Aslam Anis

Osteoarthritis (OA) has been reported as an independent risk factor for cardiovascular diseases (CVD). There is no cure for OA and non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay of OA treatment. NSAIDs are known to be associated with various cardiovascular adverse effects, but their direct impact on CVD risk among OA patients is not well studied. There is a need to understand better the underlying mechanism of the increased risk of CVD among OA patients and to what extent NSAIDs play a role. This thesis conducted three studies using health administrative data (HAD) from British Columbia (BC), Canada and the Canadian Community Health Survey (CCHS) focusing on the role of NSAIDs in the OA-CVD association. The objective of study 1 was to quantify the role of NSAIDs in the increased risk of CVD among OA patients. This longitudinal study performed a mediation analysis using a marginal structural model and showed that a substantial proportion of total CVD risk among OA patients was attributable to NSAID use. The objective of study 2 was to evaluate the overall cardiovascular safety of various NSAIDs that are used in treating OA patients. This retrospective cohort study used time-dependent Cox regression analysis to estimate CVD risk associated with NSAID use overall and four unique groups of NSAIDs, i.e., coxibs, naproxen, ibuprofen and other conventional NSAIDs. This study showed that exposure to NSAIDs substantially increased CVD risk compared to unexposed person-time. It also showed that, relative to unexposed person-time coxibs and naproxen may increase CVD risk more than conventional NSAIDs including ibuprofen. The objective of study 3 was to identify a valid approach in imputing body mass index (BMI), an important confounding variable in the OA-CVD relationship for which information is usually not available in HAD. Multiple imputation was compared with proportion-based imputation (PBI) approach using plasmode simulated dataset created from CCHS data. This study showed that multiple imputation was superior to PBI in imputing BMI category using information from an external dataset. As a collective work, this thesis provides a better understanding of OA-CVD association that hopefully will improve clinical management of OA.

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Spondyloarthritis (SpA) is an inflammatory disease comprising both ankylosing spondylitis and non-radiographic axial SpA. This thesis conducted four studies using data from DESIR, a longitudinal cohort of 708 French SpA patients, focusing on economic questions in the context of SpA treatment recommendations. The objectives of study 1 were to value health resource use and productivity loss among DESIR patients and identify factors associated with costs. Cost valuation was done using public data and factors associated with costs were identified in multivariate regression models. This study showed that anti-TNF agents were the greatest cost driver in DESIR and generated the cost outcomes necessary to perform economic evaluations using DESIR data. The objective of study 2 was to collaborate with rheumatologists to develop measurable definitions of adherence to SpA treatment recommendations. A Delphi survey was conducted with 15 rheumatologists, who developed measurable definitions for 6/11 recommendations. The study uncovered differences of opinion between rheumatologists and generated the classification system necessary to explore adherence to recommendations among DESIR patients. The objective of study 3 was to examine the effect of adherence to anti-TNF use recommendations on outcomes in DESIR. Employing alternate definitions of adherence, patients were classed as adherent anti-TNF users, non-adherent anti-TNF users, adherent non-users, and non-adherent non-users. Following one potential definition, non-adherent anti-TNF users had significantly increased non-biologic costs compared to adherent users, while non-adherent non-users had significantly worse health outcomes than adherent anti-TNF users. This study showed that the impact of adherence to anti-TNF recommendations is sensitive to the definition of adherence and highlighted the need to validate methods to measure adherence. The objective of study 4 was to explore whether the French anti-TNF access restrictions are the most cost-effective in that setting relative to other potential restrictions. Five separate datasets were created comprising DESIR patients satisfying different sets of anti-TNF access criteria. Incremental cost-effectiveness ratios (ICERs) associated with anti-TNF use were calculated in each subset in basecase and sensitivity analyses. A sensitivity analysis simulating a 24-week stopping rule among anti-TNF non-responders demonstrated the effect of non-response on anti-TNF cost-effectiveness. The study underscored the need for evidence-informed anti-TNF access restrictions.

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Traditionally, productivity loss has been measured according to illness-related absence from work (absenteeism) only. However, there is increasing evidence that presenteeism (reduced intensity and/or quality of labour input) is an even greater source of productivity losses. In addition to empirical measurement issues, there are theoretical issues with regard to productivity valuation. The traditional human capital method assumes that the value of productivity loss to society should be measured as the present values of lost time according to the wage, which is supposed to be equal to the marginal productivity of labour in a competitive labour market. The alternative, friction cost method, is based on the same assumption except that it adjusts for unemployment. However, these methods ignore the effects of risk aversion and team production which cause the wage to be lower than the marginal productivity. Existing productivity questionnaires did not capture sufficient information to enable the proper measurement and valuation of productivity loss from a societal perspective. A new questionnaire, Valuation of Lost Productivity (VOLP), was developed to capture all the time input loss components(absenteeism, presenteeism, employment status changes, and unpaid work productivity loss) as well as information on job and workplace characteristics, based on which wage multipliers can be calculated to value the productivity loss attributable to the reduced time input of workers. The thesis provides evidence for the validity of the VOLP in measuring time input loss due to poor health and its feasibility in evaluating the treatment effect on productivity in people with rheumatoid arthritis. The equality between wage and marginal productivity was tested using the Workplace and Employ Survey, a linked employer-employee database in Canada. Some evidence suggests that team workers are underpaid compared with their relatively higher iii productivity. In small firms, higher absenteeism results in lower productivity and wage, and the marginal productivity loss with respect to team worker absenteeism is higher than the wage loss. Furthermore, for team workers, health-related frequent reduction at work results in lower productivity and the resulted productivity loss is more than the wage differentials.

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Background: Opioid dependence is a chronic disease characterized by periods of relapse and remission. Methadone maintenance treatment (MMT) can be effective, though not all patients can be successfully maintained in treatment. Further, treatment entrants often use multiple illicit drugs, a fact whose motive and effect are under-studied. Rigorous evaluation at the aggregate- and patient-level is required to maximize the public health benefits of substance abuse treatment. Objectives: (1) identify the determinants of the time to discontinuation of MMT across multiple treatment episodes; (2) determine the effect of price on drug consumption among polydrug users; (3) identify trends in compliance to MMT dosing guidelines in British Columbia, Canada from 1996-2007; (4) provide a comparative analysis of the psychometric properties of eight measures of health status for opioid users; (5) evaluate differences in trajectories of health status among opioid users following treatment enrolment.Methods: We draw upon longitudinal data collected in administrative databases (study 1 and 3), experimental (study 4 and 5) and observational cohort studies (study 2) to shed light on the life course of treatment and relapse that opioid addicts experience, their decisions to consume addictive substances, and treatment evaluation at the aggregate- and patient-levels.Results: This collection of studies found (1) patients experiencing multiple treatment episodes tended to stay in treatment for progressively longer periods in later episodes; (2) While heroin and crack cocaine were price inelastic polydrug users treated crack cocaine as a substitute for heroin. In terms of treatment evaluation at the aggregate-level, compliance to minimally effective dose guidelines, along with 12-month retention figures have fallen in the past 5 years in British Columbia (study 3). At the patient-level each of the health status measures assessed in the North American Opiate Medication Initiative (NAOMI) trial showed limitations (study 4), however health status can be meaningfully improved through effective, patient-centered opioid substitution treatment (study 5). Conclusions: The results of these novel empirical studies suggest that while MMT can be an effective treatment option for opioid dependence, the individual and program-related factors that limit its effectiveness must be addressed to maximize the public health impact of this treatment.

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