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.

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.

Responding to Reviewers and Editors About Statistical Significance Testing

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.

Acute Hospital Care at Home in the United States: The Early National Experience

Fatal and Nonfatal Firearm Injury Rates by Race and Ethnicity in the United States, 2019 to 2020

Background: Racial disparities in firearm injury death in the United States are well established. Less is known about the magnitude of nonfatal and total firearm injury. Objective: To combine health care data with death certificate data to estimate total firearm injuries in various racial and ethnic groups. Design: Retrospective, cross-sectional study. Setting: Fatal injury data were collected from the Centers for Disease Control and Prevention. Data on nonfatal injuries were collected from the Nationwide Emergency Department Sample (NEDS), a 20% stratified sample of U.S. emergency department visits, weighted to provide national estimates for the United States, 2019 to 2020. Participants: All firearm injuries and deaths in the United States. Intervention: Race and ethnicity were classified into 5 mutually exclusive categories: Asian or Pacific Islander, Black, Hispanic, Native American, and White. International Classification of Diseases, 10th Revision codes were used to classify firearm injury intent. Measurements: Incidence of fatal and nonfatal injury in the U.S. population and case-fatality ratios (CFRs). Results: There were 252 376 total firearm injuries, including 84 908 deaths from firearm injures. Of all firearm injuries, 37.8% were unintentional, 37.3% were assault related, 21.0% were self-harm, and 1.3% were law enforcement associated. Self-harm had the highest CFRs (90.9% overall). Unintentional injuries accounted for just 1021 (1.2%) deaths but 94 433 (56.4%) of nonfatal injuries. Rates of self-harm were highest among White persons (11.0 per 100 000 population in 2020) followed by Native Americans (8.6 per 100 000). Rates of assault were highest among Black persons (70.1 per 100 000), as were unintentional injuries (56.1 per 100 000). Limitation: Findings are limited by the accuracy of discharge coding in NEDS, particularly regarding injury intent and patient race and ethnicity. Conclusion: From 2019 to 2020, the total burden of firearm injuries amounts to an average of 1 injury every 4 minutes and 1 death every 12 minutes in the United States. Racial disparities in firearm injury death are mirrored in nonfatal injury. Primary Funding Source: None.

Cardiovascular Health of Middle-Aged U.S. Adults by Income Level, 1999 to March 2020: A Serial Cross-Sectional Study: Annals of Internal Medicine: Vol 176, No 12

Background: Although cardiovascular mortality has increased among middle-aged U.S. adults since 2011, how the burden of cardiovascular risk factors has changed for this population by income level over the past 2 decades is unknown. Objective: To evaluate trends in the prevalence, treatment, and control of cardiovascular risk factors among low-income and higher-income middle-aged adults and how social determinants contribute to recent associations between income and cardiovascular health. Design: Serial cross-sectional study. Setting: NHANES (National Health and Nutrition Examination Survey), 1999 to March 2020. Participants: Middle-aged adults (aged 40 to 64 years). Measurements: Age-standardized prevalence of hypertension, diabetes, hyperlipidemia, obesity, and cigarette use; treatment rates for hypertension, diabetes, and hyperlipidemia; and rates of blood pressure, glycemic, and cholesterol control. Results: The study population included 20 761 middle-aged adults. The prevalence of hypertension, diabetes, and cigarette use was consistently higher among low-income adults between 1999 and March 2020. Low-income adults had an increase in hypertension over the study period (37.2% [95% CI, 33.5% to 40.9%] to 44.7% [CI, 39.8% to 49.5%]) but no changes in diabetes or obesity. In contrast, higher-income adults did not have a change in hypertension but had increases in diabetes (7.8% [CI, 5.0% to 10.6%] to 14.9% [CI, 12.4% to 17.3%]) and obesity (33.0% [CI, 26.7% to 39.4%] to 44.0% [CI, 40.2% to 47.7%]). Cigarette use was high and stagnant among low-income adults (33.2% [CI, 28.4% to 38.0%] to 33.9% [CI, 29.6% to 38.3%]) but decreased among their higher-income counterparts (18.6% [CI, 13.5% to 23.7%] to 11.5% [CI, 8.7% to 14.3%]). Treatment and control rates for hypertension were unchanged in both groups (>80%), whereas diabetes treatment rates improved only among the higher-income group (58.4% [CI, 44.4% to 72.5%] to 77.4% [CI, 67.6% to 87.1%]). Income-based disparities in hypertension, diabetes, and cigarette use persisted in more recent years even after adjustment for insurance coverage, health care access, and food insecurity. Limitation: Sample size limitations could preclude detection of small changes in treatment and control rates. Conclusion: Over 2 decades in the United States, hypertension increased in low-income middle-aged adults, whereas diabetes and obesity increased in their higher-income counterparts. Income-based disparities in hypertension, diabetes, and smoking persisted even after adjustment for other social determinants of health. Primary Funding Source: National Institutes of Health.

Asthma Disparities in the United States Narrowed During the COVID-19 Pandemic: Findings From a National Survey, 2019 to 2022