Using Electronic Health Care Records for Drug Safety Signal Detection A Comparative Evaluation of Statistical Methods

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Population-based analysis of non-steroidal anti-inflammatory drug use among children in four European countries in the SOS project: What size of data platforms and which study designs do we need to assess safety issues?

Background: Data on utilization patterns and safety of non-steroidal anti-inflammatory drugs (NSAIDs) in children are scarce. The purpose of this study was to investigate the utilization of NSAIDs among children in four European countries as part of the Safety Of non-Steroidal anti-inflammatory drugs (SOS) project.Methods: We used longitudinal patient data from seven databases (GePaRD, IPCI, OSSIFF, Pedianet, PHARMO, SISR, and THIN) to calculate prevalence rates of NSAID use among children (0-18 years of age) from Germany, Italy, Netherlands, and United Kingdom. All databases contained a representative population sample and recorded demographics, diagnoses, and drug prescriptions. Prevalence rates of NSAID use were stratified by age, sex, and calendar time. The person-time of NSAID exposure was calculated by using the duration of the prescription supply. We calculated incidence rates for serious adverse events of interest. For these adverse events of interest, sample size calculations were conducted (alpha = 0.05; 1-beta = 0.8) to determine the amount of NSAID exposure time that would be required for safety studies in children.Results: The source population comprised 7.7 million children with a total of 29.6 million person-years of observation. Of those, 1.3 million children were exposed to at least one of 45 NSAIDs during observation time. Overall prevalence rates of NSAID use in children differed across countries, ranging from 4.4 (Italy) to 197 (Germany) per 1000 person-years in 2007. For Germany, United Kingdom, and Italian pediatricians, we observed high rates of NSAID use among children aged one to four years. For all four countries, NSAID use increased with older age categories for children older than 11. In this analysis, only for ibuprofen (the most frequently used NSAID), enough exposure was available to detect a weak association (relative risk of 2) between exposure and asthma exacerbation (the most common serious adverse event of interest).Conclusions: Patterns of NSAID use in children were heterogeneous across four European countries. The SOS project platform captures data on more than 1.3 million children who were exposed to NSAIDs. Even larger data platforms and the use of advanced versions of case-only study designs may be needed to conclusively assess the safety of these drugs in children

Risk of acute myocardial infarction during use of individual NSAIDs: A nested case-control study from the SOS project

OBJECTIVES: To estimate the risk of AMI for individual NSAIDs.METHODS: A nested case-control study was performed from a cohort of new NSAID users ≥18 years (1999-2011) match

Increased risk of fatal prostate cancer may explain the rise in mortality in The Netherlands

BACKGROUND: Several lines of evidence suggest that, as a result of improved diagnostic techniques, the increase in incidence of prostate cancer is due largely to increased detection of subclinical cases. Between 1971 and 1989, a considerable increase in incidence was found in Southeastern Netherlands among men aged under 60 years without an improvement in prognosis. We hypothesized that in addition to the increase due to increased detection, a genuine increase in incidence has occurred in the last two decades and that this should be reflected in national mortality rates. METHODS: Age-specific and age-adjusted mortality rates were calculated to determine whether mortality due to prostate cancer continued to increase after 1990. Using log-linear Poisson modelling according to Clayton and Schifflers, we estimated the contribution of period and cohort effects to prostate cancer mortality between 1955 and 1994. RESULTS: The age-adjusted mortality increased from 22 in 1955-1959 to 33 per 10(5) in 1990-1994 (European standardized rate). For men under 65, the rates stabilized after 1989. The age-cohort model fitted the data better than the age-period model. Therefore, the increase in mortality can be explained largely by the increasing risk for successive birth cohorts for men born until 1930. However, more frequent reporting of prostate cancer as the underlying cause of death (partly attributable to a decline in competing causes of death) may have occurred as well. CONCLUSIONS: Our findings suggest an increased risk of fatal prostate cancer in The Netherlands between 1955 and 1994

Relation Between Different Measures of Glycemic Exposure and Microvascular and Macrovascular Complications in Patients with Type 2 Diabetes Mellitus: An Observational Cohort Study

textabstractIntroduction: This retrospective cohort study investigated the relation between different measures of glycemic exposure and micro- and macrovascular complications among patients with type 2 diabetes. Methods: The analysis included patients receiving oral antihyperglycemic agents between 1 January 2006 and 31 December 2014 from the General Practitioner Database from the PHARMO Database Network. All recorded HbA1c levels during follow-up were used to express glycemic exposure in four ways: index HbA1c, time-dependent HbA1c, exponential moving average (EMA) and glycemic burden. Association between glycemic exposure and micro-/macrovascular complications was analyzed by estimating hazard ratios and 95% confidence intervals using an adjusted (time-dependent) Cox proportional hazards model. Results: The analysis included 32,725 patients (median age, 65 years; 47% female). Median follow-up was 5.4 years; median number of HbA1c measurements per patient was 18.0. From all measures, HbA1c at index showed the weakest relation between all micro-/macrovascular complications, with coronary artery disease (CAD) having the highest HR (95% CI): 1.18 (1.04–1.34) for HbA1c ≥64 mmol/mol (8%). The time-dependent HbA1c model showed a significant association only for microvascular complications, with retinopathy having the highest HR (95% CI): 1.55 (1.40–1.73) for HbA1c ≥64 mmol/mol (8%). EMA-defined exposure showed similar findings, although the effect of retinopathy was more pronounced [HR (95% CI): 1.81 (1.63–2.02) for HbA1c ≥64 mmol/mol (8%)] and was also predictive for CAD [HR (95% CI): 1.29 (1.10–1.50) for HbA1c ≥64 mmol/mol (8%)]. A statistically significant relation with glycemic burden was found for all selected micro-/macrovascular complications, with retinopathy having the highest HR (95%): 2.60 (2.19–3.07) for glycemic burden years >3. Conclusion: This study shows that greater and more prolonged exposure to hyperglycemia increases the risk of micro- and macrovascular complications. Funding: Janssen Pharmaceutica NV