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The global COVID-19 pandemic has generated enormous morbidity and mortality, as well as large health system disruptions including changes in use of prescription medications, outpatient encounters, emergency department admissions, and hospitalizations. These pandemic-related disruptions are reflected in real-world data derived from electronic medical records, administrative claims, disease/medication registries, and mobile devices. We discuss how pandemic-related disruptions in healthcare utilization may impact the conduct of non-interventional studies designed to characterize the utilization and estimate the effects of medical interventions on health-related outcomes. Using hypothetical studies, we highlight consequences that the pandemic may have on study design elements including participant selection and ascertainment of exposures, outcomes, and covariates. We discuss the implications of these pandemic-related disruptions on possible threats to external validity (participant selection) and internal validity (e.g., confounding, selection bias, missing data bias). These concerns may be amplified in populations disproportionately impacted by COVID-19, such as racial/ethnic minorities, rural residents, or people experiencing poverty. We propose a general framework for researchers to carefully consider during the design and analysis of non-interventional studies that use real-world data from the COVID-19 era.

ObjectiveTo quantify the effect of the unemployment created by COVID-19 on access to (sales of) statin drugs in the United States population.MethodsApproximately half a billion transactions for statin drugs in the United States between January 2018 and September 2020 are analyzed. We studied the potential causal relation between abnormal levels of unemployment during the first wave of COVID-19 in the U.S. and abnormal levels of sales of statin products (both variables defined at the state/week level). Variables are analyzed using the Two-Stage Least Squares (2SLS) method, which exploits comparisons of statin sales between states where, given the occupational distribution of their workforce, unemployment was more structurally vulnerable to mobility restrictions derived from COVID-19 against states where it was less structurally vulnerable.ResultsWhile we do not find unemployment effects on statin sales on most of the population, our estimates link COVID-fueled unemployment with a sharp sales reduction among Medicaid-insured populations, particularly those in working age. For the period between March and August of 2020, these estimates imply a 31% drop of statin sales among this population.DiscussionCOVID-fueled unemployment may have had a negative and significant effect on access to statin populations among Medicaid-insured populations.

Many commonly used prescription medications have cardiovascular adverse effects, yet the cumulative risk of cardiovascular events associated with the concurrent use of these medications is unknown. We examined the association between the concurrent use of prescription medications with known risk of a major adverse cardiovascular event (MACE) ("MACE medications") and the risk of such events among older adults.A multi-center, population-based study from the Atherosclerosis Risk in Communities (ARIC) study of a cohort of 3669 community-dwelling adults aged 61-86 years with no history of cardiovascular disease who reported the use of at least one medication between September 2006 and August 2013 were followed up until August 2015. Exposure defined as time-varying and time-fixed use of 1, 2 or ≥3 MACE medications with non-MACE medications serving as negative control. Primary outcome was incident MACE defined as coronary artery revascularization, myocardial infarction, fatal coronary heart disease, stroke, cardiac arrest, or death.In fully adjusted models, there was an increased risk of MACE associated with use of 1, 2, or ≥3 MACE medications (1 MACE: hazards ratio [HR], 1.21; 95% confidence interval [CI], 0.94-1.57); 2 MACE: HR 1.89, CI 1.42-2.53; ≥3 MACE: HR 2.22, CI 1.61-3.07) compared to use of non-MACE medications. These associations persisted in propensity score-matched analyses and among new users of MACE medications, never users of cardiovascular medications and subgroups of participants with increased risk of MACE. There was no association between the number of non-MACE medications used and MACE.In this community-based cohort of older adults with no prior cardiovascular disease, the use of MACE medications was independently and consistently associated with an increased risk of such events in a dose-response fashion.

Objectives To assess the cost-effectiveness of systemic treatments for metastatic castration-sensitive prostate cancer from the US healthcare sector perspective with a lifetime horizon. Methods We built a partitioned survival model based on a network meta-analysis of 7 clinical trials with 7287 patients aged 36 to 94 years between 2004 and 2018 to predict patient health trajectories by treatment. We tested parameter uncertainties with probabilistic sensitivity analyses. We estimated drug acquisition costs using the Federal Supply Schedule and adopted generic drug prices when available. We measured cost-effectiveness by an incremental cost-effectiveness ratio (ICER). Results The mean costs were approximately $392 000 with androgen deprivation therapy (ADT) alone and approximately $415 000, $464 000, $597 000, and $959 000 with docetaxel, abiraterone acetate, enzalutamide, and apalutamide, added to ADT, respectively. The mean quality-adjusted life-years (QALYs) were 3.38 with ADT alone and 3.92, 4.76, 3.92, and 5.01 with docetaxel, abiraterone acetate, enzalutamide, and apalutamide, added to ADT, respectively. As add-on therapy to ADT, docetaxel had an ICER of $42 069 per QALY over ADT alone; abiraterone acetate had an ICER of $58 814 per QALY over docetaxel; apalutamide had an ICER of $1 979 676 per QALY over abiraterone acetate; enzalutamide was dominated. At a willingness to pay below $50 000 per QALY, docetaxel plus ADT is likely the most cost-effective treatment; at any willingness to pay between $50 000 and $200 000 per QALY, abiraterone acetate plus ADT is likely the most cost-effective treatment. Conclusions These findings underscore the value of abiraterone acetate plus ADT given its relative cost-effectiveness to other systemic treatments for metastatic castration-sensitive prostate cancer.

Objectives To evaluate health care utilization and costs for patients with systemic lupus erythematosus (SLE) by disease severity. Methods We searched PubMed and Embase from January 2000 to June 2020 for observational studies examining health care utilization and costs associated with SLE among adults in the United States. Two independent reviewers reviewed the selected full-text articles to determine the final set of included studies. Costs were converted to 2020 US $. Results We screened 9224 articles, of which 51 were included. Mean emergency department visits were 0.3–3.5 per year, and mean hospitalizations were 0.1–2.4 per year (mean length of stay 0.4–13.0 days). Patients averaged 10–26 physician visits/year. Mean annual direct total costs were $17,258–$63,022 per patient and were greater for patients with moderate or severe disease ($19,099–$82,391) compared with mild disease ($12,242–$29,233). Mean annual direct costs were larger from commercial claims ($24,585–$63,022) than public payers (Medicare and Medicaid: $18,302–$27,142). Conclusions SLE remains a significant driver of health care utilization and costs. Patients with moderate to severe SLE use more health care services and incur greater direct and indirect costs than those with mild disease.

Anticoagulation among patients with cancer and atrial fibrillation is challenging due to elevated risk of bleeding and stroke. We characterized use of oral anticoagulants among patients with cancer and non-valvular atrial fibrillation (NVAF).We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data and included patients with cancer aged ≥66 years with an incident diagnosis of NVAF from 2010 to 2016. We used a Cox proportional hazard model and multivariable logistic regression to identify factors associated with anticoagulant use versus no use and direct oral anticoagulants (DOACs) versus warfarin use, respectively.Of 27,702 patients with cancer and NVAF, 4469 (16.1%) used DOACs and 3577 (12.9%) used warfarin. Among 8046 anticoagulant users, DOACs use increased from 21.8% in 2011 to 76.2% in 2016, with a corresponding decline in warfarin use from 78.2% to 23.8%. Nearly 7 out of 10 patients with cancer and NVAF did not initiate anticoagulation in 2016. Anticoagulant use was more likely among those with higher CHA₂DS₂-VASc scores (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.27-1.90 for score ≥6 vs. 1) or with lower HAS-BLED scores (HR 1.96, 95% CI 1.67-2.30 for score 1 vs. ≥6). Among anticoagulant users, DOAC use was less likely than warfarin in those with higher CHA₂DS₂-VASc scores (odds ratio [OR] 0.53, 95% CI 0.33-0.84 for score ≥6 vs. 1).Nearly 7 out of 10 patients with cancer and NVAF did not receive anticoagulation. Use of DOACs increased from 2010 to 2016, with a corresponding decline in warfarin use. DOACs are used less than warfarin among those at higher risk of stroke.

Chapter 4.4 provides a reference case for vaccine economic evaluation using a novel COVID-19 vaccine program Markov model. For this exercise, the model is provided with interactive data to make it fully functional and generate analyzable results. It is highly recommended that readers engage with the Excel model simultaneously to studying the exercise. What readers will find as they engage in this model is that Markov models operate much differently than decision trees, as they require more data and time-steps to complete a Markov trace. Ultimately, these models could provide more helpful information about value over time, which in turn can inform important data for return-on-investment calculations and other economic statistics that depend on time and efficiency, considering the rapid spread of infectious diseases such as COVID-19.

Background There is an urgent need to understand the real-world effectiveness of remdesivir in the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods This was a retrospective comparative effectiveness study. Individuals hospitalized in a large private healthcare network in the United States from 23 February 2020 through 11 February 2021 with a positive test for SARS-CoV-2 and ICD-10 diagnosis codes consistent with symptomatic coronavirus disease 2019 (COVID-19) were included. Remdesivir recipients were matched to controls using time-dependent propensity scores. The primary outcome was time to improvement with a secondary outcome of time to death. Results Of 96 859 COVID-19 patients, 42 473 (43.9%) received at least 1 remdesivir dose. The median age of remdesivir recipients was 65 years, 23 701 (55.8%) were male, and 22 819 (53.7%) were non-White. Matches were found for 18 328 patients (43.2%). Remdesivir recipients were significantly more likely to achieve clinical improvement by 28 days (adjusted hazard ratio [aHR] 1.19, 95% confidence interval [CI], 1.16–1.22). Remdesivir patients on no oxygen (aHR 1.30, 95% CI, 1.22–1.38) or low-flow oxygen (aHR 1.23, 95% CI, 1.19–1.27) were significantly more likely to achieve clinical improvement by 28 days. There was no significant impact on the likelihood of mortality overall (aHR 1.02, 95% CI, .97–1.08). Remdesivir recipients on low-flow oxygen were significantly less likely to die than controls (aHR 0.85, 95% CI, .77–.92; 28-day mortality 8.4% [865 deaths] for remdesivir patients, 12.5% [1334 deaths] for controls). Conclusions These results support the use of remdesivir for hospitalized COVID-19 patients on no or low-flow oxygen. Routine initiation of remdesivir in more severely ill patients is unlikely to be beneficial.

ObjectiveThe goal of this work is to evaluate if there is an increase in the risk of thromboembolic events (TEEs) due to concomitant exposure to dexamethasone and apixaban or rivaroxaban. Direct oral anticoagulants (DOACs), as well as corticosteroid dexamethasone, are commonly used to treat individuals hospitalised with COVID-19. Dexamethasone induces cytochrome P450-3A4 enzyme that also metabolises DOACs apixaban and rivaroxaban. This raises a concern about possible interaction between dexamethasone and DOACs that may reduce the efficacy of the DOACs and result in an increased risk of TEE.DesignWe used nested case–control study design.SettingThis study was conducted in the National COVID Cohort Collaborative (N3C), the largest electronic health records repository for COVID-19 in the USA.ParticipantsStudy participants were adults over 18 years who were exposed to a DOAC for 10 or more consecutive days. Exposure to dexamethasone was at least 5 or more consecutive days.Primary and secondary outcome measuresOur primary exposure variable was concomitant exposure to dexamethasone for 5 or more days after exposure to either rivaroxaban or apixaban for 5 or more consecutive days. We used McNemar’s Χ2test and adjusted logistic regression to evaluate association between concomitant use of dexamethasone with either apixaban or rivaroxaban.ResultsMcNemar’s Χ2test did not find a discernible association of TEE in patients concomitantly exposed to dexamethasone and a DOAC (χ2=0.5, df=1, p=0.48). In addition, a conditional logistic regression model did not find an increase in the risk of TEE (adjusted OR 1.15, 95% CI 0.32 to 4.18).ConclusionThis nested case–control study did not find evidence of an association between concomitant exposure to dexamethasone and a DOAC with an increase in risk of TEE. Due to small sample size, an association cannot be completely ruled out.

Purpose Antithrombotic agents have a role in coronavirus disease 2019 (COVID-19) treatment, but the pandemic disrupted medication supply. This study examined changes in the volume of oral and parenteral anticoagulant and antiplatelet medications at US hospitals during the pandemic. Methods IQVIA National Sales Perspective (NSP) data was used to determine the monthly volume of anticoagulants and antiplatelets purchased at US hospitals between January 2018 and February 2021. Mean monthly medication volumes, reported as extended units (EUs), and year-over-year changes in medication volume were determined. A single-group interrupted time series analysis was used to evaluate changes in the rate of growth of monthly medication volumes before (January 2019-February 2020) and during (March 2020-February 2021) the COVID-19 pandemic. Results Overall, there was a 43.4% decline in the total volume of anticoagulants and antiplatelets at US hospitals in March 2020, driven by a decrease in heparin volume. Mean monthly volumes decreased significantly (P < 0.05) for parenteral anticoagulants (–106,691,340 EU [95% CI, –200,033,910 to –13,348,780]), oral anticoagulants (–354,800 EU [95% CI, –612,180 to –97,420]), and parenteral antiplatelets (–391,880 EU [95% CI, –535,420 to –248,330]). During the pandemic, the monthly volume of oral anticoagulants, parenteral anticoagulants, and parenteral antiplatelets grew significantly more than in the prepandemic period. This growth was primarily seen in volumes of apixaban, argatroban, enoxaparin, heparin, eptifibatide, and tirofiban. Apixaban and heparin volumes continued a prepandemic uptrend, while argatroban and eptifibatide volumes reversed trend. Conclusion Rapid changes in anticoagulant and antiplatelet volume at US hospitals during the COVID-19 pandemic highlight the need for institutional protocols to manage fluctuating medication volume demands.

Background: While clinical guidelines recommend direct-acting oral anticoagulants (DOAC) over warfarin to treat isolated nonvalvular atrial fibrillation, guidelines are silent regarding nonvalvular atrial fibrillation treatment among individuals with cancer, reflecting the paucity of evidence in this setting. We quantified relative risk of ischemic stroke or systemic embolism and major bleeding (primary outcomes), and all-cause and cardiovascular death (secondary outcomes) among older individuals with cancer and nonvalvular atrial fibrillation comparing DOACs and warfarin. Methods: This retrospective cohort study used Surveillance, Epidemiology, and End Results cancer registry and linked US Medicare data from 2010 through 2016, and included individuals diagnosed with cancer and nonvalvular atrial fibrillation who newly initiated DOAC or warfarin. We used inverse probability of treatment weighting to control confounding. We used competing risk regression for primary outcomes and cardiovascular death, and Cox proportional hazard regression for all-cause death. Results: Among 7675 individuals included in the cohort, 4244 (55.3%) received DOACs and 3431 (44.7%) warfarin. In the inverse probability of treatment weighting analysis, there was no statistically significant difference among DOAC and warfarin users in the risk of ischemic stroke or systemic embolism (1.24 versus 1.19 events per 100 person-years, adjusted hazard ratio 1.41 [95% CI, 0.92–2.14]), major bleeding (3.08 versus 4.49 events per 100 person-years, adjusted hazard ratio 0.90 [95% CI, 0.70–1.17]), and cardiovascular death (1.88 versus 3.14 per 100 person-years, adjusted hazard ratio 0.82 [95% CI, 0.59–0.1.13]). DOAC users had significantly lower risk of all-cause death (7.09 versus 13.3 per 100 person-years, adjusted hazard ratio 0.81 [95% CI, 0.69–0.94]) compared to warfarin users. Conclusions: Older adults with cancer and atrial fibrillation exposed to DOACs had similar risks of stroke and systemic embolism and major bleeding as those exposed to warfarin. Relative to warfarin, DOAC use was associated with a similar risk of cardiovascular death and a lower risk of all-cause death.

The COVID-19 pandemic's impact on buprenorphine treatment for opioid use disorder among adolescents and young adults (AYAs) is unknown.We used IQVIA Longitudinal Prescription Claims, including US AYAs aged 12-29 with at least 1 buprenorphine fill between January 2018 and August 2020, stratifying by age group and insurance. We compared buprenorphine prescriptions in March-August 2019 to March-August 2020.The monthly buprenorphine prescription rate increased 8.3% among AYAs aged 12-17 but decreased 7.5% among 18- to 24-year-olds and decreased 5.1% among 25- to 29-year-olds. In these age groups, Medicaid prescriptions did not significantly change, whereas commercial insurance prescriptions decreased 12.9% among 18- to 24-year-olds and 11.8% in 25- to 29-year-olds, and cash/other prescriptions decreased 18.7% among 18- to 24-year-olds and 19.9% in 25- to 29-year-olds (p.001 for all).Buprenorphine prescriptions paid with commercial insurance or cash among young adults significantly decreased early in the pandemic, suggesting a possible unmet treatment need among this group.

Background Evidence of whether people living with HIV are at elevated risk of adverse COVID-19 outcomes is inconclusive. We aimed to investigate this association using the population-based National COVID Cohort Collaborative (N3C) data in the USA. Methods We included all adult (aged ≥18 years) COVID-19 cases with any health-care encounter from 54 clinical sites in the USA, with data being deposited into the N3C. The outcomes were COVID-19 disease severity, hospitalisation, and mortality. Encounters in the same health-care system beginning on or after January 1, 2018, were also included to provide information about pre-existing health conditions (eg, comorbidities). Logistic regression models were employed to estimate the association of HIV infection and HIV markers (CD4 cell count, viral load) with hospitalisation, mortality, and clinical severity of COVID-19 (multinomial). The models were initially adjusted for demographic characteristics, then subsequently adjusted for smoking, obesity, and a broad range of comorbidities. Interaction terms were added to assess moderation effects by demographic characteristics. Findings In the harmonised N3C data release set from Jan 1, 2020, to May 8, 2021, there were 1 436 622 adult COVID-19 cases, of these, 13 170 individuals had HIV infection. A total of 26 130 COVID-19 related deaths occurred, with 445 among people with HIV. After adjusting for all the covariates, people with HIV had higher odds of COVID-19 death (adjusted odds ratio 1·29, 95% CI 1·16–1·44) and hospitalisation (1·20, 1·15–1·26), but lower odds of mild or moderate COVID-19 (0·61, 0·59–0·64) than people without HIV. Interaction terms revealed that the elevated odds were higher among older age groups, male, Black, African American, Hispanic, or Latinx adults. A lower CD4 cell count (

BACKGROUND AND AIMS Despite prescribing declines between 2011 and 2019, opioid morbidity and mortality in the United States continued to rise during this period. We estimated the relationship between opioid prescribing, opioid use disorder (OUD) and fatal opioid overdose in the United States. DESIGN Dynamic Markov model. SETTING United States, using data from the National Survey on Drug Use and Health, Centers for Disease Control and Prevention, National Health and Nutrition Examination Survey and National Epidemiologic Survey on Alcohol and Related Conditions III. PARTICIPANTS Simulated US individuals 12+ years of age from the general population or with prescription opioid medical use, prescription opioid non-medical use, illicit opioid (e.g. heroin, illicit fentanyl) use, prescription OUD, illicit OUD with a history of prior prescription opioid non-medical use or non-fatal or fatal opioid overdose. MEASUREMENTS Active OUD cases and fatal prescription opioid overdoses. FINDINGS Between 2010 and 2019, opioid prescribing declined 42.5%. Although fatal opioid overdoses increased by 103.2%, these reductions in opioid prescribing averted an estimated 9600 [95% uncertainty interval (UI) = 7205, 15 478] deaths starting in 2011 relative to continued prescribing at 2010 levels-and are projected to avert another 50 918 (95% UI = 38 829, 79 795) overdose deaths between 2020 and 2029. The median time from initial opioid prescription to fatal opioid overdose was 5.2 years. Of the 2.4 million (95% UI = 2.2 million, 2.7 million) individuals in the United States with estimated active OUD in 2019, 65% (95% UI = 59%, 71%) were attributable to initial opioid use occurring prior to 2011, whereas 14% (95% UI = 12%, 17%) were attributable to initial opioid use occurring between 2017 and 2019. The impact, by 2029, of additional reductions in prescribing initiated in 2020 would be more than three times greater than that of similar reductions initiated in 2025. CONCLUSIONS Observed reductions in opioid prescribing volume in the United States from 2010 to 2019 appear to have saved approximately 9600 lives by 2019 and are anticipated to avert more than 50 000 fatal overdoses by 2029.

BACKGROUND: Relatively little is known about the use patterns of potential pharmacologic treatments of COVID-19 in the United States. OBJECTIVE: To use the National COVID Cohort Collaborative (N3C), a large, multicenter, longitudinal cohort, to characterize the use of hydroxychloroquine, remdesivir, and dexamethasone, overall as well as across individuals, health systems, and time. DESIGN: Retrospective cohort study. SETTING: 43 health systems in the United States. PARTICIPANTS: 137 870 adults hospitalized with COVID-19 between 1 February 2020 and 28 February 2021. MEASUREMENTS: Inpatient use of hydroxychloroquine, remdesivir, or dexamethasone. RESULTS: Among 137 870 persons hospitalized with confirmed or suspected COVID-19, 8754 (6.3%) received hydroxychloroquine, 29 272 (21.2%) remdesivir, and 53 909 (39.1%) dexamethasone during the study period. Since the release of results from the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial in mid-June, approximately 78% to 84% of people who have had invasive mechanical ventilation have received dexamethasone or other glucocorticoids. The use of hydroxychloroquine increased during March 2020, peaking at 42%, and started declining by April 2020. By contrast, remdesivir and dexamethasone use gradually increased over the study period. Dexamethasone and remdesivir use varied substantially across health centers (intraclass correlation coefficient, 14.2% for dexamethasone and 84.6% for remdesivir). LIMITATION: Because most N3C data contributors are academic medical centers, findings may not reflect the experience of community hospitals. CONCLUSION: Dexamethasone, an evidence-based treatment of COVID-19, may be underused among persons who are mechanically ventilated. The use of remdesivir and dexamethasone varied across health systems, suggesting variation in patient case mix, drug access, treatment protocols, and quality of care. PRIMARY FUNDING SOURCE: National Center for Advancing Translational Sciences; National Heart, Lung, and Blood Institute; and National Institute on Aging.

Objective While several prescription drug-based risk indices have been developed, their design, performance, and application has not previously been synthesized. Study design and setting We searched Ovid MEDLINE, CINAHL and Embase from inception through March 3, 2020 and included studies that developed or updated a prescription drug-based risk index. Two reviewers independently performed screening and extracted information on data source, study population, cohort sizes, outcomes, study methodology and performance. Predictive performance was evaluated using C statistics for binary outcomes and R2 for continuous outcomes. The PROSPERO ID for this review is CRD42020165498. Results Of 19,112 articles that were retrieved, 124 were full-text screened and 25 were included, each of which represented a de novo or updated drug-based index. The indices were customized to varied age groups and clinical populations and most commonly evaluated outcomes including mortality (36%), hospitalization (24%) and healthcare costs (24%). C statistics ranged from 0.62 to 0.92 for mortality and 0.59 to 0.72 for hospitalization, while adjusted R2 for healthcare costs ranged from 0.06 to 0.62. Seven of the 25 risk indices included used global drug classification algorithms. Conclusions More than two-dozen prescription drug-based risk indices have been developed and they differ significantly in design, performance and application.

Abstract Objectives To characterize and compare glucose-lowering medication use in type 2 diabetes in the US, Sweden, and Israel, including adoption of newer medications and prescribing patterns. Research Design and Methods We used data from the National Health and Nutrition Examination Survey (NHANES) from the US, Stockholm CREAtinine Measurements project (SCREAM) from Sweden, and Maccabi Healthcare Services from Israel. Specific pharmacotherapy for type 2 diabetes between 2007 and 2018 were examined. Results Use of glucose-lowering medications among patients with type 2 diabetes was substantially lower in the US and SCREAM than in Maccabi (66.0% in NHANES, 68.4% in SCREAM, and 88.1% in Maccabi in 2017-2018). Among patients who took at least one glucose-lowering medication in 2017-2018, metformin use was also lower in the US and SCREAM (74.1% in NHANES, 75.9% in SCREAM, and 92.6% in Maccabi) whereas sulfonylureas use was greater in the US (31.5% in NHANES, 16.0% in SCREAM, and 14.9% in Maccabi). Adoption of DPP4i and SGLT2i were slower in the US and SCREAM than Maccabi. History of atherosclerotic cardiovascular disease, heart failure, reduced kidney function, and albuminuria were not consistently associated with greater use of SGLT2i or GLP1RA across the three countries. Conclusions There were substantial differences in real-world use of glucose-lowering medications across the US, Sweden, and Israel, with more optimal pharmacologic management in Israel. Variation in access to care and medication cost across countries may have contributed to these differences. SGLT2i and GLP1RA use in high-risk patients was limited in all three countries during this time period.

This Viewpoint discusses the settlement agreements reached against several major pharmaceutical distributors resulting from the US opioid epidemic and how those funds will be distributed amongst the states.

It is unclear how the efficacy of tezepelumab, approved for the treatment of type 2 ("T2") high and low asthma, compares to the efficacy of other biologics for T2-high asthma.To conduct an indirect comparison of tezepelumab to dupilumab, benralizumab, and mepolizumab in the treatment of eosinophilic asthma.We conducted a systematic review and Bayesian network meta-analyses. We identified randomized controlled trials (RCTs) indexed in PubMed, Embase, or CENTRAL between January 1, 2000, and August 12, 2022. Outcomes included exacerbation rates, prebronchodilator Forced Expiratory Volume (FEV1), and the Asthma Control Questionnaire (ACQ). (PROSPERO CRD42021232084) RESULTS: Ten RCTs (n = 9201) met eligibility. Tezepelumab (relative risk 0.63, 95% credible intervals [CI] 0.46-0.86) was associated with significantly lower exacerbation rates than benralizumab; and larger improvements in FEV1 compared to mepolizumab (mean difference, MD, 66, CI -33 to 170) and benralizumab (MD, 62, CI -22 to 150), though the CI crossed the null value of 0. Mepolizumab improved ACQ the most but was not significantly different from tezepelumab (tezepelumab vs. mepolizumab, MD, 0.14, CI -0.10 to 0.38). For efficacy by clinically important thresholds, tezepelumab, mepolizumab, and dupilumab achieved a99% probability of reducing exacerbation rates by ≥50% compared to placebo, but benralizumab had only a 66% probability of doing so. Tezepelumab and dupilumab had a probability of 1.00 of improving prebronchodilator FEV1 by ≥100 mL above placebo. Compared to mepolizumab, dupilumab had90% chance for improving FEV1 by ≥50 mL, but none of the differences between biologics exceeded 100 mL.In individuals with eosinophilic asthma, tezepelumab and dupilumab were associated with greater improvements in exacerbation rates and lung function than benralizumab or mepolizumab, although below clinical thresholds.

BACKGROUND: Older adults have many comorbidities contributing to mortality. OBJECTIVE: To develop a summary Elixhauser (S-Elixhauser) comorbidity score to predict 30-day, in-hospital, and 1-year mortality in older adults using the 38 comorbidities operationalized by the Agency for Healthcare Research and Quality (AHRQ). DESIGN: Retrospective cohort study. SETTING: Medicare beneficiaries from 2017 to 2019. PATIENTS: Persons hospitalized in 2018 (n = 899 844) and 3 disease-specific hospitalized cohorts. MEASUREMENTS: Weights were derived for 38 comorbidities to predict 30-day, in-hospital, and 1-year mortality. The S-Elixhauser score was internally validated and calibrated. Individual Elixhauser comorbidity indicators (38 comorbidities), the modified application of the AHRQ-derived Elixhauser summary score, the Charlson comorbidity indicators (17 comorbidities), and the Charlson summary score were externally validated. The c-statistic was used to evaluate discrimination of a comorbidity score model. RESULTS: The S-Elixhauser score was well calibrated and internally validated, with a c-statistic of 0.705 (95% CI, 0.703 to 0.707) in predicting 30-day mortality, 0.654 (CI, 0.651 to 0.657) for in-hospital mortality, and 0.743 (CI, 0.741 to 0.744) for 1-year mortality. In external validation of other comorbidity indices for 30-day mortality, the c-statistic was 0.711 (CI, 0.709 to 0.713) for the individual Elixhauser comorbidity indicators, 0.688 (CI, 0.686 to 0.690) for the AHRQ Elixhauser score, 0.696 (CI, 0.694 to 0.698) for the Charlson comorbidity indicators, and 0.690 (CI, 0.688 to 0.693) for the Charlson summary score. In 3 disease-specific populations, the discrimination of the S-Elixhauser score in predicting 30-day mortality ranged from 0.657 to 0.732. LIMITATIONS: Validation of the S-Elixhauser comorbidity score and head-to-head comparison with other comorbidity scores in an external population are needed to evaluate comparative performance. CONCLUSION: The S-Elixhauser comorbidity score is well calibrated and internally validated but its advantage over the AHRQ Elixhauser and Charlson summary scores is unclear. PRIMARY FUNDING SOURCE: National Institute on Aging.

Background and ObjectivesTo determine the risk of hospitalization and death associated with pimavanserin use.MethodsWe conducted a retrospective cohort study of adults 65 years and older with Parkinson disease between November 1, 2015, and December 31, 2018, using an administrative dataset on residents of Medicare-certified long-term care facilities and linked Medicare claims data. Propensity score–based inverse probability of treatment weighting (IPTW) was used to balance pimavanserin users and nonusers on 24 baseline characteristics. Fine-Gray competing risk and Cox proportional hazards regression models were used to estimate the risk of hospitalization and death up to 1 year, respectively.ResultsThe study cohort included 2,186 pimavanserin users and 18,212 nonusers. There was a higher risk of 30-day hospitalization with pimavanserin use vs nonuse (IPTW-adjusted hazard ratio [aHR] 1.24, 95% confidence intervals [CI] 1.06–1.43). There was no association of pimavanserin use with 90-day hospitalization (aHR 1.10, CI 0.99–1.24) or with 30-day mortality (aHR 0.76, CI 0.56–1.03). Pimavanserin use vs nonuse was associated with increased 90-day mortality (aHR 1.20, CI 1.02–1.41) that persisted after 180 days (aHR 1.28, CI 1.13–1.45) and 1 year (aHR 1.56, CI 1.42–1.72).DiscussionPimavanserin use vs nonuse in older adults was associated with an increased risk of hospitalization at 1 month of initiation and a higher risk of death for up to 1 year following initiation. These findings, in a large real-world cohort within long-term care facilities, may help to inform decisions regarding its risk/benefit balance among patients with Parkinson disease.Classification of EvidenceThis study provides Class II evidence that in patients with Parkinson disease who are 65 or older and residing in Medicare-certified long-term care facilities, pimavanserin is associated with an increased risk of 30-day hospitalization and higher 90-, 180-, and 365-day mortality.

Stratification of patients with post-acute sequelae of SARS-CoV-2 infection (PASC, or long COVID) would allow precision clinical management strategies. However, long COVID is incompletely understood and characterised by a wide range of manifestations that are difficult to analyse computationally. Additionally, the generalisability of machine learning classification of COVID-19 clinical outcomes has rarely been tested.We present a method for computationally modelling PASC phenotype data based on electronic healthcare records (EHRs) and for assessing pairwise phenotypic similarity between patients using semantic similarity. Our approach defines a nonlinear similarity function that maps from a feature space of phenotypic abnormalities to a matrix of pairwise patient similarity that can be clustered using unsupervised machine learning.We found six clusters of PASC patients, each with distinct profiles of phenotypic abnormalities, including clusters with distinct pulmonary, neuropsychiatric, and cardiovascular abnormalities, and a cluster associated with broad, severe manifestations and increased mortality. There was significant association of cluster membership with a range of pre-existing conditions and measures of severity during acute COVID-19. We assigned new patients from other healthcare centres to clusters by maximum semantic similarity to the original patients, and showed that the clusters were generalisable across different hospital systems. The increased mortality rate originally identified in one cluster was consistently observed in patients assigned to that cluster in other hospital systems.Semantic phenotypic clustering provides a foundation for assigning patients to stratified subgroups for natural history or therapy studies on PASC.NIH (TR002306/OT2HL161847-01/OD011883/HG010860), U.S.D.O.E. (DE-AC02-05CH11231), Donald A. Roux Family Fund at Jackson Laboratory, Marsico Family at CU Anschutz.

To examine the use of step therapy, prior authorization, and Part D formulary exclusion by 4 large Medicare Advantage (MA) insurers to manage 20 physician-administered drugs with the highest total Medicare expenditures (top 20 drugs).We collected data for United Healthcare, CVS/Aetna, Humana, and Kaiser plans to create a database of 2020 Part B coverage restrictions and conducted a retrospective analysis of 2018-2020 Part D formularies.For each insurer, we calculated the number of top 20 physician-administered drugs subject to prior authorization and step therapy. For physician-administered drugs for which there were no similar or interchangeable alternatives, we examined which insurers required prior authorization or step therapy. Finally, we examined whether insurers restricted access to physician-administered drugs by reducing coverage on Part D formularies.Of the top 20 physician-administered drugs, 17 were subject to prior authorization and 10 were subject to step therapy by at least 1 insurer. For 5 physician-administered drugs without a similar or interchangeable alternative, none were subject to step therapy and all were subject to prior authorization by at least 1 insurer. Across the 4 insurers, 16 physician-administered drugs were covered on all or some of the Part D formularies in 2018, which decreased to 6 in 2020.Four large MA insurers managed access to expensive physician-administered drugs with a combination of prior authorization, step therapy, and Part D formulary design. When a low-cost alternative exists, these tools can help reduce wasteful spending, but the administrative barriers may also reduce access.

OBJECTIVE To characterize and compare glucose-lowering medication use in type 2 diabetes in the U.S., Sweden, and Israel, including adoption of newer medications and prescribing patterns. RESEARCH DESIGN AND METHODS We used data from the National Health and Nutrition Examination Survey (NHANES) from the U.S., the Stockholm CREAtinine Measurements (SCREAM) project from Sweden, and Maccabi Healthcare Services (Maccabi) from Israel. Specific pharmacotherapy for type 2 diabetes between 2007 and 2018 was examined. RESULTS Use of glucose-lowering medications among patients with type 2 diabetes was substantially lower in NHANES and SCREAM than in Maccabi (66.0% in NHANES, 68.4% in SCREAM, and 88.1% in Maccabi in 2017–2018). Among patients who took at least one glucose-lowering medication in 2017–2018, metformin use was also lower in NHANES and SCREAM (74.1% in NHANES, 75.9% in SCREAM, and 92.6% in Maccabi) whereas sulfonylureas use was greater in NHANES (31.5% in NHANES, 16.0% in SCREAM, and 14.9% in Maccabi). Adoption of dipeptidyl peptidase 4 inhibitors and sodium–glucose cotransporter 2 inhibitors (SGLT2i) was slower in NHANES and SCREAM than in Maccabi. History of atherosclerotic cardiovascular disease, heart failure, reduced kidney function, or albuminuria was not consistently associated with greater use of SGLT2i or glucagon-like peptide 1 receptor agonists (GLP1RA) across the three countries. CONCLUSIONS There were substantial differences in real-world use of glucose-lowering medications across the U.S., Sweden, and Israel, with more optimal pharmacologic management in Israel. Variation in access to care and medication cost across countries may have contributed to these differences. SGLT2i and GLP1RA use in patients at high risk was limited in all three countries during this time period.

The accessibility of pharmacies may be an overlooked contributor to persistent racial and ethnic disparities in the use of prescription medications and essential health care services within urban areas in the US. We examined the availability and geographic accessibility of pharmacies across neighborhoods based on their racial/ethnic composition in the thirty most populous US cities. In all cities examined, we found persistently fewer pharmacies located in Black and Hispanic/Latino neighborhoods than White or diverse neighborhoods throughout 2007-15. In 2015 there were disproportionately more pharmacy deserts in Black or Hispanic/Latino neighborhoods than in White or diverse neighborhoods, including those that are not federally designated Medically Underserved Areas. These disparities were most pronounced in Chicago, Illinois; Los Angeles, California; Baltimore, Maryland; Philadelphia, Pennsylvania; Milwaukee, Wisconsin; Dallas, Texas; Boston, Massachusetts; and Albuquerque, New Mexico. We also found that Black and Hispanic/Latino neighborhoods were more likely to experience pharmacy closures compared with other neighborhoods. Our findings suggest that efforts to increase access to medications and essential health care services, including in response to COVID-19, should consider policies that ensure equitable pharmacy accessibility across neighborhoods in US cities. Such efforts could include policies that encourage pharmacies to locate in pharmacy deserts, including increases to Medicaid and Medicare reimbursement rates for pharmacies most at risk for closure.

Telepharmacies, which dispense medications on-site under the supervision of an off-site pharmacist using telecommunication technologies, have been proposed as a means to ameliorate the impact of pharmacy closures and improve access to medications.To examine whether adherence varies among individuals filling prescription medications through a telepharmacy versus a traditional pharmacy in an urban neighborhood.We conducted a retrospective cohort study using dispensing records of a traditional pharmacy and a telepharmacy, located in the same low-income Chicago neighborhood, from January 2016 to December 2018. We focused on individuals using statins (n = 1044), angiotensin-converting enzyme inhibitors (ACEs)/angiotensin II receptor blockers (ARBs) (n = 1003), or noninsulin diabetes medications (NIDMs) (n = 692). We defined adherence as a proportion of days covered greater than 80% over 12-months. We examined the association between telepharmacy use and medication adherence using logistic regressions adjusted for demographics (age and sex) and index prescription characteristics (method of payment, e-prescription, 90-day supply).Telepharmacy users were less adherent to statins (37.6% vs. 54.3%, adjusted odds ratio 0.54 [95% CI 0.38-0.76], P0.01) and ACEs/ARBs (41.4% vs, 56.5%, 0.61 [0.44-0.84], P0.01) than users of the traditional pharmacy. However, adherence to NIDMs was similar among users of the tele- and traditional pharmacies (65.5% vs. 60.1%, 1.47 [0.92-2.35], P = 0.11). Our findings were similar when we conducted a series of sensitivity analyses, including restricting our cohorts to those who only used their index pharmacy and analyzing cohorts of new rather than continuing users of these medications.In this analysis, medication adherence was lower among users of telepharmacy than users of a traditional pharmacy in some but not all drug classes examined. Further research is needed to identify whether other interventions to improve adherence, such as longer hours of operation, at-home delivery, or 90-day supply, may be coupled with telepharmacies to increase their use in urban areas.

ImportanceAlthough manufacturer-sponsored coupons are commonly used, little is known about how patients use them within a treatment episode.ObjectivesTo examine when and how frequently patients use manufacturer coupons during a treatment episode for a chronic condition, and to characterize factors associated with more frequent use.Design, Setting, and ParticipantsThis is a retrospective cohort study of a 5% nationally representative sample of anonymized longitudinal retail pharmacy claims data from October 1, 2017, to September 30, 2019, obtained from IQVIA’s Formulary Impact Analyzer. The data were analyzed from September to December 2022. Patients with new treatment episodes using at least 1 manufacturer coupon over a 12-month period were identified. This study focused on patients with 3 or more fills for a given drug and characterized the association of the outcomes of interest with patient, drug, and drug class characteristics.Main Outcomes and MeasuresThe primary outcomes were (1) the frequency of coupon use, measured as the proportion of prescription fills accompanied by manufacturer coupon within the treatment episode, and (2) the timing of first coupon use relative to the first prescription fill within the treatment episode.ResultsA total of 36 951 treatment episodes accounted for 238 474 drug claims and 35 352 unique patients (mean [SD] age, 48.1 [18.2] years; 17 676 women [50.0%]). Among these episodes, nearly all instances (35 103 episodes [95.0%]) of first coupon use occurred within the first 4 prescription fills. Approximately two-thirds of treatment episodes (24 351 episodes [65.9%]) used a coupon for the incident fill. Coupons were used for a median (IQR) of 3 (2-6) fills. The median (IQR) proportion of fills with a coupon was 70.0% (33.3%-100.0%), and many patients discontinued the drug after the last coupon. After adjustment for covariates, there was no significant association between an individual’s out-of-pocket costs or neighborhood-level income and the frequency of coupon use. The estimated proportion of fills with a coupon was greater for products in competitive (19.5% increase; 95% CI, 2.1%-36.9%) or oligopolistic (14.5% increase; 95% CI, 3.5%-25.6%) markets than monopoly markets when there is only 1 drug in the therapeutic class.Conclusions and RelevanceIn this retrospective cohort analysis of individuals receiving pharmaceutical treatment for chronic diseases, the frequency of manufacturer-sponsored drug coupon use was associated with the degree of market competition, rather than patients’ out-of-pocket costs.