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.