Chronic Obstructive Pulmonary Disease Exacerbations and Pneumonia Hospitalizations Among New Users of Combination Maintenance Inhalers.

Importance: Clinical guidelines on chronic obstructive pulmonary disease (COPD) recommend inhalers containing long-acting muscarinic antagonists (LAMAs) and long-acting ß-agonists (LABAs) over inhalers containing inhaled corticosteroids (ICSs) and LABAs. However, data from randomized clinical trials comparing these combination inhalers (LAMA-LABAs vs ICS-LABAs) have been conflicting and raised concerns of generalizability. Objective: To assess whether LAMA-LABA therapy is associated with reduced COPD exacerbations and pneumonia hospitalizations compared with ICS-LABA therapy in routine clinical practice. Design, Setting, and Participants: This was a 1:1 propensity score-matched cohort study using Optum's Clinformatics Data Mart, a large commercial insurance-claims database. Patients must have had a diagnosis of COPD and filled a new prescription for a combination LAMA-LABA or ICS-LABA inhaler between January 1, 2014, and December 31, 2019. Patients younger than 40 years were excluded, as were those with a prior diagnosis of asthma. The current analysis was performed from February 2021 to March 2023. Exposures: Combination LAMA-LABA inhalers (aclidinium-formoterol, glycopyrronium-formoterol, glycopyrronium-indacaterol, tiotropium-olodaterol, or umeclidinium-vilanterol) and combination ICS-LABA inhalers (budesonide-formoterol, fluticasone-salmeterol, fluticasone-vilanterol, or mometasone-formoterol). Main Outcome: The primary effectiveness outcome was first moderate or severe COPD exacerbation, and the primary safety outcome was first pneumonia hospitalization. Propensity score matching was used to control for confounding between the 2 groups. Logistic regression analysis was used to estimate propensity scores. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models stratified on matched pairs. Results: Among 137 833 patients (mean [SD] age, 70.2 [9.9] years; 69 530 [50.4%] female) (107 004 new ICS-LABA users and 30 829 new LAMA-LABA users), 30 216 matched pairs were identified for the primary analysis. Compared with ICS-LABA use, LAMA-LABA use was associated with an 8% reduction in the rate of first moderate or severe COPD exacerbation (HR, 0.92; 95% CI, 0.89-0.96) and a 20% reduction in the rate of first pneumonia hospitalization (HR, 0.80; 95% CI, 0.75-0.86). These findings were robust across a range of prespecified subgroup and sensitivity analyses. Conclusion: In this cohort study, LAMA-LABA therapy was associated with improved clinical outcomes compared with ICS-LABA therapy, suggesting that LAMA-LABA therapy should be preferred for patients with COPD.

Prospective validation of a dynamic prognostic model for identifying COVID-19 patients at high risk of rapid deterioration.

BACKGROUND: We sought to develop and prospectively validate a dynamic model that incorporates changes in biomarkers to predict rapid clinical deterioration in patients hospitalized for COVID-19. METHODS: We established a retrospective cohort of hospitalized patients aged ≥18 years with laboratory-confirmed COVID-19 using electronic health records (EHR) from a large integrated care delivery network in Massachusetts including >40 facilities from March to November 2020. A total of 71 factors, including time-varying vital signs and laboratory findings during hospitalization were screened. We used elastic net regression and tree-based scan statistics for variable selection to predict rapid deterioration, defined as progression by two levels of a published severity scale in the next 24 h. The development cohort included the first 70% of patients identified chronologically in calendar time; the latter 30% served as the validation cohort. A cut-off point was estimated to alert clinicians of high risk of imminent clinical deterioration. RESULTS: Overall, 3706 patients (2587 in the development and 1119 in the validation cohort) met the eligibility criteria with a median of 6 days of follow-up. Twenty-four variables were selected in the final model, including 16 dynamic changes of laboratory results or vital signs. Area under the ROC curve was 0.81 (95% CI, 0.79-0.82) in the development set and 0.74 (95% CI, 0.71-0.78) in the validation set. The model was well calibrated (slope = 0.84 and intercept = -0.07 on the calibration plot in the validation set). The estimated cut-off point, with a positive predictive value of 83%, was 0.78. CONCLUSIONS: Our prospectively validated dynamic prognostic model demonstrated temporal generalizability in a rapidly evolving pandemic and can be used to inform day-to-day treatment and resource allocation decisions based on dynamic changes in biophysiological factors.

Association between initiation of fluoroquinolones and hospital admission or emergency department visit for suicidality: population based cohort study.

OBJECTIVE: To evaluate the association between initiation of fluoroquinolones and hospital admission or emergency department visit for suicidality. DESIGN: Population based cohort study. SETTING: IBM MarketScan database, USA. PARTICIPANTS: 2 756 268 adults (≥18 years) who initiated an oral fluoroquinolone (ciprofloxacin, levofloxacin, moxifloxacin, gemifloxacin, ofloxacin, gatifloxacin, norfloxacin, lomefloxacin, besifloxacin) or comparator antibiotic (January 2003 to September 2015) and had at least six months of continuous health plan enrollment and a diagnosis of pneumonia or urinary tract infection (UTI) three days or less before the drug initiation date. Comparator antibiotics were azithromycin in the pneumonia cohort and trimethoprim-sulfamethoxazole in the UTI cohort. Participants were matched 1:1 within each cohort on a propensity score, calculated from a multivariable logistic regression model that included 57 baseline covariates. MAIN OUTCOMES MEASURE: Primary outcome was hospital admission or emergency department visit for suicidal ideation or self-harm within 60 days after treatment initiation. Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals. RESULTS: The pneumonia cohort included 551 042 individuals, and the UTI cohort included 2 205 526 individuals. During the 60 day follow-up, 181 events were observed in the pneumonia cohort and 966 in the UTI cohort. The adjusted hazard ratios for fluoroquinolones were 1.01 (95% confidence interval 0.76 to 1.36) versus azithromycin in the pneumonia cohort and 1.03 (0.91 to 1.17) versus trimethoprim-sulfamethoxazole in the UTI cohort. Results were consistent across sensitivity analyses and subgroups of sex, age, or history of mental illnesses. CONCLUSION: Initiation of fluoroquinolones was not associated with a substantially increased risk of admission to hospital or emergency department visits for suicidality compared with azithromycin or trimethoprim-sulfamethoxazole.

Partition testing for real-world evidence studies.

Traditional approaches to hypothesis testing in comparative post-approval safety and effectiveness studies of medical products are often inadequate because of a limited scope of possible inferences (e.g., superiority or inferiority). Often there is interest in simultaneously testing for superiority, equivalence, inferiority, non-inferiority, and non-superiority, which can be achieved using a partition testing framework. Partition testing only requires selection of an equivalence margin and calculation of a two-sided Wald confidence interval. In addition to permitting a broader range of inferences, the strengths of the approach include: mitigating publication bias, avoiding use of a clinically irrelevant nil hypothesis, and more transparent and impartial appraisal of the clinical importance of a study's findings by pre-specifying an equivalence margin. However, a challenge in implementing the approach can be the process for identifying an equivalence margin. The methodology is illustrated using a published study of the safety of Ondansetron for the off-label treatment of nausea and vomiting during pregnancy. Applying the method to the study results would have led to a conclusion that women exposed to Ondansetron in comparison to those that are not, are equivalent with respect to risk of cardiac malformations and oral clefts. These conclusions are more in line with the magnitude of the observed effects than the conclusions resulting from a traditional inferiority/superiority testing conducted by the study authors.

Comparative Risk of Opioid Overdose With Concomitant Use of Prescription Opioids and Skeletal Muscle Relaxants.

BACKGROUND AND OBJECTIVES: The concomitant use of prescription opioids and skeletal muscle relaxants has been associated with opioid overdose, but little data exist on the head-to-head safety of these drug combinations. The objective of this study was to compare the risk of opioid overdose among patients on long-term opioid therapy who concurrently initiate skeletal muscle relaxants. METHODS: We conducted an active comparator cohort study spanning 2000 to 2019 using healthcare utilization data from 4 US commercial and public insurance databases. Individuals were required to have at least 180 days of continuous enrollment and at least 90 days of continuous prescription opioid use immediately before and on the date of skeletal muscle relaxant initiation. Exposures were the concomitant use of prescription opioids and skeletal muscle relaxants, and the main outcome was the hazard ratio (HR) and bootstrapped 95% CI of opioid overdose resulting in an emergency department visit or hospitalization. The primary analysis quantified opioid overdose risk across 7 prescription opioid-skeletal muscle relaxant therapies and a negative control outcome (sepsis) to assess potential confounding by unmeasured illicit opioid use. Secondary analyses evaluated two-group and five-group comparisons in patients with similar baseline characteristics; individuals without previous recorded substance abuse; and subgroups stratified by baseline opioid dosage, benzodiazepine codispensing, and oxycodone or hydrocodone use. RESULTS: Weighted HR of opioid overdose relative to cyclobenzaprine was 2.52 (95% CI 1.29-4.90) for baclofen; 1.64 (95% CI 0.81-3.34) for carisoprodol; 1.14 (95% CI 0.53-2.46) for chlorzoxazone/orphenadrine; 0.46 (95% CI 0.17-1.24) for metaxalone; 1.00 (95% CI 0.45-2.20) for methocarbamol; and 1.07 (95% CI 0.49-2.33) for tizanidine in the 30-day intention-to-treat analysis. Findings were similar in the as-treated analysis, 2-group and 5-group comparisons, and patients without previous recorded substance abuse. None of the therapies relative to cyclobenzaprine were associated with sepsis, and no subgroups indicated an increased risk of opioid overdose. DISCUSSION: Concomitant use of prescription opioids and baclofen relative to cyclobenzaprine is associated with opioid overdose. Clinical interventions may focus on prescribing alternatives in the same drug class or providing access to opioid antagonists if treatment with both medications is necessary for pain management.

Association of Type of Oral Anticoagulant Dispensed With Adverse Clinical Outcomes in Patients Extending Anticoagulation Therapy Beyond 90 Days After Hospitalization for Venous Thromboembolism.

Importance: Guidelines for managing venous thromboembolism (VTE) recommend at least 90 days of therapy with oral anticoagulants. Limited evidence exists about the optimal drug for continuing therapy beyond 90 days. Objective: To compare having prescriptions dispensed for apixaban, rivaroxaban, or warfarin after an initial 90 days of anticoagulation therapy for the outcomes of hospitalization for recurrent VTE, major bleeding, and death. Design, Setting, and Participants: This exploratory retrospective cohort study used data from fee-for-service Medicare (2009-2017) and from 2 commercial health insurance (2004-2018) databases and included 64 642 adults who initiated oral anticoagulation following hospitalization discharge for VTE and continued treatment beyond 90 days. Exposures: Apixaban, rivaroxaban, or warfarin prescribed after an initial 90-day treatment for VTE. Main Outcomes and Measures: Primary outcomes included hospitalization for recurrent VTE and hospitalization for major bleeding. Analyses were adjusted using propensity score weighting. Patients were followed up from the end of the initial 90-day treatment episode until treatment cessation, outcome, death, disenrollment, or end of available data. Weighted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs. Results: The study included 9167 patients prescribed apixaban (mean [SD] age, 71 [14] years; 5491 [59.9%] women), 12 468 patients prescribed rivaroxaban (mean [SD] age, 69 [14] years; 7067 [56.7%] women), and 43 007 patients prescribed warfarin (mean [SD] age, 70 [15] years; 25 404 [59.1%] women). The median (IQR) follow-up was 109 (59-228) days for recurrent VTE and 108 (58-226) days for major bleeding outcome. After propensity score weighting, the incidence rate of hospitalization for recurrent VTE was significantly lower for apixaban compared with warfarin (9.8 vs 13.5 per 1000 person-years; HR, 0.69 [95% CI, 0.49-0.99]), but the incidence rates were not significantly different between apixaban and rivaroxaban (9.8 vs 11.6 per 1000 person-years; HR, 0.80 [95% CI, 0.53-1.19]) or rivaroxaban and warfarin (HR, 0.87 [95% CI, 0.65-1.16]). Rates of hospitalization for major bleeding were 44.4 per 1000 person-years for apixaban, 50.0 per 1000 person-years for rivaroxaban, and 47.1 per 1000 person-years for warfarin, yielding HRs of 0.92 (95% CI, 0.78-1.09) for apixaban vs warfarin, 0.86 (95% CI, 0.71-1.04) for apixaban vs rivaroxaban, and 1.07 (95% CI, 0.93-1.24) for rivaroxaban vs warfarin. Conclusions and Relevance: In this exploratory analysis of patients prescribed extended-duration oral anticoagulation therapy after hospitalization for VTE, prescription dispenses for apixaban beyond 90 days, compared with warfarin beyond 90 days, were significantly associated with a modestly lower rate of hospitalization for recurrent VTE, but no significant difference in rate of hospitalization for major bleeding. There were no significant differences for comparisons of apixaban vs rivaroxaban or rivaroxaban vs warfarin.

Risk of Opioid Overdose Associated With Concomitant Use of Oxycodone and Selective Serotonin Reuptake Inhibitors.

Importance: Some selective serotonin reuptake inhibitors (SSRIs) inhibit the enzymes responsible for the metabolism of oxycodone, a potent prescription opioid. The clinical consequences of this interaction on the risk of opioid overdose have not been elucidated. Objective: To compare opioid overdose rates in patients initiating oxycodone while taking SSRIs that are potent inhibitors of the cytochrome-P450 2D6 enzyme (CYP2D6) vs SSRIs that are not. Design, Setting, and Participants: This cohort study included adults who initiated oxycodone while receiving SSRI therapy between 2000 and 2020 whose data were included in 3 US health insurance databases. Exposures: Use of SSRIs that strongly inhibit CYP2D6 enzyme (fluoxetine or paroxetine) vs use of other SSRIs at the time of oxycodone initiation. Main Outcomes and Measures: Opioid overdose hospitalization or emergency department visit. Outcomes were assessed within 365 days of oxycodone initiation; in primary analyses, patients were followed up until the discontinuation of either oxycodone or their index SSRI group. Propensity score matching weights were used to adjust for confounding. Crude and weighted (adjusted) incidence rates and hazard ratios were estimated using Cox regression models, separately within each database and overall, stratifying on database. Results: A total of 2 037 490 initiated oxycodone while taking SSRIs (1 475 114 [72.4%] women; mean [SD] age, 50.1 [15.3] years). Most (1 418 712 [69.6%]) were receiving other SSRIs at the time of oxycodone initiation. In the primary analysis, we observed 1035 overdose events (0.05% of the study cohort). The adjusted incidence rate of opioid overdose in those using inhibiting SSRIs at the time of oxycodone initiation (9.47 per 1000 person-years) was higher than in those using other SSRIs (7.66 per 1000 person-years), indicating a greater risk of overdose among patients using CYP2D6-inhibiting SSRIs (adjusted hazard ratio, 1.23; 95% CI, 1.06-1.31). Results were consistent across multiple subgroup and sensitivity analyses. Conclusions and Relevance: In this cohort study of US adults, initiating oxycodone in patients treated with paroxetine or fluoxetine was associated with a small increased risk of opioid overdose.

Transparency of high-dimensional propensity score analyses: Guidance for diagnostics and reporting.

PURPOSE: The high-dimensional propensity score (HDPS) is a semi-automated procedure for confounder identification, prioritisation and adjustment in large healthcare databases that requires investigators to specify data dimensions, prioritisation strategy and tuning parameters. In practice, reporting of these decisions is inconsistent and this can undermine the transparency, and reproducibility of results obtained. We illustrate reporting tools, graphical displays and sensitivity analyses to increase transparency and facilitate evaluation of the robustness of analyses involving HDPS. METHODS: Using a study from the UK Clinical Practice Research Datalink that implemented HDPS we demonstrate the application of the proposed recommendations. RESULTS: We identify seven considerations surrounding the implementation of HDPS, such as the identification of data dimensions, method for code prioritisation and number of variables selected. Graphical diagnostic tools include assessing the balance of key confounders before and after adjusting for empirically selected HDPS covariates and the identification of potentially influential covariates. Sensitivity analyses include varying the number of covariates selected and assessing the impact of covariates behaving empirically as instrumental variables. In our example, results were robust to both the number of covariates selected and the inclusion of potentially influential covariates. Furthermore, our HDPS models achieved good balance in key confounders. CONCLUSIONS: The data-adaptive approach of HDPS and the resulting benefits have led to its popularity as a method for confounder adjustment in pharmacoepidemiological studies. Reporting of HDPS analyses in practice may be improved by the considerations and tools proposed here to increase the transparency and reproducibility of study results.

Longitudinal Data Discontinuity in Electronic Health Records and Consequences for Medication Effectiveness Studies.

Electronic health record (EHR) discontinuity (i.e., receiving care outside of the study EHR system), can lead to information bias in EHR-based real-world evidence (RWE) studies. An algorithm has been previously developed to identify patients with high EHR-continuity. We sought to assess whether applying this algorithm to patient selection for inclusion can reduce bias caused by data-discontinuity in four RWE examples. Among Medicare beneficiaries aged >=65 years from 2007 to 2014, we established 4 cohorts assessing drug effects on short-term or long-term outcomes, respectively. We linked claims data with two US EHR systems and calculated %bias of the multivariable-adjusted effect estimates based on only EHR vs. linked EHR-claims data because the linked data capture medical information recorded outside of the study EHR. Our study cohort included 77,288 patients in system 1 and 60,309 in system 2. We found the subcohort in the lowest quartile of EHR-continuity captured 72-81% of the short-term and only 21-31% of the long-term outcome events, leading to %bias of 6-99% for the short-term and 62-112% for the long-term outcome examples. This trend appeared to be more pronounced in the example using a nonuser comparison rather than an active comparison. We did not find significant treatment effect heterogeneity by EHR-continuity for most subgroups across empirical examples. In EHR-based RWE studies, investigators may consider excluding patients with low algorithm-predicted EHR-continuity as the EHR data capture relatively few of their actual outcomes, and treatment effect estimates in these patients may be unreliable.

Comparison of measures of medication adherence from pharmacy dispensing and insurer claims data.

OBJECTIVE: Medication nonadherence is linked to worsened clinical outcomes and increased costs. Existing system-level adherence interventions rely on insurer claims for patient identification and outcome measurement, yet suffer from incomplete capture and lags in data acquisition. Data from pharmacies regarding prescription filling, captured in retail dispensing, may be more efficient. DATA SOURCES: Pharmacy fill and insurer claims data. STUDY DESIGN: We compared adherence measured using pharmacy fill data to adherence using insurer claims data, expressed as proportion of days covered (PDC) over 12 months. Agreement was evaluated using correlation/validation metrics. We also explored the relationship between adherence in both sources and disease control using prediction modeling. DATA EXTRACTION METHODS: Large pragmatic trial of cardiometabolic disease in an integrated delivery network. PRINCIPAL FINDINGS: Among 1113 patients, adherence was higher in pharmacy fill (mean = 50.0%) versus claims data (mean = 47.4%), although they had moderately high correlation (R = 0.57, 95% CI: 0.53-0.61) with most patients (86.9%) being similarly classified as adherent or nonadherent. Sensitivity and specificity of pharmacy fill versus claims data were high (0.89, 95% CI: 0.86-0.91 and 0.80, 95% CI: 0.75-0.85). Pharmacy fill-based PDC predicted better disease control slightly more than claims-based PDC, although the difference was nonsignificant. CONCLUSIONS: Pharmacy fill data may be an alternative to insurer claims for adherence measurement.

Using a Simple Prescription Gap to Determine Warfarin Discontinuation Can Lead to Substantial Misclassification.

BACKGROUND: Warfarin remains widely used and a key comparator in studies of other direct oral anticoagulants. As longer-than-needed warfarin prescriptions are often provided to allow for dosing adjustments according to international normalized ratios (INRs), the common practice of using a short allowable gap between dispensings to define warfarin discontinuation may lead to substantial misclassification of warfarin exposure. We aimed to quantify such misclassification and determine the optimal algorithm to define warfarin discontinuation. METHODS: We linked Medicare claims data from 2007 to 2014 with a multicenter electronic health records system. The study cohort comprised patients ≥65 years with atrial fibrillation and venous thromboembolism initiating warfarin. We compared results when defining warfarin discontinuation by (1) different gaps (3, 7, 14, 30, and 60 days) between dispensings and (2) having a gap ≤60 days or bridging larger gaps if there was INR ordering at least every 42 days (60_INR). Discontinuation was considered misclassified if there was an INR ≥2 within 7 days after the discontinuation date. RESULTS: Among 3,229 patients, a shorter gap resulted in a shorter mean follow-up time (82, 95, 117, 159, 196, and 259 days for gaps of 3, 7, 14, 30, 60, and 60_INR, respectively; p < 0.001). Incorporating INR (60_INR) can reduce misclassification of warfarin discontinuation from 68 to 4% (p < 0.001). The on-treatment risk estimation of clinical endpoints varied significantly by discontinuation definitions. CONCLUSION: Using a short gap between warfarin dispensings to define discontinuation may lead to substantial misclassification, which can be improved by incorporating intervening INR codes.

Broadening the reach of the FDA Sentinel system: A roadmap for integrating electronic health record data in a causal analysis framework.

The Sentinel System is a major component of the United States Food and Drug Administration's (FDA) approach to active medical product safety surveillance. While Sentinel has historically relied on large quantities of health insurance claims data, leveraging longitudinal electronic health records (EHRs) that contain more detailed clinical information, as structured and unstructured features, may address some of the current gaps in capabilities. We identify key challenges when using EHR data to investigate medical product safety in a scalable and accelerated way, outline potential solutions, and describe the Sentinel Innovation Center's initiatives to put solutions into practice by expanding and strengthening the existing system with a query-ready, large-scale data infrastructure of linked EHR and claims data. We describe our initiatives in four strategic priority areas: (1) data infrastructure, (2) feature engineering, (3) causal inference, and (4) detection analytics, with the goal of incorporating emerging data science innovations to maximize the utility of EHR data for medical product safety surveillance.

Frailty and Clinical Outcomes of Direct Oral Anticoagulants Versus Warfarin in Older Adults With Atrial Fibrillation : A Cohort Study.

BACKGROUND: The role of differing levels of frailty in the choice of oral anticoagulants for older adults with atrial fibrillation (AF) is unclear. OBJECTIVE: To examine the outcomes of direct oral anticoagulants (DOACs) versus warfarin by frailty levels. DESIGN: 1:1 propensity score-matched analysis of Medicare data, 2010 to 2017. SETTING: Community. PATIENTS: Medicare beneficiaries with AF who initiated use of dabigatran, rivaroxaban, apixaban, or warfarin. MEASUREMENTS: Composite end point of death, ischemic stroke, or major bleeding by frailty levels, defined by a claims-based frailty index. RESULTS: In the dabigatran-warfarin cohort (n = 158 730; median follow-up, 72 days), the event rate per 1000 person-years was 63.5 for dabigatran initiators and 65.6 for warfarin initiators (hazard ratio [HR], 0.98 [95% CI, 0.92 to 1.05]; rate difference [RD], -2.2 [CI, -6.5 to 2.1]). For nonfrail, prefrail, and frail persons, HRs were 0.81 (CI, 0.68 to 0.97), 0.98 (CI, 0.90 to 1.08), and 1.09 (CI, 0.96 to 1.23), respectively. In the rivaroxaban-warfarin cohort (n = 275 944; median follow-up, 82 days), the event rate per 1000 person-years was 77.8 for rivaroxaban initiators and 83.7 for warfarin initiators (HR, 0.98 [CI, 0.94 to 1.02]; RD, -5.9 [CI, -9.4 to -2.4]). For nonfrail, prefrail, and frail persons, HRs were 0.88 (CI, 0.77 to 0.99), 1.04 (CI, 0.98 to 1.10), and 0.96 (CI, 0.89 to 1.04), respectively. In the apixaban-warfarin cohort (n = 218 738; median follow-up, 84 days), the event rate per 1000 person-years was 60.1 for apixaban initiators and 92.3 for warfarin initiators (HR, 0.68 [CI, 0.65 to 0.72]; RD, -32.2 [CI, -36.1 to -28.3]). For nonfrail, prefrail, and frail persons, HRs were 0.61 (CI, 0.52 to 0.71), 0.66 (CI, 0.61 to 0.70), and 0.73 (CI, 0.67 to 0.80), respectively. LIMITATIONS: Residual confounding and lack of clinical frailty assessment. CONCLUSION: For older adults with AF, apixaban was associated with lower rates of adverse events across all frailty levels. Dabigatran and rivaroxaban were associated with lower event rates only among nonfrail patients. PRIMARY FUNDING SOURCE: National Institute on Aging.

Factors Associated With Generic Drug Uptake in the United States, 2012 to 2017.

OBJECTIVES: In the United States, brand-name prescription drugs remain expensive until market exclusivity ends and lower-cost generics become available. Delayed generic drug uptake may increase spending and worsen medication adherence and patient outcomes. We assessed recent trends and factors associated with generic uptake. METHODS: Among 227 drugs facing new generic competition from 2012 to 2017, we used a national claims database to measure generic uptake in the first and second year after generic entry, defined as the proportion of claims for a generic version of the drug. Using linear regression, we evaluated associations between generic uptake and key drug characteristics. RESULTS: Mean generic uptake was 66.1% (standard deviation 22.1%) in the first year and 82.7% (standard deviation 21.6%) in the second year after generic entry. From 2012 to 2017 generic uptake decreased 4.3% per year in the first year (95% confidence interval, 2.8%-5.8%, P < .001) and 3.2%/year in the second year (95% confidence interval, 1.2%-5.1%). Generic uptake was lower for injected than oral drugs in the first year (38.5% vs 70.0%, P < .001) and second year (50.3% vs 86.9%, P < .001). In the second year, generic uptake was higher among drugs with an authorized generic (86.1 vs 80.1%, P = .045) and those with ≥3 generic competitors (87.7% vs 78.6%, P = .055). CONCLUSION: Early generic uptake decreased over the past several years. This trend may adversely affect patients and increase prescription drug spending. Policies are needed to encourage generic competition, particularly among injected drugs administered in a hospital or clinic setting.

Coprescription of Opioids With Other Medications and Risk of Opioid Overdose.

Polypharmacy is common among patients taking prescription opioids long-term, and the codispensing of interacting medications may further increase opioid overdose risk. To identify nonopioid medications that may increase opioid overdose risk in this population, we conducted a case-crossover-based screening of electronic claims data from IBM MarketScan and Optum Clinformatics Data Mart spanning 2003 through 2019. Eligible patients were 18 years of age or older and had at least 180 days of continuous enrollment and 90 days of prescription opioid use immediately before an opioid overdose resulting in an emergency room visit or hospitalization. The main analysis quantified the odds ratio (OR) between opioid overdose and each nonopioid medication dispensed in the 90 days immediately before the opioid overdose date after adjustment for prescription opioid dosage and benzodiazepine codispensing. Additional analyses restricted to patients without cancer diagnoses and individuals who used only oxycodone for 90 days immediately before the opioid overdose date. The false discovery rate (FDR) was used to account for multiple testing. We identified 24,866 individuals who experienced opioid overdose. Baclofen (OR 1.56; FDR < 0.01; 95% confidence interval (CI), 1.29 to 1.89), lorazepam (OR 1.53; FDR < 0.01; 95% CI, 1.25 to 1.88), and gabapentin (OR 1.16; FDR = 0.09; 95% CI, 1.04 to 1.28), among other nonopioid medications, were associated with opioid overdose. Similar patterns were observed in noncancer patients and individuals who used only oxycodone. Interventions may focus on prescribing safer alternatives when a potential for interaction exists.

A Multi-modal Approach to Evaluate the Impact of Risk Evaluation and Mitigation Strategy (REMS) Programs.

INTRODUCTION: Since 2007, the US Food and Drug Administration has had the authority to require risk evaluation and mitigation strategy (REMS) programs for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks. Such programs can include requirements for patient monitoring, restrictions on dispensing or administration, and physician and pharmacy training and certification. However, there has been only scattered evidence on the impact of REMS programs on informed decision making, medication access, or patient outcomes. OBJECTIVE: The objective of this article was to describe a study that researchers at Brigham and Women's Hospital and Harvard Medical School will conduct in partnership with the Food and Drug Administration's Office of Surveillance and Epidemiology to investigate systematically how REMS programs have operated in practice. METHODS: Investigations include health insurance claims-based analyses to understand patterns of drug use, adherence to safety requirements, and patient outcomes under REMS programs; surveys and interviews to understand physician and patient experiences with REMS; and REMS program material-based and interview-based analyses to understand the effectiveness of risk communication in REMS programs. CONCLUSIONS: These research activities will evaluate the performance of REMS programs, provide information on the benefits and burdens to patients and healthcare providers, and generate recommendations for actionable steps to improve REMS programs overall.