The Benefits and Risks of Receiving Investigational Solid Tumor Drugs in Randomized Trials: A Systematic Review and Meta-analysis: Annals of Internal Medicine: Vol 177, No 6

Background: Many patients participate in cancer trials to access new therapies. The extent to which new treatments produce clinical benefit for trial participants is unclear. Purpose: To estimate the progression-free survival (PFS) and overall survival (OS) advantage of assignment to experimental groups in randomized trials for 6 solid tumors. Data Sources: ClinicalTrials.gov was searched for trials of investigational drugs with results posted between 2017 and 2021. Study Selection: Investigational drugs were defined as those not yet having full approval from the U.S. Food and Drug Administration for the study indication. Trials were included if they were randomized and tested drugs or biologics. Data Extraction: Data extraction was completed by 2 independent reviewers. Data were pooled using a random-effects model. Data Synthesis: The sample included 128 trials comprising 141 comparisons of a new drug and a comparator. These comparisons included 47 050 patients. The pooled hazard ratio for PFS was 0.80 (95% CI, 0.75 to 0.85), indicating statistically significant benefit for patients in experimental groups. This corresponded to a median PFS advantage of 1.25 months (CI, 0.80 to 1.68 months). The pooled hazard ratio for OS was 0.92 (CI, 0.88 to 0.95), corresponding to a survival gain of 1.18 months (CI, 0.72 to 1.71 months). The absolute risk for a serious adverse event for comparator group patients was 29.56% (CI, 26.64% to 32.65%), with an increase in risk of 7.40% (CI, 5.66% to 9.14%) for patients in experimental groups. Limitations: Trials in this sample were heterogeneous. Comparator group interventions were assumed to reflect standard of care. Conclusion: Assignment to experimental groups produces statistically significant survival gains. However, the absolute survival gain is small, and toxicity is statistically significantly greater. The findings of this review provide reassuring evidence that patients are not meaningfully disadvantaged by assignment to comparator groups. Primary Funding Source: Canadian Institutes of Health Research.

Diagnostic Discordance, Uncertainty, and Treatment Ambiguity in Community-Acquired Pneumonia: A National Cohort Study of 115 U.S. Veterans Affairs Hospitals: Annals of Internal Medicine: Vol 177, No 9

Background: Evidence-based practice in community-acquired pneumonia often assumes an accurate initial diagnosis. Objective: To examine the evolution of pneumonia diagnoses among patients hospitalized from the emergency department (ED). Design: Retrospective nationwide cohort. Setting: 115 U.S. Veterans Affairs medical centers. Patients: Aged 18 years or older and hospitalized from the ED between 1 January 2015 and 31 January 2022. Measurements: Discordances between initial pneumonia diagnosis, discharge diagnosis, and radiographic diagnosis identified by natural language processing of clinician text, diagnostic coding, and antimicrobial treatment. Expressions of uncertainty in clinical notes, patient illness severity, treatments, and outcomes were compared. Results: Among 2 383 899 hospitalizations, 13.3% received an initial or discharge diagnosis and treatment of pneumonia: 9.1% received an initial diagnosis and 10.0% received a discharge diagnosis. Discordances between initial and discharge occurred in 57%. Among patients discharged with a pneumonia diagnosis and positive initial chest image, 33% lacked an initial diagnosis. Among patients diagnosed initially, 36% lacked a discharge diagnosis and 21% lacked positive initial chest imaging. Uncertainty was frequently expressed in clinical notes (58% in ED; 48% at discharge); 27% received diuretics, 36% received corticosteroids, and 10% received antibiotics, corticosteroids, and diuretics within 24 hours. Patients with discordant diagnoses had greater uncertainty and received more additional treatments, but only patients lacking an initial pneumonia diagnosis had higher 30-day mortality than concordant patients (14.4% [95% CI, 14.1% to 14.7%] vs. 10.6% [CI, 10.4% to 10.7%]). Patients with diagnostic discordance were more likely to present to high-complexity facilities with high ED patient load and inpatient census. Limitation: Retrospective analysis; did not examine causal relationships. Conclusion: More than half of all patients hospitalized and treated for pneumonia had discordant diagnoses from initial presentation to discharge. Treatments for other diagnoses and expressions of uncertainty were common. These findings highlight the need to recognize diagnostic uncertainty and treatment ambiguity in research and practice of pneumonia-related care. Primary Funding Source: The Gordon and Betty Moore Foundation.

Historical Redlining and Present-Day Nonsuicide Firearm Fatalities

Background: Redlining began in the 1930s with the Home Owners’ Loan Corporation (HOLC); this discriminatory practice limited mortgage availability and reinforced concentrated poverty that still exists today. It is important to understand the potential health implications of this federally sanctioned segregation. Objective: To examine the relationship between historical redlining policies and present-day nonsuicide firearm fatalities. Design: Maps from the HOLC were overlaid with incidence of nonsuicide firearm fatalities from 2014 to 2022. A multilevel negative binomial regression model tested the association between modern-day firearm fatalities and HOLC historical grading (A [“best”] to D [“hazardous”]), controlling for year, HOLC area–level demographics, and state-level factors as fixed effects and a random intercept for city. Incidence rates (IRs) per 100 000 persons, incidence rate ratios (IRRs), and adjusted IRRs (aIRRs) for each HOLC grade were estimated using A-rated areas as the reference. Setting: 202 cities with areas graded by the HOLC in the 1930s. Participants: Population of the 8597 areas assessed by the HOLC. Measurements: Nonsuicide firearm fatalities. Results: From 2014 to 2022, a total of 41 428 nonsuicide firearm fatalities occurred in HOLC-graded areas. The firearm fatality rate increased as the HOLC grade progressed from A to D. In A-graded areas, the IR was 3.78 (95% CI, 3.52 to 4.05) per 100 000 persons per year. In B-graded areas, the IR, IRR, and aIRR relative to A areas were 7.43 (CI, 7.24 to 7.62) per 100 000 persons per year, 2.12 (CI, 1.94 to 2.32), and 1.42 (CI, 1.30 to 1.54), respectively. In C-graded areas, these values were 11.24 (CI, 11.08 to 11.40) per 100 000 persons per year, 3.78 (CI, 3.47 to 4.12), and 1.90 (CI, 1.75 to 2.07), respectively. In D-graded areas, these values were 16.26 (CI, 16.01 to 16.52) per 100 000 persons per year, 5.51 (CI, 5.05 to 6.02), and 2.07 (CI, 1.90 to 2.25), respectively. Limitation: The Gun Violence Archive relies on media coverage and police reports. Conclusion: Discriminatory redlining policies from 80 years ago are associated with nonsuicide firearm fatalities today. Primary Funding Source: Fred Lovejoy Housestaff Research and Education Fund.

Association of Medicare Advantage Enrollment With Financial Burden of Care: A Retrospective Cohort Study: Annals of Internal Medicine: Vol 177, No 7

Background: Compared with traditional Medicare (TM), Medicare Advantage (MA) plans typically offer supplemental benefits and lower copayments for in-network services and must include an out-of-pocket spending limit. Objective: To examine whether the financial burden of care decreased for persons switching from TM to MA (TM-to-MA switchers) relative to those remaining in TM (TM stayers). Design: Retrospective longitudinal cohort study comparing changes in financial outcomes between TM-to-MA switchers and TM stayers. Setting: Population-based. Participants: 7054 TM stayers and 1544 TM-to-MA switchers from the Medical Expenditure Panel Survey, 2014 to 2021. Measurements: Individual health care costs (out-of-pocket spending and cost sharing), financial burden (high and catastrophic), and subjective financial hardship (difficulty paying medical bills, paying medical bills over time, and inability to pay medical bills). Results: Compared with TM stayers, TM-to-MA switchers had small differences in out-of-pocket spending ($168 [95% CI, −$133 to $469]) and proportions of total health expenses paid out of pocket (cost sharing) (0.2 percentage point [CI, −1.3 to 1.7 percentage points]), families with out-of-pocket spending greater than 20% of their income (high financial burden) (0.3 percentage point [CI, −2.5 to 3.0 percentage points]), families reporting out-of-pocket spending greater than 40% of their income (catastrophic financial burden) (0.7 percentage point [CI, −0.1 to 1.6 percentage points]), families reporting paying medical bills over time (−0.2 percentage point [CI, −1.7 to 1.4 percentage points]), families having problems paying medical bills (−0.4 percentage point [CI, −2.7 to 1.8 percentage points]), and families reporting being unable to pay medical bills (0.4 percentage point [CI, −1.3 to 2.0 percentage points]). Limitation: Inability to account for all medical care and cost needs and variations across MA plans, small baseline differences in out-of-pocket spending, and potential residual confounding. Conclusion: Differences in financial outcomes between beneficiaries who switched from TM to MA and those who stayed with TM were small. Differences in financial burden ranged across outcomes and did not have a consistent pattern. Primary Funding Source: The National Research Foundation of Korea.

Evaluation of Strategies for Transitioning to Annual SARS-CoV-2 Vaccination Campaigns in the United States

Background: The U.S. Food and Drug Administration has proposed administering annual SARS-CoV-2 vaccines. Objective: To evaluate the effectiveness of an annual SARS-CoV-2 vaccination campaign, quantify the health and economic benefits of a second dose provided to children younger than 2 years and adults aged 50 years or older, and optimize the timing of a second dose. Design: An age-structured dynamic transmission model. Setting: United States. Participants: A synthetic population reflecting demographics and contact patterns in the United States. Intervention: Vaccination against SARS-CoV-2 with age-specific uptake similar to that of influenza vaccination. Measurements: Incidence, hospitalizations, deaths, and direct health care cost. Results: The optimal timing between the first and second dose delivered to children younger than 2 years and adults aged 50 years or older in an annual vaccination campaign was estimated to be 5 months. In direct comparison with a single-dose campaign, a second booster dose results in 123 869 fewer hospitalizations (95% uncertainty interval [UI], 121 994 to 125 742 fewer hospitalizations) and 5524 fewer deaths (95% UI, 5434 to 5613 fewer deaths), averting $3.63 billion (95% UI, $3.57 billion to $3.69 billion) in costs over a single year. Limitations: Population immunity is subject to degrees of immune evasion for emerging SARS-CoV-2 variants. The model was implemented in the absence of nonpharmaceutical interventions and preexisting vaccine-acquired immunity. Conclusion: The direct health care costs of SARS-CoV-2, particularly among adults aged 50 years or older, would be substantially reduced by administering a second dose 5 months after the initial dose. Primary Funding Source: Natural Sciences and Engineering Research Council of Canada, Notsew Orm Sands Foundation, National Institutes of Health, Centers for Disease Control and Prevention, and National Science Foundation.

Target Trial Emulation for Evaluating Health Policy

Target trial emulation is an approach to designing rigorous nonexperimental studies by “emulating” key features of a clinical trial. Most commonly used outside of policy contexts, this approach is also valuable for policy evaluation as policies typically are not randomly assigned. In this article, we discuss the application of the target trial emulation framework in a policy evaluation context. The policy trial emulation framework includes 7 components: the units and eligibility criteria, definitions of the exposure and comparison conditions, assignment mechanism, baseline (“time zero”) and follow-up, outcomes, causal estimand, and statistical analysis and assumptions. Policy evaluations that emulate a randomized trial across these dimensions can yield estimates of the causal effects of the policy on outcomes. Using the policy trial emulation framework to conduct and report on research design and methods supports transparent assessment of threats to causal inference in nonexperimental studies intended to assess the effect of a health policy on clinical or population health outcomes.

Health Care Contact Days Among Older Adults in Traditional Medicare: A Cross-Sectional Study: Annals of Internal Medicine: Vol 177, No 2

Background: Days spent obtaining health care outside the home can represent not only access to needed care but also substantial time, effort, and cost, especially for older adults and their care partners. Yet, these “health care contact days” have not been characterized. Objective: To assess composition of, variation and patterns in, and factors associated with contact days among older adults. Design: Cross-sectional study. Setting: Nationally representative 2019 Medicare Current Beneficiary Survey data linked to claims. Participants: Community-dwelling adults aged 65 years and older in traditional Medicare. Measurements: Ambulatory contact days (days with a primary care or specialty care office visit, test, imaging, procedure, or treatment) and total contact days (ambulatory days plus institutional days in a hospital, emergency department, skilled-nursing facility, or hospice facility); multivariable mixed-effects Poisson regression to identify patient factors associated with contact days. Results: In weighted results, 6619 older adults (weighted: 29 694 084) had means of 17.3 ambulatory contact days (SD, 22.1) and 20.7 total contact days (SD, 27.5) in the year; 11.1% had 50 or more total contact days. Older adults spent most contact days on ambulatory care, including primary care visits (mean [SD], 3.5 [5.0]), specialty care visits (5.7 [9.6]), tests (5.3 [7.2]), imaging (2.6 [3.9]), procedures (2.5 [6.4]), and treatments (5.7 [13.3]). Half of the test and imaging days were not on the same days as office visits (48.6% and 50.1%, respectively). Factors associated with more ambulatory contact days included younger age, female sex, White race, non-Hispanic ethnicity, higher income, higher educational attainment, urban residence, more chronic conditions, and care-seeking behaviors (for example, “go to the doctor…as soon as (I)…feel bad”). Limitation: Study population limited to those in traditional Medicare. Conclusion: On average, older adults spent 3 weeks in the year getting care outside the home. These contact days were mostly ambulatory and varied widely not only by number of chronic conditions but also by sociodemographic factors, geography, and care-seeking behaviors. These results show factors beyond clinical need that may drive overuse and underuse of contact days and opportunities to optimize this person-centered measure to reduce patient burdens, for example, via care coordination. Primary Funding Source: National Institute on Aging.

Development and Validation of a Protein Risk Score for Mortality in Heart Failure: A Community Cohort Study: Annals of Internal Medicine: Vol 177, No 1

Background: Heart failure (HF) is a complex clinical syndrome with high mortality. Current risk stratification approaches lack precision. High-throughput proteomics could improve risk prediction. Its use in clinical practice to guide the management of patients with HF depends on validation and evidence of clinical benefit. Objective: To develop and validate a protein risk score for mortality in patients with HF. Design: Community-based cohort. Setting: Southeast Minnesota. Participants: Patients with HF enrolled between 2003 and 2012 and followed through 2021. Measurements: A total of 7289 plasma proteins in 1351 patients with HF were measured using the SomaScan Assay (SomaLogic). A protein risk score was derived using least absolute shrinkage and selection operator regression and temporal validation in patients enrolled between 2003 and 2007 (development cohort) and 2008 and 2012 (validation cohort). Multivariable Cox regression was used to examine the association between the protein risk score and mortality. The performance of the protein risk score to predict 5-year mortality risk was assessed using calibration plots, decision curves, and relative utility analyses and compared with a clinical model, including the Meta‐Analysis Global Group in Chronic Heart Failure mortality risk score and N-terminal pro–B-type natriuretic peptide. Results: The development (n = 855; median age, 78 years; 50% women; 29% with ejection fraction <40%) and validation cohorts (n = 496; median age, 76 years; 45% women; 33% with ejection fraction <40%) were mostly similar. In the development cohort, 38 unique proteins were selected for the protein risk score. Independent of ejection fraction, the protein risk score demonstrated good calibration, reclassified mortality risk particularly at the extremes of the risk distribution, and showed greater clinical utility compared with the clinical model. Limitation: Participants were predominantly of European ancestry, potentially limiting the generalizability of the findings to different patient populations. Conclusion: Validation of the protein risk score demonstrated good calibration and evidence of predicted benefits to stratify the risk for death in HF superior to that of clinical methods. Further studies are needed to prospectively evaluate the score’s performance in diverse populations and determine risk thresholds for interventions. Primary Funding Source: Division of Intramural Research at the National Heart, Lung, and Blood Institute of the National Institutes of Health.

Assessing Clinician Utilization of Next-Generation Antibiotics Against Resistant Gram-Negative Infections in U.S. Hospitals: A Retrospective Cohort Study: Annals of Internal Medicine: Vol 177, No 5

Background: The U.S. antibiotic market failure has threatened future innovation and supply. Understanding when and why clinicians underutilize recently approved gram-negative antibiotics might help prioritize the patient in future antibiotic development and potential market entry rewards. Objective: To determine use patterns of recently U.S. Food and Drug Administration (FDA)-approved gram-negative antibiotics (ceftazidime–avibactam, ceftolozane–tazobactam, meropenem–vaborbactam, plazomicin, eravacycline, imipenem–relebactam–cilastatin, and cefiderocol) and identify factors associated with their preferential use (over traditional generic agents) in patients with gram-negative infections due to pathogens displaying difficult-to-treat resistance (DTR; that is, resistance to all first-line antibiotics). Design: Retrospective cohort. Setting: 619 U.S. hospitals. Participants: Adult inpatients. Measurements: Quarterly percentage change in antibiotic use was calculated using weighted linear regression. Machine learning selected candidate variables, and mixed models identified factors associated with new (vs. traditional) antibiotic use in DTR infections. Results: Between quarter 1 of 2016 and quarter 2 of 2021, ceftolozane–tazobactam (approved 2014) and ceftazidime–avibactam (2015) predominated new antibiotic usage whereas subsequently approved gram-negative antibiotics saw relatively sluggish uptake. Among gram-negative infection hospitalizations, 0.7% (2551 [2631 episodes] of 362 142) displayed DTR pathogens. Patients were treated exclusively using traditional agents in 1091 of 2631 DTR episodes (41.5%), including “reserve” antibiotics such as polymyxins, aminoglycosides, and tigecycline in 865 of 1091 episodes (79.3%). Patients with bacteremia and chronic diseases had greater adjusted probabilities and those with do-not-resuscitate status, acute liver failure, and Acinetobacter baumannii complex and other nonpseudomonal nonfermenter pathogens had lower adjusted probabilities of receiving newer (vs. traditional) antibiotics for DTR infections, respectively. Availability of susceptibility testing for new antibiotics increased probability of usage. Limitation: Residual confounding. Conclusion: Despite FDA approval of 7 next-generation gram-negative antibiotics between 2014 and 2019, clinicians still frequently treat resistant gram-negative infections with older, generic antibiotics with suboptimal safety–efficacy profiles. Future antibiotics with innovative mechanisms targeting untapped pathogen niches, widely available susceptibility testing, and evidence demonstrating improved outcomes in resistant infections might enhance utilization. Primary Funding Source: U.S. Food and Drug Administration; NIH Intramural Research Program.

Food Insecurity Among Low-Income U.S. Adults During the COVID-19 Pandemic