Incidence of fibrosing colonopathy with pancreatic enzyme replacement therapy in patients with cystic fibrosis.

BACKGROUND: High daily doses of pancreatic enzyme replacement therapy (PERT) were historically associated with risk of fibrosing colonopathy (FC) in people with cystic fibrosis (pwCF), leading to development of PERT dosing guidelines and reformulated products. This study quantified incidence of FC in pwCF treated with PERT following those measures. METHODS: This large prospective cohort study included eligible pwCF enrolled in the Cystic Fibrosis Foundation Patient Registry with ≥1 clinic visit in 2012-2014 and follow-up through 2020. Data on PERT exposure, demographics, and medical history were collected. Clinical data, imaging, and histopathology of suspected cases were examined by an independent adjudication panel of physicians familiar with this complication. RESULTS: Base Study Population included 26,025 pwCF who contributed 155,814 person-years [mean (SD) 6.0 (2.0) years] of follow-up. Over 7.8 years, 29 pwCF had suspected FC; three cases were confirmed by adjudication, 22 cases were confirmed as not FC, and four cases were indeterminate. There were 22,161 pwCF exposed to any PERT, with mean PERT use time of 5.583 person-years and mean daily dose of 8328 U lipase per kg per day. All three confirmed cases and four indeterminate cases of FC occurred during current use of PERT. Incidence rates per 1000 person-years exposed were 0.0242 (95 % CI [0.0050, 0.0709]) for confirmed FC and 0.0566 (95 % CI [0.0227, 0.1166]) for indeterminate or confirmed FC. CONCLUSIONS: The incidence of FC in pwCF is very low in the era of current treatment guidelines and more stringent quality standards for PERT products.

Risk of retinal detachment and exposure to fluoroquinolones, common antibiotics, and febrile illness using a self-controlled case series study design: Retrospective analyses of three large healthcare databases in the US.

OBJECTIVE: The risk of retinal detachment (RD) following exposure to fluoroquinolone (FQ) has been assessed in multiple studies, however, results have been mixed. This study was designed to estimate the risk of RD following exposure to FQ, other common antibiotics, and febrile illness not treated with antibiotics (FINTA) using a self-controlled case series (SCCS) study design to reduce risk of confounding from unreported patient characteristics. DESIGN: Retrospective database analysis-SCCS. SETTING: Primary and Secondary Care. STUDY POPULATION: 40,981 patients across 3 US claims databases (IBM® MarketScan® commercial and Medicare databases, Optum Clinformatics). OUTCOME: RD. METHODS: Exposures included FQ as a class of drugs, amoxicillin, azithromycin, trimethoprim with and without sulfamethoxazole, and FINTA. For the primary analysis, all drug formulations were included. For the post hoc sensitivity analyses, only oral tablets were included. Risk windows were defined as exposure period (or FINTA duration) plus 30 days. Patients of all ages with RD and exposures in 3 US claims databases between 2012 to 2017 were included. Diagnostics included p value calibration and pre-exposure outcome analyses. Incidence rate ratios (IRR) and 95% confidence interval (CI) comparing risk window time with other time were calculated. RESULTS: Our primary analysis showed an increased risk for RD in the 30 days prior to exposure to FQ or trimethoprim without sulfamethoxazole. This risk decreased but remained elevated for 30 days following first exposure. Our post-hoc analysis, which excluded ophthalmic drops, showed no increased risk for RD at any time, with FQ and other antibiotics. CONCLUSION: Our results did not suggest an association between FQ and RD. Oral FQ was not associated with an increased risk for RD during the pre- or post-exposure period. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03479736-March 21, 2018.

Hip Fracture Risk After Treatment with Tramadol or Codeine: An Observational Study.

INTRODUCTION: Hip fractures among older people are a major public health issue, which can impact quality of life and increase mortality within the year after they occur. A recent observational study found an increased risk of hip fracture in subjects who were new users of tramadol compared with codeine. These drugs have somewhat different indications. Tramadol is indicated for moderate to severe pain and can be used for an extended period; codeine is indicated for mild to moderate pain and cough suppression. OBJECTIVE: In this observational study, we compared the risk of hip fracture in new users of tramadol or codeine, using multiple databases and analytical methods. METHODS: Using data from the Clinical Practice Research Datalink and three US claims databases, we compared the risk of hip fracture after exposure to tramadol or codeine in subjects aged 50-89 years. To ensure comparability, large-scale propensity scores were used to adjust for confounding. RESULTS: We observed a calibrated hazard ratio of 1.10 (95% calibrated confidence interval 0.99-1.21) in the Clinical Practice Research Datalink database, and a pooled estimate across the US databases yielded a calibrated hazard ratio of 1.06 (95% calibrated confidence interval 0.97-1.16). CONCLUSIONS: Our results did not demonstrate a statistically significant difference between subjects treated for pain with tramadol compared with codeine for the outcome of hip fracture risk.

Baseline risk characterization of early versus later adopters of long-acting paliperidone palmitate formulations.

Early Post-Marketing Phase Vigilance (EPPV) is a unique system that encourages reporting of serious adverse reactions for medications newly introduced to Japan. When a once-monthly paliperidone palmitate formulation (PP1M) was introduced in Japan in 2013, EPPV detected a signal of increased mortality, but this signal was not subsequently confirmed. To clarify whether that signal reflected increased adverse event reporting or an atypically high baseline mortality risk among early adopters of PP1M, we evaluated the baseline risk characteristics of early, mid, and later adopters of PP1M in a Japanese database and did a similar evaluation of PP1M and the three-monthly formulation (PP3M) in two US databases. In Japan, early adopters compared with later adopters were older (mean 39.16 vs 33.70 years) but had a lower proportion of male patients (32.0% vs 44.44%), and a lower mean number of antipsychotic medications (distinct active medical substances) other than paliperidone (2.62 vs 2.85). In the United States, the baseline characteristics of early adopters of PP1M and PP3M did not suggest higher mortality risk than later adopters. These results offer no convincing evidence that the unconfirmed early signal of increased mortality with PP1M was due to increased baseline mortality risk among early adopters.

Risk of aortic aneurysm and dissection following exposure to fluoroquinolones, common antibiotics, and febrile illness using a self-controlled case series study design: Retrospective analyses of three large healthcare databases in the US.

OBJECTIVE: Recent observational studies suggest increased aortic aneurysm or dissection (AAD) risk following fluoroquinolone (FQ) exposure but acknowledge potential for residual bias from unreported patient characteristics. The objective of our study is to evaluate the potential association between FQ, other common antibiotics and febrile illness with risk of AAD using a self-controlled case series (SCCS) study design. DESIGN: Retrospective database analysis-SCCS. SETTING: Primary and Secondary Care. STUDY POPULATION: 51,898 patients across 3 US claims databases (IBM® MarketScan® commercial and Medicare databases, Optum Clinformatics). EXPOSURE: FQ or other common antibiotics or febrile illness. OUTCOME: AAD. METHODS: We studied patients with exposures and AAD between 2012 and 2017 in 3 databases. Risk windows were defined as exposure period plus 30 days. Diagnostic analyses included p-value calibration to account for residual error using negative control exposures (NCE), and pre-exposure outcome analyses to evaluate exposure-outcome timing. The measure of association was the incidence rate ratio (IRR) comparing exposed and unexposed time. RESULTS: Most NCEs produced effect estimates greater than the hypothetical null, indicating positive residual error; calibrated p (Cp) values were therefore used. The IRR following FQ exposure ranged from 1.13 (95% CI: 1.04-1.22 -Cp: 0.503) to 1.63 (95% CI: 1.45-1.84 -Cp: 0.329). An AAD event peak was identified 60 days before first FQ exposure, with IRR increasing between the 60- to 30- and 29- to 1-day pre-exposure periods. It is uncertain how much this pre-exposure AAD event peak reflects confounding versus increased antibiotic use after a surgical correction of AADs. CONCLUSION: This study does not confirm prior studies. Using Cp values to account for residual error, the observed FQ-AAD association cannot be interpreted as significant. Additionally, an AAD event surge in the 60 days before FQ exposure is consistent with confounding by indication, or increased use of antibiotics post-surgery. REGISTRATION: NCT03479736.

Medications for attention-deficit/hyperactivity disorder in Japan: A retrospective cohort study of label compliance.

AIM: To assess label compliance in prescription of medications approved for treatment of attention-deficit/hyperactivity disorder (ADHD) in Japan at the time of this study: methylphenidate (MPH), atomoxetine, and guanfacine. METHODS: Retrospective descriptive study was conducted in prevalent-user cohorts from the Japan Medical Data Center database. Patients who were prescribed a study drug between January 1, 2013 and September 30, 2018 and were in the database for ≥30 days were included. A prescription was considered compliant if all 4 criteria were satisfied: appropriate age, daily dose not exceeding the approved maximum, no contraindicated concurrent medications, and no contraindicated conditions. RESULTS: Among 17 418 patients who were prescribed a study drug during 2013-2018, 73% were male and 53% were children (aged <18 years). Fewer than 2% of prescriptions were for patients outside the approved age, 10%-13% of patients in the atomoxetine and MPH cohorts received ≥1 prescription exceeding maximum approved dose, no patients were co-prescribed a contraindicated medication, and 16%-18% of patients in the MPH cohorts had ≥1 contraindicated condition. During their first 500 days of use, for approximately 73%-86% of patients, all prescriptions were compliant with all label requirements. CONCLUSIONS: Among patients exposed to ADHD medications in Japan during 2013-2018, nearly all prescriptions for these medications were label-compliant for age. For >85% of patients, all prescriptions were label-compliant for dose, and for approximately 80%, all prescriptions were label-compliant for contraindicated conditions. We did not find evidence of widespread abuse or noncompliant use of prescribed ADHD medications.

Stroke Risk Among Non-Elderly Users of Haloperidol or First-Generation Antipsychotics vs Second-Generation Antipsychotics: A Cohort Study from a US Health Insurance Claims Database.

BACKGROUND: Previous studies have reported an increased risk of stroke in patients taking antipsychotics. However, most of these studies have been conducted in the elderly population. OBJECTIVE: We estimated stroke risk in new users of any first-generation antipsychotic or haloperidol, vs second-generation antipsychotics among patients aged 18-64 years without a recent dementia diagnosis and, separately, regardless of a recent dementia diagnosis. METHODS: Data were obtained from IBM MarketScan® Commercial Database (1 January, 2001-31 December, 2017). Among new users without a recent dementia diagnosis, stroke risk for first-generation antipsychotics (FGAw/oD cohort) or haloperidol (HALw/oD cohort) was compared with second-generation antipsychotics (SGAw/oD cohort). A similar comparison was conducted among new users regardless of dementia diagnosis: first-generation antipsychotics (FGA cohort) or haloperidol (HAL cohort) vs second-generation antipsychotics (SGA cohort). Crude incident stroke rates within each cohort were determined. For hazard ratios, three propensity score matching strategies were used: unadjusted (crude), Sentinel propensity score strategy, and large-scale regularized regression model (adapted propensity score strategy). RESULTS: Each cohort included ≥12,000 patients. The incident rates for stroke per 1000 person-years were 3.10 (FGAw/oD), 5.99 (HALw/oD), 0.85 (SGAw/oD), 3.14 (FGA), 6.12 (HAL), and 0.90 (SGA). Pre-planned analysis with adapted propensity score strategy matching yielded calibrated hazard ratios for stroke: FGAw/oD vs SGAw/oD: 2.05 (calibrated confidence interval 1.13-3.89); HALw/oD vs SGAw/oD: 2.47 (1.14-5.48), FGA vs SGA: 1.64 (0.94-2.97), and HAL vs SGA: 1.98 (0.99-4.00). A post-hoc sensitivity analysis to address potential bias introduced by the 2015 change from the International Classification of Diseases, Ninth Revision to the International Classification of Diseases, Tenth Revision yielded calibrated hazard ratios for FGAw/oD vs SGAw/oD: 1.59 (0.87-3.01), HALw/oD vs SGAw/oD: 2.79 (1.24-6.42), FGA vs SGA: 1.41 (0.79-2.62), and HAL vs SGA: 3.47 (1.63-7.92). CONCLUSIONS: Among adults aged ≤64 years, without a recent dementia diagnosis, stroke risk is higher among those exposed to haloperidol compared with those exposed to second-generation antipsychotics.

Understanding patient journey in ulcerative colitis prior to biologic initiation: a 5-year exploration.

BACKGROUND: There has been a more pronounced shift toward earlier, more aggressive therapies in Crohn's disease than in ulcerative colitis (UC). The aim of this study was to describe the pre-biologic treatment and health care experience, including co-morbidities and overall health care utilization, for UC patients who initiated biologic therapies, in the 5 years prior to the initiation of the first biologic agent. METHODS: UC patients who initiated a biologic agent approved for UC between 9/15/2005 and 1/30/2018 were identified from the IBM® MarketScan® Commercial Database, a large US database. The date of the first recorded UC biologic exposure was defined as the index date, and ≥ 5 years of pre-index records were required to evaluate patients' treatment, disease progression and overall health care utilization prior to initiating biologic agents. RESULTS: Among the 1891 eligible patients, treatment with oral corticosteroids, 5-aminosalicylates, and other non-biologic immunomodulators, all increased progressively across the 5 years prior to the index. From within year-five to within year-one prior to the index, the median duration of oral corticosteroid treatment increased from 34 to 88 days per year and the proportion of patients who experienced more extensive/pancolitis disease increased from 16 to 59%. Overall, the frequency of all-cause health care visits also increased. CONCLUSIONS: Patients with UC experienced increasing morbidity and treatment burden in the 5 years prior to initiating biologic therapy. To achieve reduced corticosteroids in UC management, better risk stratification is needed to help identify patients for more timely biologic treatment.

Stroke Risk Among Elderly Users of Haloperidol and Typical Antipsychotics Versus Atypical Antipsychotics: A Real-World Study From a US Health Insurance Claims Database.

BACKGROUND: We estimated stroke risk associated with new exposure to haloperidol, or any typical antipsychotic, versus atypical antipsychotic among patients aged ≥65 years regardless of dementia status. METHODS: IBM MarketScan Medicare Supplemental Database data (January 1, 2001 to December 31, 2017) were used. Stroke risk for new users of typical antipsychotics (T1 cohort) or haloperidol (T2 cohort) was compared with new users of atypical antipsychotics (C1 cohort) aged ≥65 years. Crude incidence rate (IR) and incidence proportion of stroke were estimated within each cohort and gender subgroup. Three propensity score (PS) matching strategies were employed: Unadjusted (crude), Sentinel PS replication, and a large-scale regularized regression model (adapted PS). RESULTS: Overall, 36,734 (T1), 24,074 (T2), and 226,990 (C1) patients were included. Crude IRs for stroke per 1000 person-years were 17.67 (T1), 23.74 (T2), and 14.17 (C1). In preplanned analyses, PS-matched calibrated hazard ratio (cHR) for stroke T1 versus C1 cohort was 1.08 (95% calibrated confidence interval [cCI] = 0.75, 1.55) with Sentinel PS strategy and 1.31 (95% cCI = 1.07, 1.60) with adapted PS strategy. The cHR for stroke in patients of T2 versus C1 was 1.69 (95% cCI = 1.08, 2.75) with Sentinel PS strategy and 1.45 (95% cCI = 1.17, 1.80) with adapted PS strategy. CONCLUSION: Stroke risk in elderly new users of haloperidol was elevated compared to new users of atypical antipsychotics and was elevated for typical antipsychotics using the adapted PS strategy.

Evaluation of disability in patients exposed to fluoroquinolones.

BACKGROUND: Fluoroquinolones are used for conditions including sinusitis, bronchitis, and urinary tract infections. It has been suggested that exposure to fluoroquinolones for these conditions is associated with disability resulting from adverse events in 2 or more organ systems. The objectives were to: describe: 1) fluoroquinolone, azithromycin, and sulfamethoxazole / trimethoprim utilization for these infections; 2) the rate of disability associated with exposure to each of these antibiotic classes and adverse events in 2 or more system organ classes, and 3) compare outcome rates for each of the antibiotic classes. METHODS: This study was conducted using administrative data to mitigate the limitations of spontaneous reports. The sampling frame was a U.S. population with both medical and disability insurance, including patients with the above uncomplicated infections who were prescribed the antibiotics of interest. The primary outcome was an incident short-term disability claim associated with adverse events in 2 different organ systems within 120 days of exposure. A matched analysis was used to compare the outcome for patients receiving each of the drug classes. RESULTS: After propensity score matching, there were 119,653 individuals in each of the exposure groups. There were 264 fluoroquinolone associated disability events and 243 azithromycin/ sulfamethoxazole associated disability events (relative risk =1.09 (95% CI: 0.92-1.30; calibrated p = 0.84)). The results were not significantly different from the null hypothesis of no difference between groups. CONCLUSION: Comparative assessments are difficult to conduct in spontaneous reports. This examination of disability associated with adverse events in different system organ classes showed no difference between fluoroquinolones and azithromycin or sulfamethoxazole in administrative data.

Channeling Bias in the Analysis of Risk of Myocardial Infarction, Stroke, Gastrointestinal Bleeding, and Acute Renal Failure with the Use of Paracetamol Compared with Ibuprofen.

INTRODUCTION: Observational studies estimating severe outcomes for paracetamol versus ibuprofen use have acknowledged the specific challenge of channeling bias. A previous study relying on negative controls suggested that using large-scale propensity score (LSPS) matching may mitigate bias better than models using limited lists of covariates. OBJECTIVE: The aim was to assess whether using LSPS matching would enable the evaluation of paracetamol, compared to ibuprofen, and increased risk of myocardial infarction, stroke, gastrointestinal (GI) bleeding, or acute renal failure. STUDY DESIGN AND SETTING: In a new-user cohort study, we used two propensity score model strategies for confounder controls. One replicated the approach of controlling for a hand-picked list. The second used LSPSs based on all available covariates for matching. Positive and negative controls assessed residual confounding and calibrated confidence intervals. The data source was the Clinical Practices Research Datalink (CPRD). RESULTS: A substantial proportion of negative controls were statistically significant after propensity score matching on the publication covariates, indicating considerable systematic error. LSPS adjustment was less biased, but residual error remained. The calibrated estimates resulted in very wide confidence intervals, indicating large uncertainty in effect estimates once residual error was incorporated. CONCLUSIONS: For paracetamol versus ibuprofen, when using LSPS methods in the CPRD, it is only possible to distinguish true effects if those effects are large (hazard ratio > 2). Due to their smaller hazard ratios, the outcomes under study cannot be differentiated from null effects (represented by negative controls) even if there were a true effect. Based on these data, we conclude that we are unable to determine whether paracetamol is associated with an increased risk of myocardial infarction, stroke, GI bleeding, and acute renal failure compared to ibuprofen, due to residual confounding.

Developing Predictive Models to Determine Patients in End-of-Life Care in Administrative Datasets.

INTRODUCTION: In observational studies with mortality endpoints, one needs to consider how to account for subjects whose interventions appear to be part of 'end-of-life' care. OBJECTIVE: The objective of this study was to develop a diagnostic predictive model to identify those in end-of-life care at the time of a drug exposure. METHODS: We used data from four administrative claims datasets from 2000 to 2017. The index date was the date of the first prescription for the last new drug subjects received during their observation period. The outcome of end-of-life care was determined by the presence of one or more codes indicating terminal or hospice care. Models were developed using regularized logistic regression. Internal validation was through examination of the area under the receiver operating characteristic curve (AUC) and through model calibration in a 25% subset of the data held back from model training. External validation was through examination of the AUC after applying the model learned on one dataset to the three other datasets. RESULTS: The models showed excellent performance characteristics. Internal validation resulted in AUCs ranging from 0.918 (95% confidence interval [CI] 0.905-0.930) to 0.983 (95% CI 0.978-0.987) for the four different datasets. Calibration results were also very good, with slopes near unity. External validation also produced very good to excellent performance metrics, with AUCs ranging from 0.840 (95% CI 0.834-0.846) to 0.956 (95% CI 0.952-0.960). CONCLUSION: These results show that developing diagnostic predictive models for determining subjects in end-of-life care at the time of a drug treatment is possible and may improve the validity of the risk profile for those treatments.

All-cause mortality in patients with treatment-resistant depression: a cohort study in the US population.

BACKGROUND: Treatment-resistant depression (TRD) may represent a substantial proportion of major depressive disorder (MDD); however, the risk of mortality in TRD is still incompletely assessed. METHODS: Data were obtained from Optum Clinformatics™ Extended, a US claims database. Date of the first antidepressant (AD) dispensing was designated as the index date for study entry and 6 months prior to that was considered the baseline period. Patients with MDD aged ≥ 18 years, index date between January 1, 2008 and September 30, 2015, no AD claims during baseline, and continuous enrollment in the database during baseline were included. Patients who started a third AD regimen after two regimens of appropriate duration were included in the TRD cohort. All-cause mortality was compared between patients with TRD and non-TRD MDD using a proportional hazards model and Kaplan-Meier estimate with TRD status being treated as a time-varying covariate. The model was adjusted for study year, age, gender, depression diagnosis, substance use disorder, psychiatric comorbidities, and Charlson comorbidity index. RESULTS: Out of 355,942 patients with MDD, 34,176 (9.6%) met the criterion for TRD. TRD was associated with a significantly higher mortality compared with non-TRD MDD (adjusted HR: 1.29; 95% CI 1.22-1.38; p < 0.0001). Survival time was significantly shorter in the TRD cohort compared with the non-TRD MDD cohort (p < 0.0001). CONCLUSIONS: Patients with TRD had a higher all-cause mortality compared with non-TRD MDD patients.

Awareness of, and Compliance with, Domperidone Revised Labeling After a Risk-Minimization Activity in Europe.

BACKGROUND AND OBJECTIVE: Risk-minimization measures (RMM), including label revisions were implemented in Europe for domperidone because of evidence of increased incidence of cardiac arrhythmia and sudden cardiac death. In accordance with the guideline on good pharmacovigilance practices, the European Medicines Agency Pharmacovigilance Risk Assessment Committee requested to conduct two studies to evaluate the effectiveness of these risk minimization measures. METHODS: In Belgium, France, Germany, Spain, and the UK, surveys were conducted to assess physicians' knowledge on the updated domperidone labeling information, and a drug-utilization study (DUS) was conducted using healthcare databases to assess domperidone prescribing patterns before and after the RMM. Four DUS sensitivity analyses (scenarios) evaluated uncertainty regarding domperidone treatment duration and indication. RESULTS: Among 1805 physicians participating in the survey, most were aware of the approved indication (nausea and vomiting, 80%), treatment duration (≤ 7 days, 70%), and maximum adult daily dose (10 mg three times daily, 84%). Only 33% selected the on-label indication from a list of indications for which they would prescribe domperidone. Awareness was low for medications contraindicated for concomitant use (26%) and contraindicated conditions (4%). In the DUS, under the optimistic scenario, a large improvement in labeling compliance from pre- to post-implementation period was observed in France (27% vs. 69%), while Belgium, Germany, Spain, and the UK showed small improvements (< 10%). In the other scenarios, there was little to no improvement in compliance with the revised labeling from the pre- to post-implementation periods in most countries. CONCLUSIONS: The survey findings documented that most physicians in all five countries were aware of the main aspects of the revised labeling. Results of the DUS were inconclusive regarding the effect of the RMM and compliance with the revised labeling for all countries except France.

Corrigendum to "Treatment resistant depression incidence estimates from studies of health insurance databases depend strongly on the details of the operating definition" [Heliyon 4 (7) (July 2018) e00707].

[This corrects the article DOI: 10.1016/j.heliyon.2018.e00707.].

Treatment resistant depression incidence estimates from studies of health insurance databases depend strongly on the details of the operating definition.

Background: Health services databases provide population-based data that have been used to describe the epidemiology and costs of treatment resistant depression (TRD). This retrospective cohort study estimated TRD incidence and, via sensitivity analyses, assessed the variation of TRD incidence within the range of implementation choices. Methods: In three US databases widely used for observational studies, we defined TRD as failure of two medications as evidenced by their replacement or supplementation by other medications, and set maximum durations (caps) for how long a medication regimen could remain in use and still be eligible to fail. Results: TRD incidence estimates varied approximately 2-fold between the two databases (CCAE, Medicaid) that described socioeconomically different non-elderly populations; for a given cap varied 2-fold to 4-fold within each database across the other implementation choices; and if the cap was also allowed to vary, varied 6-fold or 7-fold within each database. Limitations: The main limitations were typical of studies from health services databases and included the lack of complete -rather than recent - medical histories, the limited amount of clinical information, and the assumption that medication dispensed was consumed as directed. Conclusion: In retrospective cohort studies from health services databases, TRD incidence estimates vary widely depending on the implementation choices. Unless a firm basis for narrowing the range of these choices can be found, or a different analytic approach not dependent on such choices is adopted, TRD incidence and prevalence estimates from such databases will be difficult to compare or interpret.

Database Studies of Treatment-Resistant Depression Should Take Account of Adequate Dosing.

BACKGROUND: The objective of this study was to estimate how commonly patients with pharmacologically treated depression (PTD) do not receive adequate doses of antidepressant (AD) medications. Such prescribing would have epidemiologic and clinical implications. Patients with PTD have treatment-resistant depression (TRD) if they do not benefit from ≥ 2 AD medications taken with reasonable compliance for adequate durations at adequate doses. Some database studies of TRD do not assess AD medication dose and would, therefore, overestimate TRD incidence unless physicians treating PTD patients routinely prescribe AD medications at adequate doses before changing medications. METHODS: Using data from 3 US health services databases from September 1, 2010, through December 31, 2014, we created PTD cohorts and defined an AD medication era as a sequence of dispensings with ≤ 30 days between the end of the days' supply of each dispensing and the start of the next. We classified AD medication eras according to whether they had ≥ 1 dispensing at or above the minimum therapeutic dose. RESULTS: The proportion of AD medication eras with ≥ 1 dose at or above the minimum therapeutic dose varied from 59.6% in the Medicaid database to 66.0% in a database of privately insured patients. CONCLUSIONS: In the population at risk for TRD, a substantial proportion of AD medication dispensing eras do not reach the minimum therapeutic dose. TRD incidence is likely to be overestimated in database studies that do not take account of dose. Clinicians should be aware that AD medication regimens are often stopped without reaching the minimum therapeutic dose, which may cause unnecessary switching.

Medication changes after switching from CONCERTA® brand methylphenidate HCl to a generic long-acting formulation: A retrospective database study.

BACKGROUND: Observational studies of switching from branded to generic formulations of the same drug substance often lack appropriate comparators for the subjects who switched. Three generic formulations were deemed equivalent to Concerta: an authorized generic (AG) identical except for external packaging, and two other generics (EG). OBJECTIVE: Compare the incidence of a combined endpoint (switching back to Concerta, changing the use of immediate release methylphenidate (MPH), stopping all long-acting methylphenidate, or starting a new medication) among people switched from Concerta to the AG versus the EG. METHODS: Cohort study from the Truven CCAE database of people aged 6 to 65 diagnosed with ADHD, treated with Concerta, and switched to the EG or to the AG formulation. RESULTS: In the EG arm 24.6% and in the AG arm 19.7% of subjects switched back to Concerta. The proportion of subjects meeting the combined endpoint was 39.5% in the EG arm, 32.9% in the AG arm, a crude risk ratio of 1.20 (95% CI 0.94, 1.54). After adjustment by propensity score stratification, the adjusted odds ratio (OR) was 1.23 (95% CI 0.90, 1.70). In an unplanned analysis using a different method of adjustment, the adjusted OR was 1.00 (95% CI 0.69, 1.44). DISCUSSION: This study did not detect a difference between the proportion of people who met the study endpoint in the two study arms, i.e. between those who switched to a generic formulation that was identical to Concerta except for external packaging and those who switched to the comparison generics. The high incidence of the combined endpoint in the AG arm demonstrates the need for an appropriate comparator in studies of this type. TRIAL REGISTRATION: ClinicalTrials.gov NCT02730572.

Inferring pregnancy episodes and outcomes within a network of observational databases.

Administrative claims and electronic health records are valuable resources for evaluating pharmaceutical effects during pregnancy. However, direct measures of gestational age are generally not available. Establishing a reliable approach to infer the duration and outcome of a pregnancy could improve pharmacovigilance activities. We developed and applied an algorithm to define pregnancy episodes in four observational databases: three US-based claims databases: Truven MarketScan® Commercial Claims and Encounters (CCAE), Truven MarketScan® Multi-state Medicaid (MDCD), and the Optum ClinFormatics® (Optum) database and one non-US database, the United Kingdom (UK) based Clinical Practice Research Datalink (CPRD). Pregnancy outcomes were classified as live births, stillbirths, abortions and ectopic pregnancies. Start dates were estimated using a derived hierarchy of available pregnancy markers, including records such as last menstrual period and nuchal ultrasound dates. Validation included clinical adjudication of 700 electronic Optum and CPRD pregnancy episode profiles to assess the operating characteristics of the algorithm, and a comparison of the algorithm's Optum pregnancy start estimates to starts based on dates of assisted conception procedures. Distributions of pregnancy outcome types were similar across all four data sources and pregnancy episode lengths found were as expected for all outcomes, excepting term lengths in episodes that used amenorrhea and urine pregnancy tests for start estimation. Validation survey results found highest agreement between reviewer chosen and algorithm operating characteristics for questions assessing pregnancy status and accuracy of outcome category with 99-100% agreement for Optum and CPRD. Outcome date agreement within seven days in either direction ranged from 95-100%, while start date agreement within seven days in either direction ranged from 90-97%. In Optum validation sensitivity analysis, a total of 73% of algorithm estimated starts for live births were in agreement with fertility procedure estimated starts within two weeks in either direction; ectopic pregnancy 77%, stillbirth 47%, and abortion 36%. An algorithm to infer live birth and ectopic pregnancy episodes and outcomes can be applied to multiple observational databases with acceptable accuracy for further epidemiologic research. Less accuracy was found for start date estimations in stillbirth and abortion outcomes in our sensitivity analysis, which may be expected given the nature of the outcomes.

Finding treatment-resistant depression in real-world data: How a data-driven approach compares with expert-based heuristics.

BACKGROUND: Depression that does not respond to antidepressants is treatment-resistant depression (TRD). TRD definitions include assessments of treatment response, dose and duration, and implementing these definitions in claims databases can be challenging. We built a data-driven TRD definition and evaluated its performance. METHODS: We included adults with depression, ≥1 antidepressant, and no diagnosis of mania, dementia, or psychosis. Subjects were stratified into those with and without proxy for TRD. Proxies for TRD were electroconvulsive therapy, deep brain, or vagus nerve stimulation. The index date for subjects with proxy for TRD was the procedure date, and for subjects without, the date of a randomly selected visit. We used three databases. We fit decision tree predictive models. We included number of distinct antidepressants, with and without adequate doses and duration, number of antipsychotics and psychotherapies, and expert-based definitions, 3, 6, and 12 months before index date. To assess performance, we calculated area under the curve (AUC) and transportability. RESULTS: We analyzed 33,336 subjects with no proxy for TRD, and 3,566 with the proxy. Number of antidepressants and antipsychotics were selected in all periods. The best model was at 12 months with an AUC = 0.81. The rule transported well and states that a subject with ≥1 antipsychotic or ≥3 antidepressants in the last year has TRD. Applying this rule, 15.8% of subjects treated for depression had TRD. CONCLUSION: The definition that best discriminates between subjects with and without TRD considers number of distinct antidepressants (≥3) or antipsychotics (≥1) in the last year.