Catherine B. Johannes

Purpose: To evaluate the positive predictive value (PPV) of an endometrial cancer case finding algorithm using International Classification of Disease 10th revision Clinical Modification (ICD‐10‐CM) diagnosis codes from US insurance claims for implementation in a planned post‐marketing safety study. Two algorithm variants were evaluated.Methods: Provisional incident endometrial cancer cases were identified from 2016 through 2020 among women aged ≥50 years. One algorithm variant used diagnosis codes for malignant neoplasms of uterine sites (C54.x), excluding C54.2 (malignant neoplasm of myometrium); the other used only C54.1 (malignant neoplasm of endometrium). A random sample of medical records of recent incident provisional cases (2018–2020) was requested for adjudication. Confirmed cases showed biopsy evidence of endometrial cancer, documentation of cancer staging, or hysterectomy following diagnosis. We estimated the PPV of the variants with 95% confidence intervals (CI) excluding cases that had insufficient information.Results: Of 294 provisional cases adjudicated, 85% were from outpatient settings (n = 249). Mean age at diagnosis was 69.3 years. Among the 294 adjudicated cases (identified with the broader algorithm variant), the same 223 were confirmed endometrial cancer cases by both algorithm variants. The PPV (95% CI) for the broader algorithm variant was 84.2% (79.2% and 88.3%), and for the variant using only C54.1 was 85.8% (80.9% and 89.8%).Conclusion: We developed and validated an algorithm using ICD‐10‐CM diagnosis codes to identify endometrial cancer cases in health insurance claims with a sufficiently high PPV to use in a planned post‐marketing safety study.

Introduction At the time of dapagliflozin’s approval in Europe (2012) to treat patients with type 2 diabetes mellitus, concerns regarding acute liver injury and severe complications of urinary tract infection (sUTI) led to two post-authorization safety (PAS) studies of these outcomes to monitor the safety of dapagliflozin in real-world use. Objective To investigate the incidence of hospitalization for acute liver injury (hALI) or sUTI (pyelonephritis or urosepsis) among patients initiating dapagliflozin compared with other glucose-lowering drugs (GLDs). Methods These two noninterventional cohort studies identified initiators of dapagliflozin and comparator GLDs in November 2012–February 2019 using data from three longitudinal, population-based data sources: Clinical Practice Research Datalink (UK), the HealthCore Integrated Research Database (USA), and the Medicare database (USA). Outcomes (hALI and sUTI) were identified with electronic algorithms. Incidence rates were estimated by exposure group. Incidence rate ratios (IRRs) were calculated comparing dapagliflozin to comparator GLDs, using propensity score trimming and stratification to address confounding. The sUTI analyses were conducted separately by sex. Results In all data sources, hALI and sUTI incidence rates were generally lower in dapagliflozin initiators than comparator GLD initiators. The adjusted IRR (95% confidence interval) pooled across data sources for hALI was 0.85 (0.59–1.24) and for sUTI was 0.76 (0.60–0.96) in females and 0.74 (0.56–1.00) in males. Findings from sensitivity analyses were largely consistent with the primary analyses. Conclusions These real-world studies do not suggest increased risks of hALI or sUTI, and they suggest a potential decreased risk of sUTI with dapagliflozin exposure compared with other GLDs.

Introduction Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor approved to treat type 2 diabetes mellitus (T2DM), among other conditions. When dapagliflozin was approved in Europe for treating T2DM (2012), potential safety concerns regarding its effect on kidney function resulted in this post-authorization safety study to assess hospitalization for acute kidney injury (hAKI) among dapagliflozin initiators in a real-world setting. Objective The aim of this study was to evaluate the incidence of hAKI in adults with T2DM initiating dapagliflozin compared with other glucose-lowering drugs (GLDs). Methods This noninterventional cohort study identified new users of dapagliflozin and comparator GLDs from November 2012 to February 2019 from three longitudinal, population-based data sources: Clinical Practice Research Datalink (CPRD; United Kingdom), the HealthCore Integrated Research Database (HIRD; United States [US]), and Medicare (US). Electronic algorithms identified occurrences of hAKI, from which a sample underwent validation. Incidence rates for hAKI were calculated, and incidence rate ratios (IRRs) compared hAKI in dapagliflozin with comparator GLDs. Propensity score trimming and stratification were conducted for confounding adjustment. Results In all data sources, dapagliflozin initiators had a lower hAKI incidence rate than comparator GLD initiators (adjusted IRRs: CPRD, 0.44 [95% confidence interval (CI), 0.22–0.86]; HIRD, 0.76 [95% CI, 0.62–0.93]; Medicare, 0.69 [95% CI, 0.59–0.79]). The adjusted IRR pooled across the data sources was 0.70 (95% CI, 0.62–0.78). Results from sensitivity and stratified analyses were consistent with the primary analysis. Conclusions This study, with > 34,000 person-years of real-world dapagliflozin exposure, suggests a decreased risk of hAKI in patients with T2DM exposed to dapagliflozin, aligning with results from dapagliflozin clinical trials. Study registration European Union Post-Authorisation Studies Register, EUPAS 11684; ClinicalTrials.gov, NCT02695082.

Purpose: Compare the risk of melanoma between initiators of rasagiline or other antiparkinsonian drugs (APDs) in a Parkinson's disease (PD) population.Methods: A retrospective cohort study was conducted in the US Medicare claims research database (2006–2015) in adults aged ≥65 years with PD claims. Other APD initiators were randomly matched (4:1) to rasagiline initiators on age, sex, and cohort entry year. Cutaneous melanoma events were identified by a validated claims algorithm. Incidence rates (IRs), incidence rate ratios (IRRs), and Cox‐adjusted hazard ratios (HRs) for melanoma comparing rasagiline with other APD initiators were calculated and analyzed by duration of study medication use and cumulative dose of rasagiline. Potential indicators of surveillance bias were explored.Results: Among 23 708 rasagiline initiators and 96 552 matched APD initiators, the crude IR of melanoma/100 000 person‐years was 334.3 (95% confidence interval [CI], 291.5–381.6) and 208.2 (95% CI, 190.1–227.5), respectively (crude IRR 1.61; 95% CI, 1.36–1.89). The adjusted HR was 1.37 (95% CI, 1.14–1.65) and increased with longer rasagiline exposure and higher cumulative rasagiline doses. Rasagiline initiators more frequently had dermatologist visits or skin biopsies before cohort entry than APD initiators and had a higher incidence of nonmelanoma skin cancer during follow‐up (crude IRR, 1.44; 95% CI, 1.35–1.54).Conclusions: A small increased incidence of melanoma with exposure to rasagiline compared with other APDs was observed. Although the pattern with dose and duration is consistent with a hypothesized biologic effect, the increased skin cancer surveillance among rasagiline users suggests surveillance bias as a contributing explanation for the observed results.

Long-acting beta agonists (LABAs) when used without concomitant inhaled corticosteroids (ICS) increase the risk of asthma-related deaths, but the effect on asthma-related death of LABA used in combination with ICS therapy is unknown. To address this question, we explored the feasibility of conducting an observational study using multiple US health care data sources. Retrospective cohort study to evaluate the likelihood of getting an upper 95% confidence limit ≤1.4 for the asthma mortality rate ratio and ≤0.40 per 10 000 person-years for the mortality rate difference, assuming no effect of new use of combined LABA + ICS (versus non-LABA maintenance therapy) on asthma mortality. Ten research institutions executed centrally distributed analytic code based on a standard protocol using an extracted (2000–2010) persistent asthma cohort (asthma diagnosis and ≥4 asthma medications in 12 months). Pooled results were analyzed by the coordinating center. Asthma deaths were ascertained by linkage with the National Death Index. In a cohort of 994 627 persistent asthma patients (2.4 million person-years; 278 asthma deaths), probabilities of the upper 95% confidence limit for effect estimates being less than targeted values, assuming a null relation, were about 0.05. Modifications in cohort and exposure definitions increased exposed person-time and outcome events, but study size remained insufficient to attain study goals. Even with 10 data sources and a 10-year study period, the rarity of asthma deaths among patients using certain medications made it infeasible to study the association between combined LABA + ICS and asthma mortality with our targeted level of study precision. Copyright © 2016 John Wiley & Sons, Ltd.

Introduction Epidemiological studies have linked domperidone use with serious cardiac arrhythmias, including sudden cardiac death, but data on age, dose, and duration of use are limited. Objectives The aim of this study was to assess the risk of out-of-hospital sudden cardiac death associated with domperidone use versus proton pump inhibitors (PPIs), metoclopramide, or non-use of all three medications, and to evaluate the risk of sudden cardiac death in relation to age and domperidone dose. Methods This was a population-based case-control study nested in a cohort of subjects aged ≥2 years in the Clinical Practice Research Datalink with one or more prescriptions for domperidone, any PPI, or metoclopramide from 2005 to 2011. Out-of-hospital sudden cardiac death was assessed by linkage with Hospital Episode Statistics and death certificates. Controls were matched on age, sex, and medical practice. The risk of sudden cardiac death in domperidone users versus risk in users of PPIs or metoclopramide was evaluated with multivariable conditional logistic regression; case-crossover analysis addressed possible residual confounding. Results From the study cohort (n = 681,104), 3239 sudden cardiac death cases were matched to 12,572 controls. The adjusted odds ratio (95 % confidence interval) for sudden cardiac death with current use of domperidone alone was 1.71 (0.92–3.18) versus non-use of study medications, 1.26 (0.68–2.34) versus current PPI use, and 0.40 (0.17–0.94) current metoclopramide use. The adjusted odds ratio (95 % confidence interval) relative to exposure to no study drug for domperidone >30 mg/day (eight cases, five controls) was 3.20 (0.59–17.3) and 1.65 (0.89–3.07) for age ≥61 years (27 cases, 49 controls). The odds ratio (95 % confidence interval) was 3.17 (1.72–5.83) for within-person periods of domperidone use versus non-use in the case-crossover analysis. Conclusions Compared with non-use of any study drug, current domperidone use was associated with sudden cardiac death in nested case-control and case-crossover analyses, with a suggestion of higher risk in older persons and users of higher daily doses.

Purpose: Limited information from spontaneous reports and results of two case‐control studies raised concern about the cardiotoxicity of oral domperidone therapy. This case‐control study nested in a retrospective cohort evaluated the combined risk of serious ventricular arrhythmia (SVA) and sudden cardiac death (SCD) in users of domperidone compared with users of proton pump inhibitors (PPIs), or non‐users of these medications.Methods: A cohort of users of domperidone or a PPI from 1990 to 2005 was identified from existing electronic databases of Saskatchewan Health. Possible cases of SVA/SCD were identified using hospital discharge and vital statistics codes. SVA cases were validated by cardiologist review of abstracted hospital medical charts. Up to four controls were matched to each case by index date, year of birth, sex, and diabetes status. The odds ratio (OR) of current domperidone exposure relative to non‐use or to current PPI exposure was estimated and adjusted for possible confounding variables using conditional logistic regression.Results: From 83 212 individuals in the exposure cohort we identified 1608 cases, 49 SVA and 1559 SCD (mean age 79.4 years, females 52.9%, diabetes 22.3%) and 6428 matched controls. The adjusted OR for SVA/SCD with current domperidone use compared with non‐use was (1.59, 95%CI: 1.28–1.98), or compared with current PPI use was (1.44, 95%CI: 1.12–1.86). In stratified analyses adjusted ORs were numerically higher in males, older subjects, and non‐diabetics.Conclusions: The increased risk of SVA/SCD for current domperidone users remained after adjustment for multiple covariates. The risk may vary among subgroups of exposed individuals. Copyright © 2010 John Wiley & Sons, Ltd.

With data from the population-based Prevalence of Female Sexual Problems Associated with Distress and Determinants of Treatment Seeking (PRESIDE) study, which has previously estimated the prevalence of sexual problems and sexually related personal distress in United States women, the prevalence of sexual disorders of desire, arousal, and orgasm was re-estimated, taking concurrent depression into consideration. Current depression was defined in 3 ways as (1) self-reported symptoms alone, (2) antidepressant medication use alone, or (3) symptoms and/or antidepressant use. The unadjusted population prevalence for each distressing sexual problem in the 31,581 respondents was calculated first irrespective of concurrent depression and then in women without concurrent depression, thus determining the size of the population with both conditions present. The unadjusted population-based prevalence of desire disorder was 10.0% and was reduced to 6.3% for those without concurrent depression, leading to an estimate of 3.7% for those with both conditions present. The same pattern was observed for arousal and orgasm disorders, although overall prevalence estimates were lower. Our findings indicate that about 40% of those with a sexual disorder of desire, arousal, or orgasm have concurrent depression, As this study was cross-sectional, causality versus comorbidity cannot be determined. However, our findings stress the importance of evaluating depression along with sexual problems in routine clinical practice and epidemiology research.