Racial and Ethnic Disparities in Initiation of Direct Oral Anticoagulants Among Medicare Beneficiaries.

Importance: The influence of race and ethnicity on initiation of direct oral anticoagulants (DOACs) is relatively understudied in Medicare data. Objective: To investigate disparities in the initiation of DOACs compared with warfarin by race, ethnicity, and social vulnerability. Design, Setting, and Participants: This retrospective cohort study used a 50% sample of Medicare fee-for-service data from January 1, 2010, to December 31, 2019 (mean patient enrollment duration, 7.7 years). Analysis took place between January 2023 and February 2024. A cohort of older adults (aged ≥65 years) with atrial fibrillation who newly initiated warfarin or DOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) was identified. Exposure: Patients were classified as non-Hispanic White, non-Hispanic Black, and Hispanic. Main Outcomes and Measures: The likelihood of starting use of DOACs compared with warfarin was modeled, adjusting for race, ethnicity, age, sex, county-level social vulnerability, and other clinical factors. Results: Among 950 698 anticoagulation initiations, consisting of 680 974 DOAC users and 269 724 warfarin users (mean [SD] age, 78.5 [7.6] years; 52.6% female), 5.2% were Black, 4.3% were Hispanic, and 86.7% were White. During the 10-year study period, DOAC use increased for all demographic groups. After adjustment, compared with White patients, Black patients were 23% less likely (adjusted odds ratio [AOR, 0.77; 95% CI, 0.75-0.79) and Hispanic patients were 13% less likely (AOR, 0.87; 95% CI, 0.85-0.89) to initiate DOAC use. Disparities in DOAC initiation were greatest among Black patients in the earlier years but attenuated during the study period. For instance, in 2010, the OR of Black patients initiating DOACs was 0.54 (95% CI, 0.50-0.57), attenuating linearly over time to 0.69 by 2013 (95% CI, 0.65-0.74) and 0.83 (95% CI, 0.78-0.89) by 2017. By 2019, these differences became nonsignificant (OR, 1.08; 95% CI, 0.99-1.18). Conclusions and Relevance: In this cohort study of Medicare patients with atrial fibrillation, Black and Hispanic patients were less likely to initiate DOACs for atrial fibrillation, although these differences diminished over time. Identifying the factors behind these early disparities is crucial for ensuring equitable access to novel therapies as they emerge for Black and Hispanic populations.

Prescribing trends of SGLT2 inhibitors among HFrEF and HFpEF patients with and without T2DM, 2013-2021.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are recommended for treatment of heart failure (HF), regardless of type 2 diabetes (T2DM) status. However, limited data exist on SGLT2i prescribing in HF patients without T2DM or across HF subtypes. METHODS: This was a serial, cross-sectional study of US MarketScan commercial and Medicare claims (2013-2021). Prevalence of SGLT2i was calculated by calendar year among HFrEF and HFpEF patients and stratified by T2DM status. RESULTS: Among 218,066 HFrEF patients [mean (SD): 54.9 (8.92) years; 66.4% male], the prevalence of SGLT2i use increased from 0.3 to 18.6%, while among 150,437 HFpEF patients [56.5 (7.77) years; 47.6% male], it rose from 0.5 to 9.9%. These increases were driven by the subgroup with comorbid T2DM. SGLT2i prevalence use ratios among patients with T2DM compared to those without decreased from > 100 in 2018 to 3.8 in 2021 among HFrEF patients, and from 83.1 in 2018 to 17.5 in 2021, coinciding with the publication of landmark trials and corresponding changes in clinical guidelines. CONCLUSIONS: SGLT2i use rose rapidly following changes in guidelines but remained low among those without T2DM. By the end of the study, approximately 1 in 3 HFrEF and 1 in 5 HFpEF patients with T2DM were using an SGLT2i, compared to only 1 in 11 HFrEF and 1 in 85 HFpEF patients without T2DM. Future work identifying barriers with the uptake of GDMT, including SGLT2i, among HF patients is needed.

Antihypertensive Medication and Fracture Risk in Older Veterans Health Administration Nursing Home Residents.

Importance: Limited evidence exists on the association between initiation of antihypertensive medication and risk of fractures in older long-term nursing home residents. Objective: To assess the association between antihypertensive medication initiation and risk of fracture. Design, Setting, and Participants: This was a retrospective cohort study using target trial emulation for data derived from 29 648 older long-term care nursing home residents in the Veterans Health Administration (VA) from January 1, 2006, to October 31, 2019. Data were analyzed from December 1, 2021, to November 11, 2023. Exposure: Episodes of antihypertensive medication initiation were identified, and eligible initiation episodes were matched with comparable controls who did not initiate therapy. Main Outcome and Measures: The primary outcome was nontraumatic fracture of the humerus, hip, pelvis, radius, or ulna within 30 days of antihypertensive medication initiation. Results were computed among subgroups of residents with dementia, across systolic and diastolic blood pressure thresholds of 140 and 80 mm Hg, respectively, and with use of prior antihypertensive therapies. Analyses were adjusted for more than 50 baseline covariates using 1:4 propensity score matching. Results: Data from 29 648 individuals were included in this study (mean [SD] age, 78.0 [8.4] years; 28 952 [97.7%] male). In the propensity score-matched cohort of 64 710 residents (mean [SD] age, 77.9 [8.5] years), the incidence rate of fractures per 100 person-years in residents initiating antihypertensive medication was 5.4 compared with 2.2 in the control arm. This finding corresponded to an adjusted hazard ratio (HR) of 2.42 (95% CI, 1.43-4.08) and an adjusted excess risk per 100 person-years of 3.12 (95% CI, 0.95-6.78). Antihypertensive medication initiation was also associated with higher risk of severe falls requiring hospitalizations or emergency department visits (HR, 1.80 [95% CI, 1.53-2.13]) and syncope (HR, 1.69 [95% CI, 1.30-2.19]). The magnitude of fracture risk was numerically higher among subgroups of residents with dementia (HR, 3.28 [95% CI, 1.76-6.10]), systolic blood pressure of 140 mm Hg or higher (HR, 3.12 [95% CI, 1.71-5.69]), diastolic blood pressure of 80 mm Hg or higher (HR, 4.41 [95% CI, 1.67-11.68]), and no recent antihypertensive medication use (HR, 4.77 [95% CI, 1.49-15.32]). Conclusions and Relevance: Findings indicated that initiation of antihypertensive medication was associated with elevated risks of fractures and falls. These risks were numerically higher among residents with dementia, higher baseline blood pressures values, and no recent antihypertensive medication use. Caution and additional monitoring are advised when initiating antihypertensive medication in this vulnerable population.

Impairment in recognition memory may be associated with near-term risk for suicide attempt in a high-risk sample.

INTRODUCTION: Prior work has implicated several neurocognitive domains, including memory, in patients with a history of prior suicide attempt. The current study evaluated whether a delayed recognition test could enhance prospective prediction of near-term suicide outcomes in a sample of patients at high-risk for suicide. METHODS: 132 Veterans at high-risk for suicide completed a computer-based recognition memory test including semantically-related and -unrelated words. Outcomes were coded as actual suicide attempt (ASA), other suicide-related event (OtherSE) such as aborted/interrupted attempt or preparatory behavior, or neither (noSE), within 90 days after testing. RESULTS: Reduced performance was a significant predictor of upcoming ASA, but not OtherSE, after controlling for standard clinical variables such as current suicidal ideation and history of prior suicide attempt. However, compared to the noSE reference group, the OtherSE group showed a reduction in the expected benefit of semantic relatedness in recognizing familiar words. A computational model, the drift diffusion model (DDM), to explore latent cognitive processes, revealed the OtherSE group had decreased decisional efficiency for semantically-related compared to semantically-unrelated familiar words. LIMITATIONS: This study was a secondary analysis of an existing dataset, involving participants in a treatment trial, and requires replication; ~10 % of the sample was excluded from analysis due to failure to master the practice tasks and/or apparent noncompliance. CONCLUSION: Impairments in recognition memory may be associated with near-term risk for suicide attempt, and may provide a tool to improve prediction of when at-risk individuals may be transitioning into a period of heightened risk for suicide attempt.

The impact of drug shortages on drug prices: evidence from China.

Introduction: Drug shortages pose a serious global public health challenge, affecting China and other countries. Evidence from USA shows that short-supplied drugs demonstrated a very high price growth during and after a shortage. However, the effect of shortages on drug prices in China remains unknown. This paper aims to understand the impact of drug shortages on prices and explore implications for shortage prevention policy. Methods: We collected the purchase prices and delivery rates of 120 drugs from April 2019 to December 2021 across whole China. We examined price progression of affected drugs using linear mixed-effects models and performed subgroup analyses based on the number of manufacturers and the severity of shortage. Results: Non-shortage cohort had an annual price growth of 11.62% (95% confidence interval [CI] 8.34 to 14.98). Shortage cohort demonstrated an annual price growth of 8.08% (95%CI 0.12 to 16.77) in the period preceding a shortage, 27.57% (95%CI 6.17 to 52.87) during a shortage, and 9.38% (95%CI -12.64 to 36.39) in the post-shortage period. Drug shortages' impact on prices varied across subgroups. Compared with that of drug markets supplied by a single manufacturer, the price growth rate of markets supplied by more than one manufacture declined more after the shortage resolution. Conclusion: Shortages resulted in significant price increases of study markets, especially the low-priced markets, while the shortage resolution slowed the growth. The primary shortage driver has shifted from the low price to others drivers, such as unavailability of active pharmaceutical ingredients. For currently sole-supplied drugs, the expedited review of applications from other manufacturers should be considered.

Initiation Patterns of Disease-Modifying Therapies for Multiple Sclerosis Among US Adults and Children, 2001 Through 2020.

Importance: Many disease-modifying therapies (DMTs) have been approved for multiple sclerosis (MS) in the past 2 decades. Research evaluating how these approvals have changed real-world prescribing patterns is scarce. Objective: To evaluate patterns in DMT initiations between 2001 and 2020 among commercially insured US adults and children with MS. Design, Setting, and Participants: This serial cross-sectional study was conducted from 2001 through 2020 (mean patient enrollment duration, 4.8 years) and used US commercial claims data (MarketScan). Analysis took place between January 2022 and March 2023. Of 287 084 patients with MS identified, 113 583 patients (113 095 adults and 488 children) with MS newly initiated at least 1 DMT. Exposure: New initiation episode of a DMT, defined as no claim for the same DMT in the previous year. Main Outcome Measure: The proportion of total DMT initiations per year attributable to each DMT. Trends in initiations were evaluated annually. Results: The study team identified 153 846 DMT initiation episodes among adults (median age, 46 [IQR, 38-53) years]; 86 133 female [76.2%]) and 583 among children (median age, 16 (IQR, 14-17) years; 346 female [70.9%]). Among adults, use of platform injectables showed an absolute decline of 73.8% over the study period, driven by a 61.2% reduction in interferon ß initiations (P < .001 for trend). In contrast, the 2010 introduction of oral DMTs led to a rise in their use from 1.1% (2010) to 62.3% (2020) of all DMT initiations (P = .002 for trend). Infusion therapy initiations remained relatively low, accounting for 3.2% of all initiations since their introduction in 2004 but increased modestly annually after ocrelizumab was introduced (2017), reaching 8.2% of all initiations in 2020 (P < .001 for trend). Children showed similar initiation patterns, except for preferred oral therapy. Between 2019 and 2020, dimethyl fumarate was the most commonly initiated DMT in adults (23.3% to 27.2% of all initiations), while in children fingolimod was the most commonly initiated (34.8% to 68.8%). Conclusions and Relevance: Current MS treatment guidelines emphasize shared decision-making between patients and clinicians to balance treatment efficacy, safety, cost, and convenience. This study found that oral DMTs were the predominant DMT type initiated by 2020. The cause of this shift cannot be determined from this study, but may reflect several factors, including convenience of administration, direct-to-consumer advertising, or insurance restrictions.

Cardiovascular outcomes with SGLT2 inhibitors versus DPP4 inhibitors and GLP-1 receptor agonists in patients with heart failure with reduced and preserved ejection fraction.

BACKGROUND: No study has compared the cardiovascular outcomes for sodium-glucose cotransporter-2 inhibitors (SGLT2i) head-to-head against other glucose-lowering therapies, including dipeptidyl peptidase 4 inhibitor (DDP4i) or glucagon-like peptide-1 receptor agonist (GLP-1RA)-which also have cardiovascular benefits-in patients with heart failure with reduced (HFrEF) or preserved (HFpEF) ejection fraction. METHODS: Medicare fee-for-service data (2013-2019) were used to create four pair-wise comparison cohorts of type 2 diabetes patients with: (1a) HFrEF initiating SGLT2i versus DPP4i; (1b) HFrEF initiating SGLT2i versus GLP-1RA; (2a) HFpEF initiating SGLT2i versus DPP4i; and (2b) HFpEF initiating SGLT2i versus GLP-1RA. The primary outcomes were (1) hospitalization for heart failure (HHF) and (2) myocardial infarction (MI) or stroke hospitalizations. Adjusted hazards ratios (HR) and 95% CIs were estimated using inverse probability of treatment weighting. RESULTS: Among HFrEF patients, initiation of SGLT2i versus DPP4i (cohort 1a; n = 13,882) was associated with a lower risk of HHF (adjusted Hazard Ratio [HR (95% confidence interval)], 0.67 (0.63, 0.72) and MI or stroke (HR: 0.86 [0.75, 0.99]), and initiation of SGLT2i versus GLP-1RA (cohort 1b; n = 6951) was associated with lower risk of HHF (HR: 0.86 [0.79, 0.93]), but not MI or stroke (HR: 1.02 [0.85, 1.22]). Among HFpEF patients, initiation of SGLT2i versus DPP4i (cohort 2a; n = 17,493) was associated with lower risk of HHF (HR: 0.65 [0.61, 0.69]) but not MI or stroke (HR: 0.90 [0.79, 1.02]), and initiation of SGLT2i versus GLP-1RA (cohort 2b; n = 9053) was associated with lower risk of HHF (0.89 [0.83, 0.96]), but not MI or stroke (HR: 0.97 [0.83, 1.14]). Results were robust across range of secondary outcomes (e.g., all-cause mortality) and sensitivity analyses. CONCLUSIONS: Bias from residual confounding cannot be ruled out. Use of SGLT2i was associated with reduced risk of HHF against DPP4i and GLP-1RA, reduced risk of MI or stroke against DPP4i within the HFrEF subgroup, and comparable risk of MI or stroke against GLP-1RA. Notably, the magnitude of cardiovascular benefit conferred by SGLT2i was similar among patients with HFrEF and HFpEF.

Validity of International Classification of Diseases (ICD)-10 Diagnosis Codes for Identification of Acute Heart Failure Hospitalization and Heart Failure with Reduced Versus Preserved Ejection Fraction in a National Medicare Sample.

BACKGROUND: Heart failure (HF) is a leading cause of hospitalization in older adults. Medicare data have been used to assess HF outcomes. However, the validity of ICD-10 diagnosis codes (used since 2015) to identify acute HF hospitalization or distinguish reduced (heart failure with reduced ejection fraction) versus preserved ejection fraction (HFpEF) is unknown in Medicare data. METHODS: Using Medicare data (2015-2017), we randomly sampled 200 HF hospitalizations with ICD-10 diagnosis codes for HF in the first/second claim position in a 1:1:2 ratio for systolic HF (I50.2), diastolic HF (I50.3), and other HF (I50.X). The primary gold standards included recorded HF diagnosis by a treating physician for HF hospitalization, ejection fraction (EF)≤50 for heart failure with reduced ejection fraction, and EF>50 for HFpEF. If the quantitative EF was not present, then qualitative descriptions of EF were used for heart failure with reduced ejection fraction/HFpEF gold standards. Multiple secondary gold standards were also tested. Gold standard data were extracted from medical records using standardized forms and adjudicated by cardiology fellows/staff. We calculated positive predictive values with 95% CIs. RESULTS: The 200-chart validation sample included 50 systolic, 50 diastolic, 47 combined dysfunction, and 53 unspecified HF patients. The positive predictive values of acute HF hospitalization was 98% [95% CI, 95-100] for first-position ICD-10 HF diagnosis and 66% [95% CI, 58-74] for first/second-position diagnosis. Quantitative EF was available for ≥80% of patients with systolic, diastolic, or combined dysfunction ICD-10 codes. The positive predictive value of systolic HF codes was 90% [95% CI, 82-98] for EFs≤50% and 72% [95% CI, 60-85] for EFs≤40%. The positive predictive value was 92% [95% CI, 85-100] for HFpEF for EFs>50%. The ICD-10 codes for combined or unspecified HF poorly predicted heart failure with reduced ejection fraction or HFpEF. CONCLUSIONS: ICD-10 principal diagnosis identified acute HF hospitalization with a high positive predictive value. Systolic and diastolic ICD-10 diagnoses reliably identified heart failure with reduced ejection fraction and HFpEF when EF 50% was used as the cutoff.

Improving the prospective prediction of a near-term suicide attempt in veterans at risk for suicide, using a go/no-go task.

BACKGROUND: Neurocognitive testing may advance the goal of predicting near-term suicide risk. The current study examined whether performance on a Go/No-go (GNG) task, and computational modeling to extract latent cognitive variables, could enhance prediction of suicide attempts within next 90 days, among individuals at high-risk for suicide. METHOD: 136 Veterans at high-risk for suicide previously completed a computer-based GNG task requiring rapid responding (Go) to target stimuli, while withholding responses (No-go) to infrequent foil stimuli; behavioral variables included false alarms to foils (failure to inhibit) and missed responses to targets. We conducted a secondary analysis of these data, with outcomes defined as actual suicide attempt (ASA), other suicide-related event (OtherSE) such as interrupted/aborted attempt or preparatory behavior, or neither (noSE), within 90-days after GNG testing, to examine whether GNG variables could improve ASA prediction over standard clinical variables. A computational model (linear ballistic accumulator, LBA) was also applied, to elucidate cognitive mechanisms underlying group differences. RESULTS: On GNG, increased miss rate selectively predicted ASA, while increased false alarm rate predicted OtherSE (without ASA) within the 90-day follow-up window. In LBA modeling, ASA (but not OtherSE) was associated with decreases in decisional efficiency to targets, suggesting differences in the evidence accumulation process were specifically associated with upcoming ASA. CONCLUSIONS: These findings suggest that GNG may improve prediction of near-term suicide risk, with distinct behavioral patterns in those who will attempt suicide within the next 90 days. Computational modeling suggests qualitative differences in cognition in individuals at near-term risk of suicide attempt.

Healthcare costs associated with comorbid cardiovascular and renal conditions among persons with diabetes, 2008-2019.

BACKGROUND: There is paucity of data examining healthcare costs among persons with comorbid diabetes and cardiorenal conditions. OBJECTIVE: To elucidate the longitudinal trends and quantify the incremental healthcare costs associated with the following cardiorenal conditions: atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and kidney disease, among persons with diabetes. METHODS: Medical Expenditure Panel Survey data (2008-2019) were used to identify adults with diabetes and comorbid cardiorenal conditions. Overall, medical and pharmaceutical costs were ascertained (in 2019 US dollars). Analyses were adjusted for 14 variables using a two-part regression model. RESULTS: Among 32,519 adults with diabetes, the mean (standard error [SE]) annual healthcare costs were $13,829 ($213), with medical and prescription components contributing $9301 ($172) and $4528 ($98), respectively. Overall healthcare costs rose by 26.8% from $12,791 (2008-2009) to $16,215 (2018-2019) over the study period, driven by 42.5% and 20.3% increase in pharmaceutical and medical spending, respectively. Similar trends were observed for subgroup of persons with cardiorenal conditions. Compared to their counterparts without cardiorenal conditions and prior to adjustment, persons with ASCVD, HF and kidney disease incurred healthcare costs that were approximately 2.2, 3.3, and 2.7 times greater. After adjustment, comorbid ASCVD, HF and kidney disease were associated with annual excess spending of $8651 (95% CI $7729-$9573), $9373 (95% CI $9010-$9736), and $9995 (95% CI $8781-$11,209), respectively. CONCLUSIONS: Study results are generalizable to non-institutionalized US persons. Healthcare costs associated with the management of diabetes are high-especially among those with comorbid cardiorenal conditions, and have risen in recent years.

Trends in Prescribing Preferences for Antidiabetic Medications Among Patients With Type 2 Diabetes in the U.K. With and Without Chronic Kidney Disease, 2006-2020.

OBJECTIVE: To evaluate trends in antidiabetic medication initiation patterns among patients with type 2 diabetes mellitus (T2DM) with and without chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS: A retrospective cohort study using the UK Clinical Practice Research Datalink (2006-2020) was conducted to evaluate the overall, first-, and second line (after metformin) medication initiation patterns among patients with CKD (n = 38,622) and those without CKD (n = 230,963) who had T2DM. RESULTS: Relative to other glucose-lowering therapies, metformin initiations declined overall but remained the first-line treatment of choice for both patients with and those without CKD. Sodium-glucose cotransporter-2 (SGLT2i) use increased modestly among patients with CKD, but this increase was more pronounced among patients without CKD; by 2020, patients without CKD, compared with patients with CKD, were three (28.5% vs. 9.4%) and six (46.3% vs. 7.9%) times more likely to initiate SGLT2i overall and as second-line therapy, respectively. Glucagon-like peptide 1 receptor agonist (GLP-1RA) use was minimal regardless of CKD status (<5%), whereas both dipeptidyl peptidase-4 inhibitor (DPP4i) and sulfonylurea use remained high among patients with CKD. For instance, by 2020, and among patients with CKD, DPP4i and sulfonylureas constituted 28.3% and 20.6% of all initiations, and 57.4% and 30.3% of second-line initiations, respectively. CONCLUSIONS: SGLT2i use increased among patients with T2DM, but this increase was largely driven by patients without CKD. Work is needed to identify barriers associated with the uptake of therapies with proven cardiorenal benefits (e.g., SGLT2i, GLP-1RA) among patients with CKD.

Frailty Risks of Prescription Analgesics and Sedatives across Frailty Models: the Health and Retirement Study.

INTRODUCTION: Limited evidence for incident frailty risks associated with prescription analgesics and sedatives in older (≥ 65 years) community-living adults prompted a more comprehensive investigation. METHODS: We used data from older Health and Retirement Study respondents and three frailty models (frailty index, functional domain, frailty phenotype with 8803, 10,470, and 6850 non-frail individuals, respectively) and estimated sub-hazard ratios of regular prescription drug use (co-use, analgesic use, and sedative use), by frailty model. We addressed confounding with covariate adjustment and propensity score matching approaches. RESULTS: The baseline prevalence of analgesic and sedative co-use, analgesic use, and sedative use among non-frail respondents was 1.8%, 12.8%, and 4.7% for the frailty index model, 4.2%, 16.2%, and 5.3% for the functional domain model, and 4.3%, 15.4%, and 6.1% for the frailty phenotype model, respectively. Cumulative frailty incidence over 10 years was 39.3%, 36.1%, and 14.2% for frailty index, functional domain, and frailty phenotype models, respectively; covariate-adjusted sub-hazard ratio estimates were 2.00 (1.63-2.45), 1.83 (1.57-2.13), and 1.68 (1.21-2.33) for co-use; 1.72 (1.56-1.89), 1.38 (1.27-1.51), and 1.51 (1.27-1.79) for analgesic use; and 1.46 (1.24-1.72), 1.25 (1.07-1.46), and 1.31 (0.97-1.76) for sedative use. Frailty risk ranking (co-use > analgesic use > sedative use) persisted across all model sensitivity analyses. DISCUSSION: Consistently significant frailty risk estimates of regular prescription analgesic and sedative co-use and of prescription analgesic use support existing clinical, public health, and regulatory guidance on opioid and benzodiazepine co-prescription, on opioid prescription, and on NSAID prescription. Frailty phenotype measurement administration limited power to detect significant frailty risks. Research into specific pharmaceutical exposures and comparison of results across cohorts will be required to contribute to the deprescribing evidence base.

Risks for Anaphylaxis With Intravenous Iron Formulations : A Retrospective Cohort Study.

BACKGROUND: The risks for anaphylaxis among intravenous (IV) iron products currently in use have not been assessed. OBJECTIVE: To compare risks for anaphylaxis among 5 IV iron products that are used frequently. DESIGN: Retrospective cohort study using a target trial emulation framework. SETTING: Medicare fee-for-service data with Part D coverage between July 2013 and December 2018. PARTICIPANTS: Older adults receiving their first administration of IV iron. MEASUREMENTS: The primary outcome was the occurrence of anaphylaxis within 1 day of IV iron administration, ascertained using a validated case definition. Analysis was adjusted for 40 baseline covariates using inverse probability of treatment weighting. The adjusted incidence rates (IRs) for anaphylaxis per 10 000 first administrations and odds ratios (ORs) were computed. RESULTS: The adjusted IRs for anaphylaxis per 10 000 first administrations were 9.8 cases (95% CI, 6.2 to 15.3 cases) for iron dextran, 4.0 cases (CI, 2.5 to 6.6 cases) for ferumoxytol, 1.5 cases (CI, 0.3 to 6.6 cases) for ferric gluconate, 1.2 cases (CI, 0.6 to 2.5 cases) for iron sucrose, and 0.8 cases (CI, 0.3 to 2.6 cases) for ferric carboxymaltose. Using iron sucrose as the referent category, the adjusted ORs for anaphylaxis were 8.3 (CI, 3.5 to 19.8) for iron dextran and 3.4 (CI, 1.4 to 8.3) for ferumoxytol. When cohort entry was restricted to the period after withdrawal of high-molecular-weight iron dextran from the U.S. market in 2014, the risk for anaphylaxis associated with low-molecular-weight iron dextran (OR, 8.4 [CI, 2.8 to 24.7]) did not change appreciably. Anaphylactic reactions requiring hospitalizations were observed only among patients using iron dextran or ferumoxytol. LIMITATION: Generalizability to non-Medicare populations. CONCLUSION: The rates of anaphylaxis were very low with all IV iron products but were 3- to 8-fold greater for iron dextran and ferumoxytol than for iron sucrose. PRIMARY FUNDING SOURCE: None.

Risk of clinically relevant hyperglycemia with metoprolol compared to carvedilol in older adults with heart failure and diabetes.

BACKGROUND: Although prior literature suggests that metoprolol may worsen glucose control compared to carvedilol, whether this has clinical relevance among older adults with diabetes and heart failure (HF) remains an open question. METHODS: This was a US retrospective cohort study utilizing data sourced from a 50% national sample of Medicare fee-for-service claims of patients with part D prescription drug coverage (2007-2017). Among patients with diabetes and HF, we identified initiators of metoprolol or carvedilol, which were 1:1 propensity score matched on >90 variables. The primary outcome was initiation of a new oral or injectable antidiabetic medication (proxy for uncontrolled diabetes); secondary outcomes included initiation of insulin and severe hyperglycemic event (composite of emergency room visits or hospitalizations related to hyperglycemia). RESULTS: Among 24 239 propensity score-matched pairs (mean [SD] age 77.7 [8.0] years; male [39.1%]), there were 8150 (incidence rate per 100 person-years [IR] = 33.5) episodes of antidiabetic medication initiation among metoprolol users (exposure arm) compared to 8576 (IR = 33.4) among carvedilol users (comparator arm) compared to corresponding to an adjusted hazard ratio (aHR) of 0.97 (95% confidence interval [CI]: 0.94, 1.01). Similarly, metoprolol was not associated with a significant increase in the risk of secondary outcomes including insulin initiation: aHR of 0.98 (95% CI: 0.93, 1.04) and severe hyperglycemic events: aHR of 0.98 (95% CI: 0.93, 1.02). CONCLUSIONS: In this large study of older adults with HF and diabetes, initiation of metoprolol compared to carvedilol was not associated with an increase in the risk of clinically relevant hyperglycemia.

Risk of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Addition of SGLT2 Inhibitors Versus Sulfonylureas to Baseline GLP-1RA Therapy.

BACKGROUND: Several glucagon-like peptide receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated cardiovascular benefit in type 2 diabetes in large randomized controlled trials in patients with established cardiovascular disease or multiple risk factors. However, few trial participants were on both agents, and it remains unknown whether the addition of SGLT2i to GLP-1RA therapy has further cardiovascular benefits. METHODS: Patients adding either SGLT2i or sulfonylureas to baseline GLP-1RA were identified within 3 US claims datasets (2013-2018) and were 1:1 propensity score-matched, adjusting for >95 baseline covariates. The primary outcomes were a composite cardiovascular end point (comprising myocardial infarction, stroke, and all-cause mortality) and heart failure hospitalization. Adjusted hazard ratios (HRs) and 95% CIs were estimated in each dataset and pooled through fixed-effects meta-analysis. RESULTS: Among 12 584 propensity score-matched pairs (mean [SD] age, 58.3 [10.9] years; 48.2% male) across the 3 datasets, there were 107 composite cardiovascular end point events (incidence rate per 1000 person-years, 9.9 [95% CI, 8.1-11.9]) among SGLT2i initiators compared with 129 events (incidence rate, 13.0 [95% CI, 10.9-15.3]) among sulfonylurea initiators, corresponding to an adjusted pooled HR of 0.76 (95% CI, 0.59-0.98); this decrease in composite cardiovascular end point was driven by numeric decreases in the risk of myocardial infarction (HR, 0.71 [95% CI, 0.51-1.003]) and all-cause mortality (HR, 0.68 [95% CI, 0.40-1.14]) but not stroke (HR, 1.05 [95% CI, 0.62-1.79]). For the outcome of heart failure hospitalization, there were 141 events (incidence rate, 13.0 [95% CI, 11.0-15.2]) among SGLT2i initiators versus 206 events (incidence rate, 20.8 [95% CI, 18.1-23.8]) among sulfonylurea initiators, corresponding to an adjusted pooled HR of 0.65 (95% CI, 0.50-0.82). CONCLUSIONS: Risk of residual confounding cannot be fully excluded. Individual therapeutic agents within each class may have different magnitudes of effect. In this large real-world cohort of patients with diabetes already on GLP-1RA, addition of SGLT2i conferred greater cardiovascular benefit compared with addition of sulfonylurea. The magnitude of the cardiovascular risk reduction was comparable with the benefit seen in cardiovascular outcome trials of SGLT2i versus placebo, where baseline GLP-1RA use was minimal.

Estimating The Cost Of Delayed Generic Drug Entry To Medicaid.

Delays in market entry of generic drugs are common. This study sought to identify the prevalence of delayed entry, the reasons for the delays, and the delays' effects on Medicaid spending in a recent cohort of brand-name medications. We estimated excess Medicaid spending in 2010-16 in the delayed quarter-years after accounting for market average predictions of brand-name market share, ratios of generic to brand-name prices, and Medicaid rebates (60 percent for brand-name and 15 percent for generic drugs). Among sixty-nine brand-name drugs that were predicted to lose market exclusivity, generic entry occurred either before or within a quarter-year of the expected date for thirty-eight products (55 percent), was delayed by more than one quarter for twenty products (29 percent), and did not occur for eleven products (16 percent). For the thirty-one products (45 percent) for which generic entry was delayed by more than one quarter or did not occur, Medicaid spent an estimated excess of $761 million over seven years ($109 million annually). Patent litigation was the most common cause of generic entry delays. Policies that expedite the resolution of patent challenges are needed to ensure the timely entry of generic drugs.

Trends in Clinical Characteristics and Prescribing Preferences for SGLT2 Inhibitors and GLP-1 Receptor Agonists, 2013-2018.

OBJECTIVE: There is a paucity of data evaluating recent changes in clinical and prescriber characteristics of patients initiating sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA). RESEARCH DESIGN AND METHODS: U.S.-based administrative claims data (July 2013 to June 2018) were used to identify initiators of SGLT2i and GLP-1RA. RESULTS: Over 5 years, empagliflozin initiation (as a proportion of SGLT2i) increased by 57.1% (P < 0.001 for trend), while canagliflozin initiation declined by 75.1% (P < 0.001). Empagliflozin was the only agent within SGLT2i with an increase in the proportion of patients with myocardial infarction, stroke, or heart failure (collectively called CVD-HF) (P < 0.001). Liraglutide initiation (as a proportion of total GLP-1RA) declined by 32.1% (P < 0.001), and dulaglutide initiation increased by 34.1% (P < 0.001); the proportion of patients with CVD-HF increased the most in liraglutide initiators (5.1% increase; P < 0.001). Most prescribers were internists or endocrinologists; cardiologist prescribing remained low (<1%). CONCLUSIONS: For SGLT2i, shifts in preference for empagliflozin followed changes in drug labels and guidelines, while for GLP-1RA, other factors such as price or ease of administration may have led to a preference for dulaglutide over liraglutide.

Prescription Opioid Epidemic and Trends in the Clinical Development of New Pain Medications.

OBJECTIVE: To evaluate trends in the clinical development of new pain and reformulated pain medications given the ongoing opioid crisis and the public health burden of inadequately controlled pain. METHODS: We conducted a retrospective cohort study of new drugs starting clinical testing between January 1, 2000, and December 31, 2015. We searched two comprehensive commercial databases of global research and development activity. The primary outcomes were trends in new and reformulated pain drugs starting clinical testing, proportion of new pain drugs targeting a novel biological pathway, and rates and reasons for discontinuation of development. RESULTS: The proportion of new pain drugs entering phase 1 testing (relative to all new drug trials) declined from 2.5% between 2000 and 2002 to 1.7% between 2013 and 2015. No significant changes in the proportion of new pain drugs entering phase 2 or phase 3 trials were observed. Most new pain drugs failed to reach late-stage clinical development, with 52% of pain drugs successfully advancing from phase 1 to phase 2 and 11% advancing from phase 2 to phase 3 trials. The number of reformulated products starting clinical testing increased over the study period and was greater than that for new analgesics in 2012 and every year thereafter. CONCLUSION: Pain drug development activity has largely shifted from new therapeutics to reformulated ones. New policies, such as increased funding for basic pain research, may help address the urgent need for new therapies for pain.