Assessment of the Risk Evaluation and Mitigation Strategy (REMS) for Phentermine-Topiramate to Prevent Exposure During Pregnancy.

BACKGROUND: The U.S. Food and Drug Administration approved phentermine-topiramate for obesity in 2012 and required a Risk Evaluation and Mitigation Strategy (REMS) to prevent prenatal exposure. No such requirement was introduced for topiramate. OBJECTIVE: To evaluate the rate of prenatal exposure, contraceptive use, and pregnancy testing among patients with phentermine-topiramate compared with topiramate or other antiobesity medications (AOMs). DESIGN: Retrospective cohort study. SETTING: Nationwide health insurance claims database. PARTICIPANTS: Females aged 12 to 55 years with no infertility diagnosis or sterilization procedure. Patients with other indications for topiramate were excluded to identify a cohort that was likely treated for obesity. MEASUREMENTS: Patients initiated use of phentermine-topiramate, topiramate, or an AOM (liraglutide, lorcaserin, or bupropion-naltrexone). Pregnancy at treatment initiation, conception during treatment, contraceptive use, and pregnancy testing outcomes were ascertained. Measurable confounders were adjusted for, and extensive sensitivity analyses were done. RESULTS: A total of 156 280 treatment episodes were observed. Adjusted prevalence of pregnancy at treatment initiation was 0.9 versus 1.6 per 1000 episodes (prevalence ratio, 0.54 [95% CI, 0.31 to 0.95]) for phentermine-topiramate versus topiramate. The incidence rate of conception during treatment was 9.1 versus 15.0 per 1000 person-years (rate ratio, 0.61 [CI, 0.40 to 0.91]) for phentermine-topiramate versus topiramate. Both outcomes were similarly lower for phentermine-topiramate compared with AOM. Prenatal exposure was marginally lower in topiramate users compared with AOM users. Approximately 20% of patients in all cohorts had at least 50% of treatment days covered by contraceptives. Few patients had pregnancy tests before treatment (≤5%), but this was more common among phentermine-topiramate users. LIMITATIONS: Outcome misclassification; unmeasured confounding due to lack of prescriber data to account for possible clustering and spillover effects. CONCLUSION: Prenatal exposure seemed to be significantly lower among phentermine-topiramate users under the REMS. Pregnancy testing and contraceptive use appeared to be inadequate for all groups, which deserves attention to prevent the remaining potential exposures. PRIMARY FUNDING SOURCE: None.

Utilization of chronic lung disease treatment before the respiratory syncytial virus season as palivizumab prophylaxis qualifier in the American Academy of Pediatrics Guidelines.

Guidelines from the American Academy of Pediatrics recommend palivizumab immunoprophylaxis for children with CLD in their second year of life if they continue to need treatment within 6 months before the RSV season. The utilization patterns of treatment (chronic corticosteroid therapy, diuretic therapy, or supplemental oxygen) are not well understood. We examined variations in CLD treatment for ten consecutive 20-day segments preceding RSV season onset. Among infants and children with CLD (n = 19,026), 35.2% received one or more medical treatments for CLD any time within 200 days before entering the second RSV season: 8.6%, 3.2%, and 29.7% received supplemental oxygen, diuretics, and corticosteroids, respectively. Utilization decreased as infants' age increased with corticosteroids surpassing oxygen and diuretics. To avoid the capture of intermittent use of corticosteroids for acute infections, we found requiring a minimum of 45 days cumulative exposure was reasonable to determine chronic use. What is Known: • Guidelines from the American Academy of Pediatrics recommend palivizumab immunoprophylaxis for children with CLD in their second year of life if they continue to need treatment within 6 months before the RSV season. • The utilization patterns of treatment (chronic corticosteroid therapy, diuretic therapy, or supplemental oxygen) are not well understood. A definition of chronic corticosteroid therapy in this setting is not available. What is New: • Among infants and children with CLD of prematurity, 35.2% received one or more medical treatments for CLD any time within 200 days before entering the second RSV season: 8.6%, 3.2%, and 29.7% received oxygen, diuretics, and corticosteroids, respectively. Utilization decreased as infants' age increased with corticosteroids surpassing oxygen and diuretics. • A minimum of 45 days cumulative corticosteroid use within the past 90 days would accurately capture chronic use to fulfill criteria for immunoprophylaxis while limiting the inclusion of intermittent use of corticosteroids for acute infections.

Validation of algorithms to estimate gestational age at birth in the Medicaid Analytic eXtract-Quantifying the misclassification of maternal drug exposure during pregnancy.

PURPOSE: Accurate ascertainment of gestational age (GA) has been a challenge in perinatal epidemiologic research. To date, no study has validated GA algorithms in Medicaid Analytic eXtract (MAX). METHODS: We linked livebirths of mothers enrolled in Medicaid ≥30 days after delivery in 1999-2010 MAX to state birth certificates. We used clinical/obstetric estimate of gestation on the birth certificates as gold standard to validate claims-based GA algorithms. We calculated the proportions of deliveries with algorithm-estimated GA within 1-/2-weeks of the gold standard, the sensitivity, specificity, and positive/negative predictive value (PPV/NPV) of exposure to select medications during specific gestation windows, and quantified the impact of exposure misclassification on hypothetical relative risk (RR) estimates. RESULTS: We linked 1 336 495 eligible deliveries. Within 1-week agreement was 77%-80% overall and 47%-56% for preterm deliveries. The trimester-specific drug exposure status had high sensitivities and PPVs (88.5%-98.5%), and specificities and NPVs (>99.0%). Assuming a hypothetical RR of 2.0, bias associated with exposure misclassification during first trimester ranged from 10% to 40% under non-differential/differential misclassification assumptions. CONCLUSIONS: Claims-based GA algorithms had good agreement with the gold standard overall, but lower agreement among preterm deliveries, potentially resulting in biased risk estimated for pregnancy exposure evaluations.

Data linkage in pharmacoepidemiology: A call for rigorous evaluation and reporting.

PURPOSE: The purpose of this paper is to provide guidance on the evaluation of data linkage quality through the development of a checklist for reporting key elements of the linkage process. METHODS: Responding to a call for manuscripts from the International Society for Pharmacoepidemiology (ISPE), a working group including international representation from the academic, industry, and contract research, and regulatory sectors was formed to develop a checklist for evaluation of data linkage performance and reporting data linkage specifically for pharmacoepidemiologic research. This checklist expands on the reporting of studies conducted using observational routinely collected health data specific to pharmacoepidemiology (RECORD-PE) guidelines. RESULTS: A key aspect of data linkage evaluation for pharmacoepidemiology is to articulate how a linkage process was performed and its accuracy in terms of validation and verification of the resulting linked data. This study generates a checklist, which covers domains including data sources, linkage variables, linkage methods, linkage results, and linkage evaluation. For each domain, specific recommendations provide a clear and transparent assessment of the linkage process. CONCLUSIONS: Linking data sources can help to enrich analytic databases to more accurately define study populations, enable adjustment for confounding, and improve the capture of health outcomes. Clear and transparent reporting of data linkage processes will help to increase confidence in the evidence generated from these data by allowing researchers and end users to critically assess the potential for bias owing to the data linkage process.

Usability of encounter data for Medicaid comprehensive managed care vs traditional Medicaid fee-for-service claims among pregnant women.

BACKGROUND: The completeness of medical encounters capture among Medicaid enrollees in comprehensive managed care (CMC) has been shown to vary across states and years. CMC penetration has grown, and CMC encounter capture specific to pregnancy care is understudied. OBJECTIVES: To compare the completeness of encounter data for pregnant beneficiaries in CMC versus traditional fee-for-service (FFS) in Texas and Florida between 2007 and 2010. METHODS: Using Medicaid Analytic eXtract (MAX) data linked to Florida and Texas birth certificate records, for each state and study year, we compared proportions using seven themes: (a) delivery; (b) prenatal visits; (c) dispensed prescriptions during pregnancy; (d) gestational diabetes and blood glucose testing; (e) antidiabetics and diagnosis of diabetes mellitus; (f) antibiotics for urinary tract infection and outpatient encounter; and (g) bacterial vaginosis and dispensing for metronidazole or clindamycin. We considered CMC data to be acceptable if proportions were no less than 10% below the corresponding (2007 to 2010) FFS control values. RESULTS: Pregnancy-related characteristics of FFS vs CMC denominators were comparable. Proportions for the seven measures among FFS controls ranged from 26% to 98%. In Texas, CMC encounter data met the thresholds for all measures between 2007 and 2010. Florida had usable CMC encounter data starting from 2009 with incomplete medical and pharmacy records in 2007 and 2008. CONCLUSIONS: The quality of CMC encounter data in MAX files for pregnant women varied in Florida and Texas and improved over time. Use of pregnancy-specific measures can aid researchers in selecting states and years with acceptable encounter data quality.

Misclassification in Assessment of First Trimester In-utero Exposure to Drugs Used Proximally to Conception: the Example of Letrozole Utilization for Infertility Treatment.

Letrozole is an aromatase inhibitor that has an unapproved use for ovulation induction with infertility. Because of the proximity of this use to conception, we selected letrozole to study the effect of 3 different methods for identifying the pregnancy start date and their impact on exposure misclassification. Using electronic health data from the US Sentinel database (2001-2015), we identified live-birth pregnancies conceived through in-vitro fertilization or intrauterine insemination. The pregnancy start was calculated using 1) a validated algorithm to estimate the last menstrual period (LMP), 2) LMP + 14 days (i.e., conception estimate), and 3) the fertility-procedure date. We identified 47,628 live-births after intrauterine insemination (n = 24,962) and in-vitro fertilization (n = 22,666), in which 2,458 (5.3%) mothers received letrozole. The algorithm-based conception estimate occurred within 14 days of the fertility procedure for 78.3% of pregnancies. Defining pregnancy start as LMP (45.7/1,000 pregnancies) or LMP + 14 days (12.7/1,000 pregnancies) overestimated letrozole exposure during pregnancy by 8.4-fold and 2.3-fold, respectively, compared with defining it at the date of the fertility procedure (5.5/1,000 pregnancies). While most studies of drug utilization in pregnancy use LMP as the conventional pregnancy start, this introduced substantial exposure misclassification in the example of letrozole. LMP + 14 days was less biased. Researchers should carefully consider the impact of the method for identifying the pregnancy start date on the potential for exposure misclassification.

Validation of mother-infant linkage using Medicaid Case ID variable within the Medicaid Analytic eXtract (MAX) database.

PURPOSE: The state-assigned Case ID number in the Medicaid Analytic eXtract (MAX) allows for potential linkage of mothers to infants. No validation of respective linkage algorithms is available. We established and validated an algorithm within MAX that links mothers to infants and to identify factors influencing successful mother-infant linkage. METHODS: We identified all mother-infant pairs in FL and TX birth certificates records (BCR) that could be linked individually to MAX records (1999-2005 for FL and 1999-2010 for TX) based on Social Security Number (gold standard pairs). Case ID linkage performance was evaluated as the proportion of gold standard mother-infant pairs that were identified by the algorithm (sensitivity) and the proportion of algorithm defined mother-infant pairs that were correctly linked. Generalized estimating equations were used to calculate the probability for successful Case ID algorithm linkage versus non-linkage using maternal and infant characteristics. RESULTS: We identified 323,160 gold standard pairs in FL BCR and MAX and 1,025,350 in TX BCR and MAX. Depending on Medicaid enrollment the algorithm sensitivity ranged from 85.51% to 87.96% in FL and 19.60% to 35.75% in TX. In both states, positive predictive value exceeded 99%, regardless of enrollment periods. Determinants for successful linkage varied across states, but suggested better results for younger mothers, minority women, and those with lower educational achievement. CONCLUSIONS: Our algorithm can correctly link liveborn infants to their mothers. The algorithm's sensitivity in identifying pairs varied across states, but PPV was consistently high. Linkage performance was associated with certain characteristics that may affect representativeness of successfully linked pairs.

Safety assessment of niacin in the US Food and Drug Administration's mini-sentinel system.

PURPOSE: The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial found higher incidence rates of adverse reactions, including bleeding, in patients receiving the combination of extended-release niacin and laropiprant versus placebo. It is not known whether these adverse events are attributable to laropiprant, not approved in the USA, or to extended-release niacin. We compared rates of major gastrointestinal bleeding and intracranial hemorrhage among initiators of extended-release niacin and initiators of fenofibrate. METHODS: We used Mini-Sentinel (now Sentinel) to conduct an observational, new user cohort analysis. We included data from 5 Data Partners covering the period from January 1, 2007 to August 31, 2013. Individuals who initiated extended-release niacin were propensity score-matched to individuals who initiated fenofibrate. Within the matched cohorts, we used Cox proportional hazards models to compare rates of hospitalization for major gastrointestinal bleeding events and intracranial hemorrhage assessed using validated claims-based algorithms. RESULTS: A total of 234 242 eligible extended-release niacin initiators were identified, of whom 210 389 (90%) were 1:1 propensity score-matched to eligible fenofibrate initiators. In propensity score-matched analyses, no differences were observed between exposure groups in rates of major gastrointestinal bleeding (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.82 to 1.18) or intracranial hemorrhage (HR, 1.21; 95% CI, 0.66 to 2.22). Results were similar in pre-specified sensitivity and subgroup analyses. CONCLUSIONS: We did not observe evidence for an association between extended-release niacin versus fenofibrate and rates of major gastrointestinal bleeding or intracranial hemorrhage.

Utilization of drugs with pregnancy exposure registries during pregnancy.

PURPOSE: To describe the utilization of drugs with pregnancy exposure registries by trimester during pregnancy, in comparison with matched nonpregnant episodes and a pre-pregnancy period. METHODS: We identified live-born deliveries from women aged 10 to 54 years and matched the pregnancies 1:1 with nonpregnant episodes from a comparator cohort not delivering live-born infants, using data from 2001 to 2013 in the Sentinel Distributed Database. We evaluated the utilization of 34 drugs with pregnancy exposure registries, comparing utilization during pregnancy to the matched nonpregnant episodes, and to the 90 days before pregnancy. RESULTS: We identified 1 895 597 pregnancies ending in live births in 1 598 697 women and 1 895 597 matched nonpregnant episodes in 1 582 581 women. We observed a lower prevalence of use for most drugs during pregnancy compared with the matched nonpregnant episodes, and the 90-day pre-pregnancy period. The median (interquartile range) prevalence ratio of use, at any time during pregnancy, for all products was 0.2 (0.1-0.3) comparing pregnant to nonpregnant episodes. Overall, there was a decrease in drug utilization by trimester; from 2.6% in the 90 days preceding pregnancy to 2.1% in the first trimester, 1.1% in the second trimester, and 0.9% in the third trimester. CONCLUSIONS: Among drugs with pregnancy exposure registries, use was less during pregnancy compared with before pregnancy and to the matched nonpregnant episodes. The lower utilization during pregnancy suggests that women may be avoiding these drugs to minimize potentially harmful exposure during pregnancy. This lower utilization may increase the challenges of further studying the safety of these drugs using pregnancy exposure registries.

Sentinel Modular Program for Propensity Score-Matched Cohort Analyses: Application to Glyburide, Glipizide, and Serious Hypoglycemia.

Sentinel is a program sponsored by the US Food and Drug Administration to monitor the safety of medical products. We conducted a cohort assessment to evaluate the ability of the Sentinel Propensity Score Matching Tool to reproduce in an expedited fashion the known association between glyburide (vs. glipizide) and serious hypoglycemia. Thirteen data partners who contribute to the Sentinel Distributed Database participated in this analysis. A pretested and customizable analytic program was run at each individual site. De-identified summary results from each data partner were returned and aggregated at the Sentinel Operations Center. We identified a total of 198,550 and 379,507 new users of glyburide and glipizide, respectively. The incidence of emergency department visits and hospital admissions for serious hypoglycemia was 19 per 1000 person-years (95% confidence interval = 17.9, 19.7) for glyburide users and 22 (21.6, 22.7) for glipizide users. In cohorts matched by propensity score based on predefined variables, the hazard ratio (HR) for glyburide was 1.36 (1.24, 1.49) versus glipizide. In cohorts matched on a high-dimensional propensity score based on empirically selected variables, for which the program ran to completion in five data partners, the HR was 1.49 (1.31, 1.70). In cohorts matched on propensity scores based on both predefined and empirically selected variables via the high-dimensional propensity score algorithm (the same five data partners), the HR was 1.51 (1.32, 1.71). These findings are consistent with the literature, and demonstrate the ability of the Sentinel Propensity Score Matching Tool to reproduce this known association in an expedited fashion.See video abstract at, http://links.lww.com/EDE/B275.

A systematic review of pregnancy exposure registries: examination of protocol-specified pregnancy outcomes, target sample size, and comparator selection.

PURPOSE: Our study sought to systematically evaluate protocol-specified study methodology in prospective pregnancy exposure registries including pre-specified pregnancy outcomes, power calculations for sample size, and comparator group selection. METHODS: U.S. pregnancy exposure registries designed to evaluate safety of drugs or biologics were identified from www.clinicaltrials.gov, the FDA's Office of Women's Health website, and the FDA's list of postmarketing studies. Protocols or similar documentation were obtained. RESULTS: We identified 35 U.S. registries for drugs or biologic use during pregnancy. All registries assessed risk for overall major congenital malformations. Pre-specified target enrollment was stated for 18 (51%) registries, and ranged from 150 to 500 exposed pregnancies (median 300). Thirty-two (91%) registries identified at least one comparison group, but only nine (26%) planned to use an internal comparator. The most common external comparator group (n = 24, 69%) was the Metropolitan Atlanta Congenital Defects Program (MACDP). CONCLUSIONS: No registries were designed to have sufficient power to assess specific malformations, despite the plausibility that most teratogens cause specific defects. Only half of the registries included a power analysis. Despite their common use, external comparators, including MACDP, have important limitations. In the absence of randomized controlled trial data in pregnant women, pregnancy registries remain an important tool as part of a comprehensive pregnancy surveillance program; however, pregnancy registries alone may not be sufficient to obtain adequate data regarding risks of specific malformations. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Risk for Hospitalized Heart Failure Among New Users of Saxagliptin, Sitagliptin, and Other Antihyperglycemic Drugs: A Retrospective Cohort Study.

BACKGROUND: Recent postmarketing trials produced conflicting results about the risk for hospitalized heart failure (hHF) associated with dipeptidyl peptidase-4 (DPP-4) inhibitors, creating uncertainty about the safety of these antihyperglycemic agents. OBJECTIVE: To examine the associations of hHF with saxagliptin and sitagliptin. DESIGN: Population-based, retrospective, new-user cohort study. SETTING: 18 health insurance and health system data partners in the U.S. Food and Drug Administration's Mini-Sentinel program. PATIENTS: Patients aged 18 years or older with type 2 diabetes who initiated therapy with saxagliptin, sitagliptin, pioglitazone, second-generation sulfonylureas, or long-acting insulin products from 2006 to 2013. MEASUREMENTS: Hospitalized HF, identified by International Classification of Diseases, Ninth Revision, Clinical Modification codes 402.x1, 404.x1, 404.x3, and 428.xx recorded as the principal discharge diagnosis. RESULTS: 78 553 saxagliptin users and 298 124 sitagliptin users contributed an average of 7 to 9 months of follow-up data to 1 or more pairwise comparisons. The risk for hHF was not higher with DPP-4 inhibitors than with the other study drugs. The hazard ratios from the disease risk score (DRS)-stratified analyses were 0.83 (95% CI, 0.70 to 0.99) for saxagliptin versus sitagliptin, 0.63 (CI, 0.47 to 0.85) for saxagliptin versus pioglitazone, 0.69 (CI, 0.54 to 0.87) for saxagliptin versus sulfonylureas, and 0.61 (CI, 0.50 to 0.73) for saxagliptin versus insulin. The DRS-stratified hazard ratios were 0.74 (CI, 0.64 to 0.85) for sitagliptin versus pioglitazone, 0.86 (CI, 0.77 to 0.95) for sitagliptin versus sulfonylureas, and 0.71 (CI, 0.64 to 0.78) for sitagliptin versus insulin. Results from the 1:1 propensity score-matched analyses were similar. Results were also similar in subgroups of patients with and without prior cardiovascular disease and in a subgroup defined by the 2 highest DRS deciles. LIMITATION: Residual confounding and short follow-up. CONCLUSION: In this large cohort study, a higher risk for hHF was not observed in users of saxagliptin or sitagliptin compared with other selected antihyperglycemic agents. PRIMARY FUNDING SOURCE: U.S. Food and Drug Administration.

Notes from the Field: Pediatric Emergency Department Visits for Buprenorphine/Naloxone Ingestion - United States, 2008-2015.

Expanding access to office-based medication-assisted treatment with buprenorphine/naloxone for opioid dependence is a key part of the national strategy to address the opioid abuse epidemic (1). However, as buprenorphine/naloxone prescribing increased, emergency department (ED) visits and hospitalizations for unsupervised ingestions by young children began to increase, with buprenorphine/naloxone ingestions becoming the most common cause of hospitalization for medication ingestions by young children during 2010-2011 (2). Buprenorphine ingestions might be asymptomatic or can cause drowsiness, vomiting, or respiratory depression, which if untreated can result in death (3). Buprenorphine/naloxone was available only as tablets in multidose child-resistant bottles (Suboxone) until late 2010, when film strips packaged in unit-dose, child-resistant pouches were introduced. In 2013, tablets became available in unit-dose packaging (Zubsolv). Because unit-dose, child-resistant packaging encloses each dose until opened, it might limit unintended ingestions by young children compared with traditional child-resistant bottles that must be resecured after every use (4). This study compared ED visits for pediatric buprenorphine/naloxone ingestions before and after these product packaging/formulation changes.

Patient understanding of drug risks: an evaluation of medication guide assessments.

PURPOSE: When a Medication Guide (MG) is part of Risk Evaluation and Mitigation Strategy (REMS), manufacturers assess the effectiveness of MGs through patient surveys, which have not undergone systematic evaluation. We aimed to characterize knowledge rates from these patient surveys, describe their design and respondent characteristics, and explore predictors of acceptable knowledge rates. METHODS: We analyzed MG assessments submitted to the Food and Drug Administration from September 2008 through June 2012. We evaluated the prevalence of specific characteristics, and calculated knowledge rates, whereby we defined "acceptable knowledge" when ≥ 80% of respondents correctly answered questions about the primary drug risk. Univariate logistic models were used to investigate the predictors of acceptable knowledge rates. RESULTS: We analyzed the first completed MG assessment for each drug with a patient survey, resulting in 66 unique MG assessments. The mean knowledge rate was 63.8%, with 20 MG assessments (30.3%) achieving the 80% threshold. Compared to assessments that did not reach acceptable knowledge rates, those that did were more likely associated with additional REMS elements (e.g. Elements to Assure Safe Use or Communication Plans). Other factors, including mean age, reading or understanding the MG, and being offered or accepting counseling were not associated with knowledge rates. There was considerable variation in the design of MG assessments. CONCLUSIONS: Most MG assessments did not reach the 80% knowledge threshold, but those associated with additional interventions were more likely to achieve it. Our study highlights the need to improve patient-directed information and the methods of assessing it.

Validity of laboratory-based surveillance for detection of respiratory syncytial virus seasons.

In this study, we validated the Centers for Disease Control and Prevention's use of a 10% threshold of median proportion of positive laboratory tests (median proportion positive (MPP)) to identify respiratory syncytial virus (RSV) seasons against a standard based on hospitalization claims. Medicaid fee-for-service recipients under 2 years of age from California, Florida, Illinois, and Texas (1999-2004), continuously eligible since birth, were categorized for each week as high-risk or low-risk with regard to RSV-related hospitalization based on medical and pharmacy claims data and birth certificates. Weeks were categorized as on-season if the RSV hospitalization incidence rate in high-risk children exceeded the seasonal peak of the incidence rate in low-risk children. Receiver operating characteristic (ROC) curves were used to measure the ability of MPP to discriminate between on-season and off-season weeks as determined from hospitalization data. Areas under the ROC curve ranged from 0.88 (95% confidence interval: 0.83, 0.92) in Illinois to 0.96 (95% confidence interval: 0.94, 0.98) in California. Requiring at least 5 positive tests in addition to the 10% MPP threshold optimized accuracy, as indicated by minimized root mean square errors. The 10% MPP with the added requirement of at least 5 positive tests is a valid method for identifying clinically significant RSV seasons across geographically diverse states.

Adaptability of High Dimensional Propensity Score Procedure in the Transition from ICD-9 to ICD-10 in the US Healthcare System.

Background: High-Dimensional Propensity Score procedure (HDPS) is a data-driven approach to assist control for confounding in pharmacoepidemiologic research. The transition to the International Classification of Disease (ICD-9/10) in the US health system may pose uncertainty in applying the HDPS procedure. Methods: We assembled a base cohort of patients in MarketScan® Commercial Claims Database who had newly initiated celecoxib or traditional NSAIDs to compare gastrointestinal bleeding risk. We then created bootstrapped hypothetical cohorts from the base cohort with predefined patient selection patterns from the ICD eras. Three strategies for HDPS deployment were tested: 1) split the cohort by ICD era, deploy HDPS twice, and pool the relative risks (pooled RR), 2) consider codes from each ICD era as a separate data dimension and deploy HDPS in the entire cohort (data dimensions) and 3) map ICD codes from both eras to Clinical Classifications Software (CCS) concepts before deploying HDPS in the entire cohort (CCS mapping). We calculated percent bias and root-mean-squared error to compare the strategies. Results: A similar bias reduction was observed in cohorts where patient selection pattern from each ICD era was comparable between the exposure groups. In the presence of considerable disparity in patient selection, we observed a bimodal distribution of propensity scores in the data dimensions strategy, indicating instrument-like covariates. Moreover, the CCS mapping strategy resulted in at least 30% less bias than pooled RR and data dimensions strategies (RMSE: 0.14, 0.19, 0.21, respectively) in this scenario. Conclusion: Mapping ICD codes to a stable terminology like CCS serves as a helpful strategy to reduce residual bias when deploying HDPS in pharmacoepidemiologic studies spanning both ICD eras.

Effectiveness of palivizumab prophylaxis in infants and children in Florida.

PURPOSE: Palivizumab effectiveness data on respiratory syncytial virus (RSV) infections are limited to trial settings and vary considerably between selected high-risk populations. This study aimed to evaluate effectiveness in a community-based sample. METHODS: We conducted a cohort study of children with ≥ 3 months Florida Medicaid fee-for-service eligibility between 1998 and 2004 who also had matching birth certificates. Children entered the cohort at the beginning of the RSV season, after a minimum of 60 days in ambulatory care, and were followed until the earliest of the following: season end, second birthday, loss of eligibility, hospitalization, or death. Study endpoint was the first RSV-related hospitalization. To evaluate the presence of confounding, a second endpoint, hospitalizations for pneumonia or bronchiolitis secondary to specified bacterial or viral pathogens other than RSV, was used. Palivizumab exposure defined as first use (day 1-30 of first dose), subsequent use (days 1-30 of each subsequent dose), and former use (days 31-60 after any dose if delays or no readministration occurred) was compared with non-use with a Cox regression model, adjusting for confounders. RESULTS: Hazard ratios (HRs) for RSV hospitalizations were 0.89 (95%CI, 0.71-1.12), 0.56 (95%CI, 0.46-0.69), and 0.71 (95%CI, 0.51-0.97) for first, subsequent, and former use, respectively. HRs for hospitalization because of non-RSV infections were 1.31 (95%CI, 1.04-1.65), 1.03 (95%CI, 0.86-1.23), and 1.05 (95%CI, 0.78-1.41), indicating residual confounding for first but not for subsequent and former use. CONCLUSION: In this community-based study, palivizumab was associated with a reduction in severe RSV infections of a magnitude comparable to the lower clinical trial efficacy estimates. Protection appears to extend beyond the currently recommended monthly dosing schedule.

An algorithm to identify preterm infants in administrative claims data.

PURPOSE: To develop and validate an algorithm to identify preterm infants in the absence of birth certificates within Medicaid data. METHODS: Medicaid fee-for-service claims data from Florida (FL) and Texas (TX) were linked to vital statistics data for infants who were continuously eligible during the first 3 months following birth or died within that period. Prematurity was defined as less than 34 weeks gestational age. Using FL as exploratory dataset and vital statistics birth data as gold standard, we developed a logistic regression model from diagnostic and procedure codes commonly associated with preterm care, creating a prematurity score for each infant. A score cutoff was selected that maximized sensitivity while maintaining a positive predictive value (PPV) ≥ 90%. Confirmatory analyses were conducted in the TX datasets. RESULTS: The prevalence of prematurity was 5.2% (95%CI: 5.1-5.2) and 4.5% (95%CI: 4.4-4.6) in FL and TX, respectively. Using only gestational age International Classification of Disease version 9, Clinical Modification (ICD-9-CM) codes (765.20-765.27) associated with inpatient claims achieved sensitivity of 25.7% (FL) and 12.5% (TX), specificity of 99.9% (FL) and (TX), and PPV of 91.7% (FL) and 84.8% (TX). The model had excellent discriminatory validity with a c-statistic of 0.928 (95%CI: 0.925-0.931). The selected cutoff point achieved sensitivity of 52.6%, specificity of 99.8%, and PPV of 91.7% in FL. In TX, sensitivity was 46.8%, specificity was 99.9%, and PPV was 82.2%. CONCLUSION: Identification of prematurity based on gestational age ICD-9-CM codes is not sensitive. The prematurity score has superior construct validity and allows more comprehensive identification of preterm infants in the absence of birth certificates.