Validation of an international classification of disease, tenth revision, clinical modification (ICD-10-CM) algorithm in identifying severe hypoglycaemia events for real-world studies.

AIM: The transition to the ICD-10-CM coding system has reduced the utility of hypoglycaemia algorithms based on ICD-9-CM diagnosis codes in real-world studies of antidiabetic drugs. We mapped a validated ICD-9-CM hypoglycaemia algorithm to ICD-10-CM codes to create an ICD-10-CM hypoglycaemia algorithm and assessed its performance in identifying severe hypoglycaemia. MATERIALS AND METHODS: We assembled a cohort of Medicare patients with DM and linked electronic health record (EHR) data to the University of North Carolina Health System and identified candidate severe hypoglycaemia events from their Medicare claims using the ICD-10-CM hypoglycaemia algorithm. We confirmed severe hypoglycaemia by EHR review and computed a positive predictive value (PPV) of the algorithm to assess its performance. We refined the algorithm by removing poor performing codes (PPV ≤0.5) and computed a Cohen's κ statistic to evaluate the agreement of the EHR reviews. RESULTS: The algorithm identified 642 candidate severe hypoglycaemia events, and we confirmed 455 as true severe hypoglycaemia events, PPV of 0.709 (95% confidence interval: 0.672, 0.744). When we refined the algorithm, the PPV increased to 0.893 (0.862, 0.918) and missed <2.42% (<11) true severe hypoglycaemia events. Agreement between reviewers was high, κ = 0.93 (0.89, 0.97). CONCLUSIONS: We translated an ICD-9-CM hypoglycaemia algorithm to an ICD-10-CM version and found its performance was modest. The performance of the algorithm improved by removing poor performing codes at the trade-off of missing very few severe hypoglycaemia events. The algorithm has the potential to be used to identify severe hypoglycaemia in real-world studies of antidiabetic drugs.

Incidence of new outpatient long-acting reversible contraceptive insertions among a commercially insured, US population from 2010 to 2020.

Objectives: Characterize new use of long-acting reversible contraceptives (LARCs), highly effective contraceptive methods, in a broad population over time. Study Design: We constructed a retrospective cohort of commercially insured individuals aged 15 to 54 years from 2010 to 2020 and estimated monthly incidence of new LARC insertions. Results: The monthly standardized incidence increased from 6.0 insertions per 10,000 individuals in January 2010 to 14.1 in December 2020, with a dip in insertions after March 2020. Hormonal intrauterine devices were consistently the most inserted LARC; implants were increasingly favored over time. Conclusions: LARCs are increasingly popular forms of contraception among commercially insured individuals. Implications: Given the increasing popularity, ensuring access to LARCs is critical.

Physician experiences with and perceptions of risk evaluation and mitigation strategy programs with elements to assure safe use.

PURPOSE: The US Food and Drug Administration (FDA) Amendments Act of 2007 authorized the FDA to require risk evaluation and mitigation strategy (REMS) programs for drugs with important safety concerns. REMS can have elements to assure safe use (ETASU), such as patient registries, dispensing restrictions, and physician training and certification requirements. We aimed to understand physician experiences with and perceptions of a selection of ETASU REMS. METHODS: Physicians prescribing 1 of 4 ETASU REMS-covered drugs: natalizumab, riociguat, sodium oxybate, and vigabatrin. STUDY DESIGN: Descriptive phenomenological study based on semi-structured phone interviews. DATA COLLECTION/EXTRACTION METHODS: Qualitative content analysis to summarize physician responses to open-ended questions. RESULTS: Of 31 physicians (14 female), 6 prescribed riociguat, 6 vigabatrin, 7 sodium oxybate, and 12 natalizumab (5 for Crohn's disease, 7 for multiple sclerosis), most demonstrated good understanding of the rationale for and requirements of the ETASU REMS but believed that the programs had limited effect on clinical practice. Some physicians reported that the ETASU REMS made them more comfortable with prescribing covered drugs due to heightened oversight, facilitated discussions about treatment, and were likely more beneficial for non-specialists. Concerns were raised about the administrative effort needed to comply with the programs and the potential misuse of patient health information transmitted to manufacturers. CONCLUSIONS: Physicians are generally aware of ETASU REMS and get reassurance from the additional oversight, but the programs can be better integrated into clinical workflows and can be designed to better protect patient health information.

Patient and Caregiver Experiences With and Perceptions of Risk Evaluation and Mitigation Strategy Programs With Elements to Assure Safe Use.

Importance: The US Food and Drug Administration (FDA) Amendments Act of 2007 authorized the FDA to impose safety requirements on drugs with important risks, such as prescriber certification or routine laboratory testing, to ensure that the benefits of use outweighed the risks. However, little is known about patient and caregiver experiences with these Risk Evaluation and Mitigation Strategy (REMS) programs with Elements to Assure Safe Use (ETASU). Objective: To understand patient and caregiver experiences with and perceptions of REMS programs with ETASU. Design, Setting, and Participants: This qualitative study included semistructured qualitative phone interviews conducted between 2016 and 2017, with initial analysis performed in 2017 and reanalysis performed in 2021. Adult patients prescribed natalizumab or sodium oxybate, adult patients or caregivers of adult patients prescribed vigabatrin, and adult female patients of reproductive age prescribed riociguat were included. Main Outcomes and Measures: Assessment of knowledge, decision-making, medication access, and perceptions of medical privacy. Results: Among 63 participants, 46 (73%) were female. Twenty-five participants (40%) had taken natalizumab, 10 (16%) riociguat, 15 (24%) sodium oxybate, and 10 (16%) vigabatrin. One participant had taken both natalizumab and vigabatrin; 4 (6%) were caregivers of patients using vigabatrin. Most participants expressed knowledge of REMS program requirements, but many lacked the insight that these requirements were part of an FDA-mandated special safety program and expressed difficulty understanding program education materials. REMS requirements made some participants more likely to initiate treatment. However, many reported burdens accessing medication, including the need to travel to certified prescribers or pharmacies. Manufacturer access to personal health information was also controversial, although some participants expressed an altruistic desire to assist others. Conclusions and Relevance: This qualitative study found that REMS programs with ETASU reassured patients and their caregivers about drug safety and helped support medication initiation. However, steps are needed to improve the quality of REMS educational materials, promote efficient medication access, and protect patient privacy.

Long-Term Outcomes After Midurethral Mesh Sling Surgery for Stress Urinary Incontinence.

OBJECTIVES: Although midurethral mesh slings are the criterion standard surgical treatment for stress urinary incontinence (SUI), limited data exist regarding long-term outcomes. Thus, our objectives were to evaluate the long-term risk of sling revision and the risk of repeat SUI surgery up to 15 years after the initial sling procedure and to identify predictors of these outcomes. METHODS: Using a population-based cohort of commercially insured individuals in the United States, we identified women aged 18 years or older who underwent a sling procedure between 2001 and 2018. For sling revision, we evaluated indications (mesh exposure or urinary retention). We estimated the cumulative risks of sling revision and repeat SUI surgery annually using Kaplan-Meier survival curves and evaluated predictors using Cox proportional hazards models. RESULTS: We identified 334,601 mesh sling surgical procedures. For sling revision, the 10-year and 15-year risks were 6.9% (95% confidence interval [CI], 6.7-7.0) and 7.9% (95% CI, 7.5-8.3), with 48.7% of sling revisions associated with mesh exposure. The 10-year and 15-year risks of repeat SUI surgery were 14.5% (95% CI, 14.2-14.8) and 17.9% (95% CI, 17.3-18.6). Women aged 18-29 years had an elevated risk for both sling revision (hazard ratio, 1.20; 95% CI, 1.15-1.25) and repeat SUI surgery (hazard ratio, 1.30; 95% CI, 1.25-1.37) compared with women 70 years and older. CONCLUSIONS: In our study population, the 15-year risk of sling revision was 7.9%, with nearly half of revisions due to mesh exposure. These findings provide critical long-term data to support informed decisions for women and health care providers considering midurethral mesh slings.

Comparative Risk of Diabetes Mellitus in Patients With Rheumatoid Arthritis Treated With Biologic or Targeted Synthetic Disease-Modifying Drugs: A Cohort Study.

OBJECTIVE: The objective of this study is to compare the risk of incident diabetes mellitus (DM) in patients with rheumatoid arthritis (RA) treated with biologic or targeted synthetic disease-modifying antirheumatic drugs. METHODS: A new-user observational cohort study was conducted using data from a US commercial (Truven MarketScan, 2005-2016) claims database and a public insurance (Medicare, 2010-2014) claims database. Patients with RA who did not have DM were selected into one of eight exposure groups (abatacept, infliximab, adalimumab, golimumab, certolizumab, etanercept, tocilizumab, or tofacitinib) and observed for the outcome of incident DM, defined as a combination of a diagnosis code and initiation of a hypoglycemic treatment. A stabilized inverse probability-weighted Cox proportional hazards model was used to account for 56 confounding variables and estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All analyses were conducted separately in two databases, and estimates were combined using inverse variance meta-analysis. RESULTS: Among a total of 50 505 patients with RA from Truven and 17 251 patients with RA from Medicare, incidence rates (95% CI) for DM were 6.8 (6.1-7.6) and 6.6 (5.4-7.9) per 1000 person-years, respectively. After confounding adjustment, the pooled HRs (95% CI) indicated a significantly higher risk of DM among adalimumab (2.00 [1.11-3.03]) and infliximab initiators (2.34 [1.38-3.98]) compared with abatacept initiators. The pooled HR (95% CI) for the etanercept versus abatacept comparison was elevated but not statistically significant (1.65 [0.91-2.98]). The effect estimates for certolizumab, golimumab, tocilizumab, and tofacitinib, compared with abatacept, were highly imprecise because of a limited sample size. CONCLUSION: Initiation of abatacept was associated with a lower risk of incident DM in patients with RA compared with infliximab or adalimumab.

Validation of algorithms to identify adverse perinatal outcomes in the Medicaid Analytic Extract database.

BACKGROUND: The Medicaid Analytic eXtract (MAX) is a health care utilization database from publicly insured individuals that has been used for studies of drug safety in pregnancy. Claims-based algorithms for defining many important maternal and neonatal outcomes have not been validated. OBJECTIVE: To validate claims-based algorithms for identifying selected pregnancy outcomes in MAX using hospital medical records. METHODS: The medical records of mothers who delivered between 2000 and 2010 within a single large healthcare system were linked to their claims in MAX. Claims-based algorithms for placental abruption, preeclampsia, postpartum hemorrhage, small for gestational age, and noncardiac congenital malformation were defined. Fifty randomly sampled cases for each outcome identified using these algorithms were selected, and their medical records were independently reviewed by two physicians to confirm the presence of the diagnosis of interest; disagreements were resolved by a third physician reviewer. Positive predictive values (PPVs) and 95% confidence intervals (CIs) of the claims-based algorithms were calculated using medical records as the gold standard. RESULTS: The linked cohort included 10,899 live-birth pregnancies. The PPV was 92% (95% CI, 82%-97%) for placental abruption, 82% (95% CI, 70%-91%) for preeclampsia, 74% (95% CI, 61%-85%) for postpartum hemorrhage, 92% (95% CI, 82%-97%) for small for gestational age, and 86% (95% CI, 74%-94%) for noncardiac congenital malformation. CONCLUSIONS: Across the perinatal outcomes considered, PPVs ranged between 74% and 92%. These PPVs can inform bias analyses that correct for outcome misclassification.

Comparative Outcomes of Treatment Initiation With Brand vs. Generic Warfarin in Older Patients.

The anticoagulant response to warfarin, a narrow therapeutic index drug, increases with age, which may make older patients susceptible to adverse outcomes resulting from small differences in bioavailability between generic and brand products. Using US Medicare claims linked to electronic medical records from two large hospitals in Boston, we designed a cohort study of ≥ 65-year-old patients. Patients were followed for a composite effectiveness outcome of ischemic stroke or venous thromboembolism, a composite safety outcome, including major hemorrhage, and a 1-year all-cause mortality outcome. After propensity score fine-stratification and weighting to account for > 90 confounders, hazard ratios comparing brand vs. generic warfarin initiators (95% confidence intervals) for the effectiveness, safety, and all-cause mortality outcomes, were 0.97 (0.65-1.46), 0.94 (0.65-1.35), and 0.84 (0.62-1.13), respectively. Results from subgroup analyses of patients with atrial fibrillation, CHADS-VASc score ≥ 3, and HAS-BLED score ≥ 3 were consistent with the primary analysis.

Stepped-wedge randomised trial to evaluate population health intervention designed to increase appropriate anticoagulation in patients with atrial fibrillation.

BACKGROUND: Clinical guidelines recommend anticoagulation for patients with atrial fibrillation (AF) at high risk of stroke; however, studies report 40% of this population is not anticoagulated. OBJECTIVE: To evaluate a population health intervention to increase anticoagulation use in high-risk patients with AF. METHODS: We used machine learning algorithms to identify patients with AF from electronic health records at high risk of stroke (CHA2DS2-VASc risk score ≥2), and no anticoagulant prescriptions within 12 months. A clinical pharmacist in the anticoagulation service reviewed charts for algorithm-identified patients to assess appropriateness of initiating an anticoagulant. The pharmacist then contacted primary care providers of potentially undertreated patients and offered assistance with anticoagulation management. We used a stepped-wedge design, evaluating the proportion of potentially undertreated patients with AF started on anticoagulant therapy within 28 days for clinics randomised to intervention versus usual care. RESULTS: Of 1727 algorithm-identified high-risk patients with AF in clinics at the time of randomisation to intervention, 432 (25%) lacked evidence of anticoagulant prescriptions in the prior year. After pharmacist review, only 17% (75 of 432) of algorithm-identified patients were considered potentially undertreated at the time their clinic was randomised to intervention. Over a third (155 of 432) were excluded because they had a single prior AF episode (transient or provoked by serious illness); 36 (8%) had documented refusal of anticoagulation, the remainder had other reasons for exclusion. The intervention did not increase new anticoagulant prescriptions (intervention: 4.1% vs usual care: 4.0%, p=0.86). CONCLUSIONS: Algorithms to identify underuse of anticoagulation among patients with AF in healthcare databases may not capture clinical subtleties or patient preferences and may overestimate the extent of undertreatment. Changing clinician behaviour remains challenging.

Comparative effectiveness of generic and brand-name medication use: A database study of US health insurance claims.

BACKGROUND: To the extent that outcomes are mediated through negative perceptions of generics (the nocebo effect), observational studies comparing brand-name and generic drugs are susceptible to bias favoring the brand-name drugs. We used authorized generic (AG) products, which are identical in composition and appearance to brand-name products but are marketed as generics, as a control group to address this bias in an evaluation aiming to compare the effectiveness of generic versus brand medications. METHODS AND FINDINGS: For commercial health insurance enrollees from the US, administrative claims data were derived from 2 databases: (1) Optum Clinformatics Data Mart (years: 2004-2013) and (2) Truven MarketScan (years: 2003-2015). For a total of 8 drug products, the following groups were compared using a cohort study design: (1) patients switching from brand-name products to AGs versus generics, and patients initiating treatment with AGs versus generics, where AG use proxied brand-name use, addressing negative perception bias, and (2) patients initiating generic versus brand-name products (bias-prone direct comparison) and patients initiating AG versus brand-name products (negative control). Using Cox proportional hazards regression after 1:1 propensity-score matching, we compared a composite cardiovascular endpoint (for amlodipine, amlodipine-benazepril, and quinapril), non-vertebral fracture (for alendronate and calcitonin), psychiatric hospitalization rate (for sertraline and escitalopram), and insulin initiation (for glipizide) between the groups. Inverse variance meta-analytic methods were used to pool adjusted hazard ratios (HRs) for each comparison between the 2 databases. Across 8 products, 2,264,774 matched pairs of patients were included in the comparisons of AGs versus generics. A majority (12 out of 16) of the clinical endpoint estimates showed similar outcomes between AGs and generics. Among the other 4 estimates that did have significantly different outcomes, 3 suggested improved outcomes with generics and 1 favored AGs (patients switching from amlodipine brand-name: HR [95% CI] 0.92 [0.88-0.97]). The comparison between generic and brand-name initiators involved 1,313,161 matched pairs, and no differences in outcomes were noted for alendronate, calcitonin, glipizide, or quinapril. We observed a lower risk of the composite cardiovascular endpoint with generics versus brand-name products for amlodipine and amlodipine-benazepril (HR [95% CI]: 0.91 [0.84-0.99] and 0.84 [0.76-0.94], respectively). For escitalopram and sertraline, we observed higher rates of psychiatric hospitalizations with generics (HR [95% CI]: 1.05 [1.01-1.10] and 1.07 [1.01-1.14], respectively). The negative control comparisons also indicated potentially higher rates of similar magnitude with AG compared to brand-name initiation for escitalopram and sertraline (HR [95% CI]: 1.06 [0.98-1.13] and 1.11 [1.05-1.18], respectively), suggesting that the differences observed between brand and generic users in these outcomes are likely explained by either residual confounding or generic perception bias. Limitations of this study include potential residual confounding due to the unavailability of certain clinical parameters in administrative claims data and the inability to evaluate surrogate outcomes, such as immediate changes in blood pressure, upon switching from brand products to generics. CONCLUSIONS: In this study, we observed that use of generics was associated with comparable clinical outcomes to use of brand-name products. These results could help in promoting educational interventions aimed at increasing patient and provider confidence in the ability of generic medicines to manage chronic diseases.

Evaluation of Socioeconomic Status Indicators for Confounding Adjustment in Observational Studies of Medication Use.

Methodologic research evaluating confounding due to socioeconomic status (SES) in observational studies of medications is limited. We identified 7,109 patients who initiated brand or generic atorvastatin from Medicare claims (2011-2013) linked to electronic medical records and census data. We created a propensity score (PS) containing only claims-based covariates and augmented it with additional claims-based proxies for SES, ZIP code, and block group level SES. Cox models with PS fine-stratification and weighting were used to compare rates of a cardiovascular end point and emergency department visits. Adjustment with only claims-based variables substantially improved balance on all SES variables compared with the unadjusted. Although inclusion of SES in PS models further improved balance on SES variables compared with models with claims-based covariates only, it did not materially change point estimates for either outcome. Inclusion of claims-based proxies may mitigate confounding by SES when aggregate-level SES information is unavailable.

Differences in rates of switchbacks after switching from branded to authorized generic and branded to generic drug products: cohort study.

OBJECTIVES: To compare rates of switchbacks to branded drug products for patients switched from branded to authorized generic drug products, which have the same active ingredients, appearance, and excipients as the branded product, with patients switched from branded to generic drug products, which have the same active ingredients as the branded product but may differ in appearance and excipients. DESIGN: Observational cohort study. SETTING: Private (a large commercial health plan) and public (Medicaid) insurance programs in the US. PARTICIPANTS: Beneficiaries of a large US commercial health insurer between 2004 and 2013 (primary cohort) and Medicaid beneficiaries between 2000 and 2010 (replication cohort). MAIN OUTCOME MEASURES: Patients taking branded products for one of the study drugs (alendronate tablets, amlodipine tablets, amlodipine-benazepril capsules, calcitonin salmon nasal spray, escitalopram tablets, glipizide extended release tablets, quinapril tablets, and sertraline tablets) were identified when they switched to an authorized generic or a generic drug product after the date of market entry of generic drug products. These patients were followed for switchbacks to the branded drug product in the year after their switch to an authorized generic or a generic drug product. Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals after adjusting for demographics, including age, sex, and calendar year. Inverse variance meta-analysis was used to pool adjusted hazard ratios across all drug products. RESULTS: A total of 94 909 patients switched from branded to authorized generic drug products and 116 017 patients switched from branded to generic drug products and contributed to the switchback analysis. Unadjusted incidence rates of switchback varied across drug products, ranging from a low of 3.8 per 100 person years (for alendronate tablets) to a high of 17.8 per 100 person years (for amlodipine-benazepril capsules), with an overall rate of 8.2 per 100 person years across all drug products. Adjusted switchback rates were consistently lower for patients who switched from branded to authorized generic drug products compared with branded to generic drug products in the primary cohort (pooled hazard ratio 0.72, 95% confidence interval 0.64 to 0.81). Similar results (0.75, 0.62 to 0.91) were observed in the replication cohort. CONCLUSION: Switching from branded to authorized generic drug products was associated with lower switchback rates compared with switching from branded to generic drug products.

A Bias in the Evaluation of Bias Comparing Randomized Trials with Nonexperimental Studies.

In a recent BMJ article, the authors conducted a meta-analysis to compare estimated treatment effects from randomized trials with those derived from observational studies based on routinely collected data (RCD). They calculated a pooled relative odds ratio (ROR) of 1.31 (95% confidence interval [CI]: 1.03-1.65) and concluded that RCD studies systematically over-estimated protective effects. However, their meta-analysis inverted results for some clinical questions to force all estimates from RCD to be below 1. We evaluated the statistical properties of this pooled ROR, and found that the selective inversion rule employed in the original meta-analysis can positively bias the estimate of the ROR. We then repeated the random effects meta-analysis using a different inversion rule and found an estimated ROR of 0.98 (0.78-1.23), indicating the ROR is highly dependent on the direction of comparisons. As an alternative to the ROR, we calculated the observed proportion of clinical questions where the RCD and trial CIs overlap, as well as the expected proportion assuming no systematic difference between the studies. Out of 16 clinical questions, 50% CIs overlapped for 8 (50%; 25 to 75%) compared with an expected overlap of 60% assuming no systematic difference between RCD studies and trials. Thus, there was little evidence of a systematic difference in effect estimates between RCD and RCTs. Estimates of pooled RORs across distinct clinical questions are generally not interpretable and may be misleading.

Risk of serious infections associated with use of immunosuppressive agents in pregnant women with autoimmune inflammatory conditions: cohort study.

Objective To compare the risk of serious infections associated with use of systemic steroids, non-biologic agents, or tumor necrosis factor α (TNF) inhibitors in pregnancy.Design Observational cohort study.Setting Public (Medicaid, 2001-10) or private (Optum Clinformatics, 2004-15) health insurance programs in the US.Participants 4961 pregnant women treated with immunosuppressive drugs for rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriatic arthritis, or inflammatory bowel disease.Exposure for observational studies Exposure was classified into steroid, non-biologic, or TNF inhibitors on first filled prescription during pregnancy. Because TNF inhibitors are not used to treat systemic lupus erythematosus, patients with this condition were excluded from comparisons involving TNF inhibitors.Main outcome measure The main outcome was occurrence of serious infections during pregnancy, defined by hospital admission for bacterial or opportunistic infections. Hazard ratios were derived using Cox proportional hazard regression models after adjustment for confounding with propensity score fine stratification. A logistic regression model was used to conduct a dose-response analysis among women filling at least one steroid prescription.Results 71 out of 4961 pregnant women (0.2%) treated with immunosuppressive agents experienced serious infections. The crude incidence rates of serious infections per 100 person years among 2598 steroid users, 1587 non-biologic users, and 776 TNF inhibitors users included in this study were 3.4 (95% confidence interval 2.5 to 4.7), 2.3 (1.5 to 3.5), and 1.5 (0.7 to 3.0), respectively. No statistically significant differences in the risk of serious infections during pregnancy were observed among users of the three immunosuppressive drug classes: non-biologics v steroids, hazard ratio 0.81 (95% confidence interval 0.48 to 1.37), TNF inhibitors v steroids 0.91 (0.36 to 2.26), and TNF inhibitors v non-biologics 1.36 (0.47 to 3.93). In the dose-response analysis, higher steroid dose was associated with an increased risk of serious infections during pregnancy (coefficient for each unit increase in average prednisone equivalent mg daily dose=0.019, P=0.02).Conclusions Risk of serious infections is similar among pregnant women with systemic inflammatory conditions using steroids, non-biologics, and TNF inhibitors. However, high dose steroid use is an independent risk factor of serious infections in pregnancy.

Patient and Physician Perceptions of Drug Safety Information for Sleep Aids: A Qualitative Study.

INTRODUCTION: The US Food and Drug Administration uses drug safety communications (DSCs) to release emerging information regarding post-market safety issues, but it is unclear the extent of awareness by patients and providers of these communications and their specific recommendations. OBJECTIVE: We conducted semi-structured interviews with patients and physicians to evaluate their awareness and understanding of emerging drug safety information related to two sleep aids: zolpidem or eszopiclone. METHODS: We conducted interviews with 40 patients and ten physicians recruited from a combination of insurer claims databases and online sources. We evaluated (1) sources of drug safety information; (2) discussions between patients and physicians about the two medications; (3) their knowledge of the DSC; and (4) preferences for learning about future drug safety information. Interviews were transcribed and analyzed thematically. RESULTS: Patients cited their physicians, pharmacy inserts, and the Internet as sources of drug safety information. Physicians often referred to medical journals and online medical sources. Most patients reported being aware of information contained in the DSC summaries they were read. Almost all patients and physicians reported discussing side effects during patient-provider conversations, but almost no patients mentioned that physicians had communicated with them key messaging from the DSCs at issue: the risk of next-morning impairment with zolpidem and the lower recommended initial dose for women. CONCLUSIONS: Some risks of medications are effectively communicated to patients and physicians; however, there is still a noticeable gap between information issued by the Food and Drug Administration and patient and physician awareness of this knowledge, as well as patients' decisions to act on this information. Disseminators of emerging drug safety information should explore ways of providing user-friendly resources to patients and healthcare professionals that can update them on new risks in a timely manner.

Media Coverage of FDA Drug Safety Communications about Zolpidem: A Quantitative and Qualitative Analysis.

FDA issues Drug Safety Communications (DSCs) to alert health care professionals and the public about emerging safety information affecting prescription and over-the-counter drugs. News media may amplify DSCs, but it is unclear how DSC messaging is transmitted through the media. We conducted a content analysis of the lay media coverage reaching the broadest audience to characterize the amount and content of media coverage of two zolpidem DSCs from 2013. After the first DSC, zolpidem news stories increased from 19 stories/week in the preceding 3 months to 153 following its release. Most (81%) appeared in the lay media, and 64% focused on the DSC content. After the second DSC, news stories increased from 24 stories/week in the preceding 3 months to 39 following. Among the 100 unique lay media news stories, at least half correctly reported three key DSC messages: next-day impairment and drowsiness as common safety hazards, lower doses for some but not all zolpidem products, and women's higher risk for impairment. Other DSC messages were reported in fewer than one-third of stories, such as the warning that impairment can happen even when people feel fully awake. The first-but not the second-zolpidem DSC generated high-profile news coverage. The finding that some messages were widely reported but others were not emphasizes the importance of ensuring translation of key DSC content.

Angiotensin-Converting Enzyme Inhibitors and the Risk of Congenital Malformations.

OBJECTIVE: To examine the association between first-trimester angiotensin-converting enzyme (ACE) inhibitor exposure and the risk of overall major congenital, cardiac, and central nervous system malformations. METHODS: We used a cohort of completed pregnancies linked to liveborn neonates derived from Medicaid claims from 2000 to 2010. We examined the risk of malformations associated with first-trimester exposure to an ACE inhibitor. Propensity score-based methods were used to control for potential confounders including maternal demographics, medical conditions, exposure to other medications, and measures of health care utilization. RESULTS: The cohort included 1,333,624 pregnancies, of which 4,107 (0.31%) were exposed to ACE inhibitors during the first trimester. The prevalence of overall malformations in the ACE inhibitor-exposed pregnancies was 5.9% compared with 3.3% in the unexposed (unadjusted relative risk, 1.82; 95% confidence interval [CI] 1.61-2.06), of cardiac malformations was 3.4% compared with 1.2% (relative risk 2.95, 95% CI 2.50-3.47), and of central nervous system malformations was 0.27% compared with 0.18% (relative risk 1.46, 95% CI 0.81-2.64). After restricting the cohort to pregnancies complicated by chronic hypertension (both exposed and unexposed) and accounting for other confounding factors, there was no significant increase in the risk of any of the outcomes assessed. Relative risks associated with first-trimester ACE inhibitor exposure were 0.89 (95% CI 0.75-1.06) for overall malformations, 0.95 (95% CI 0.75-1.21) for cardiac malformations, and 0.54 (95% CI 0.26-1.11) for CNS malformations. CONCLUSIONS: After accounting for confounders, among women with hypertension, exposure to ACE inhibitors during the first trimester was not associated with an increased risk of major congenital malformations.

Antipsychotic Use in Pregnancy and the Risk for Congenital Malformations.

IMPORTANCE: The frequency of antipsychotic (AP) use during pregnancy has approximately doubled during the last decade. However, little is known about their safety for the developing fetus, and concerns have been raised about a potential association with congenital malformations. OBJECTIVE: To examine the risk for congenital malformations overall and cardiac malformations associated with first-trimester exposure to APs. DESIGN, SETTING, AND PARTICIPANTS: This nationwide sample of 1 360 101 pregnant women enrolled in Medicaid with a live-born infant constituted the pregnancy cohort nested in the Medicaid Analytic Extract database, which included data from January 1, 2000, to December 31, 2010. Participants were enrolled in Medicaid from 3 months before their last menstrual period through at least 1 month after delivery. Relative risks (RRs) were estimated using generalized linear models with fine stratification on the propensity score to control for the underlying psychiatric disorders and other potential confounders. Data were analyzed during 2015. EXPOSURES: Use of APs during the first trimester, the etiologically relevant period for organogenesis. MAIN OUTCOMES AND MEASURES: Major congenital malformations overall and cardiac malformations identified during the first 90 days after delivery. RESULTS: Of the 1 341 715 pregnancies that met inclusion criteria (mean [SD] age of women, 24.02 [5.77] years), 9258 (0.69%) filled at least 1 prescription for an atypical AP and 733 (0.05%) filled at least 1 prescription for a typical AP during the first trimester. Overall, 32.7 (95% CI, 32.4-33.0) per 1000 births not exposed to APs were diagnosed with congenital malformations compared with 44.5 (95% CI, 40.5-48.9) per 1000 births exposed to atypical and 38.2 (95% CI, 26.6-54.7) per 1000 births exposed to typical APs. Unadjusted analyses suggested an increased risk for malformations overall for atypical APs (RR, 1.36; 95% CI, 1.24-1.50) but not for typical APs (RR, 1.17; 95% CI, 0.81-1.68). After confounding adjustment, the RR was reduced to 1.05 (95% CI, 0.96-1.16) for atypical APs and 0.90 (95% CI, 0.62-1.31) for typical APs. The findings for cardiac malformations were similar. For the individual agents examined, a small increased risk in overall malformations (RR, 1.26; 95% CI, 1.02-1.56) and cardiac malformations (RR, 1.26; 95% CI, 0.88-1.81) was found for risperidone that was independent of measured confounders. CONCLUSIONS AND RELEVANCE: Evidence from this large study suggests that use of APs early in pregnancy generally does not meaningfully increase the risk for congenital malformations overall or cardiac malformations in particular. The small increase in the risk for malformations observed with risperidone requires additional study.