Reweighting Randomized Controlled Trial Evidence to Better Reflect Real Life - A Case Study of the Innovative Medicines Initiative.

Evidence from randomized controlled trials available for timely health technology assessments of new pharmacological treatments and regulatory decision making may not be generalizable to local patient populations, often resulting in decisions being made under uncertainty. In recent years, several reweighting approaches have been explored to address this important question of generalizability to a target population. We present a case study of the Innovative Medicines Initiative to illustrate the inverse propensity score reweighting methodology, which may allow us to estimate the expected treatment benefit if a clinical trial had been run in a broader real-world target population. We learned that identifying treatment effect modifiers, understanding and managing differences between patient characteristic data sets, and balancing the closeness of trial and target patient populations with effective sample size are key to successfully using this methodology and potentially mitigating some of this uncertainty around local decision making.

Determinants of time to institutionalisation and related healthcare and societal costs in a community-based cohort of patients with Alzheimer's disease dementia.

OBJECTIVES: To examine the costs of caring for community-dwelling patients with Alzheimer's disease (AD) dementia in relation to the time to institutionalisation. METHODS: GERAS was a prospective, non-interventional cohort study in community-dwelling patients with AD dementia and their caregivers in three European countries. Using identified factors associated with time to institutionalisation, models were developed to estimate the time to institutionalisation for all patients. Estimates of monthly total societal costs, patient healthcare costs and total patient costs (healthcare and social care together) prior to institutionalisation were developed as a function of the time to institutionalisation. RESULTS: Of the 1495 patients assessed at baseline, 307 (20.5%) were institutionalised over 36 months. Disease severity at baseline [based on Mini-Mental State Examination (MMSE) scores] was associated with risk of being institutionalised during follow up (p < 0.001). Having a non-spousal informal caregiver was associated with a faster time to institutionalisation (944 fewer days versus having a spousal caregiver), as was each one-point worsening in baseline score of MMSE, instrumental activities of daily living and behavioural disturbance (67, 50 and 30 fewer days, respectively). Total societal costs, total patient costs and, to a lesser extent, patient healthcare-only costs were associated with time to institutionalisation. In the 5 years pre-institutionalisation, monthly total societal costs increased by more than £1000 (€1166 equivalent for 2010) from £1900 to £3160 and monthly total patient costs almost doubled from £770 to £1529. CONCLUSIONS: Total societal costs and total patient costs rise steeply as community-dwelling patients with AD dementia approach institutionalisation.

Practical implications of using real-world evidence (RWE) in comparative effectiveness research: learnings from IMI-GetReal.

In light of increasing attention towards the use of real-world evidence (RWE) in decision making in recent years, this commentary aims to reflect on the experiences gained in accessing and using RWE for comparative effectiveness research as a part of the Innovative Medicines Initiative GetReal Consortium and discuss their implications for RWE use in decision-making.

What Drives Country Differences in Cost of Alzheimer's Disease? An Explanation from Resource Use in the GERAS Study.

BACKGROUND: Country differences in resource use and costs of Alzheimer's disease (AD) may be driven by differences in health care systems and resource availability. OBJECTIVE: To compare country resource utilization drivers of societal costs for AD dementia over 18 months. METHODS: GERAS is an observational study in France (n = 419), Germany (n = 550), and the UK (n = 526). Resource use of AD patients and caregivers contributing to >1% of total societal costs (year 2010) was assessed for country differences, adjusting for participant characteristics. RESULTS: Mean 18-month societal costs per patient were France €33,339, Germany €38,197, and UK €37,899 (£32,501). Caregiver time spent on basic and instrumental activities of daily living (ADL) contributed the most to societal costs (54% France, 64% Germany, 65% UK). Caregivers in France spent less time on ADL than UK caregivers and missed fewer work days than in other countries. Compared with other countries, patients in France used more community care services overall and were more likely to use home aid. Patients in Germany were least likely to use temporary accommodation or to be institutionalized at 18 months. UK caregivers spent the most time on instrumental ADL, UK patients used fewest outpatient resources, and UK patients/caregivers were most likely to receive financial support. CONCLUSION: Caregiver time on ADL contributed the most to societal costs and differed across countries, possibly due to use of community care services and institutionalization. Other resources had different patterns of use across countries, reflecting country-specific health and social care systems.

Clinical and cost implications of amyloid beta detection with amyloid beta positron emission tomography imaging in early Alzheimer's disease - the case of florbetapir.

OBJECTIVE: Amyloid beta (Aß) positron emission tomography (PET) imaging helps estimate Aß neuritic plaque density in patients with cognitive impairment who are under evaluation for Alzheimer's disease (AD). This study aims to evaluate the cost-effectiveness of the Aß-PET scan as an adjunct to standard diagnostic assessment for diagnosis of AD in France, using florbetapir as an example. METHODS: A state-transition probability analysis was developed adopting the French Health Technology Assessment (HTA) perspective per guidance. Parameters included test characteristics, rate of cognitive decline, treatment effect, costs, and quality of life. Additional scenarios assessed the validity of the analytical framework, including: (1) earlier evaluation/treatment; (2) cerebrospinal fluid (CSF) as a comparator; and (3) use of other diagnostic procedures. Outputs included differences in quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). All benefits and costs were discounted for time preferences. Sensitivity analyses were performed to assess the robustness of findings and key influencers of outcomes. RESULTS: Aß-PET used as an adjunct to standard diagnostic assessment increased QALYs by 0.021 years and 10 year costs by €470 per patient. The ICER was €21,888 per QALY gained compared to standard diagnostic assessment alone. When compared with CSF, Aß-PET costs €24,084 per QALY gained. In other scenarios, Aß-PET was consistently cost-effective relative to the commonly used affordability threshold (€40,000 per QALY). Over 95% of simulations in the sensitivity analysis were cost-effective. CONCLUSION: Aß-PET is projected to affordably increase QALYs from the French HTA perspective per guidance over a range of clinical scenarios, comparators, and input parameters.

How to deal with missing longitudinal data in cost of illness analysis in Alzheimer's disease-suggestions from the GERAS observational study.

BACKGROUND: Missing data are a common problem in prospective studies with a long follow-up, and the volume, pattern and reasons for missing data may be relevant when estimating the cost of illness. We aimed to evaluate the effects of different methods for dealing with missing longitudinal cost data and for costing caregiver time on total societal costs in Alzheimer's disease (AD). METHODS: GERAS is an 18-month observational study of costs associated with AD. Total societal costs included patient health and social care costs, and caregiver health and informal care costs. Missing data were classified as missing completely at random (MCAR), missing at random (MAR) or missing not at random (MNAR). Simulation datasets were generated from baseline data with 10-40 % missing total cost data for each missing data mechanism. Datasets were also simulated to reflect the missing cost data pattern at 18 months using MAR and MNAR assumptions. Naïve and multiple imputation (MI) methods were applied to each dataset and results compared with complete GERAS 18-month cost data. Opportunity and replacement cost approaches were used for caregiver time, which was costed with and without supervision included and with time for working caregivers only being costed. RESULTS: Total costs were available for 99.4 % of 1497 patients at baseline. For MCAR datasets, naïve methods performed as well as MI methods. For MAR, MI methods performed better than naïve methods. All imputation approaches were poor for MNAR data. For all approaches, percentage bias increased with missing data volume. For datasets reflecting 18-month patterns, a combination of imputation methods provided more accurate cost estimates (e.g. bias: -1 % vs -6 % for single MI method), although different approaches to costing caregiver time had a greater impact on estimated costs (29-43 % increase over base case estimate). CONCLUSIONS: Methods used to impute missing cost data in AD will impact on accuracy of cost estimates although varying approaches to costing informal caregiver time has the greatest impact on total costs. Tailoring imputation methods to the reason for missing data will further our understanding of the best analytical approach for studies involving cost outcomes.

Excess Costs Associated with Possible Misdiagnosis of Alzheimer's Disease Among Patients with Vascular Dementia in a UK CPRD Population.

BACKGROUND: Prior diagnosis of Alzheimer's disease (AD) among patients later diagnosed with vascular dementia (VaD) has been associated with excess costs, suggesting potential benefits of earlier rule-out of AD diagnosis. OBJECTIVE: To investigate whether prior diagnosis with AD among patients with VaD is associated with excess costs in the UK. METHODS: Patients with a final VaD diagnosis, continuous data visibility for≥6 months prior to index date, and linkage to Hospital Episode Statistics data were retrospectively selected from de-identified Clinical Practice Research Datalink data. Patients with AD diagnosis before a final VaD diagnosis were matched to similar patients with no prior AD diagnosis using propensity score methods. Annual excess healthcare costs were calculated for 5 years post-index, stratified by time to final diagnosis. RESULTS: Of 9,311 patients with VaD, 508 (6%) had prior AD diagnosis with a median time to VaD diagnosis exceeding 2 years from index date. Over the entire follow-up period, patients with prior AD diagnosis had accumulated healthcare costs that were approximately GBP2,000 higher than those for matched counterparts (mostly due to higher hospitalization costs). Cost differentials peaked particularly in the period including the final VaD diagnosis, with excess costs quickly declining thereafter. CONCLUSION: Potential misdiagnosis of AD among UK patients with VaD resulted in substantial excess costs. The decline in excess costs following a final VaD diagnosis suggests potential benefits from earlier rule-out of AD.

Do You Want to Hear the Bad News? The Value of Diagnostic Tests for Alzheimer's Disease.

OBJECTIVE: The diagnosis of Alzheimer's disease (AD) remains difficult. Lack of diagnostic certainty or possible distress related to a positive result from diagnostic testing could limit the application of new testing technologies. The objective of this paper is to quantify respondents' preferences for obtaining AD diagnostic tests and to estimate the perceived value of AD test information. METHODS: Discrete-choice experiment and contingent-valuation questions were administered to respondents in Germany and the United Kingdom. Choice data were analyzed by using random-parameters logit. A probit model characterized respondents who were not willing to take a test. RESULTS: Most respondents indicated a positive value for AD diagnostic test information. Respondents who indicated an interest in testing preferred brain imaging without the use of radioactive markers. German respondents had relatively lower money-equivalent values for test features compared with respondents in the United Kingdom. CONCLUSIONS: Respondents preferred less invasive diagnostic procedures and tests with higher accuracy and expressed a willingness to pay up to €700 to receive a less invasive test with the highest accuracy.

Cost-Effectiveness of Florbetapir-PET in Alzheimer's Disease: A Spanish Societal Perspective.

BACKGROUND: The rising prevalence of Alzheimer's disease (AD), and other diseases associated with dementia, imposes significant burden to various stakeholders who care for the elderly. Management of AD is complicated by multiple factors including disease-specific features which make it difficult to diagnose accurately during milder stages. Florbetapir F18 positron emission tomography (florbetapir-PET) is an approved imaging tool used to capture beta-amyloid neuritic plaque density in brains of cognitively impaired adults undergoing evaluation for AD and other causes of cognitive impairment. It has the potential to help improve healthcare outcomes as it may help clinicians identify patients with AD early so that treatments are initiated when most effective. AIMS OF THE STUDY: Evaluate the potential long-term clinical and economic outcomes of adopting florbetapir-PET--adjunctive to standard clinical evaluation (SCE)--versus SCE alone in the diagnostic assessment of cognitively impaired patients with suspected AD. METHODS: A decision analysis with a ten-year time horizon was developed in compliance with Good Research Practices and CHEERS guidelines. The target population was comprised of Spanish patients who were undergoing initial assessment for cognitive impairment (Mini-Mental State Examination [MMSE] score=20). Diagnostic accuracy, rate of cognitive decline, effect of drugs on cognition and dwelling status, economic burden (direct and indirect costs), and quality of life (QoL) were based on relevant clinical studies and published literature. Scenario analysis was applied to explore outcomes under different conditions, which included: (i) use of florbetapir-PET earlier in disease progression (MMSE score=22); and (ii) the addition of fluorodeoxyglucose (FDG)-PET to SCE. RESULTS: Adjunctive florbetapir-PET increased quality-adjusted life years (QALYs) by 0.008 years and increased costs by 36 compared to SCE alone (incremental cost-effectiveness ratio [ICER], 4,769). Use of florbetapir-PET was dominant in alternate scenarios. Sensitivity analyses indicated rates of institutionalization (by MMSE) and MMSE score upon initiation of acetylcholinesterase inhibitor (AChEI) treatment most influenced the primary outcome (ICER) in the base case scenario. Over 82% of probabilistic simulations were cost-effective using the Spanish threshold (30,000/QALY). DISCUSSION: The addition of florbetapir-PET to SCE is expected to improve the accuracy of AD diagnoses for patients experiencing cognitive impairment; it is cost-effective due to decreased healthcare costs and caregiver burden. Prospective studies of the clinical utility of florbetapir-PET are necessary to evaluate the long-term implications of adopting florbetapir-PET on clinical outcomes and costs in real-world settings. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: Florbetapir-PET is expected to improve decision-making regarding appropriate and sufficient care for cognitively impaired patients with suspected AD, while cost-effective. IMPLICATIONS FOR HEALTH POLICIES: Earlier and more accurate diagnosis of AD may help to improve patient's health status and reduce treatment costs by effectively allocating healthcare resources and maximizing the benefit of treatments and supportive services. IMPLICATIONS FOR FURTHER RESEARCH: Use of florbetapir-PET may help accurately identify patients with AD. The development of novel therapeutics for use with companion diagnostics may provide additional benefits by slowing or halting progressive cognitive decline with AD, increase QoL and prolong survival.

Determinants of societal costs in Alzheimer's disease: GERAS study baseline results.

BACKGROUND: To identify the main factors associated with societal costs of Alzheimer's disease (AD) in community-dwelling patients across three European countries. METHODS: Baseline cost data from a prospective, observational study were used. Assessments included patients' cognition, activities of daily living (ADLs) and behavioral symptoms, and caregiver burden. Cost calculations (2010) from the societal perspective were based on patient/caregiver resource use. Generalized linear models estimated factors associated with costs. RESULTS: Mean monthly costs per patient differed for France (€1881), Germany (€2349), and the UK (€2016), with informal care costs accounting for 50% to 61%. Independent factors associated with costs across all countries were ADL total score, patient living arrangements, caregiver working status, and caregiver burden (all P < .05). Additional factors were significant for the pooled cohort or individual countries. CONCLUSIONS: Several patient and caregiver factors, including factors associated with informal care, should be included when evaluating care options for patients with AD.

Long-acting olanzapine versus long-acting risperidone for schizophrenia in Spain - a cost-effectiveness comparison.

BACKGROUND: In schizophrenia, medication adherence is critical to achieve better patient outcomes and to avoid relapses, which are responsible for a significant proportion of total healthcare costs for this chronic illness. The aim of this study was to assess the cost-effectiveness of olanzapine long-acting injection (OLAI) compared with risperidone long-acting injection (RLAI) in patients with schizophrenia in Spain. METHODS: A discrete event simulation (DES) model was developed from a Spanish healthcare system perspective to estimate clinical and economic outcomes for patients with schizophrenia over a five-year period. Patients who had earlier responded to oral medication and have a history of relapse due to adherence problems were considered. Identical model populations were treated with either OLAI or RLAI. In the absence of a head-to-head clinical trial, discontinuation and relapse rates were obtained from open-label studies. The model accounted for age, gender, risks of relapse and discontinuation, relapse management, hospitalization, treatment switching and adverse events. Direct medical costs for the year 2011 and outcomes including relapse avoided, life years (LYs), and quality-adjusted life years (QALYs) were discounted at a rate of 3%. RESULTS: When comparing RLAI and OLAI, the model predicts that OLAI would decrease 5-year costs by €2,940 (Standard Deviation between replications 300.83), and result in a QALY and LY gains of 0.07 (SD 0.019) and 0.04 (SD 0.025), respectively. Patients on OLAI had fewer relapses compared to RLAI (1.392 [SD 0.035] vs. 1.815 [SD 0.035]) and fewer discontinuations (1.222 [SD 0.031] vs. 1.710 [SD 0.039]). Sensitivity analysis indicated that the study was robust and conclusions were largely unaffected by changes in a wide range of parameters. CONCLUSIONS: The present evaluation results in OLAI being dominant over RLAI, meaning that OLAI represents a more effective and less costly alternative compared to RLAI in the treatment of patients with schizophrenia in the Spanish setting.

Health care resource utilisation in primary care prior to and after a diagnosis of Alzheimer's disease: a retrospective, matched case-control study in the United Kingdom.

BACKGROUND: This study examined medical resource utilisation patterns in the United Kingdom (UK) prior to and following Alzheimer's disease (AD) diagnosis. METHODS: A patient cohort aged 65 years and older with newly diagnosed AD between January 2008 and December 2010 was identified through the UK's Clinical Practice Research Datalink (CPRD). Patients with a continuous record in the CPRD (formerly the General Practice Research Database [GPRD]) for both the 3 years prior to, and the 1 year following, AD diagnosis were eligible for inclusion. A control cohort was identified by matching general older adult (GOA) patients to patients with AD based on year of birth, gender, region, and Charlson Comorbidity Index at a ratio of 2:1. Medical resource utilisation was calculated in 6-month intervals over the 4-year study period. Comparisons between AD and GOA control cohorts were conducted using conditional logistic regression for patient characteristics and a generalised linear model for resource utilisation. RESULTS: Data for the AD cohort (N = 3,896) and matched GOA control cohort (N = 7,792) were extracted from the CPRD. The groups were 65% female and the AD cohort had a mean age of 79.9 years (standard deviation 6.5 years) at the date of diagnosis. Over the entire study period, the AD cohort had a significantly higher mean primary care consultation rate than the GOA cohort (p < .0001). While the GOA cohort primary care consultation rate gradually increased over the 4-year period (ranging from 5 to 7 consultations per 6-month period), increases were more pronounced in the AD cohort (ranging from 6 to 11 consultations per 6-month period, peaking during the 6-month periods immediately prior to and post diagnosis). The AD cohort also had a higher overall specialty referral rate than the GOA cohort over the 4-year period (37% vs. 25%, respectively; p < .0001); the largest difference was during the 6 months immediately prior to AD diagnosis (17% vs. 5%, respectively; p < .0001). CONCLUSIONS: In the UK, AD diagnosis is associated with significant increases in primary and secondary care resource utilisation, continuing beyond diagnosis. This evidence may be important to health care commissioners to facilitate effective mobilisation of appropriate AD-related health care resources.

Cost effectiveness of duloxetine for osteoarthritis: a Quebec societal perspective.

OBJECTIVE: To assess the cost effectiveness of duloxetine compared to other oral postacetaminophen treatments for osteoarthritis (OA) from a Quebec societal perspective. METHODS: A cost-utility analysis was performed enhancing the Markov model from the 2008 OA guidelines of the National Institute for Health and Clinical Excellence (NICE). The NICE model was extended to include opioid and antidepressant comparators, adding titration, discontinuation, and relevant adverse events (AEs). Comparators included duloxetine, celecoxib, diclofenac, naproxen, hydromorphone, and oxycodone extended release (oxycodone). AEs included gastrointestinal and cardiovascular events associated with nonsteroidal antiinflammatory drugs (NSAIDs), as well as fracture, opioid abuse, and constipation, among others. Costs and incremental cost-effectiveness ratios (ICERs) were estimated in 2011 Canadian dollars. The base case modeled a cohort of 55-year-old patients with OA for a 12-month period of treatment, followed by treatment from a basket of post-discontinuation oral therapies until death. Sensitivity analyses (one-way and probabilistic) were conducted. RESULTS: Overall, naproxen was the least expensive treatment, whereas oxycodone was the most expensive. Duloxetine accumulated the highest number of quality-adjusted life years (QALYs), with an ICER of $36,291 per QALY versus celecoxib. Duloxetine was dominant over opioids. In subgroup analyses, ICERs for duloxetine versus celecoxib were $15,619 and $20,463 for patients at high risk of NSAID-related AEs and patients ages >65 years, respectively. CONCLUSION: Duloxetine was cost effective for a cohort of 55-year-old patients with OA, and more so in older patients and those with greater AE risks.

Systematic literature review and meta-analysis of diagnostic test accuracy in Alzheimer's disease and other dementia using autopsy as standard of truth.

BACKGROUND: Early diagnosis of Alzheimer's disease (AD) is crucial to implement the latest treatment strategies and management of AD symptoms. Diagnostic procedures play a major role in this detection process but evidence on their respective accuracy is still limited. OBJECTIVE: To conduct a systematic literature on the sensitivity and specificity of different test modalities to identify AD patients and perform meta-analyses on the test accuracy values of studies focusing on autopsy-confirmation as the standard of truth. METHODS: The systematic review identified all English papers published between 1984 and 2011 on diagnostic imaging tests and cerebrospinal fluid biomarkers including results on the newest technologies currently investigated in this area. Meta-analyses using bivariate fixed and random-effect models and hierarchical summary receiver operating curve (HSROC) random-effect model were applied. RESULTS: Out of the 1,189 records, 20 publications were identified to report the accuracy of diagnostic tests in distinguishing autopsy-confirmed AD patients from other dementia types and healthy controls. Looking at all tests and comparator populations together, sensitivity was calculated at 85.4% (95% confidence interval [CI]: 80.9%-90.0%) and specificity at 77.7% (95% CI: 70.2%-85.1%). The area under the HSROC curve was 0.88. Sensitivity and specificity values were higher for imaging procedures, and slightly lower for CSF biomarkers. Test-specific random-effect models could not be calculated due to the small number of studies. CONCLUSION: The review and meta-analysis point to a slight advantage of imaging procedures in correctly detecting AD patients but also highlight the limited evidence on autopsy-confirmations and heterogeneity in study designs.

The efficacy of duloxetine, non-steroidal anti-inflammatory drugs, and opioids in osteoarthritis: a systematic literature review and meta-analysis.

BACKGROUND: This meta-analysis assessed the efficacy of duloxetine versus other oral treatments used after failure of acetaminophen for management of patients with osteoarthritis. METHODS: A systematic literature review of English language articles was performed in PUBMED, EMBASE, MedLine In-Process, Cochrane Library, and ClinicalTrials.gov between January 1985 and March 2013. Randomized controlled trials of duloxetine and all oral non-steroidal anti-inflammatory drugs and opioids were included if treatment was ≥12 weeks and the Western Ontario and McMaster Universities Index (WOMAC) total score was available. Studies were assessed for quality using the assessment tool from the National Institute for Health and Clinical Excellence guidelines for single technology appraisal submissions.WOMAC baseline and change from baseline total scores were extracted and standardized. A frequentist meta-analysis, meta-regression, and indirect comparison were performed using the DerSimonian-Laird and Bucher methods. Bayesian analyses with and without adjustment for study-level covariates were performed using noninformative priors. RESULTS: Thirty-two publications reported 34 trials (2 publications each reported 2 trials) that met inclusion criteria. The analyses found all treatments except oxycodone (frequentist) and hydromorphone (frequentist and Bayesian) to be more effective than placebo. Indirect comparisons to duloxetine found no significant differences for most of the compounds. Some analyses showed evidence of a difference with duloxetine for etoricoxib (better), tramadol and oxycodone (worse), but without consistent results between analyses. Forest plots revealed positive trends in overall efficacy improvement with baseline scores. Adjusting for baseline, the probability duloxetine is superior to other treatments ranges between 15% to 100%.Limitations of this study include the low number of studies included in the analyses, the inclusion of only English language publications, and possible ecological fallacy associated with patient level characteristics. CONCLUSIONS: This analysis suggests no difference between duloxetine and other post-first line oral treatments for osteoarthritis (OA) in total WOMAC score after approximately 12 weeks of treatment. Significant results for 3 compounds (1 better and 2 worse) were not consistent across performed analyses.

Effectiveness of duloxetine compared with pregabalin and gabapentin in diabetic peripheral neuropathic pain: results from a German observational study.

OBJECTIVES: This study aimed to compare the effectiveness of duloxetine (DLX) and the anticonvulsants pregabalin (PGB) and gabapentin (GBP) for the treatment of diabetic peripheral neuropathic pain (DPNP) in routine clinical care. MATERIALS AND METHODS: Data from a 6-month, noninterventional study involving 2575 patients in whom treatment of DPNP was initiated with or changed to DLX, PGB, or GBP (n=1523) were analyzed post hoc; patients treated with other medications or combinations were excluded from this analysis. Propensity scoring was used to compare patient groups, assessing Brief Pain Inventory (BPI), Clinical and Patient Global Impression (CGI/PGI), the Hospital Anxiety and Depression Scale (HADS), the Sheehan Disability Scale (SDS), and the Short Form Health Survey (SF 12). RESULTS: Mean median daily dosage over 6 months was 53.9 mg for DLX (N=931), 173.5 mg for PGB (N=248), and 727.8 mg for GBP (N=351). BPI average pain severity (last observation carried forward, mean [SD]) decreased by 2.3 [2.30] points for DLX patients, and by 1.9 [2.22] in PGB, and 1.1 [2.15] in GBP patients. This difference remained statistically significant (DLX vs. PGB: P=0.029; DLX vs. GBP: P<0.001) after adjustment by propensity scores. Similar findings were also seen for the BPI interference score, CGI and PGI, the HADS anxiety score, the HADS depression score. DISCUSSION: When compared with DLX, the low doses of PGB and GBP used in this noninterventional study might have contributed to the lower effectiveness found for both anticonvulsants in the treatment of patients with DPNP.

Impact of pretreatment with antidepressants on the efficacy of duloxetine in terms of mood symptoms and functioning: an analysis of 15 pooled major depressive disorder studies.

OBJECTIVE: This post hoc analysis aimed to determine whether patients with major depressive disorder (MDD) in duloxetine trials who were antidepressant naive or who were previously exposed to antidepressants exhibited differences in efficacy and functioning. METHOD: Data were pooled from 15 double-blind, placebo- and/or active-controlled duloxetine trials of adult patients with MDD conducted by Eli Lilly and Company. The individual studies took place between March 2000 and November 2009. Data were analyzed using 4 pretreatment subgroups: first-episode never treated, multiple-episode never treated, treated previously only with selective serotonin reuptake inhibitors (SSRIs), and previously treated with antidepressants other than just SSRIs. Measures included the 17-item Hamilton Depression Rating Scale (HDRS-17) total and somatic symptom subscale scores, Montgomery-Asberg Depression Rating Scale (MADRS) total score, and Sheehan Disability Scale total score. Response rates (50% and 30%) were based on the HDRS-17 total score and remission rates on either the HDRS-17 or MADRS total score. RESULTS: Response and remission rates were significantly greater (P < .05 in 11 of 12 comparisons) for duloxetine versus placebo in the 4 subgroups. A trend of greater response and remission occurred for first-episode versus multiple-episode patients; both groups were generally higher than the antidepressant-treated groups. Mean changes in efficacy measures were mostly significantly greater (P < .05 in 13 of 16 comparisons) for duloxetine versus placebo within each pretreatment subgroup, with some (P < .05 in 2 of 24 comparisons) significant interaction effects between subgroups on HDRS-17 total and somatic symptoms scores. CONCLUSIONS: Duloxetine was generally superior to placebo on response and remission rates and in mean change on efficacy measures. Response and remission rates were numerically greater for first-episode versus multiple-episode and drug-treated patients. Mean change differences on efficacy measures among the 4 subgroups were inconsistent. Duloxetine showed a similar therapeutic effect independent of episode frequency and antidepressant pretreatment.

Cost-effectiveness analyses of osteoarthritis oral therapies: a systematic review.

BACKGROUND: Cost-effectiveness analyses (CEAs) have been performed for oral non-disease-altering osteoarthritis (OA) treatments for well over a decade. During that period the methods for performing these analyses have evolved as pharmacoeconomic methods have advanced, new treatments have been introduced, and the knowledge of associated adverse events (AEs) has improved. OBJECTIVE: The objective of this systematic review was to trace the development of CEAs for oral non-disease-altering treatments in OA. METHODS: A systematic search for CEAs of OA oral treatments was performed of the English-language medical literature using the following databases: PubMed, EMBASE, MEDLINE In-Process, EconLit, and Cochrane. Key requirements for inclusion were that the population described patients with OA or arthritis and that the analysis reported at least one incremental cost-effectiveness ratio. Each identified publication was assessed for inclusion. Thirteen characteristics and all AEs appearing in each included CEA were extracted and organized. Reference lists from these CEAs were also searched. A chronology of key CEAs in the field was compiled, noting the characteristics that advanced the state of the art in modeling oral OA treatments. RESULTS: Thirty publications of 28 CEAs were identified and evaluated. Developments in CEAs included an expanded set of comparators that broadened from non-steroidal anti-inflammatory drugs (NSAIDs) only to NSAIDs plus gastroprotective agents, cyclooxygenase-2 inhibitors, and opioids. In turn, AEs expanded from gastrointestinal (GI) events to also include cardiovascular (CV) and neurological events. Efficacy, which initially was presumed to be equivalent for all treatments, evolved to treatment-specific efficacies. Decision-tree analyses were generally replaced by Markov models or, occasionally, stochastic or discrete event simulation. Finally, outcomes have progressed from GI-centric measures to also include quality-adjusted life-years. CONCLUSION: Methods used by CEAs of oral non-disease-altering OA treatments have evolved in response to changing treatments with different safety profiles and efficacies as well as technical advances in the application of decision science to health care.

Incidence of diabetic peripheral neuropathic pain in primary care - a retrospective cohort study using the United Kingdom General Practice Research Database.

PURPOSE: To determine the incidence of diabetic peripheral neuropathic pain (DPNP) in the United Kingdom (UK) primary care population using the General Practice Research Database (GPRD). PATIENTS AND METHODS: This retrospective cohort study identified incident cases of DPNP in the UK GPRD between July 1, 2002 and June 30, 2011, using diagnostic codes. Trends in the incidence rate were examined by dividing the study period into 3-year periods: (1) July 1, 2002-June 30, 2005; (2) July 1, 2005-June 30, 2008; and (3) July 1, 2008-June 30, 2011. Patient characteristics (age, sex, comorbidities) and initial pharmacological treatment were described; the proportion of patients with incident DPNP, who had previously been screened for neuropathic symptoms, was determined. RESULTS: Among almost 7.5 million persons contributing 38,118,838 person-years of observations in the GPRD, 6,779 new cases of DPNP were identified (45.5%, women), giving an incidence rate of 17.8 per 100,000 person-years (95% confidence interval [CI] 17.4-18.2). The incidence of DPNP increased with age, but it was stable over the three consecutive 3-year periods: 17.9, 17.2, and 18.4 cases per 100,000 person-years. Of the 6,779 patients with incident DPNP, 15.5% had prior neuropathic screening during the study period. The majority of patients with incident DPNP (84.5%) had a treatment for pain initiated within 28 days of first diagnosis. The most common first-line treatments prescribed were tricyclic antidepressants (27.2%), anticonvulsants (17.0%), and nonsteroidal anti-inflammatory drugs (14.9%), with 26.6% of patients receiving combination therapy as their initial treatment. CONCLUSION: The incidence of DPNP in UK primary care has remained steady over the past 10 years. Our results suggest that DPNP is underdiagnosed, and initial treatment prescribed does not follow clinical guidelines.