Estimating Breast Cancer Overdiagnosis After Screening Mammography Among Older Women in the United States

Background: Overdiagnosis is increasingly recognized as a harm of breast cancer screening, particularly for older women. Objective: To estimate overdiagnosis associated with breast cancer screening among older women by age. Design: Retrospective cohort study comparing the cumulative incidence of breast cancer among older women who continued screening in the next interval with those who did not. Analyses used competing risk models, stratified by age. Setting: Fee-for-service Medicare claims, linked to the SEER (Surveillance, Epidemiology, and End Results) program. Patients: Women 70 years and older who had been recently screened. Measurements: Breast cancer diagnoses and breast cancer death for up to 15 years of follow-up. Results: This study included 54 635 women. Among women aged 70 to 74 years, the adjusted cumulative incidence of breast cancer was 6.1 cases (95% CI, 5.7 to 6.4) per 100 screened women versus 4.2 cases (CI, 3.5 to 5.0) per 100 unscreened women. An estimated 31% of breast cancer among screened women were potentially overdiagnosed. For women aged 75 to 84 years, cumulative incidence was 4.9 (CI, 4.6 to 5.2) per 100 screened women versus 2.6 (CI, 2.2 to 3.0) per 100 unscreened women, with 47% of cases potentially overdiagnosed. For women aged 85 and older, the cumulative incidence was 2.8 (CI, 2.3 to 3.4) among screened women versus 1.3 (CI, 0.9 to 1.9) among those not, with up to 54% overdiagnosis. We did not see statistically significant reductions in breast cancer–specific death associated with screening. Limitations: This study was designed to estimate overdiagnosis, limiting our ability to draw conclusions on all benefits and harms of screening. Unmeasured differences in risk for breast cancer and differential competing mortality between screened and unscreened women may confound results. Results were sensitive to model specifications and definition of a screening mammogram. Conclusion: Continued breast cancer screening was associated with greater incidence of breast cancer, suggesting overdiagnosis may be common among older women who are diagnosed with breast cancer after screening. Whether harms of overdiagnosis are balanced by benefits and for whom remains an important question. Primary Funding Source: National Cancer Institute.

Effects of U.S. State Medical Cannabis Laws on Treatment of Chronic Noncancer Pain

Background: State medical cannabis laws may lead patients with chronic noncancer pain to substitute cannabis in place of prescription opioid or clinical guideline–concordant nonopioid prescription pain medications or procedures. Objective: To assess effects of state medical cannabis laws on receipt of prescription opioids, nonopioid prescription pain medications, and procedures for chronic noncancer pain. Design: Using data from 12 states that implemented medical cannabis laws and 17 comparison states, augmented synthetic control analyses estimated laws’ effects on receipt of chronic noncancer pain treatment, relative to predicted treatment receipt in the absence of the law. Setting: United States, 2010 to 2022. Participants: 583 820 commercially insured adults with chronic noncancer pain. Measurements: Proportion of patients receiving any opioid prescription, nonopioid prescription pain medication, or procedure for chronic noncancer pain; volume of each treatment type; and mean days’ supply and mean morphine milligram equivalents per day of prescribed opioids, per patient in a given month. Results: In a given month during the first 3 years of law implementation, medical cannabis laws led to an average difference of 0.05 percentage points (95% CI, −0.12 to 0.21 percentage points), 0.05 percentage points (CI, −0.13 to 0.23 percentage points), and −0.17 percentage points (CI, −0.42 to 0.08 percentage points) in the proportion of patients receiving any opioid prescription, any nonopioid prescription pain medication, or any chronic pain procedure, respectively, relative to what we predict would have happened in that month had the law not been implemented. Limitations: This study used a strong nonexperimental design but relies on untestable assumptions involving parallel counterfactual trends. Statistical power is limited by the finite number of states. Results may not generalize to noncommercially insured populations. Conclusion: This study did not identify important effects of medical cannabis laws on receipt of opioid or nonopioid pain treatment among patients with chronic noncancer pain. Primary Funding Source: National Institute on Drug Abuse.

Risk for Chronic Kidney Disease Progression After Acute Kidney Injury: Findings From the Chronic Renal Insufficiency Cohort Study

Background: Prior studies associating acute kidney injury (AKI) with more rapid subsequent loss of kidney function had methodological limitations, including inadequate control for differences between patients who had AKI and those who did not. Objective: To determine whether AKI is independently associated with subsequent kidney function trajectory among patients with chronic kidney disease (CKD). Design: Multicenter prospective cohort study. Setting: United States. Participants: Patients with CKD (n = 3150). Measurements: Hospitalized AKI was defined by a 50% or greater increase in inpatient serum creatinine (SCr) level from nadir to peak. Kidney function trajectory was assessed using estimated glomerular filtration rate (eGFR) based on SCr level (eGFRcr) or cystatin C level (eGFRcys) measured at annual study visits. Results: During a median follow-up of 3.9 years, 433 participants had at least 1 AKI episode. Most episodes (92%) had stage 1 or 2 severity. There were decreases in eGFRcr (−2.30 [95% CI, −3.70 to −0.86] mL/min/1.73 m2) and eGFRcys (−3.61 [CI, −6.39 to −0.82] mL/min/1.73 m2) after AKI. However, in fully adjusted models, the decreases were attenuated to −0.38 (CI, −1.35 to 0.59) mL/min/1.73 m2 for eGFRcr and −0.15 (CI, −2.16 to 1.86) mL/min/1.73 m2 for eGFRcys, and the CI bounds included the possibility of no effect. Estimates of changes in eGFR slope after AKI determined by either SCr level (0.04 [CI, −0.30 to 0.38] mL/min/1.73 m2 per year) or cystatin C level (−0.56 [CI, −1.28 to 0.17] mL/min/1.73 m2 per year) also had CI bounds that included the possibility of no effect. Limitations: Few cases of severe AKI, no adjudication of AKI cause, and lack of information about nephrotoxic exposures after hospital discharge. Conclusion: After pre-AKI eGFR, proteinuria, and other covariables were accounted for, the association between mild to moderate AKI and worsening subsequent kidney function in patients with CKD was small. Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

Safety and Efficacy of Combination SARS-CoV-2 Neutralizing Monoclonal Antibodies Amubarvimab Plus Romlusevimab in Nonhospitalized Patients With COVID-19

Background: Development of safe and effective SARS-CoV-2 therapeutics is a high priority. Amubarvimab and romlusevimab are noncompeting anti–SARS-CoV-2 monoclonal antibodies with an extended half-life. Objective: To assess the safety and efficacy of amubarvimab plus romlusevimab. Design: Randomized, placebo-controlled, phase 2 and 3 platform trial. (ClinicalTrials.gov: NCT04518410) Setting: Nonhospitalized patients with COVID-19 in the United States, Brazil, South Africa, Mexico, Argentina, and the Philippines. Patients: Adults within 10 days onset of symptomatic SARS-CoV-2 infection who are at high risk for clinical progression. Intervention: Combination of monoclonal antibodies amubarvimab plus romlusevimab or placebo. Measurements: Nasopharyngeal and anterior nasal swabs for SARS-CoV-2, COVID-19 symptoms, safety, and progression to hospitalization or death. Results: Eight-hundred and seven participants who initiated the study intervention were included in the phase 3 analysis. Median age was 49 years (quartiles, 39 to 58); 51% were female, 18% were Black, and 50% were Hispanic or Latino. Median time from symptom onset at study entry was 6 days (quartiles, 4 to 7). Hospitalizations and/or death occurred in 9 (2.3%) participants in the amubarvimab plus romlusevimab group compared with 44 (10.7%) in the placebo group, with an estimated 79% reduction in events (P < 0.001). This reduction was similar between participants with 5 or less and more than 5 days of symptoms at study entry. Grade 3 or higher treatment-emergent adverse events through day 28 were seen less frequently among participants randomly assigned to amubarvimab plus romlusevimab (7.3%) than placebo (16.1%) (P < 0.001), with no severe infusion reactions or drug-related serious adverse events. Limitation: The study population was mostly unvaccinated against COVID-19 and enrolled before the spread of Omicron variants and subvariants. Conclusion: Amubarvimab plus romlusevimab was safe and significantly reduced the risk for hospitalization and/or death among nonhospitalized adults with mild to moderate SARS-CoV-2 infection at high risk for progression to severe disease. Primary Funding Source: National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

Distributional Cost-Effectiveness of Equity-Enhancing Gene Therapy in Sickle Cell Disease in the United States

Background: Gene therapy is a potential cure for sickle cell disease (SCD). Conventional cost-effectiveness analysis (CEA) does not capture the effects of treatments on disparities in SCD, but distributional CEA (DCEA) uses equity weights to incorporate these considerations. Objective: To compare gene therapy versus standard of care (SOC) in patients with SCD by using conventional CEA and DCEA. Design: Markov model. Data Sources: Claims data and other published sources. Target Population: Birth cohort of patients with SCD. Time Horizon: Lifetime. Perspective: U.S. health system. Intervention: Gene therapy at age 12 years versus SOC. Outcome Measures: Incremental cost-effectiveness ratio (ICER) (in dollars per quality-adjusted life-years [QALYs] gained) and threshold inequality aversion parameter (equity weight). Results of Base-Case Analysis: Gene therapy versus SOC for females yielded 25.5 versus 15.7 (males: 24.4 vs. 15.5) discounted lifetime QALYs at costs of $2.8 million and $1.0 million (males: $2.8 million and $1.2 million), respectively, with an ICER of $176 000 per QALY (full SCD population). The inequality aversion parameter would need to be 0.90 for the full SCD population for gene therapy to be preferred per DCEA standards. Results of Sensitivity Analysis: SOC was favored in 100.0% (females) and 87.1% (males) of 10 000 probabilistic iterations at a willingness-to-pay threshold of $100 000 per QALY. Gene therapy would need to cost less than $1.79 million to meet conventional CEA standards. Limitation: Benchmark equity weights (as opposed to SCD-specific weights) were used to interpret DCEA results. Conclusion: Gene therapy is cost-ineffective per conventional CEA standards but can be an equitable therapeutic strategy for persons living with SCD in the United States per DCEA standards. Primary Funding Source: Yale Bernard G. Forget Scholars Program and Bunker Endowment.

Risk for Bleeding-Related Hospitalizations During Use of Amiodarone With Apixaban or Rivaroxaban in Patients With Atrial Fibrillation: A Retrospective Cohort Study: Annals of Internal Medicine: Vol 176, No 6

Background: Amiodarone, the most effective antiarrhythmic drug in atrial fibrillation, inhibits apixaban and rivaroxaban elimination, thus possibly increasing anticoagulant-related risk for bleeding. Objective: For patients receiving apixaban or rivaroxaban, to compare risk for bleeding-related hospitalizations during treatment with amiodarone versus flecainide or sotalol, antiarrhythmic drugs that do not inhibit these anticoagulants’ elimination. Design: Retrospective cohort study. Setting: U.S. Medicare beneficiaries aged 65 years or older. Patients: Patients with atrial fibrillation began anticoagulant use between 1 January 2012 and 30 November 2018 and subsequently initiated treatment with study antiarrhythmic drugs. Measurements: Time to event for bleeding-related hospitalizations (primary outcome) and ischemic stroke, systemic embolism, and death with or without recent (past 30 days) evidence of bleeding (secondary outcomes), adjusted with propensity score overlap weighting. Results: There were 91 590 patients (mean age, 76.3 years; 52.5% female) initiating use of study anticoagulants and antiarrhythmic drugs, 54 977 with amiodarone and 36 613 with flecainide or sotalol. Risk for bleeding-related hospitalizations increased with amiodarone use (rate difference [RD], 17.5 events [95% CI, 12.0 to 23.0 events] per 1000 person-years; hazard ratio [HR], 1.44 [CI, 1.27 to 1.63]). Incidence of ischemic stroke or systemic embolism did not increase (RD, −2.1 events [CI, −4.7 to 0.4 events] per 1000 person-years; HR, 0.80 [CI, 0.62 to 1.03]). The risk for death with recent evidence of bleeding (RD, 9.1 events [CI, 5.8 to 12.3 events] per 1000 person-years; HR, 1.66 [CI, 1.35 to 2.03]) was greater than that for other deaths (RD, 5.6 events [CI, 0.5 to 10.6 events] per 1000 person-years; HR, 1.15 [CI, 1.00 to 1.31]) (HR comparison: P = 0.003). The increased incidence of bleeding-related hospitalizations for rivaroxaban (RD, 28.0 events [CI, 18.4 to 37.6 events] per 1000 person-years) was greater than that for apixaban (RD, 9.1 events [CI, 2.8 to 15.3 events] per 1000 person-years) (P = 0.001). Limitation: Possible residual confounding. Conclusion: In this retrospective cohort study, patients aged 65 years or older with atrial fibrillation treated with amiodarone during apixaban or rivaroxaban use had greater risk for bleeding-related hospitalizations than those treated with flecainide or sotalol. Primary Funding Source: National Heart, Lung, and Blood Institute.

Effect of Medicare Advantage on Hospital Readmission and Mortality Rankings

Background: Medicare links hospital performance on readmissions and mortality to payment solely on the basis of outcomes among fee-for-service (FFS) beneficiaries. Whether including Medicare Advantage (MA) beneficiaries, who account for nearly half of all Medicare beneficiaries, in the evaluation of hospital performance affects rankings is unknown. Objective: To determine if the inclusion of MA beneficiaries in readmission and mortality measures reclassifies hospital performance rankings compared with current measures. Design: Cross-sectional. Setting: Population-based. Participants: Hospitals participating in the Hospital Readmissions Reduction Program or Hospital Value-Based Purchasing Program. Measurements: Using the 100% Medicare files for FFS and MA claims, the authors calculated 30-day risk-adjusted readmissions and mortality for acute myocardial infarction, heart failure, chronic obstructive pulmonary disease, and pneumonia on the basis of only FFS beneficiaries and then both FFS and MA beneficiaries. Hospitals were divided into quintiles of performance based on FFS beneficiaries only, and the proportion of hospitals that were reclassified to a different performance group with the inclusion of MA beneficiaries was calculated. Results: Of the hospitals in the top-performing quintile for readmissions and mortality based on FFS beneficiaries, between 21.6% and 30.2% were reclassified to a lower-performing quintile with the inclusion of MA beneficiaries. Similar proportions of hospitals were reclassified from the bottom performance quintile to a higher one across all measures and conditions. Hospitals with a higher proportion of MA beneficiaries were more likely to improve in performance rankings. Limitation: Hospital performance measurement and risk adjustment differed slightly from those used by Medicare. Conclusion: Approximately 1 in 4 top-performing hospitals is reclassified to a lower performance group when MA beneficiaries are included in the evaluation of hospital readmissions and mortality. These findings suggest that Medicare's current value-based programs provide an incomplete picture of hospital performance. Primary Funding Source: Laura and John Arnold Foundation.

Temporal Trends in the Use of Computed Tomographic Pulmonary Angiography for Suspected Pulmonary Embolism in the Emergency Department: A Retrospective Analysis: Annals of Internal Medicine: Vol 176, No 6

Background: Recently, validated clinical decision rules have been developed that avoid unnecessary use of computed tomographic pulmonary angiography (CTPA) in patients with suspected pulmonary embolism (PE) in the emergency department (ED). Objective: To measure any resulting change in CTPA use for suspected PE. Design: Retrospective analysis. Setting: 26 European EDs in 6 countries. Patients: Patients with CTPA performed for suspected PE in the ED during the first 7 days of each odd month between January 2015 and December 2019. Measurements: The primary end points were the CTPAs done for suspected PE in the ED and the number of PEs diagnosed in the ED each year adjusted to an annual census of 100 000 ED visits. Temporal trends were estimated using generalized linear mixed regression models. Results: 8970 CTPAs were included (median age, 63 years; 56% female). Statistically significant temporal trends for more frequent use of CTPA (836 per 100 000 ED visits in 2015 vs. 1112 in 2019; P < 0.001), more diagnosed PEs (138 per 100 000 in 2015 vs. 164 in 2019; P = 0.028), a higher proportion of low-risk PEs (annual percent change [APC], 13.8% [95% CI, 2.6% to 30.1%]) with more ambulatory management (APC, 19.3% [CI, 4.1% to 45.1%]), and a lower proportion of intensive care unit admissions (APC, −8.9% [CI, −17.1% to −0.3%]) were observed. Limitation: Data were limited to 7 days every 2 months. Conclusion: Despite the recent validation of clinical decision rules to limit the use of CTPA, an increase in the CTPA rate along with more diagnosed PEs and especially low-risk PEs were instead observed. Primary Funding Source: None specific for this study.

Prevalence and Management of Obesity in U.S. Adults With Type 1 Diabetes

Effectiveness of Molnupiravir and Nirmatrelvir–Ritonavir in Hospitalized Patients With COVID-19: A Target Trial Emulation Study: Annals of Internal Medicine: Vol 176, No 4

Background: Whether hospitalized patients benefit from COVID-19 oral antivirals is uncertain. Objective: To examine the real-world effectiveness of molnupiravir and nirmatrelvir–ritonavir in hospitalized patients with COVID-19 during the Omicron outbreak. Design: Target trial emulation study. Setting: Electronic health databases in Hong Kong. Participants: The molnupiravir emulated trial included hospitalized patients with COVID-19 aged 18 years or older between 26 February and 18 July 2022 (n = 16 495). The nirmatrelvir–ritonavir emulated trial included hospitalized patients with COVID-19 aged 18 years or older between 16 March and 18 July 2022 (n = 7119). Intervention: Initiation of molnupiravir or nirmatrelvir–ritonavir within 5 days of hospitalization with COVID-19 versus no initiation of molnupiravir or nirmatrelvir–ritonavir. Measurements: Effectiveness against all-cause mortality, intensive care unit (ICU) admission, or use of ventilatory support within 28 days. Results: The use of oral antivirals in hospitalized patients with COVID-19 was associated with a lower risk for all-cause mortality (molnupiravir: hazard ratio [HR], 0.87 [95% CI, 0.81 to 0.93]; nirmatrelvir–ritonavir: HR, 0.77 [CI, 0.66 to 0.90]) but no significant risk reduction in terms of ICU admission (molnupiravir: HR, 1.02 [CI, 0.76 to 1.36]; nirmatrelvir–ritonavir: HR, 1.08 [CI, 0.58 to 2.02]) or the need for ventilatory support (molnupiravir: HR, 1.07 [CI, 0.89 to 1.30]; nirmatrelvir–ritonavir: HR, 1.03 [CI, 0.70 to 1.52]). There was no significant interaction between drug treatment and the number of COVID-19 vaccine doses received, thereby supporting the effectiveness of oral antivirals regardless of vaccination status. No significant interaction between nirmatrelvir–ritonavir treatment and age, sex, or Charlson Comorbidity Index was observed, whereas molnupiravir tended to be more effective in older people. Limitation: The outcome of ICU admission or need for ventilatory support may not capture all severe COVID-19 cases; unmeasured confounders, such as obesity and health behaviors, may exist. Conclusion: Molnupiravir and nirmatrelvir–ritonavir reduced all-cause mortality in both vaccinated and unvaccinated hospitalized patients. No significant reduction in ICU admission or the need for ventilatory support was observed. Primary Funding Source: Health and Medical Research Fund Research on COVID-19, Government of the Hong Kong Special Administrative Region; Research Grants Council, Collaborative Research Fund; and Health Bureau, Government of the Hong Kong Special Administrative Region.