomes (myocardial infarction, stroke, death). No restrictions were placed on language or publication date. DATA SOURCES: Two reviewers searched Medline, Embase, Scopus, and Cochrane databases from inception until December 2009. Consensus settled discrepancies. DATA SYNTHESIS: Poisson regression quantified the relationship between glucose quantile and outcomes. Beta values were combined with inverse variance weightings using a random effects meta-analytic model. RESULTS: We found 36 articles with 141 datasets examining the relationship between blood glucose (32 fasting, 52 2-hour postprandial, 37 1-hour postprandial, 20 casual) in 191,249 patients without diabetes (73% male) for 3 million person-years. There were 12,537 (6.6%) cardiovascular deaths, 14,445 (7.6%) cardiovascular events, 6862 (3.6%) cardiac and 3412 (1.7%) stroke deaths. Relative risks/unit increase in blood glucose were all significant for total cardiovascular events (RRs ranged from 1.09-1.51, all p-values < 0.005) and cardiovascular deaths (RR = 1.05-1.24, p < 0.007), and all for cardiac deaths (p < 0.05) except casual glucose; stroke mortality was less clear. The two strongest relationships were found between fasting levels and all events (RR = 1.51, CI: 1.20-1.89) and with cardiovascular mortality (RR = 1.40, CI: 1.18-1.60). With 2-hour postprandial levels, the respective RRs were 1.22 (1.17-1.28) and 1.24 (1.19-1.30). A limitation is the assumption of a continuous relationship between variables. CONCLUSIONS: We have provided refined estimates confirming the association between elevated blood glucose and subsequent cardiovascular events.

Relationship between blood glucose and carotid intima media thickness: A meta-analysis.

BACKGROUND: Increased coronary intima media thickness (CIMT) has been associated with adverse cardiovascular outcomes, as have increased glucose levels. The link has not been established between glucose and CIMT; therefore, we sought to assess the relationship between glucose and CIMT. METHODS: Medline, EMBASE, Scopus, and Cochrane databases were searched from inception through 2009 for original research reporting both postprandial glucose levels and CIMT measurements. Glucose was classified as normal, impaired, or diabetic. Outputs included inverse variance weighted effect size and also average correlation (using the Wang and Bushman approach). Data were combined using a random effects meta-analytic model. Heterogeneity as assessed using chi(2) and I(2); bias was examined using Egger plots and Begg-Mazumdar tau. Polynomial functions (i.e., linear, quadratic, cubic, quartic) were fit to the data and the Akaike Information Criteria were used to select the optimal model. RESULTS: We identified 172 papers; 161 were rejected (19 inappropriate design, 8 had selected patients, 101 inappropriate outcomes) leaving 11 accepted. We used data from 15,592 patients (8250 normals, 3013 impaired glucose, 4329 diabetics). There was no evidence of heterogeneity or publication bias. The overall correlation was 0.082 (CI95%:0.066-0.098); the overall effect size was 0.294 (0.245-0.343) between diabetics and normals and 0.137 (0.072-0.202) between normals and those with impaired glucose. The equation of best fit was linear (CIMT = 0.828 + 0.009*glucose). CONCLUSIONS: There is a small but significant relationship between postprandial glucose levels and CIMT, which have both been associated with adverse cardiovascular outcomes.

Advanced cutaneous malignant melanoma: a systematic review of economic and quality-of-life studies.

OBJECTIVE: Metastatic melanoma (MM), a major concern for health-care providers, is increasing. We systematically reviewed published articles describing the impact of interventions (drugs and screening) on quality of life (QoL) in patients with MM, and articles that measured QoL in MM. METHODS: We searched secondary databases including MEDLINE, Embase, CINAHL, Cochrane, and DARE from inception to 2006 using MESH terms "melanoma" and "metastases." Economic articles were subject to established quality assessment procedures. RESULTS: We found 13 QoL and five economic studies (three cost-effectiveness, two cost-utility; average quality = 83% +/- 7%). No strong evidence was found in this review for cost-effectiveness of interferons in Canada (incremental cost-effectiveness ratio [ICER] = $55,090/quality-adjusted life-year) or temozolomide in the United States (ICER = $36,990/Life-year gained based on nonsignificant efficacy differences). Melanoma screening was not cost-effective in the United States ($150,000-931,000/life-saved) or Germany (no survival benefit). From the 13 QoL studies,eight measured baseline QoL; six studied the same population, generating similar results using different approaches/outcomes. Tools used included GLQ-8, QLQ-C30, QLQ-36, QWB-SA, and SF-36. Baseline scores QoL scores ranged from 0.60 to 0.69. Another five studies (N = 959 patients) were randomized trials analyzing QoL in patients treated with dacarbazine alone, dacarbazine +/- interferon, dacarbazine + fotemustine, interleukin +/- histamine, and temozolomide. Little difference was found in QoL scores between drugs or between baseline and end point. CONCLUSIONS: Cost-effectiveness has not been widely demonstrated for treatment of MM. Only two studies with unimpressive results exist for treatments. Screening was not cost-effective in the United States or Germany. Generally, no significant improvements in QoL were found for any alternative for treating MM. A need exists for effective treatments that improve duration and QoL.