Global Safety Assessment of Adverse Events of Special Interest Following 2 Years of Use and 772 Million Administered Doses of mRNA-1273.

Background: Large-scale use of mRNA COVID-19 vaccines during the pandemic was associated with enhanced safety monitoring to ensure accurate and timely review of safety. We reviewed the mRNA-1273 (original strain) safety profile following 2 years of use (>772 million administered doses), primarily focusing on predefined safety topics (ie, adverse events of special interest [AESIs]) proposed in advance of COVID-19 vaccine use. Methods: Cumulative mRNA-1273 safety data were included from spontaneous adverse event (AE) cases reported to Moderna's global safety database between 18 December 2020 and 17 December 2022. Reporting rates of AESIs were calculated per 1 million doses of mRNA-1273 administered. Observed-to-expected (OE) ratios were computed by comparing observed rates of AESIs with the background/expected rate for these events to evaluate potential associations with mRNA-1273. Results: There were 658 759 identified case reports associated with 2 517 669 AEs. Most AEs were nonserious (83.4%; 2 098 954/2 517 669). Overall 0.7% (17 751/2 517 669) were fatal. AESIs represented 13.7% of all AEs (344 921/2 517 669), with reporting rates for most AESIs below the expected background incidence. Exceptions included anaphylaxis (OE ratio 3 days after vaccination, 2.09; 95% CI, 1.93-2.25) and, among individuals aged 12 to 40 years, myocarditis (OE ratio 7 days after any dose, 3.89 [3.50-4.32]; among men after dose 2, 8.57 [6.88-10.68]) and pericarditis (OE ratio 7 days after vaccination, 3.47; 2.89-4.16). Conclusions: This safety analysis of mRNA-1273 identified evidence of increased risk for anaphylaxis, myocarditis, and pericarditis but not for other AESIs identified for enhanced monitoring ahead of COVID-19 vaccine use.

Comparative Effectiveness of Bivalent (Original/Omicron BA.4/BA.5) COVID-19 Vaccines in Adults.

The emergence of Omicron variants coincided with declining vaccine-induced protection against SARS-CoV-2. Two bivalent mRNA vaccines, mRNA-1273.222 (Moderna) and BNT162b2 Bivalent (Pfizer-BioNTech), were developed to provide greater protection against the predominate circulating variants by including mRNA that encodes both the ancestral (original) strain and BA.4/BA.5. We estimated their relative vaccine effectiveness (rVE) in preventing COVID-19-related outcomes in the US using a nationwide dataset linking primary care electronic health records and pharmacy/medical claims data. The study population (aged ≥18 years) received either vaccine between 31 August 2022 and 28 February 2023. We used propensity score weighting to adjust for baseline differences between groups. We estimated the rVE against COVID-19-related hospitalizations (primary outcome) and outpatient visits (secondary) for 1,034,538 mRNA-1273.222 and 1,670,666 BNT162b2 Bivalent vaccine recipients, with an adjusted rVE of 9.8% (95% confidence interval: 2.6-16.4%) and 5.1% (95% CI: 3.2-6.9%), respectively, for mRNA-1273.222 versus BNT162b2 Bivalent. The incremental relative effectiveness was greater among adults ≥ 65; the rVE against COVID-19-related hospitalizations and outpatient visits in these patients was 13.5% (95% CI: 5.5-20.8%) and 10.7% (8.2-13.1%), respectively. Overall, we found greater effectiveness of mRNA-1273.222 compared with the BNT162b2 Bivalent vaccine in preventing COVID-19-related hospitalizations and outpatient visits, with increased benefits in older adults.

mRNA-1273 bivalent (original and Omicron) COVID-19 vaccine effectiveness against COVID-19 outcomes in the United States.

The bivalent (original and Omicron BA.4/BA.5) mRNA-1273 COVID-19 vaccine was authorized to offer broader protection against COVID-19. We conducted a matched cohort study to evaluate the effectiveness of the bivalent vaccine in preventing hospitalization for COVID-19 (primary outcome) and medically attended SARS-CoV-2 infection and hospital death (secondary outcomes). Compared to individuals who did not receive bivalent mRNA vaccination but received ≥2 doses of any monovalent mRNA vaccine, the relative vaccine effectiveness (rVE) against hospitalization for COVID-19 was 70.3% (95% confidence interval, 64.0%-75.4%). rVE was consistent across subgroups and not modified by time since last monovalent dose or number of monovalent doses received. Protection was durable ≥3 months after the bivalent booster. rVE against SARS-CoV-2 infection requiring emergency department/urgent care and against COVID-19 hospital death was 55.0% (50.8%-58.8%) and 82.7% (63.7%-91.7%), respectively. The mRNA-1273 bivalent booster provides additional protection against hospitalization for COVID-19, medically attended SARS-CoV-2 infection, and COVID-19 hospital death.

Impact of the extended-release/long-acting opioid analgesics risk evaluation and mitigation strategy on prescribing practices.

OBJECTIVE: To assess the impact of extended-release (ER)/long-acting (LA) opioid prescriber training on prescribing behaviors. DESIGN: Retrospective cohort study. SETTING: Prescriber training was evaluated from June 1, 2013 through December 31, 2016. The full study period was 2 years longer, from June 1, 2012 through December 31, 2017, to include data for all prescribers' 1-year pretraining and post-training periods. PARTICIPANTS: 24,428 prescribers who wrote ER/LA opioid prescriptions for eligible patients, with a record of training from the partner continuing education provider between June 1, 2013 and December 31, 2016. INTERVENTION: ER/LA opioid prescriber training. MAIN OUTCOME MEASURES: Prescribing behaviors 1-year before (pretraining) and after (post-training) prescribers completed training, specifically the proportion of opioid-nontolerant patients receiving ER/LA opioids indicated for opioid-tolerant patients and for patients receiving ≥100 morphine equivalents dose daily, and the proportion of concomitant users of central nervous system depressant drugs. RESULTS: The differences in the proportion of opioid-nontolerant patients receiving ER/LA opioids indicated for opi-oid-tolerant patients and for patients receiving ≥100 morphine equivalents dose daily were -0.69 percent (95 percent confidence interval [CI]: -1.78 percent, 0.40 percent) and -0.23 percent (95 percent CI: -1.18 percent, 0.68 percent), respectively. The differences in the proportion of concomitant users of central nervous system depressant drugs were -0.94 percent (95 percent CI: -1.39 percent; -0.48 percent) for benzodiazepines, 0.06 percent (95 percent CI: -0.13 percent; 0.25 percent) for antipsychotics, -0.41 percent (95 percent CI: -0.69 percent; -0.13 percent) for hypnotics/sedatives, and 0.08 percent (95 percent CI: -0.40 percent; 0.57 percent) for muscle relaxants. CONCLUSIONS: While prescribers showed some changes in prescribing behavior after completing training, training was not associated with clinically relevant changes in prescribing behaviors.

Analysis of Myocarditis Among 252 Million mRNA-1273 Recipients Worldwide.

BACKGROUND: Growing evidence indicates a causal relationship between SARS-CoV-2 infection and myocarditis. Post-authorization safety data have also identified myocarditis as a rare safety event following mRNA COVID-19 vaccination, particularly among adolescent and young-adult males after dose 2. We further evaluated the potential risk by querying the Moderna global safety database for myocarditis/myopericarditis reports among mRNA-1273 recipients worldwide. METHODS: Myocarditis/myopericarditis reports from 18 December 2020 to 15 February 2022 were reviewed and classified. The reported rate after any known mRNA-1273 dose was calculated according to age and sex, then compared with a population-based incidence rate to calculate observed-to-expected rate ratios (RRs). RESULTS: During the study period, 3017 myocarditis/myopericarditis cases among 252 million mRNA-1273 recipients who received at least 1 dose were reported to the Moderna global safety database. The overall reporting rate was 9.23 per 100 000 person-years, which was similar to the expected reference rate (9.0 cases per 100 000 person-years; RR [95% confidence interval (CI)], 1.03 [.97-1.08]). When stratified by sex and age, observed rates were highest for males aged <40 years, particularly those 18-24 years (53.76 per 100 000 person-years), which was higher than expected (RR [95% CI], 3.10 [2.68-3.58]). When considering only cases occurring within 7 days of a known dose, the observed rate was highest for males aged 18-24 years after dose 2 (4.23 per 100 000 doses administered). CONCLUSIONS: Myocarditis/myopericarditis rates were not higher than expected for the overall population of mRNA-1273 recipients but were higher than expected in males aged 18-24 years, with most cases occurring 7 days after dose 2.

Real-world comparative effectiveness of mRNA-1273 and BNT162b2 vaccines among immunocompromised adults identified in administrative claims data in the United States.

INTRODUCTION: Head-to-head studies comparing COVID-19 mRNA vaccine effectiveness in immunocompromised individuals, who are vulnerable to severe disease are lacking, as large sample sizes are required to make meaningful inferences. METHODS: This observational comparative effectiveness study was conducted in closed administrative claims data from the US HealthVerity database (December 11, 2020-January 10, 2022, before omicron). A 2-dose mRNA-1273 versus BNT162b2 regimen was assessed for preventing medically-attended breakthrough COVID-19 diagnosis and hospitalizations among immunocompromised adults. Inverse probability of treatment weighting was applied to balance baseline characteristics between vaccine groups. Incidence rates from patient-level data and hazard ratios (HRs) using weighted Cox proportional hazards models were calculated. RESULTS: Overall, 57,898 and 66,981 individuals received a 2-dose regimen of mRNA-1273 or BNT161b2, respectively. Among the weighted population, mean age was 51 years, 53 % were female, and baseline immunodeficiencies included prior blood transplant (8%-9%), prior organ transplant (7%), active cancer (12%-13%), primary immunodeficiency (5-6%), HIV (20%-21%), and immunosuppressive therapy use (60%-61%). Rates per 1,000 person-years (PYs; 95% confidence intervals [CI]s) of breakthrough medically-attended COVID-19 were 25.82 (23.83-27.97) with mRNA-1273 and 30.98 (28.93, 33.18) with BNT162b2 (HR, 0.83; 95% CI, 0.75-0.93). When requiring evidence of an antigen or polymerase chain reaction test before COVID-19 diagnosis, the HR for medically-attended COVID-19 was 0.78 (0.67-0.92). Breakthrough COVID-19 hospitalization rates per 1,000 PYs (95% CI) were 3.66 (2.96-4.51) for mRNA-1273 and 4.68 (3.91-5.59) for BNT162b2 (HR, 0.78; 0.59-1.03). Utilizing open and closed claims for outcome capture only, or both cohort entry/outcome capture, produced HRs (95% CIs) for COVID-19 hospitalization of 0.72 (0.57-0.92) and 0.66 (0.58-0.76), respectively. CONCLUSIONS: Among immunocompromised adults, a 2-dose mRNA-1273 regimen was more effective in preventing medically-attended COVID-19 in any setting (inpatient and outpatient) than 2-dose BNT162b2. Results were similar for COVID-19 hospitalization, although statistical power was limited when using closed claims only. STUDY REGISTRATION: NCT05366322.

Characteristics of Prescription Opioid Analgesics in Pregnancy and Risk of Neonatal Opioid Withdrawal Syndrome in Newborns.

Importance: Prescription opioids are often used during pregnancy even though they are associated with neonatal opioid withdrawal syndrome (NOWS). Most studies of adverse outcomes of opioid use for pain have assessed only the class-wide outcome despite the pharmacodynamic and pharmacokinetic heterogeneity across opioid medications. Objective: To compare the risk of NOWS across common types of opioids when prescribed as monotherapy during the last 3 months of pregnancy. Design, Setting, and Participants: This cohort study analyzed administrative claims data of Medicaid-insured mothers and newborns in 46 states and Washington DC from January 1, 2000, through December 31, 2014. Participants were mothers with 2 or more dispensed opioid prescriptions within 90 days before delivery and their eligible live-born neonates. Data were analyzed from February 2020 to March 2021. Exposure: Different types of opioid medications were compared by agonist strength (strong vs weak) and half-life (medium vs short and long vs short) of the opioid active ingredient. Main Outcomes and Measures: The primary outcome was NOWS, which was identified using an International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic code in the 30 days after delivery. Relative risks (RRs) were adjusted for an exposure propensity score, including demographic characteristics, comorbidities, other medication use, and opioid treatment characteristics (including morphine milligram equivalents), using fine stratification. Results: The cohort comprised 48 202 opioid-exposed pregnancies with live newborns. A total of 1069 neonates (2.2%) had NOWS and 559 (1.2%) had severe NOWS. Opioid exposure during pregnancy included 16 202 pregnancies exposed to codeine, 4540 to oxycodone, 1244 to tramadol, 260 to methadone (dispensed for pain), 90 to hydromorphone, and 63 to morphine compared with 25 710 exposed to hydrocodone. Demographic characteristics varied across opioids, with tramadol, oxycodone, methadone, hydromorphone, and morphine being more commonly dispensed at older maternal age (≥35 years). Compared with hydrocodone, codeine had a lower adjusted RR of NOWS (0.57; 95% CI, 0.46-0.70), with a similar adjusted RR for tramadol (RR, 1.06; 95% CI, 0.73-1.56), and 2- to 3-fold higher adjusted RRs for oxycodone (1.87; 95% CI, 1.66-2.11), morphine (2.84; 95% CI, 1.30-6.22), methadone (3.02; 95% CI, 2.45-3.73), and hydromorphone (2.03; 95% CI, 1.09-3.78). Strong agonists were associated with a higher risk of NOWS than weak agonists (RR, 1.97; 95% CI, 1.78-2.17), and long half-life opioids were associated with an increased risk compared with short half-life products (RR, 1.33; 95% CI, 1.12-1.56). Findings were consistent across sensitivity and subgroup analyses. Conclusions and Relevance: Results of this study show higher risk of NOWS and severe NOWS among neonates with in utero exposure to strong agonists and long half-life prescription opioids. Information on the opioid-specific risk of NOWS may help prescribers select opioids for pain management in late stages of pregnancy.

Ischemic Placental Disease, Preterm Delivery, and Their Association With Opioid Use During Pregnancy.

Opioids affect placental development and function in animal models, but human data on their association with ischemic placental disease are limited. Using a cohort of pregnant women in the US nationwide Medicaid Analytic eXtract (2000-2014), we compared women with ≥2 opioid dispensings in pregnancy with unexposed women. Given an uncertain etiologically relevant window, we assessed exposure occurring in early pregnancy, late and not early pregnancy, and both early and late pregnancy. For placental abruption, preterm delivery, small for gestational age (SGA), and preeclampsia, we estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) using Cox proportional hazard models adjusting for demographic factors, indications/comorbidities, and medications. Among 1,833,871 eligible pregnancies, ≥2 opioid dispensings were filled in 6.5%. We observed an early exposure aHR of 1.34 (95% CI: 1.26, 1.43) for placental abruption, 1.21 (95% CI: 1.18, 1.23) for preterm delivery, 1.13 (95% CI: 1.09, 1.17) for SGA, and 0.95 (0.91, 0.98) for preeclampsia. Estimates for late exposure were attenuated. Early and late exposure was associated with higher aHRs for placental abruption, 1.62 (95% CI: 1.47, 1.78); preterm delivery, 1.37 (95% CI: 1.33, 1.42); and SGA, 1.26 (95% CI: 1.19, 1.33); but not preeclampsia, 0.99 (95% CI: 0.93, 1.05). Prescription opioids may modestly increase risk of placental abruption, preterm birth and SGA, but they do not appear to be associated with preeclampsia.

Periconceptional nonsteroidal anti-inflammatory drug use, folic acid intake, and the risk of spina bifida.

BACKGROUND: Use of nonsteroidal anti-inflammatory drugs (NSAIDs) during pregnancy may increase risk for neural tube defects (NTDs), including spina bifida. Folic acid intake can prevent NTDs, but it is not known whether it modifies any risks associated with NSAID use. OBJECTIVES: To assess the impact of periconceptional NSAID use on the risk of spina bifida overall and stratified by folic acid intake. STUDY DESIGN: We analyzed 1998-2015 data from the Slone Epidemiology Center Birth Defects Study, a multi-site, case-control study. Mothers were interviewed to identify sociodemographic factors, behaviors, and exposures during pregnancy. Periconceptional NSAID use was defined as use of aspirin, ibuprofen, naproxen, or COX2 inhibitors within the month before or after the last menstrual period. Logistic regression models were used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for NSAID use, adjusted for study center and race/ethnicity stratified by average daily folic acid intake above ("high FA") or below ("low FA") 400 mcg/day. RESULTS: We compared mothers of 267 infants with spina bifida to mothers of 6,233 nonmalformed controls. Among control mothers, 20% used NSAIDS periconceptionally (16% ibuprofen, 4% aspirin, 3% naproxen, and <1% COX-2 inhibitors). For any NSAID use, the aORs among low FA and high FA women were 1.70 (95% CI [1.13, 2.57]) and 1.09 (95% CI [0.69, 1.71]), respectively. CONCLUSIONS: We observed a small increase in the risk for spina bifida among infants born to women who used NSAIDs periconceptionally, but this risk was limited to those who had inadequate folic acid intake.

Patient Knowledge of Safe Use of ER/LA Opioid Analgesics Following Implementation of the Class-Wide REMS: A Survey Study.

BACKGROUND/RATIONALE: The US Food and Drug Administration (FDA) approved a Risk Evaluation and Mitigation Strategy (REMS) for extended release/long-acting (ER/LA) opioids in 2012. The purpose of this study was to assess patient knowledge of the safe use of these products following implementation of the REMS and to determine possible effects of the REMS, including impact on medication access. OBJECTIVE: To assess patient knowledge of safe use of ER/LA opioids and use of REMS patient education tools such as the Medication Guide (MG) and Patient Counseling Document (PCD). METHODS: This was a cross-sectional survey of commercially insured (Commercial) and Medicare Advantage-insured (Medicare) adults with ≥1 pharmacy claim for an ER/LA opioid (10/01/2015 - 02/28/2017) in the HealthCore Integrated Research Database and Medicaid-insured (Medicaid) adult members of a research panel, about their knowledge of safe use of ER/LA opioids and receipt/comprehension of the MG and PCD. RESULTS: Survey respondents consisted of 382 Commercial, 43 Medicare and 40 Medicaid adults. While ≥95% of respondents received and read the MG, fewer were aware of the PCD (Commercial: 47%, Medicare: 65%, Medicaid: 53%). Almost 75% of the knowledge questions were answered correctly by ≥80% of all respondents; fewer respondents recognized that use of opioids as directed can lead to death (Commercial: 73%, Medicare: 56%, Medicaid: 63%), the MG should be read at each dispensing (Commercial: 78%, Medicare: 53%, Medicaid: 75%), opioids should not be stored in the medicine cabinet (Commercial: 77%, Medicare: 79%, Medicaid: 58%), missed doses should not be taken as soon as possible (Commercial: 56%, Medicare: 51%, Medicaid: 50%), and pills should not be crushed (Commercial: 85%, Medicare: 67%, Medicaid: 52%). CONCLUSION: Although most respondents reported reading and understanding the MG and exhibited knowledge of safe use of ER/LA opioids, providers' use of the PCD and increased understanding of safe use core messages need reinforcement.

Effectiveness and Safety of COPD Maintenance Therapy with Tiotropium/Olodaterol versus LABA/ICS in a US Claims Database.

INTRODUCTION: In patients with chronic obstructive pulmonary disease (COPD), treatment with long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) combination therapy significantly improves lung function versus LABA/inhaled corticosteroid (ICS). To investigate whether LAMA/LABA could provide better clinical outcomes than LABA/ICS, this non-interventional database study assessed the risk of COPD exacerbations, pneumonia, and escalation to triple therapy in patients with COPD initiating maintenance therapy with tiotropium/olodaterol versus any LABA/ICS combination. METHODS: Administrative healthcare claims and laboratory results data from the US HealthCore Integrated Research Databasesm were evaluated for patients with COPD initiating tiotropium/olodaterol versus LABA/ICS treatment (January 2013-March 2019). Patients were aged at least 40 years with a diagnosis of COPD (but not asthma) at cohort entry. A Cox proportional hazard regression model was used (as-treated analysis) to assess risk of COPD exacerbation, community-acquired pneumonia, and escalation to triple therapy, both individually and as a combined risk of any one of these events. Potential imbalance of confounding factors between cohorts was handled using fine stratification, reweighting, and trimming by exposure propensity score (high-dimensional); subgroup analyses were conducted on the basis of blood eosinophil levels and exacerbation history. RESULTS: The total population consisted of 61,985 patients (tiotropium/olodaterol n = 2684; LABA/ICS n = 59,301); after reweighting, the total was 42,953 patients (tiotropium/olodaterol n = 2600; LABA/ICS n = 40,353; mean age 65 years; female 54.5%). Patients treated with tiotropium/olodaterol versus LABA/ICS experienced a reduction in the risk of COPD exacerbations (adjusted hazard ratio 0.76 [95% confidence interval 0.68, 0.85]), pneumonia (0.74 [0.57, 0.97]), escalation to triple therapy (0.22 [0.19, 0.26]), and any one of these events (0.45 [0.41, 0.49]); the combined risk was similar irrespective of baseline eosinophils and exacerbation history. CONCLUSIONS: In patients with COPD, tiotropium/olodaterol was associated with a lower risk of COPD exacerbations, pneumonia, and escalation to triple therapy versus LABA/ICS, both individually and in combination; the combined risk was reduced irrespective of baseline eosinophils or exacerbation history. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04138758 (registered 23 October 2019).

Selective serotonin reuptake inhibitor use patterns among commercially insured US pregnancies (2005-2014).

The goal of this study was to describe patterns of selective serotonin reuptake inhibitor (SSRI) use during pregnancy in a US cohort (2005-2014) of > 1 million commercially insured women using administrative claims. We used international classification of disease (ICD-9) diagnosis and procedure and current procedural terminology codes in the OptumLabs® Data Warehouse to identify deliveries (including losses) among US women aged 15-45 (n = 1,061,023). SSRI dispensings that overlapped with the timing of pregnancy were identified using national drug codes in linked pharmacy claims. Demographic characteristics were imputed based on residential location, census data, and consumer information. We investigated patterns by trimester, agent, and demographic subgroups. A total of 46,087 of women (4.34%) were dispensed SSRIs during the estimated pregnancy period. Sertraline was the most common overall and had the highest initial use after trimester 1, including women who switched from another SSRI, although dispensing for > 1 SSRI during pregnancy was uncommon. Use of vilazodone was rare and had the highest discontinuation after trimester 1, followed by paroxetine. SSRI use was more common among women who were older, White, college-educated, higher income (≥ $100,000), or resided in the Midwest. Paroxetine and dispensings for > 1 SSRI were more common in lower education subgroups. White women had the highest proportion of use in all trimesters of pregnancy, whereas Hispanic women had the lowest. Among commercially insured US women, SSRI use during pregnancy differed by agent and demographics. More research is needed to understand whether these differences are due to symptom reporting, cultural beliefs, and/or physician preferences.

The Association Between Doctor and Pharmacy Shopping and Self-Reported Misuse and Abuse of Prescription Opioids: A Survey Study.

BACKGROUND/RATIONALE: Little is known about the reasons for visiting multiple doctors/pharmacies, known as doctor/pharmacy shopping, to obtain opioids. OBJECTIVE: To investigate patients' self-reported reasons for doctor/pharmacy shopping and assess whether doctor/pharmacy shopping behavior can be used as a surrogate measure of opioid abuse/misuse. METHODS: We conducted a cross-sectional web-based survey among adult patients with ≥2 pharmacy claims for immediate-release or extended-release/long-acting opioids between 7/1/2015 and 12/31/2016, identified from a large United States (US) commercial claims database. Patients were classified into no, mild, moderate, or severe shopping categories based on their claims. Reasons for doctor/pharmacy shopping and opioid abuse/misuse were determined from patient responses to the Prescription Opioid Misuse and Abuse Questionnaire. RESULTS: A random sample of 10,081 patients was invited to participate in the survey and 1085 (11%) completed surveys. The most frequently reported reasons for doctor/pharmacy shopping were convenience, availability, price, and multiple morbidities requiring pain management. Among patients in the no, minimal, moderate, and severe shopping categories, only 7.8%, 8.5%, 11.8% and 12.6% reported opioid abuse/misuse, respectively. CONCLUSION: In this commercially-insured population, patient-reported reasons for doctor/pharmacy shopping do not suggest opioid abuse/misuse. Less than 15% of patients with shopping behavior in the past 3 months reported any reasons attributable to opioid abuse/misuse, indicating that shopping behavior in this population may not be a good surrogate for abuse/misuse.

Incidence of Opioid Overdose Among Patients Using ER/LA Opioid Analgesics Before and After Implementation of the Class-Wide Opioid Risk Evaluation and Mitigation Strategy.

INTRODUCTION: The United States (US) Food and Drug Administration (FDA) required a Risk Evaluation and Mitigation Strategy (REMS) for extended-release and long-acting (ER/LA) opioid analgesics on 09 July 2012. METHODS: This study compared the incidence of opioid overdose before (July 2010-June 2012) and after (July 2013-September 2016) the initiation of the Risk Evaluation and Mitigation Strategy (REMS) for extended-release and long-acting (ER/LA) opioid analgesics. We identified patients with ≥1 ER/LA opioid dispensing in either time period in national data from the HealthCore Integrated Research DatabaseSM (HIRD) and in United States (US) Medicaid claims data from four states. We described each population, calculated the incidence rate (IR) of opioid overdose, and assessed crude and propensity score adjusted incidence rate ratios (IRR) comparing the overdose rate after vs before implementation of the REMS. RESULTS: A total of 121,229 commercially insured and 11,488 Medicaid patients were included in the analysis. Rates of overdose were substantially higher in Medicaid patients than in the commercially insured patients (IR 192.0, 95% confidence interval [CI] 162.60-225.18 versus 102.60, 95% CI 93.0-112.93 in the active period). The IRRs for opioid overdose were 1.01 (95% CI 0.87-1.17) in the commercially insured population and 0.70 (95% CI 0.52-0.93) in Medicaid. CONCLUSION: This leveling off of overdose rates among commercially insured patients and decline among Medicaid patients is encouraging, but it is difficult to disentangle the specific impact of the REMS from many other ongoing initiatives with similar goals.

Medical record-based ascertainment of behaviors suggestive of opioid misuse, diversion, abuse, and/or addiction among individuals showing evidence of doctor/pharmacy shopping.

OBJECTIVES: Doctor/pharmacy shopping, the practice of seeking prescriptions from multiple healthcare sources without their coordination, may be a measure of prescription medicine abuse. This cross-sectional study examined the relationship between a claims-based doctor/pharmacy shopping definition and medical record documented behaviors suggestive of misuse, diversion, abuse and/or addiction. METHODS: Patients with ≥2 opioid dispensings starting in 2012 in a US administrative claims database were grouped into doctor/pharmacy shopping categories by number of providers and pharmacies used over 18 months: no shopping, minimal shopping, moderate shopping and severe shopping. Medical charts of opioid prescribers were reviewed to identify behaviors suggestive of misuse, diversion, abuse and/or addiction. RESULTS: Among 581,940 opioid users, 78% were classified as no shopping, 11% minimal shopping, 8% moderate shopping and 3% severe shopping. Almost 40% of severe shopping patients had no medical record documented behaviors (positive predictive value: 24.3%). Compared with no shopping, the odds ratio [OR] of ≥3 behaviors was 1.70 (95% confidence interval [CI] 0.50-5.78) for minimal shopping, 1.81 (95% CI 0.54-6.03) for moderate shopping, and 8.93 (95% CI 3.12-25.54) for severe shopping. CONCLUSIONS: Claims-identified severe doctor/pharmacy shopping was strongly associated with behaviors suggestive of misuse, diversion, abuse and/or addiction, but the proportion of medical records documenting these was low.

Development of predictive models to identify advanced-stage cancer patients in a US healthcare claims database.

BACKGROUND: Although healthcare databases are a valuable source for real-world oncology data, cancer stage is often lacking. We developed predictive models using claims data to identify metastatic/advanced-stage patients with ovarian cancer, urothelial carcinoma, gastric adenocarcinoma, Merkel cell carcinoma (MCC), and non-small cell lung cancer (NSCLC). METHODS: Patients with ≥1 diagnosis of a cancer of interest were identified in the HealthCore Integrated Research Database (HIRD), a United States (US) healthcare database (2010-2016). Data were linked to three US state cancer registries and the HealthCore Integrated Research Environment Oncology database to identify cancer stage. Predictive models were constructed to estimate the probability of metastatic/advanced stage. Predictors available in the HIRD were identified and coefficients estimated by Least Absolute Shrinkage and Selection Operator (LASSO) regression with cross-validation to control overfitting. Classification error rates and receiver operating characteristic curves were used to select probability thresholds for classifying patients as cases of metastatic/advanced cancer. RESULTS: We used 2723 ovarian cancer, 6522 urothelial carcinoma, 1441 gastric adenocarcinoma, 109 MCC, and 12,373 NSCLC cases of early and metastatic/advanced cancer to develop predictive models. All models had high discrimination (C > 0.85). At thresholds selected for each model, PPVs were all >0.75: ovarian cancer = 0.95 (95% confidence interval [95% CI]: 0.94-0.96), urothelial carcinoma = 0.78 (95% CI: 0.70-0.86), gastric adenocarcinoma = 0.86 (95% CI: 0.83-0.88), MCC = 0.77 (95% CI 0.68-0.89), and NSCLC = 0.91 (95% CI 0.90 - 0.92). CONCLUSION: Predictive modeling was used to identify five types of metastatic/advanced cancer in a healthcare claims database with greater accuracy than previous methods.

Safety study of live, oral human rotavirus vaccine: A cohort study in United States health insurance plans.

As part of a regulatory commitment for post-licensure safety monitoring of live, oral human rotavirus vaccine (RV1), this study compared the incidence rates (IR) of intussusception, acute lower respiratory tract infection (LRTI) hospitalization, Kawasaki disease, convulsion, and mortality in RV1 recipients versus inactivated poliovirus vaccine (IPV) recipients in concurrent (cIPV) and recent historical (hIPV) comparison cohorts. Vaccine recipients were identified in 2 claims databases from August 2008 - June 2013 (RV1 and cIPV) and January 2004 - July 2008 (hIPV). Outcomes were identified in the 0-59 days following the first 2 vaccine doses. Intussusception, Kawasaki disease, and convulsion were confirmed via medical record review. Outcome IRs were estimated. Incidence rate ratios (IRRs) were obtained from Poisson regression models. A post-hoc self-controlled case series (SCCS) analysis compared convulsion IRs in a 0-7 day post-vaccination period to a 15-30 day post-vaccination period. We identified 57,931 RV1, 173,384 cIPV, and 159,344 hIPV recipients. No increased risks for intussusception, LRTI, Kawasaki disease, or mortality were observed. The convulsion IRRs were elevated following RV1 Dose 1 (cIPV: 2.07, 95% confidence interval [CI]: 1.27 - 3.38; hIPV: 2.05, 95% CI: 1.24 - 3.38), a finding which is inconclusive as it was observed in only one of the claims databases. The IRR following RV1 Dose 1 in the SCCS analysis lacked precision (2.40, 95% CI: 0.73 - 7.86). No increased convulsion risk was observed following RV1 Dose 2. Overall, this study supports the favorable safety profile of RV1. Continued monitoring for safety signals through routine surveillance is needed to ensure vaccine safety.

Validity of diagnostic codes to identify hospitalizations for infections among patients treated with oral anti-diabetic drugs.

PURPOSE: Identification of hospitalizations for infection is important for post-marketing surveillance of drugs, but the validity of using diagnosis codes to identify these events is unknown. Differentiating between hospitalization for and with infection is important, as the latter is common and less likely to arise from pre-admission exposure to drugs. We determined positive predictive values (PPVs) of diagnostic coding-based algorithms to identify hospitalization for infection among patients prescribed oral anti-diabetic drugs (OADs). METHODS: We identified patients initiating OADs within 2 United States claims databases (Medicare, HealthCore Integrated Research DatabaseSM [HIRDSM ]) and 2 United Kingdom electronic medical record databases (Clinical Practice Research Datalink [CPRD], The Health Improvement Network [THIN]) from 2009 to 2014. To identify potential hospitalizations for infection, we selected patients with a hospital diagnosis of infection and, within 7 days prior to hospitalization, either an outpatient/emergency department visit with an infection diagnosis or outpatient antimicrobial treatment. Hospital records were reviewed by infectious disease specialists to adjudicate hospital admissions for infection. PPVs for confirmed outcomes were determined for each database. RESULTS: Code-based algorithms to identify hospitalization for infection had PPVs exceeding 80% within Medicare (PPV, 83% [90/109]; 95% CI, 74-89%), HIRDSM (PPV, 89% [73/82]; 95% CI, 80-95%), and THIN (PPV, 86% [12/14]; 95% CI, 57-98%) but not within CPRD (PPV, 67% [14/21]; 95% CI, 43-85%). CONCLUSIONS: Algorithms identifying hospitalization for infection utilizing hospital diagnoses along with antecedent outpatient/emergency infection diagnoses or antimicrobial therapy had sufficiently high PPVs for confirmed events within Medicare, HIRDSM , and THIN to enable their use for pharmacoepidemiologic research.

Postauthorization safety study of the DPP-4 inhibitor saxagliptin: a large-scale multinational family of cohort studies of five outcomes.

OBJECTIVE: To evaluate the risk of serious adverse events among patients with type 2 diabetes mellitus initiating saxagliptin compared with oral antidiabetic drugs (OADs) in classes other than dipeptidyl peptidase-4 (DPP-4) inhibitors. RESEARCH DESIGN AND METHODS: Cohort studies using 2009-2014 data from two UK medical record data sources (Clinical Practice Research Datalink, The Health Improvement Network) and two USA claims-based data sources (HealthCore Integrated Research Database, Medicare). All eligible adult patients newly prescribed saxagliptin (n=110 740) and random samples of up to 10 matched initiators of non-DPP-4 inhibitor OADs within each data source were selected (n=913 384). Outcomes were hospitalized major adverse cardiovascular events (MACE), acute kidney injury (AKI), acute liver failure (ALF), infections, and severe hypersensitivity events, evaluated using diagnostic coding algorithms and medical records. Cox regression was used to determine HRs with 95% CIs for each outcome. Meta-analyses across data sources were performed for each outcome as feasible. RESULTS: There were no increased incidence rates or risk of MACE, AKI, ALF, infection, or severe hypersensitivity reactions among saxagliptin initiators compared with other OAD initiators within any data source. Meta-analyses demonstrated a reduced risk of hospitalization/death from MACE (HR 0.91, 95% CI 0.85 to 0.97) and no increased risk of hospitalization for infection (HR 0.97, 95% CI 0.93 to 1.02) or AKI (HR 0.99, 95% CI 0.88 to 1.11) associated with saxagliptin initiation. ALF and hypersensitivity events were too rare to permit meta-analysis. CONCLUSIONS: Saxagliptin initiation was not associated with increased risk of MACE, infection, AKI, ALF, or severe hypersensitivity reactions in clinical practice settings. TRIAL REGISTRATION NUMBER: NCT01086280, NCT01086293, NCT01086319, NCT01086306, and NCT01377935; Results.