Validity of inpatient electronic health record-based measures of oxygen-related therapy in the United States: Lessons applicable for studying COVID-19 endpoints.

INTRODUCTION: During the COVID-19 pandemic, inpatient electronic health records (EHRs) have been used to conduct public health surveillance and assess treatments and outcomes. Invasive mechanical ventilation (MV) and supplemental oxygen (O2) use are markers of severe illness in hospitalized COVID-19 patients. In a large US system (n = 142 hospitals), we assessed documentation of MV and O2 use during COVID-19 hospitalization in administrative data versus nursing documentation. METHODS: We identified 319 553 adult hospitalizations with a COVID-19 diagnosis, February 2020-October 2022, and extracted coded, administrative data for MV or O2. Separately, we developed classification rules for MV or O2 supplementation from semi-structured nursing documentation. We assessed MV and O2 supplementation in administrative data versus nursing documentation and calculated ordinal endpoints of decreasing COVID-19 disease severity. Nursing documentation was considered the gold standard in sensitivity and positive predictive value (PPV) analyses. RESULTS: In nursing documentation, the prevalence of MV and O2 supplementation among COVID-19 hospitalizations was 14% and 75%, respectively. The sensitivity of administrative data was 83% for MV and 41% for O2, with both PPVs above 91%. Concordance between sources was 97% for MV (κ = 0.85), and 54% for O2 (κ = 0.21). For ordinal endpoints, administrative data accurately identified intensive care and MV but underestimated hospitalizations with O2 requirements (42% vs. 18%). CONCLUSIONS: In comparison to nursing documentation, administrative data under-ascertained O2 supplementation but accurately estimated severe endpoints such as MV. Nursing documentation improved ascertainment of O2 among COVID-19 hospitalizations and can capture oxygen requirements in adults hospitalized with COVID-19 or other respiratory illnesses.

Treatment and care received by children hospitalized with COVID-19 in a large hospital network in the United States, February 2020 to September 2021.

We described care received by hospitalized children with COVID-19 or multi-system inflammatory syndrome (MIS-C) prior to the 2021 COVID-19 Omicron variant surge in the US. We identified hospitalized children <18 years of age with a COVID-19 or MIS-C diagnosis (COVID-19 not required), separately, from February 2020-September 2021 (n = 126 hospitals). We described high-risk conditions, inpatient treatments, and complications among these groups. Among 383,083 pediatric hospitalizations, 2,186 had COVID-19 and 395 had MIS-C diagnosis. Less than 1% had both COVID-19 and MIS-C diagnosis (n = 154). Over half were >6 years old (54% COVID-19, 70% MIS-C). High-risk conditions included asthma (14% COVID-19, 11% MIS-C), and obesity (9% COVID-19, 10% MIS-C). Pulmonary complications in children with COVID-19 included viral pneumonia (24%) and acute respiratory failure (11%). In reference to children with COVID-19, those with MIS-C had more hematological disorders (62% vs 34%), sepsis (16% vs 6%), pericarditis (13% vs 2%), myocarditis (8% vs 1%). Few were ventilated or died, but some required oxygen support (38% COVID-19, 45% MIS-C) or intensive care (42% COVID-19, 69% MIS-C). Treatments included: methylprednisolone (34% COVID-19, 75% MIS-C), dexamethasone (25% COVID-19, 15% MIS-C), remdesivir (13% COVID-19, 5% MIS-C). Antibiotics (50% COVID-19, 68% MIS-C) and low-molecular weight heparin (17% COVID-19, 34% MIS-C) were frequently administered. Markers of illness severity among hospitalized children with COVID-19 prior to the 2021 Omicron surge are consistent with previous studies. We report important trends on treatments in hospitalized children with COVID-19 to improve the understanding of real-world treatment patterns in this population.

Valsartan, Losartan and Irbesartan use in the USA, UK, Canada and Denmark after the nitrosamine recalls: a descriptive cohort study.

OBJECTIVES: To examine valsartan, losartan and irbesartan usage and switching patterns in the USA, UK, Canada and Denmark before and after July 2018, when the first Angiotensin-Receptor-Blocker (ARB) (valsartan) was recalled. DESIGN: Retrospective cohort study. SETTING: USA, Canadian administrative healthcare data, Danish National Prescription Registry and UK primary care electronic health records. PARTICIPANTS: Patients aged 18 years and older between January 2014 and December 2020. INTERVENTION: Valsartan, losartan and irbesartan. MAIN OUTCOME: Monthly percentages of individual ARB episodes, new users and switches to another ARB, ACE inhibitors (ACEI) or calcium channel blockers containing products. RESULTS: We identified 10.8, 3.2, 1.8 and 1.2 million ARB users in the USA, UK, Canada and Denmark, respectively. Overall proportions of valsartan, losartan and irbesartan use were 18.4%, 67.9% and 5.2% in the USA; 3.1%, 48.3% and 10.2% in the UK, 16.3%, 11.4% and 18.3% in Canada, 1%, 93.5% and 0.6% in Denmark. In July 2018, we observed an immediate steep decline in the proportion of valsartan use in the USA and Canada. A similar trend was observed in Denmark; however, the decline was only minimal. We observed no change in trends of ARB use in the UK. Accompanying the valsartan decline was an increase in switching to other ARBs in the USA, Canada and Denmark. There was a small increase in switching to ACEI relative to the valsartan-to-other-ARBs switch. We also observed increased switching from other affected ARBs, losartan and irbesartan, to other ARBs throughout 2019, in the USA and Canada, although the usage trends in the USA remained unchanged. CONCLUSION: The first recall notice for valsartan resulted in substantial decline in usage due to increased switching to other ARBs. Subsequent notices for losartan and irbesartan were also associated with increased switching around the time of the recall, however, overall usage trends remained unchanged.

Improving Methods of Identifying Anaphylaxis for Medical Product Safety Surveillance Using Natural Language Processing and Machine Learning.

We sought to determine whether machine learning and natural language processing (NLP) applied to electronic medical records could improve performance of automated health-care claims-based algorithms to identify anaphylaxis events using data on 516 patients with outpatient, emergency department, or inpatient anaphylaxis diagnosis codes during 2015-2019 in 2 integrated health-care institutions in the Northwest United States. We used one site's manually reviewed gold-standard outcomes data for model development and the other's for external validation based on cross-validated area under the receiver operating characteristic curve (AUC), positive predictive value (PPV), and sensitivity. In the development site 154 (64%) of 239 potential events met adjudication criteria for anaphylaxis compared with 180 (65%) of 277 in the validation site. Logistic regression models using only structured claims data achieved a cross-validated AUC of 0.58 (95% CI: 0.54, 0.63). Machine learning improved cross-validated AUC to 0.62 (0.58, 0.66); incorporating NLP-derived covariates further increased cross-validated AUCs to 0.70 (0.66, 0.75) in development and 0.67 (0.63, 0.71) in external validation data. A classification threshold with cross-validated PPV of 79% and cross-validated sensitivity of 66% in development data had cross-validated PPV of 78% and cross-validated sensitivity of 56% in external data. Machine learning and NLP-derived data improved identification of validated anaphylaxis events.

Assessing medical product safety during pregnancy using parameterizable tools in the sentinel distributed database.

PURPOSE: The US Food and Drug Administration established the Sentinel System to monitor the safety of medical products. A component of this system includes parameterizable analytic tools to identify mother-infant pairs and evaluate infant outcomes to enable the routine monitoring of the utilization and safety of drugs used in pregnancy. We assessed the feasibility of using the data and tools in the Sentinel System by assessing a known association between topiramate use during pregnancy and oral clefts in the infant. METHODS: We identified mother-infant pairs using the mother-infant linkage table from six data partners contributing to the Sentinel Distributed Database from January 1, 2000, to September 30, 2015. We compared mother-infant pairs with first-trimester exposure to topiramate to mother-infant pairs that were topiramate-unexposed or lamotrigine-exposed and used a validated algorithm to identify oral clefts in the infant. We estimated adjusted risk ratios through propensity score stratification. RESULTS: There were 2007 topiramate-exposed and 1 066 086 unexposed mother-infant pairs in the main comparison. In the active-comparator analysis, there were 1996 topiramate-exposed and 2859 lamotrigine-exposed mother-infant pairs. After propensity score stratification, the odds ratio for oral clefts was 2.92 (95% CI: 1.43, 5.93) comparing the topiramate-exposed to unexposed groups and 2.72 (95% CI: 0.75, 9.93) comparing the topiramate-exposed to lamotrigine-exposed groups. CONCLUSIONS: We found an increased risk of oral clefts after topiramate exposure in the first trimester in the Sentinel database. These results are similar to prior published observational study results and demonstrate the ability of Sentinel's data and analytic tools to assess medical product safety in cohorts of mother-infant pairs in a timely manner.

Patient characteristics, pain treatment patterns, and incidence of total joint replacement in a US population with osteoarthritis.

BACKGROUND: Currently available medications for chronic osteoarthritis pain are only moderately effective, and their use is limited in many patients because of serious adverse effects and contraindications. The primary surgical option for osteoarthritis is total joint replacement (TJR). The objectives of this study were to describe the treatment history of patients with osteoarthritis receiving prescription pain medications and/or intra-articular corticosteroid injections, and to estimate the incidence of TJR in these patients. METHODS: This retrospective, multicenter, cohort study utilized health plan administrative claims data (January 1, 2013, through December 31, 2019) of adult patients with osteoarthritis in the Innovation in Medical Evidence Development and Surveillance Distributed Database, a subset of the US FDA Sentinel Distributed Database. Patients were analyzed in two cohorts: those with prevalent use of "any pain medication" (prescription non-steroidal anti-inflammatory drugs [NSAIDs], opioids, and/or intra-articular corticosteroid injections) using only the first qualifying dispensing (index date); and those with prevalent use of "each specific pain medication class" with all qualifying treatment episodes identified. RESULTS: Among 1 992 670 prevalent users of "any pain medication", pain medications prescribed on the index date were NSAIDs (596 624 [29.9%] patients), opioids (1 161 806 [58.3%]), and intra-articular corticosteroids (323 459 [16.2%]). Further, 92 026 patients received multiple pain medications on the index date, including 71 632 (3.6%) receiving both NSAIDs and opioids. Altogether, 20.6% of patients used an NSAID at any time following an opioid index dispensing and 17.2% used an opioid following an NSAID index dispensing. The TJR incidence rates per 100 person-years (95% confidence interval [CI]) were 3.21 (95% CI: 3.20-3.23) in the "any pain medication" user cohort, and among those receiving "each specific pain medication class" were NSAIDs, 4.63 (95% CI: 4.58-4.67); opioids, 7.45 (95% CI: 7.40-7.49); and intra-articular corticosteroids, 8.05 (95% CI: 7.97-8.13). CONCLUSIONS: In patients treated with prescription medications for osteoarthritis pain, opioids were more commonly prescribed at index than NSAIDs and intra-articular corticosteroid injections. Of the pain medication classes examined, the incidence of TJR was highest in patients receiving intra-articular corticosteroids and lowest in patients receiving NSAIDs.

Utility of fertility procedures and prenatal tests to estimate gestational age for live-births and stillbirths in electronic health plan databases.

PURPOSE: Current algorithms to evaluate gestational age (GA) during pregnancy rely on hospital coding at delivery and are not applicable to non-live births. We developed an algorithm using fertility procedures and fertility tests, without relying on delivery coding, to develop a novel GA algorithm in live-births and stillbirths. METHODS: Three pregnancy cohorts were identified from 16 health-plans in the Sentinel System: 1) hospital admissions for live-birth, 2) hospital admissions for stillbirth, and 3) medical chart-confirmed stillbirths. Fertility procedures and prenatal tests, recommended within specific GA windows were evaluated for inclusion in our GA algorithm. Our GA algorithm was developed against a validated delivery-based GA algorithm in live-births, implemented within a sample of chart-confirmed stillbirths, and compared to national estimates of GA at stillbirth. RESULTS: Our algorithm, including fertility procedures and 11 prenatal tests, assigned a GA at delivery to 97.9% of live-births and 92.6% of stillbirths. For live-births (n = 4 701 207), it estimated GA within 2 weeks of a reference delivery-based GA algorithm in 82.5% of pregnancies, with a mean difference of 3.7 days. In chart-confirmed stillbirths (n = 49), it estimated GA within 2 weeks of the clinically recorded GA at delivery for 80% of pregnancies, with a mean difference of 11.1 days. Implementation of the algorithm in a cohort of stillbirths (n = 40 484) had an increased percentage of deliveries after 36 weeks compared to national estimates. CONCLUSIONS: In a population of primarily commercially-insured pregnant women, fertility procedures and prenatal tests can estimate GA with sufficient sensitivity and accuracy for utility in pregnancy studies.

Utilization of hydroxyprogesterone caproate among pregnancies with live birth deliveries in the sentinel distributed database.

BACKGROUND: The U.S. Food and Drug Administration (FDA) approved Makena® (hydroxyprogesterone caproate [HPC] injection) in February 2011 for reducing the risk of preterm birth (PTB) in women with a singleton pregnancy who had a history of singleton spontaneous PTB (sPTB). Makena was approved under accelerated approval and required a postmarketing study to verify its clinical benefits. However, the postmarketing trial (PROLONG) failed to verify Makena's clinical benefit to neonates and substantiate its effect on reducing the risk of recurrent PTB. This study examined the utilization of HPC, along with another progestogen (vaginal progesterone) used to reduce the risk of sPTB during pregnancy, to inform the landscape of HPC use in the United States. METHODS: We included pregnant women aged 10-54 years with a live birth delivery from 1 January, 2008 to 31 December, 2018 in the Sentinel Distributed Database (SDD). We examined the prevalence of injectable HPC (Makena and its generics), compounded HPC, and vaginal progesterone use during the second and third trimesters during the study period. We also assessed the proportion of these HPC-exposed pregnancies with obstetrical conditions of interest as potential reasons for use: (1) history of preterm delivery; (2) cervical shortening in the current pregnancy; and (3) preterm labor in the current pregnancy. RESULTS: We identified a total of 3,445,739 live-birth pregnancies (among 2.9 million women) between 2008 and 2018 in the SDD. Of these pregnancies, 6.5 per 1,000 pregnancies used injectable HPC, 2.3 per 1,000 pregnancies used compounded HPC, and 1.5 per 1,000 pregnancies used vaginal progesterone during the second and/or third trimesters. The yearly uptakeof pregnancies with injectable HPC use increased during the study period from 2.1 per 1,000 pregnancies in 2012 to 12.6 per 1,000 pregnancies in 2018; use of compounded HPC decreased from 3.3 per 1,000 pregnancies to 0.25 per 1,000 pregnancies over the same period. Of 16,524 pregnancies with injectable HPC use, 12,054 (73%) had at least one related obstetrical condition, including 6,439 (39%) with a recorded history of preterm delivery. In addition, 4,665 (28%) had a PTB recorded as the outcome for the current pregnancy. CONCLUSIONS: We found modest use of HPC during the second and/or third trimesters among all live-birth pregnancies in SDD. The majority of pregnancies with injectable HPC use had at least one of three obstetrical indications of interest recorded before or during the pregnancy.

Validation of an ICD-10-based algorithm to identify stillbirth in the Sentinel System.

PURPOSE: To develop and validate an International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM)-based algorithm to identify cases of stillbirth using electronic healthcare data. METHODS: We conducted a retrospective study using claims data from three Data Partners (healthcare systems and insurers) in the Sentinel Distributed Database. Algorithms were developed using ICD-10-CM diagnosis codes to identify potential stillbirths among females aged 12-55 years between July 2016 and June 2018. A random sample of medical charts (N = 169) was identified for chart abstraction and adjudication. Two physician adjudicators reviewed potential cases to determine whether a stillbirth event was definite/probable, the date of the event, and the gestational age at delivery. Positive predictive values (PPVs) were calculated for the algorithms. Among confirmed cases, agreement between the claims data and medical charts was determined for the outcome date and gestational age at stillbirth. RESULTS: Of the 110 potential cases identified, adjudicators determined that 54 were stillbirth events. Criteria for the algorithm with the highest PPV (82.5%; 95% CI, 70.9%-91.0%) included the presence of a diagnosis code indicating gestational age ≥20 weeks and occurrence of either >1 stillbirth-related code or no other pregnancy outcome code (i.e., livebirth, spontaneous abortion, induced abortion) recorded on the index date. We found ≥90% agreement within 7 days between the claims data and medical charts for both the outcome date and gestational age at stillbirth. CONCLUSIONS: Our results suggest that electronic healthcare data may be useful for signal detection of medical product exposures potentially associated with stillbirth.

Identification and Validation of Anaphylaxis Using Electronic Health Data in a Population-based Setting.

BACKGROUND: Anaphylaxis is a life-threatening allergic reaction that is difficult to identify accurately with administrative data. We conducted a population-based validation study to assess the accuracy of ICD-10 diagnosis codes for anaphylaxis in outpatient, emergency department, and inpatient settings. METHODS: In an integrated healthcare system in Washington State, we obtained medical records from healthcare encounters with anaphylaxis diagnosis codes (potential events) from October 2015 to December 2018. To capture events missed by anaphylaxis diagnosis codes, we also obtained records on a sample of serious allergic and drug reactions. Two physicians determined whether potential events met established clinical criteria for anaphylaxis (validated events). RESULTS: Out of 239 potential events with anaphylaxis diagnosis codes, the overall positive predictive value (PPV) for validated events was 64% (95% CI = 58 to 70). The PPV decreased with increasing age. Common precipitants for anaphylaxis were food (39%), medications (35%), and insect bite or sting (12%). The sensitivity of emergency department and inpatient anaphylaxis diagnosis codes for all validated events was 58% (95% CI = 51 to 65), but sensitivity increased to 95% (95% CI = 74 to 99) when outpatient diagnosis codes were included. Using information from all validated events and sampling weights, the incidence rate for anaphylaxis was 3.6 events per 10,000 person-years (95% CI = 3.1 to 4.0). CONCLUSIONS: In this population-based setting, ICD-10 diagnosis codes for anaphylaxis from emergency department and inpatient settings had moderate PPV and sensitivity for validated events. These findings have implications for epidemiologic studies that seek to estimate risks of anaphylaxis using electronic health data.

Medical chart validation of inpatient diagnosis codes for transfusion-related acute lung injury 2013-2015.

INTRODUCTION: Transfusion-related acute lung injury (TRALI), an adverse event occurring during or within 6 hours of transfusion, is a leading cause of transfusion-associated fatalities reported to the US Food and Drug Administration. There is limited information on the validity of diagnosis codes for TRALI recorded in inpatient electronic medical records (EMRs). STUDY DESIGNS AND METHODS: We conducted a validation study to establish the positive predictive value (PPV) of TRALI International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes recorded within a large hospital system between 2013 and 2015. A physician with critical care expertise confirmed the TRALI diagnosis. As TRALI is likely underdiagnosed, we used the specific code (518.7), and codes for respiratory failure (518.82) in combination with transfusion reaction (999.80, 999.89, E934.7). RESULTS: Among almost four million inpatient stays, we identified 208 potential TRALI cases with ICD-9-CM codes and reviewed 195 medical records; 68 (35%) met clinical definitions for TRALI (26 [38%] definitive, 15 [22%] possible, 27 [40%] delayed). Overall, the PPV for all inpatient TRALI diagnoses was 35% (95% confidence interval (CI), 28-42). The PPV for the TRALI-specific code was 44% (95% CI, 35-54). CONCLUSION: We observed low PPVs (<50%) for TRALI ICD-9-CM diagnosis codes as validated by medical charts, which may relate to inconsistent code use, incomplete medical records, or other factors. Future studies using TRALI diagnosis codes in EMR databases may consider confirming diagnoses with medical records, assessing TRALI ICD, Tenth Revision, Clinical Modification codes, or exploring alternative ways for of accurately identifying TRALI in EMR databases. KEY POINTS: In 169 hospitals, we identified 208 potential TRALI cases, reviewed 195 charts, and confirmed 68 (35%) cases met TRALI clinical definitions. As many potential TRALI cases identified with diagnosis codes did not meet clinical definitions, medical record confirmation may be prudent.

Phosphodiesterase type 5 inhibitor use among pregnant and reproductive-age women in the United States.

PURPOSE: To assess the prevalence and potential indications of PDE5 inhibitor use among pregnant and reproductive-age women in the United States. METHODS: We identified women 15 to 50 years with a livebirth from January 2001 through March 2018 in Sentinel Database. We assessed the prevalence of PDE5 inhibitor use prior to and during pregnancy by trimester, identified potential on- and off-label indications using predefined diagnosis codes recorded within 90 days before the estimated last menstrual period through delivery. Separately, we used data from IQVIA's National Prescription Audit and Total Patient Tracker to estimate the dispensed prescriptions for PDE5 inhibitors and the number of patients with PDE5 inhibitor prescriptions. RESULTS: We identified approximately 3.3 million pregnancies during 2001 to 2018, 96 of which had PDE5 inhibitor use during pregnancy. Prevalence of PDE5 inhibitor use was 2.61, 0.62, and 0.62 per 100, 000 live-born pregnancies during the first, second, or third trimesters, respectively. Among women exposed to a PDE5 inhibitor from 90 days before conception to the end of pregnancy, 25.0%, 31.1%, and 15.5% had a diagnosis code for fetal growth restriction, preeclampsia, and pulmonary arterial hypertension. In IQVIA data, an estimated 223, 000 prescriptions from July 2015 through June 2018 and 58, 000 women received prescriptions for PDE5 inhibitors in 2017, of whom approximately 15, 000 (26%) were aged 15 to 50 years. CONCLUSION: We found a low prevalence of PDE5 inhibitor use in pregnant and reproductive-age women. Given the very low prevalence of use and the inconsistency of neonatal mortality data across STRIDER centers, the risk to public health is low at present.

A clinical study to evaluate efficacy and safety of AHPL/AYTAB/0313 tablet in subjects suffering from osteoarthritis of knee(s).

BACKGROUND: Osteoarthritis (OA) is the most common form of arthritis with unsatisfactory treatment outcomes. OBJECTIVES: To evaluate efficacy and safety of AHPL/AYTAB/0313 tablet in subjects with OA of knee joint. STUDY DESIGN: Prospective, open-label, single-arm clinical study conducted in daily clinical practice setting. METHOD: Subjects were advised to take 2 AHPL/AYTAB/0313 tablets twice daily orally after meals for 180 days. 48 subjects completed the study. The primary endpoints were changes in mean visual analogue scale (VAS) pain score and WOMAC score. Secondary endpoints were quality of life, time to walk 50 feet, knee joint swelling, use of analgesic drug as rescue medicine, and safety parameters. RESULTS: At baseline visit, the mean index knee joint pain (VAS) score was 82.29 ± 15.19, which reduced significantly to 19.38 ± 13.75 on day 180. The mean WOMAC combined score at baseline was 39.94 ± 11.67, which reduced significantly to 09.58 ± 05.77 (76.0%) on day 180. The mean WOMAC pain score at baseline was 09.65 ± 02.91, which reduced significantly to 02.06 ± 01.46 on day 180. The mean WOMAC stiffness score at baseline was 03.48 ± 01.58, which reduced significantly to 00.63 ± 01.08 on day 180. The mean WOMAC difficulty score at baseline was 26.81 ± 09.63, which reduced significantly to 06.90 ± 04.78 on day 180. The mean walking time to walk 50 feet reduced significantly by 40% on day 180. Not a single subject was known to have knee joint swelling from 150 days onwards. Only 5 subjects were using analgesic as rescue medicine on day 180. Twenty-six subjects had adverse events (AEs). Most of the AEs were not associated with the study medication. Vitals and all the safety laboratory parameters were within normal limits both at baseline and on day 180. CONCLUSION: "AHPL/AYTOP/0113" tablet is safe and significantly effective in reducing pain, swelling, and stiffness of knee joints and improving mobility of knee joints in patients with OA. CTRI registration No. is CTRI/2015/09/006177.

Detecting schizophrenia early: Prediagnosis healthcare utilization characteristics of patients with schizophrenia may aid early detection.

INTRODUCTION: Many patients exhibit subsyndromal clinical findings of schizophrenia prior to diagnosis. Early treatment may mitigate schizophrenia development, yet little is known about comorbidities and healthcare resource utilization (HCRU) in these patients before diagnosis. METHODS: This retrospective, longitudinal cohort study, conducted between January 1, 2007 and April 30, 2016, used claims data from the US HealthCore Integrated Research Database. Newly diagnosed patients with schizophrenia (International Classification of Diseases, Ninth Revision: 295.x or ICD 10 F20.%) were identified and matched (1:4) with non-schizophrenia comparators. Patients were 15-54 years of age with either ≥1 inpatient/emergency room claim with a primary schizophrenia diagnosis, or ≥2 claims in any setting with any schizophrenia diagnosis. Demographics, comorbidities, physician specialties, medications, and related services, and other HCRU were compared between cohorts for up to 5 years before diagnosis. RESULTS: The schizophrenia cohort included 6732 patients (57.4% male, mean age 30.3 years for males and 36.2 years for females). All outcomes were more prevalent in the schizophrenia cohort than the comparator cohort. Substantial comorbidity, medication use, and HCRU were observed in the schizophrenia cohort even 4-5 years before diagnosis with increasing findings approaching diagnosis. From 4-5 years to 0-12 months before diagnosis, resource use increased from 20.5% to 53.3% for atypical antipsychotics, 29.3% to 48.2% for antidepressants, and 15.1% to 35.5% for psychiatric diagnostic examinations. CONCLUSIONS: Patients with schizophrenia extensively use healthcare resources up to 5 years before diagnosis. Our findings may help with developing predictive models to identify patients at high risk of schizophrenia.

Reproducing Protocol-Based Studies Using Parameterizable Tools-Comparison of Analytic Approaches Used by Two Medical Product Surveillance Networks.

The US Sentinel System and the Canadian Network for Observational Drug Effect Studies (CNODES) are two medical product safety surveillance networks. Using Sentinel's preprogrammed, parameterizable analytic tools, we reproduced two protocol-based studies conducted by CNODES to assess the risks of acute pancreatitis and heart failure (HF) associated with the use of incretin-based drugs, compared with use of ≥ 2 oral hypoglycemic agents. Results from the replication new-user cohort analyses aligned with those from the CNODES nested case-control studies. The adjusted hazard ratios were 0.95 (0.81-1.12; vs. 1.03 (0.87-1.22) in CNODES) for acute pancreatitis and 0.91 (0.84-1.00; vs. 0.82 (0.67-1.00) in CNODES) for HF among patients without HF history. The CNODES's common protocol approach allows studies tailored to specific safety questions, whereas the Sentinel's common data model plus pretested program approach enables more rapid analysis. Despite these differences, it is possible to obtain comparable results using both approaches.

First-Trimester Exposure to Gadolinium-based Contrast Agents: A Utilization Study of 4.6 Million U.S. Pregnancies.

BackgroundThe safety of gadolinium-based contrast agent (GBCA) exposure during pregnancy has not been established, and the use of GBCAs during pregnancy is not recommended unless it is essential to the health of the woman or fetus.PurposeTo examine the prevalence of GBCA exposure in a large sample of pregnancies resulting in a live birth.Materials and MethodsThe Sentinel Distributed Database was used to retrospectively identify U.S. pregnancies that resulted in live births between 2006 and 2017 from 16 data partners. The main outcome was the prevalence of MRI procedures with and without GBCAs, sorted by anatomic location and trimester, among pregnant and matched comparator women.ResultsAmong 4 692 744 pregnancies resulting in a live birth, we identified 6879 exposures to GBCAs in 5457 pregnancies, representing one contrast-enhanced MRI examination per 860 pregnancies (0.12% of all pregnancies). Most contrast-enhanced MRI examinations were performed in the head (n = 3499), although pelvic and abdominal MRI constituted 22.3% (n = 1536) of all contrast-enhanced MRI examinations during pregnancy. The majority (70.2%) of GBCA exposures occurred during the first trimester, with a 4.3-fold greater prevalence compared with that in the second trimester and a 5.1-fold greater prevalence compared with that in the third trimester.ConclusionThis study identified higher rates of gadolinium-based contrast agent (GBCA) exposure during the first few weeks of pregnancy compared with the later weeks of pregnancy, suggesting inadvertent exposure to GBCAs might occur before pregnancy is recognized.© RSNA, 2019Online supplemental material is available for this article.See also the editorial by Kallmes and Watson in this issue.

Health Care Resource Utilization and Exacerbation Rates in Patients with COPD Stratified by Disease Severity in a Commercially Insured Population.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality and is associated with substantial economic burden. There is a lack of data regarding COPD outcomes and costs in a real-world setting, particularly by Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity. OBJECTIVES: To (a) characterize a commercially insured U.S. population with COPD and (b) assess prevalence of exacerbations, health care resource utilization (HCRU), costs, and treatment patterns in a cohort of patients with confirmed COPD, overall and stratified by GOLD stage. METHODS: This retrospective observational cohort study used administrative claims data from the HealthCore Integrated Research Database to identify patients with ≥ 1 inpatient, emergency room (ER), or office visit claim for COPD between January 1, 2012, and November 30, 2013, and continuous enrollment for 1 year before and 2 years after the first COPD diagnosis date. Patients with a spirometry claim within 12 months were eligible for medical record abstraction to confirm COPD diagnosis (forced expiratory volume in 1 second [FEV1]/forced vital capacity ratio < 0.7) and GOLD 1-4 classification (based on postbronchodilator FEV1 percent predicted). HCRU, costs, treatment patterns, and rate of moderate/severe exacerbation were identified from diagnosis up to 24 months. Outcomes were analyzed by univariate analysis stratified by GOLD classification. Multivariable analysis was conducted to assess associations between GOLD classification and outcomes of interest. RESULTS: 53,484 patients newly diagnosed with COPD were identified who met initial inclusion criteria: 14,293 (27%) had a qualifying spirometry claim, and 1,505 had confirmed COPD (GOLD 1, 333 [22%]; GOLD 2, 823 [55%]; GOLD 3, 317 [21%]; GOLD 4, 32 [2%]). Patients with greater disease severity had higher rates of moderate/severe COPD exacerbations (GOLD 1 and 2, 40.4 and 48.9 per 100 person-years, respectively; GOLD 3 and 4, 83.6 and 89.1 per 100 person-years, respectively). All-cause and COPD-related inpatient admissions, COPD-related office visits, and COPD-related ER visits were more prevalent with more severe GOLD classification. Mean annual COPD-related medical costs increased with GOLD classification ($5,945 for GOLD 1 patients, $18,070 for GOLD 4). COPD maintenance medication was filled by 42%, 56%, 73%, and 75% of patients in GOLD 1-4 (57% overall), respectively; combination corticosteroid/long-acting beta2-agonist inhalers were the most commonly used medication, regardless of GOLD classification. Patients with more severe disease had greater adherence (range 44%-68% of days covered for GOLD 1-4) and persistence (range 107-209 days for GOLD 1-4). CONCLUSIONS: Trends toward increases in exacerbations, HCRU, and costs were observed as airflow limitation worsened. Adherence and persistence with COPD maintenance therapy was suboptimal even with severe disease. DISCLOSURES: This study was supported by Boehringer Ingelheim Pharmaceuticals (Ridgefield, CT), which was given the opportunity to review the manuscript for medical and scientific accuracy, as well as intellectual property considerations. Willey and Singer are employees of HealthCore (parent company Anthem), which received funding from Boehringer Ingelheim to complete this study. Wallace and Shinde were employed by HealthCore at the time of this study. Wallace and Singer report stock ownership in Anthem. Napier is an employee of Anthem. Kaila, Bayer, and Shaikh are employees of Boehringer Ingelheim Pharmaceuticsls. Portions of this research were presented at the following conferences: (a) A. Wallace, S. Kaila, V. Zubek, A. Shaikh, M. Shinde, V. Willey, M. Napier, and J. Singer, Healthcare resource utilization, costs, and exacerbation rates in patients with COPD stratified by GOLD airflow limitation classification in a US commercially insured population, presented at AMCP Nexus 2017; October 16-19, 2017; Dallas, TX; and (b) A.E. Wallace, V. Zubek, S. Kaila, A. Shaikh, M. Shinde, V. Willey, M.B. Napier, and J.R. Singer, Real-world treatment patterns among newly diagnosed COPD patients according to GOLD airflow limitation severity classification in a U.S. commercially insured/Medicare Advantage population, presented at CHEST 2017 Annual Meeting; October 28-November 1, 2017; Toronto, Ontario, Canada.

Comparison of claims vs patient-reported adherence measures and associated outcomes among patients with nonvalvular atrial fibrillation using oral anticoagulant therapy.

OBJECTIVE: To compare oral anticoagulant (OAC) adherence among patients with nonvalvular atrial fibrillation (NVAF) using patient-reported and claims-based measures, and to evaluate the effect of OAC adherence on health care costs and patient satisfaction with OAC therapy. METHODS: This was a hybrid US observational study consisting of a longitudinal cohort survey followed by linkage and analysis of respondents' administrative claims data. Patients with NVAF receiving warfarin, dabigatran, rivaroxaban, or apixaban completed an initial survey and follow-up surveys at 4, 8, and 12 months. Patient-reported adherence was measured at each survey by Morisky Medication Adherence Scale (MMAS-8) and pharmacy claims-determined adherence by the proportion of days covered (PDC) for the 12-month period following the initial survey date; adherence was defined as MMAS-8 score =8 and PDC ≥80%. Patient satisfaction with OAC therapy was assessed by the Duke Anticoagulation Satisfaction Scale (DASS). RESULTS: Overall, 675 patients completed at least the initial survey (warfarin, n=271; dabigatran, n=266; rivaroxaban, n=128; apixaban, n=10). Fewer than half (47.9%) were PDC adherent, 37.2% were MMAS-8 adherent, and 19.4% were adherent by both measures. Total medical costs of PDC-adherent patients were significantly lower vs PDC-nonadherent patients (US$640 vs $993 per-patient per-month, respectively, p<0.05). MMAS-8-adherent patients reported higher treatment satisfaction; total DASS score was significantly lower among MMAS-8-adherent than MMAS-8-nonadherent patients (37.3 vs 42.9, respectively, p<0.001). CONCLUSION: Using claims-based or patient-reported methods to measure OAC adherence may lead to different results when assessing impact on health care costs and satisfaction with anticoagulation medication. These results underscore the importance of considering both claims-based and patient-reported measures when evaluating treatment adherence in real-world settings.

Prenatal Exposure to Nitrosatable Drugs, Dietary Intake of Nitrites, and Preterm Birth.

Prenatal exposure to nitrosatable drugs, including secondary or tertiary amines, has been associated with preterm birth. Associations may be accentuated by higher intakes of dietary nitrites because of the increased formation of N-nitroso compounds. Using data from mothers of babies without major birth defects (controls) from the National Birth Defects Prevention Study, we examined the relationship between nitrosatable drug exposure in conjunction with dietary nitrite intake and preterm birth among 496 mothers of preterm infants and 5,398 mothers with full-term deliveries in 1997-2005. A protective association was observed with a high intake of plant nitrites (adjusted hazard ratio (AHR) = 0.72, 95% confidence interval (CI): 0.53, 0.97). Secondary amines in conjunction with high nitrite intake were associated with preterm birth during the first (AHR = 1.84, 95% CI: 1.14, 2.98), second (AHR = 1.89, 95% CI: 1.17, 3.07), and third (AHR = 2.00, 95% CI: 1.22, 3.29) trimesters. The adjusted hazard ratios for tertiary amine use in the third trimester by increasing tertiles of nitrite intake were 0.67 (95% CI: 0.35, 1.31), 1.25 (95% CI: 0.71, 2.19), and 2.02 (95% CI: 1.17, 3.49). Prenatal exposure to nitrosatable drugs, particularly secondary and tertiary amines, in conjunction with higher levels of dietary nitrite intake may increase the risk of preterm birth.

Nitrosatable Drug Exposure during Pregnancy and Preterm and Small-for-Gestational-Age Births.

BACKGROUND: Nitrosatable drugs react with nitrite in the stomach to form N-nitroso compounds, observed in animal models to result in adverse pregnancy outcomes, such as birth defects and reduced fetal weight. Previous studies examining prenatal exposure to medications classified as nitrosatable have reported an increased risk of preterm births (PTBs) and small-for-gestational-age (SGA) infants. METHODS: Using data from mothers (controls) of babies without major birth defects from the National Birth Defects Prevention Study, prenatal nitrosatable drug usage by trimester and month of gestation was examined in relation to PTBs and SGA infants. RESULTS: Positive associations were observed with nitrosatable drug use and PTBs, with the strongest relationship with second trimester exposure (adjusted hazard ratio [aHR] 1.37, [95% confidence interval (CI) 1.10, 1.70]). Of the nitrosatable functional groups, secondary amines were the most notable, with a higher association among women with second (aHR 1.37, [95% CI 1.05, 1.79]) and third (aHR 1.34, [95% CI 1.02, 1.76]) trimester exposure compared with women with no prenatal nitrosatable drug use. Among SGA infants, a borderline association was noted with amide exposure during the third trimester (adjusted odds ratio 1.43 [95% confidence interval [CI] 1.00, 2.05]). CONCLUSIONS: Prenatal exposure to nitrosatable drugs during the second and third trimester of pregnancy, particularly secondary amines, might increase the risk of PTBs. However, prenatal exposure to nitrosatable drugs was not associated with SGA infants, with the exception of amide drugs.