Stella Leung

Use of proton pump inhibitors and risk of osteoporosis-related fractures.

Background: The use of proton pump inhibitors has been associated with an increased risk of hip fracture. We sought to further explore the relation between duration of exposure to proton pump inhibitors and osteoporosis-related fractures. Methods: We used administrative claims data to identify patients with a fracture of the hip, vertebra or wrist between April 1996 and March 2004. Cases were each matched with 3 controls based on age, sex and comorbidities. We calculated adjusted odds ratios (OR) for the risk of hip fracture and all osteoporosis-related fractures for durations of proton pump inhibitor exposure ranging from 1 or more years to more than 7 years. Results: We matched 15 792 cases of osteoporosis-related fractures with 47 289 controls. We did not detect a significant association between the overall risk of an osteoportic fracture and the use of proton pump inhibitors for durations of 6 years or less. However, exposure of 7 or more years was associated with increased risk of an osteoporosis-related fracture (adjusted OR 1.92, 95% confidence interval [CI] 1.16–3.18, p = 0.011). We also found an increased risk of hip fracture after 5 or more years of exposure (adjusted OR 1.62, 95% CI 1.02–2.58, p = 0.04), with even higher risk after 7 or more years exposure (adjusted OR 4.55, 95% CI 1.68–12.29, p = 0.002). Interpretation: Use of proton pump inhibitors for 7 or more years is associated with a significantly increased risk of an osteoporosis-related fracture. There is an increased risk of hip fracture after 5 or more years exposure. Further study is required to determine the clinical importance of this finding and to determine the value of osteoprotective medications for patients with long-term use of proton pump inhibitors.

Proton-Pump Inhibitor Use Is Not Associated With Osteoporosis or Accelerated Bone Mineral Density Loss

BACKGROUNDS & AIMS Recent studies have shown an association between proton-pump inhibitor use (PPI) and hip fracture. The mechanism by which PPI use promotes the development of hip fracture is uncharacterized. Therefore, we sought to determine whether PPI use is associated with osteoporosis or accelerated bone mineral density (BMD) loss. METHODS We used the Manitoba Bone Mineral Density Database to determine the relationship between chronic PPI use and osteoporosis on an initial assessment of BMD and on BMD loss between successive assessments of BMD. In the cross-sectional study, cases with osteoporosis at the hip or lumbar vertebrae (T-score < or =-2.5) were matched to 3 controls with normal BMD (T-score > or =-1.0). In the longitudinal analysis, the change in BMD among PPI users and nonusers between successive BMD assessments was assessed. Conditional logistic regression and multivariate linear regression were used to obtain estimates of the association between PPI use and osteoporosis and of the annualized change in BMD associated with PPI use. RESULTS PPI use was not associated with having osteoporosis at either the hip (OR, 0.84; 95% CI, 0.55-1.34) or the lumbar spine (OR, 0.79; 95% CI, 0.59-1.06) for PPI use >1500 doses over the previous 5 years. In the longitudinal study no significant decrease was observed in BMD at either site attributable to PPI use. CONCLUSIONS PPI use does not appear to be associated with either the presence of osteoporosis or accelerated BMD loss. The association between PPI use and hip fracture is probably related to factors independent of osteoporosis.

The rising prevalence and changing age distribution of multiple sclerosis in Manitoba

Objective: Several studies suggest an increasing prevalence of multiple sclerosis (MS) in Canada. We aimed to validate a case definition for MS using administrative health insurance data, and to describe the incidence and prevalence of MS in Manitoba, Canada. Methods: We used provincial administrative claims data to identify persons with demyelinating disease using International Classification of Diseases 9/10 codes and prescription claims. To validate the case definition, questionnaires were mailed to 2,000 randomly selected persons with an encounter for demyelinating disease, requesting permission for medical records review. We used diagnoses abstracted from medical records as the gold standard to evaluate candidate case definitions using administrative data. Results: From 1984 to 1997, cases of MS using claims data were defined as persons with ≥7 medical contacts for MS. From 1998 onward, cases were defined as persons with ≥3 medical contacts. As compared to medical records, this definition had a positive predictive value of 80.5% and negative predictive value of 75.5%. From 1998 to 2006, the average age- and sex-adjusted annual incidence of MS per 100,000 population was 11.4 (95% confidence interval [CI] 10.7–12.0). The age-adjusted prevalence of MS per 100,000 population increased from 32.6 (95% CI 29.4–35.8) in 1984 to 226.7 (95% CI 218.1–235.3) in 2006, with the peak prevalence shifting to older age groups. Conclusion: The prevalence of multiple sclerosis (MS) in Manitoba is among the highest in the world. The rising prevalence with minimally changing incidence suggests improving survival. This study supports the use of administrative data to develop case definitions and further define the epidemiology of MS.

The Relative Efficacies of Gastroprotective Strategies in Chronic Users of Nonsteroidal Anti-inflammatory Drugs

BACKGROUND & AIMS There are numerous gastroprotective strategies recommended for reducing the risk of upper gastrointestinal (GI) complications in long-term users of nonsteroidal anti-inflammatory drugs (NSAIDs). The relative efficacy of the different strategies alone or in combination is uncertain. METHODS We used the Manitoba Population Health Research Data Repository to perform a population-based matched case-control analysis. All NSAID users (nonselective and cyclooxygenase [COX]-2-specific) users admitted to the hospital with a primary diagnosis for an upper gastrointestinal complication were matched to NSAID-using controls in the community. We used conditional logistic regression analysis to determine the relative efficacy of different gastroprotective strategies (proton pump inhibitors [PPIs], COX-2 inhibitors, and low-dose/high-dose misoprostol) either alone or in combination and to adjust for multiple pertinent covariates. RESULTS A total of 1382 NSAID/COX-2 users with upper GI complications were matched to 33,957 age- and sex-matched controls. Cotherapy with PPIs or misoprostol or use of a COX-2 inhibitor all significantly reduced the risk of upper GI complications. COX-2 inhibitors were not statistically more likely to prevent upper GI complications than PPIs, although they were superior to low-dose misoprostol. The combination of COX-2 inhibitors with a PPI was associated with the greatest degree of upper GI complication risk reduction. CONCLUSIONS All of the commonly accepted gastroprotective strategies reduce the risk of upper GI complications in NSAID users, although the combination of COX-2 inhibitors with PPIs promotes the greatest risk reduction for NSAID-related upper GI complications. Celecoxib use specifically may be superior to the combination of nonselective NSAIDs with a PPI.

Selective serotonin reuptake inhibitors are associated with a modest increase in the risk of upper gastrointestinal bleeding.

OBJECTIVES:The use of the common antidepressant class of serotonin-specific reuptake inhibitors (SSRIs) is associated with an increased risk of upper gastrointestinal bleeding (UGIB). Proton pump inhibitors (PPIs) have been demonstrated to reduce the risk of gastrointestinal bleeding secondary to other risk factors, most notably non-steroidal anti-inflammatory drug (NSAID) use. The role for PPIs in chronic SSRI users without other risk factors remains uncharacterized.METHODS:We used the Manitoba Population Health Research Data Repository to perform a population-based matched case–control analysis. All patients admitted to the hospital with a primary diagnosis of UGIB were matched to non-bleeding controls. We used conditional regression analysis to determine the risk of UGIB associated with SSRI use, and the risk reduction associated with concomitant PPI use, both for users and non-users of NSAIDs.RESULTS:SSRI use was associated with a modest increase in the risk of UGIB (odds ratio (OR), 1.43; 95% confidence interval (CI), 1.09–1.89). The addition of an SSRI to NSAID therapy did not significantly increase the risk of UGIB (OR, 1.20; 95% CI, 0.78–1.92) over use of an NSAID alone. PPI cotherapy significantly reduced the risk of SSRI-related UGIB (OR, 0.39; 95% CI, 0.16–0.94).CONCLUSIONS:SSRI use is associated with a modestly increased risk of UGIB, which may be significantly reduced with PPI cotherapy. SSRI use is not a major risk factor for NSAID-related UGIB.

Mental comorbidity and multiple sclerosis: validating administrative data to support population-based surveillance

BackgroundWhile mental comorbidity is considered common in multiple sclerosis (MS), its impact is poorly defined; methods are needed to support studies of mental comorbidity. We validated and applied administrative case definitions for any mental comorbidities in MS.MethodsUsing administrative health data we identified persons with MS and a matched general population cohort. Administrative case definitions for any mental comorbidity, any mood disorder, depression, anxiety, bipolar disorder and schizophrenia were developed and validated against medical records using a a kappa statistic (k). Using these definitions we estimated the prevalence of these comorbidities in the study populations.ResultsCompared to medical records, administrative definitions showed moderate agreement for any mental comorbidity, mood disorders and depression (all k ≥ 0.49), fair agreement for anxiety (k = 0.23) and bipolar disorder (k = 0.30), and near perfect agreement for schizophrenia (k = 1.0). The age-standardized prevalence of all mental comorbidities was higher in the MS than in the general populations: depression (31.7% vs. 20.5%), anxiety (35.6% vs. 29.6%), and bipolar disorder (5.83% vs. 3.45%), except for schizophrenia (0.93% vs. 0.93%).ConclusionsAdministrative data are a valid means of surveillance of mental comorbidity in MS. The prevalence of mental comorbidities, except schizophrenia, is increased in MS compared to the general population.

Rising prevalence of vascular comorbidities in multiple sclerosis: validation of administrative definitions for diabetes, hypertension, and hyperlipidemia.

Background: Despite the importance of comorbidity in multiple sclerosis (MS), methods for comorbidity assessment in MS are poorly developed. Objective: We validated and applied administrative case definitions for diabetes, hypertension, and hyperlipidemia in MS. Methods: Using provincial administrative data we identified persons with MS and a matched general population cohort. Case definitions for diabetes, hypertension, and hyperlipidemia were derived using hospital, physician, and prescription claims, and validated in 430 persons with MS. We examined temporal trends in the age-adjusted prevalence of these conditions from 1984–2006. Results: Agreement between various case definitions and medical records ranged from kappa (κ) =0.51–0.69 for diabetes, κ =0.21–0.71 for hyperlipidemia, and κ =0.52–0.75 for hypertension. The 2005 age-adjusted prevalence of diabetes was similar in the MS (7.62%) and general populations (8.31%; prevalence ratio [PR] 0.91; 0.81–1.03). The age-adjusted prevalence did not differ for hypertension (MS: 20.8% versus general: 22.5% [PR 0.91; 0.78–1.06]), or hyperlipidemia (MS: 13.8% versus general: 15.2% [PR 0.90; 0.67–1.22]). The prevalence of all conditions rose in both populations over the study period. Conclusion: Administrative data are a valid means of tracking diabetes, hypertension, and hyperlipidemia in MS. The prevalence of these comorbidities is similar in the MS and general populations.

Effect of comorbidity on mortality in multiple sclerosis

Objective: We aimed to compare survival in the multiple sclerosis (MS) population with a matched cohort from the general population, and to evaluate the association of comorbidity with survival in both populations. Methods: Using population-based administrative data, we identified 5,797 persons with MS and 28,807 controls matched on sex, year of birth, and region. We estimated annual mortality rates. Using Cox proportional hazards regression, we evaluated the association between comorbidity status and mortality, stratifying by birth cohort, and adjusting for sex, socioeconomic status, and region. We compared causes of death between populations. Results: Median survival from birth in the MS population was 75.9 years vs 83.4 years in the matched population. MS was associated with a 2-fold increased risk of death (adjusted hazard ratio 2.40; 95% confidence interval: 2.24–2.58). Several comorbidities were associated with increased hazard of death in both populations, including diabetes, ischemic heart disease, depression, anxiety, and chronic lung disease. The magnitude of the associations of mortality with chronic lung disease, diabetes, hypertension, and ischemic heart disease was lower in the MS population than the matched population. The most common causes of death in the MS population were diseases of the nervous system and diseases of the circulatory system. Mortality rates due to infectious diseases and diseases of the respiratory system were higher in the MS population. Conclusion: In the MS population, survival remained shorter than expected. Within the MS population, comorbidity was associated with increased mortality risk. However, comorbidity did not preferentially increase mortality risk in the MS population as compared with controls.

The prevalence of and the clinical and demographic characteristics associated with high-intensity proton pump inhibitor use.

INTRODUCTION:High-intensity proton pump inhibitor (PPI) use is often recommended by physicians, though there is little proven benefit over standard PPI dosing in many clinical situations. We therefore sought to calculate the prevalence and predictors of high-intensity PPI use.METHODS:We used a Canadian provincial administrative database to capture all PPI prescriptions between 1996 and 2004. A person was defined as a high-intensity user if he used PPIs at more than 1.5 times the standard PPI dose for greater than 45 of 90 days before the index date. The prevalence of high-intensity use was calculated at four index dates annually. Stepwise logistic regression was performed to determine clinical and demographic factors associated with high-intensity PPI use.RESULTS:The prevalence of high-intensity PPI use increased from 9.7% in 1997 to 14.2% in 2004. Polypharmacy, concomitant use of antispasmodic/promotility agents, and recent endoscopy were most strongly predictive of high-intensity PPI use. Severity of gastroesophageal reflux disease (GERD) (as assessed by the number of GERD-related physician visits) was relatively weakly predictive of high-intensity PPI use.CONCLUSIONS:High-intensity PPI use is becoming more prevalent over time, and its use is strongly associated with factors suggestive of a high degree of comorbidity and treatment failure. Further research into factors that drive high-intensity PPI prescription and use are required.

The utility of administrative data for surveillance of comorbidity in multiple sclerosis: a validation study.

Background: Although comorbidity is important in multiple sclerosis (MS), few validated methods for its assessment exist. We validated and applied administrative case definitions for several comorbidities in MS. Methods: Using provincial administrative data we identified persons with MS and a matched general population cohort. Case definitions for chronic lung disease (CLD), epilepsy, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and migraine were developed using administrative data, and validated against medical records. We applied these definitions to estimate the age-standardized prevalence of these comorbidities in the MS and matched cohorts. Results: Versus medical records, administrative case definitions showed moderate agreement for CLD (ĸ = 0.41), migraine (ĸ = 0.51), and epilepsy (ĸ = 0.44), fair agreement for IBS (ĸ = 0.36) and could not be calculated for IBD (small sample size). The 2005 prevalence of CLD was similar in the MS (15.6%) and general populations (14.4%). The prevalence of the remaining comorbidities was higher in the MS than the general populations: epilepsy (4.12 vs. 1.12%), IBD (0.78 vs. 0.65%), IBS (12.2 vs. 6.80%) and migraine (23.0 vs. 16.5%). Conclusions: Administrative data are valid for tracking CLD, epilepsy, and migraine in MS. The prevalence of epilepsy, IBD, IBS and migraine is increased in MS versus the general population.