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.

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.

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.

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.

The GERAS Study: a prospective observational study of costs and resource use in community dwellers with Alzheimer's disease in three European countries--study design and baseline findings.

To address socioeconomic challenges associated with its increasing prevalence, data are needed on country-level resource use and costs associated with Alzheimer's disease (AD). GERAS is an 18-month observational study being conducted in France, Germany, and the U.K. (with an 18-month extension in France and Germany), aimed at determining resource use and total costs associated with AD, stratified by AD severity at baseline. Resource use information and time spent on informal care by non-professional caregivers was obtained using the Resource Utilization in Dementia instrument. Total baseline societal costs were based on four cost components: patient health care costs, patient social care costs, caregiver health care costs, and caregiver informal care costs. Overall, 1,497 community-dwelling patients with AD were analyzed at baseline. Estimated mean monthly total societal costs per patient at baseline differed significantly between groups with mild, moderate, and moderately severe/severe AD (p < 0.001 in each country): euro $1,418, euro 1,737, and euro 2,453 in France; euro 1,312, euro $2,412, and euro 3,722 in Germany; and euro 1,621, euro 1,836, andeuro 2,784 in the U.K., respectively. All cost components except caregiver health care costs increased with AD severity. Informal caregiver costs were the largest cost component accounting for about half to just over 60% of total societal costs, depending on country and AD severity group. In conclusion, GERAS study baseline results showed that country-specific costs increase with AD severity. Informal care costs formed the greatest proportion of total societal costs, increasing with AD severity independent of costing method. Longitudinal data will provide information on cost trends with disease progression.

Cost-utility analysis of duloxetine in osteoarthritis: a US private payer perspective.

BACKGROUND: Duloxetine has recently been approved in the USA for chronic musculoskeletal pain, including osteoarthritis and chronic low back pain. The cost effectiveness of duloxetine in osteoarthritis has not previously been assessed. Duloxetine is targeted as post first-line (after acetaminophen) treatment of moderate to severe pain. OBJECTIVE: The objective of this study was to estimate the cost effectiveness of duloxetine in the treatment of osteoarthritis from a US private payer perspective compared with other post first-line oral treatments, including nonsteroidal anti-inflammatory drugs (NSAIDs), and both strong and weak opioids. METHODS: A cost-utility analysis was performed using a discrete-state, time-dependent semi-Markov model based on the National Institute for Health and Clinical Excellence (NICE) model documented in its 2008 osteoarthritis guidelines. The model was extended for opioids by adding titration, discontinuation and additional adverse events (AEs). A life-long time horizon was adopted to capture the full consequences of NSAID-induced AEs. Fourteen health states comprised the structure of the model: treatment without persistent AE, six during-AE states, six post-AE states and death. Treatment-specific utilities were calculated using the transfer-to-utility method and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total scores from a meta-analysis of osteoarthritis clinical trials of 12 weeks and longer. Costs for 2011 were estimated using Red Book, The Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project database, the literature and, sparingly, expert opinion. One-way and probabilistic sensitivity analyses were undertaken, as well as subgroup analyses of patients over 65 years old and a population at greater risk of NSAID-related AEs. RESULTS: In the base case the model estimated naproxen to be the lowest total-cost treatment, tapentadol the highest cost, and duloxetine the most effective after considering AEs. Duloxetine accumulated 0.027 discounted quality-adjusted life-years (QALYs) more than naproxen and 0.013 more than oxycodone. Celecoxib was dominated by naproxen, tramadol was subject to extended dominance, and strong opioids were dominated by duloxetine. The model estimated an incremental cost-effectiveness ratio (ICER) of US$47,678 per QALY for duloxetine versus naproxen. One-way sensitivity analysis identified the probabilities of NSAID-related cardiovascular AEs as the inputs to which the ICER was most sensitive when duloxetine was compared with an NSAID. When compared with a strong opioid, duloxetine dominated the opioid under nearly all sensitivity analysis scenarios. When compared with tramadol, the ICER was most sensitive to the costs of duloxetine and tramadol. In subgroup analysis, the cost per QALY for duloxetine versus naproxen fell to US$24,125 for patients over 65 years and to US$18,472 for a population at high risk of cardiovascular and gastrointestinal AEs. CONCLUSION: The model estimated that duloxetine was potentially cost effective in the base-case population and more cost effective for subgroups over 65 years or at high risk of NSAID-related AEs. In sensitivity analysis, duloxetine dominated all strong opioids in nearly all scenarios.

The cost-effectiveness of duloxetine in chronic low back pain: a US private payer perspective.

OBJECTIVE: To assess the cost-effectiveness of duloxetine in the treatment of chronic low back pain (CLBP) from a US private payer perspective. METHODS: A cost-utility analysis was undertaken for duloxetine and seven oral post-first-line comparators, including nonsteroidal anti-inflammatory drugs (NSAIDs), weak and strong opioids, and an anticonvulsant. We created a Markov model on the basis of the National Institute for Health and Clinical Excellence model documented in its 2008 osteoarthritis clinical guidelines. Health states included treatment, death, and 12 states associated with serious adverse events (AEs). We estimated treatment-specific utilities by carrying out a meta-analysis of pain scores from CLBP clinical trials and developing a transfer-to-utility equation using duloxetine CLBP patient-level data. Probabilities of AEs were taken from the National Institute for Health and Clinical Excellence model or estimated from osteoarthritis clinical trials by using a novel maximum-likelihood simulation technique. Costs were gathered from Red Book, Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project database, the literature, and, for a limited number of inputs, expert opinion. The model performed one-way and probabilistic sensitivity analyses and generated incremental cost-effectiveness ratios (ICERs) and cost acceptability curves. RESULTS: The model estimated an ICER of $59,473 for duloxetine over naproxen. ICERs under $30,000 were estimated for duloxetine over non-NSAIDs, with duloxetine dominating all strong opioids. In subpopulations at a higher risk of NSAID-related AEs, the ICER over naproxen was $33,105 or lower. CONCLUSIONS: Duloxetine appears to be a cost-effective post-first-line treatment for CLBP compared with all but generic NSAIDs. In subpopulations at risk of NSAID-related AEs, it is particularly cost-effective.

Health care costs before and after diagnosis of depression in patients with unexplained pain: a retrospective cohort study using the United Kingdom General Practice Research Database.

PURPOSE: To assess the impact of pain severity and time to diagnosis of depression on health care costs for primary care patients with pre-existing unexplained pain symptoms who subsequently received a diagnosis of depression. PATIENTS AND METHODS: This retrospective cohort study analyzed 4000 adults with unexplained pain (defined as painful physical symptoms [PPS] without any probable organic cause) and a subsequent diagnosis of depression, identified from the UK General Practice Research Database using diagnostic codes. Patients were categorized into four groups based on pain severity (milder or more severe; based on number of pain-relief medications and use of opioids) and time to diagnosis of depression (≤1 year or>1 year from PPS index date). Annual health care costs were calculated (2009 values) and included general practitioner (GP) consultations, secondary care referrals, and prescriptions for pain-relief medications for the 12 months before depression diagnosis and in the subsequent 2 years. Multivariate models of cost included time period as a main independent variable, and adjusted for age, gender, and comorbidities. RESULTS: Total annual health care costs before and after depression diagnosis for the four patient groups were higher for the groups with more severe pain (£819-£988 versus £565-£628; P < 0.001 for all pairwise comparisons) and highest for the group with more severe pain and longer time to depression diagnosis in the subsequent 2 years (P < 0.05). Total GP costs were highest in the group with more severe pain and longer time to depression diagnosis both before and after depression diagnosis (P < 0.05). In the second year following depression diagnosis, this group also had the highest secondary care referral costs (P < 0.01). The highest drug costs were in the groups with more severe pain (P < 0.001), although costs within each group were similar before and after depression diagnosis. CONCLUSION: Among patients with unexplained pain symptoms, significant pain in combination with longer time from pain symptoms to depression diagnosis contribute to higher costs for the UK health care system.

Costs associated with treatment of chronic low back pain: an analysis of the UK General Practice Research Database.

STUDY DESIGN: Retrospective cohort study of health care costs associated with the treatment of chronic low back pain (CLBP) in the United Kingdom. OBJECTIVE: To assess 12-month health care costs associated with the treatment of CLBP, using the UK General Practice Research Database. SUMMARY OF BACKGROUND DATA: CLBP is a common health problem. METHODS: Data were obtained from the General Practice Research Database, a computerized database of UK primary care patient data. Patients with CLBP were identified for the study period (January 1, 2007, to December 31, 2009) using diagnostic records and pain relief prescriptions (n = 64,167), and 1:1 matched to patients without CLBP (n = 52,986) on the basis of age, sex, and general practitioner's practice. Index date was defined as the first date of CLBP record; the same index date was assigned to matched controls. Multivariate analyses were performed to compare resource use costs (2009 values) in the 12 months after the index date between patients with and without CLBP. A sensitivity analysis was carried out with a more stringent definition for the control group by excluding a broad range of pain conditions. RESULTS: Total health care costs for patients with CLBP were double those of the matched controls (£1074 vs. £516; P < 0.05). Of the cost difference, 58.8% was accounted for by general practitioner's consultations, 22.3% by referrals to secondary care, and the rest by pain relief medications. The sensitivity analysis revealed an even greater cost difference between the 2 groups (£1052 vs. £304; P < 0.05). Because of the use of a retrospective administrative claims database, this study is subject to selection bias between study cohorts, misidentification of comorbidities, and an inability to confirm adherence to therapy or assess indirect costs and costs of over-the-counter medications. CONCLUSION: Our findings confirm the substantial economic burden of CLBP, even with direct costs only.

Cost-effectiveness of duloxetine in chronic low back pain: a Quebec societal perspective.

STUDY DESIGN: Cost-effectiveness model from a Quebec societal perspective using meta-analyses of clinical trials. OBJECTIVE: To evaluate the cost-effectiveness of duloxetine in chronic low back pain (CLBP) compared with other post-first-line oral medications. SUMMARY OF BACKGROUND DATA: Duloxetine has recently received a CLBP indication in Canada. The cost-effectiveness of duloxetine and other oral medications has not previously been evaluated for CLBP. METHODS: A Markov model was created on the basis of the economic model documented in the 2008 osteoarthritis clinical guidelines of the National Institute for Health and Clinical Excellence. Treatment-specific utilities were estimated via a meta-analysis of CLBP clinical trials and a transfer-to-utility regression estimated from duloxetine CLBP trial data. Adverse event rates of comparator treatments were taken from the National Institute for Health and Clinical Excellence model or estimated by a meta-analysis of clinical trials in osteoarthritis using a maximum-likelihood simulation technique. Costs were developed primarily from Quebec and Ontario public sources as well as the published literature and expert opinion. The 6 comparators were celecoxib, naproxen, amitriptyline, pregabalin, hydromorphone, and oxycodone. Subgroup analyses and 1-way and probabilistic sensitivity analyses were performed. RESULTS: In the base case, naproxen, celecoxib, and duloxetine were on the cost-effectiveness frontier, with naproxen the least expensive medication, celecoxib with an incremental cost-effectiveness ratio of $19,881, and duloxetine with an incremental cost-effectiveness ratio of $43,437. Other comparators were dominated. Key drivers included the rates of cardiovascular and gastrointestinal adverse events and proton pump inhibitor usage. In subgroup analysis, the incremental cost-effectiveness ratio for duloxetine fell to $21,567 for a population 65 years or older and to $18,726 for a population at higher risk of cardiovascular and gastrointestinal adverse events. CONCLUSION: The model estimates that duloxetine is a moderately cost-effective treatment for CLBP, becoming more cost-effective for populations older than 65 years or at greater risk of cardiovascular and gastrointestinal events. LEVEL OF EVIDENCE: 1.