Journal: JAMA

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<div><h4>Direct Oral Anticoagulants vs Low-Molecular-Weight Heparin and Recurrent VTE in Patients With Cancer: A Randomized Clinical Trial.</h4><i>Schrag D, Uno H, Rosovsky R, Rutherford C, ... Connors JM, CANVAS Investigators</i><br /><b>Importance</b><br />In patients with cancer who have venous thromboembolism (VTE) events, long-term anticoagulation with low-molecular-weight heparin (LMWH) is recommended to prevent recurrent VTE. The effectiveness of a direct oral anticoagulant (DOAC) compared with LMWH for preventing recurrent VTE in patients with cancer is uncertain.<br /><b>Objective</b><br />To evaluate DOACs, compared with LMWH, for preventing recurrent VTE and for rates of bleeding in patients with cancer following an initial VTE event.<br /><b>Design, setting, and participants</b><br />Unblinded, comparative effectiveness, noninferiority randomized clinical trial conducted at 67 oncology practices in the US that enrolled 671 patients with cancer (any invasive solid tumor, lymphoma, multiple myeloma, or chronic lymphocytic leukemia) who had a new clinical or radiological diagnosis of VTE. Enrollment occurred from December 2016 to April 2020. Final follow-up was in November 2020.<br /><b>Intervention</b><br />Participants were randomized in a 1:1 ratio to either a DOAC (n = 335) or LMWH (n = 336) and were followed up for 6 months or until death. Physicians and patients selected any DOAC or any LMWH (or fondaparinux) and physicians selected drug doses.<br /><b>Main outcomes and measures</b><br />The primary outcome was the recurrent VTE rate at 6 months. Noninferiority of anticoagulation with a DOAC vs LMWH was defined by the upper limit of the 1-sided 95% CI for the difference of a DOAC relative to LMWH of less than 3% in the randomized cohort that received at least 1 dose of assigned treatment. The 6 prespecified secondary outcomes included major bleeding, which was assessed using a 2.5% noninferiority margin.<br /><b>Results</b><br />Between December 2016 and April 2020, 671 participants were randomized and 638 (95%) completed the trial (median age, 64 years; 353 women [55%]). Among those randomized to a DOAC, 330 received at least 1 dose. Among those randomized to LMWH, 308 received at least 1 dose. Rates of recurrent VTE were 6.1% in the DOAC group and 8.8% in the LMWH group (difference, -2.7%; 1-sided 95% CI, -100% to 0.7%) consistent with the prespecified noninferiority criterion. Of 6 prespecified secondary outcomes, none were statistically significant. Major bleeding occurred in 5.2% of participants in the DOAC group and 5.6% in the LMWH group (difference, -0.4%; 1-sided 95% CI, -100% to 2.5%) and did not meet the noninferiority criterion. Severe adverse events occurred in 33.8% of participants in the DOAC group and 35.1% in the LMWH group. The most common serious adverse events were anemia and death.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Among adults with cancer and VTE, DOACs were noninferior to LMWH for preventing recurrent VTE over 6-month follow-up. These findings support use of a DOAC to prevent recurrent VTE in patients with cancer.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT02744092.<br /><br /><br /><br /><small>JAMA: 02 Jun 2023; epub ahead of print</small></div>
Schrag D, Uno H, Rosovsky R, Rutherford C, ... Connors JM, CANVAS Investigators
JAMA: 02 Jun 2023; epub ahead of print | PMID: 37266947
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<div><h4>Coronary Artery Calcium Score and Polygenic Risk Score for the Prediction of Coronary Heart Disease Events.</h4><i>Khan SS, Post WS, Guo X, Tan J, ... Greenland P, Kavousi M</i><br /><b>Importance</b><br />Coronary artery calcium score and polygenic risk score have each separately been proposed as novel markers to identify risk of coronary heart disease (CHD), but no prior studies have directly compared these markers in the same cohorts.<br /><b>Objective</b><br />To evaluate change in CHD risk prediction when a coronary artery calcium score, a polygenic risk score, or both are added to a traditional risk factor-based model.<br /><b>Design, setting, and participants</b><br />Two observational population-based studies involving individuals aged 45 years through 79 years of European ancestry and free of clinical CHD at baseline: the Multi-Ethnic Study of Atherosclerosis (MESA) study involved 1991 participants at 6 US centers and the Rotterdam Study (RS) involved 1217 in Rotterdam, the Netherlands.<br /><b>Exposure</b><br />Traditional risk factors were used to calculate CHD risk (eg, pooled cohort equations [PCEs]), computed tomography for the coronary artery calcium score, and genotyped samples for a validated polygenic risk score.<br /><b>Main outcomes and measures</b><br />Model discrimination, calibration, and net reclassification improvement (at the recommended risk threshold of 7.5%) for prediction of incident CHD events were assessed.<br /><b>Results</b><br />The median age was 61 years in MESA and 67 years in RS. Both log (coronary artery calcium+1) and polygenic risk score were significantly associated with 10-year risk of incident CHD (hazards ratio per SD, 2.60; 95% CI, 2.08-3.26 and 1.43; 95% CI, 1.20-1.71, respectively), in MESA. The C statistic for the coronary artery calcium score was 0.76 (95% CI, 0.71-0.79) and for the polygenic risk score, 0.69 (95% CI, 0.63-0.71). The change in the C statistic when each was added to the PCEs was 0.09 (95% CI, 0.06-0.13) for the coronary artery calcium score, 0.02 (95% CI, 0.00-0.04) for the polygenic risk score, and 0.10 (95% CI, 0.07-0.14) for both. Overall categorical net reclassification improvement was significant when the coronary artery calcium score (0.19; 95% CI, 0.06-0.28) but was not significant when the polygenic risk score (0.04; 95% CI, -0.05 to 0.10) was added to the PCEs. Calibration of the PCEs and models with coronary artery calcium and/or polygenic risk scores was adequate (all χ2<20). Subgroup analysis stratified by the median age demonstrated similar findings. Similar findings were observed for 10-year risk in RS and in longer-term follow-up in MESA (median, 16.0 years).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />In 2 cohorts of middle-aged to older adults from the US and the Netherlands, the coronary artery calcium score had better discrimination than the polygenic risk score for risk prediction of CHD. In addition, the coronary artery calcium score but not the polygenic risk score significantly improved risk discrimination and risk reclassification for CHD when added to traditional risk factors.<br /><br /><br /><br /><small>JAMA: 23 May 2023; 329:1768-1777</small></div>
Khan SS, Post WS, Guo X, Tan J, ... Greenland P, Kavousi M
JAMA: 23 May 2023; 329:1768-1777 | PMID: 37219552
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<div><h4>Transcatheter Mitral Valve Repair for Degenerative Mitral Regurgitation.</h4><i>Makkar RR, Chikwe J, Chakravarty T, Chen Q, ... Vemulapalli S, Leon MB</i><br /><b>Importance</b><br />There are limited data on the outcomes of transcatheter edge-to-edge mitral valve repair for degenerative mitral regurgitation (MR) in a real-world setting.<br /><b>Objective</b><br />To evaluate the outcomes of transcatheter mitral valve repair for degenerative MR.<br /><b>Design, setting, and participants</b><br />Cohort study of consecutive patients in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapies Registry who underwent nonemergent transcatheter mitral valve repair for degenerative MR in the US from 2014 through 2022.<br /><b>Exposure</b><br />Transcatheter edge-to-edge mitral valve repair with the MitraClip device (Abbott).<br /><b>Main outcomes and measures</b><br />The primary end point was MR success, defined as moderate or less residual MR and a mean mitral gradient of less than 10 mm Hg. Clinical outcomes were evaluated based on the degree of residual MR (mild or less MR or moderate MR) and mitral valve gradients (≤5 mm Hg or >5 to <10 mm Hg).<br /><b>Results</b><br />A total of 19 088 patients with isolated moderate to severe or severe degenerative MR who underwent transcatheter mitral valve repair were analyzed (median age, 82 years; 48% women; median Society of Thoracic Surgeons predicted risk of mortality with surgical mitral valve repair, 4.6%). MR success was achieved in 88.9% of patients. At 30 days, the incidence of death was 2.7%; stroke, 1.2%; and mitral valve reintervention, 0.97%. MR success compared with an unsuccessful procedure was associated with significantly lower mortality (14.0% vs 26.7%; adjusted hazard ratio, 0.49; 95% CI, 0.42-0.56; P < .001) and heart failure readmission (8.4% vs 16.9%; adjusted hazard ratio, 0.47; 95% CI, 0.41-0.54; P < .001) at 1 year. Among patients with MR success, the lowest mortality was observed in patients who had both mild or less residual MR and mean mitral gradients of 5 mm Hg or less compared with those with an unsuccessful procedure (11.4% vs 26.7%; adjusted hazard ratio, 0.40; 95% CI, 0.34-0.47; P < .001).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />In this registry-based study of patients with degenerative MR undergoing transcatheter mitral valve repair, the procedure was safe and resulted in successful repair in 88.9% of patients. The lowest mortality was observed in patients with mild or less residual MR and low mitral gradients.<br /><br /><br /><br /><small>JAMA: 23 May 2023; 329:1778-1788</small></div>
Makkar RR, Chikwe J, Chakravarty T, Chen Q, ... Vemulapalli S, Leon MB
JAMA: 23 May 2023; 329:1778-1788 | PMID: 37219553
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<div><h4>Reducing Opioid Use for Chronic Pain With a Group-Based Intervention: A Randomized Clinical Trial.</h4><i>Sandhu HK, Booth K, Furlan AD, Shaw J, ... Eldabe S, Underwood M</i><br /><b>Importance</b><br />Opioid use for chronic nonmalignant pain can be harmful.<br /><b>Objective</b><br />To test whether a multicomponent, group-based, self-management intervention reduced opioid use and improved pain-related disability compared with usual care.<br /><b>Design, setting, and participants</b><br />Multicentered, randomized clinical trial of 608 adults taking strong opioids (buprenorphine, dipipanone, morphine, diamorphine, fentanyl, hydromorphone, methadone, oxycodone, papaveretum, pentazocine, pethidine, tapentadol, and tramadol) to treat chronic nonmalignant pain. The study was conducted in 191 primary care centers in England between May 17, 2017, and January 30, 2019. Final follow-up occurred March 18, 2020.<br /><b>Intervention</b><br />Participants were randomized 1:1 to either usual care or 3-day-long group sessions that emphasized skill-based learning and education, supplemented by 1-on-1 support delivered by a nurse and lay person for 12 months.<br /><b>Main outcomes and measures</b><br />The 2 primary outcomes were Patient-Reported Outcomes Measurement Information System Pain Interference Short Form 8a (PROMIS-PI-SF-8a) score (T-score range, 40.7-77; 77 indicates worst pain interference; minimal clinically important difference, 3.5) and the proportion of participants who discontinued opioids at 12 months, measured by self-report.<br /><b>Results</b><br />Of 608 participants randomized (mean age, 61 years; 362 female [60%]; median daily morphine equivalent dose, 46 mg [IQR, 25 to 79]), 440 (72%) completed 12-month follow-up. There was no statistically significant difference in PROMIS-PI-SF-8a scores between the 2 groups at 12-month follow-up (-4.1 in the intervention and -3.17 in the usual care groups; between-group difference: mean difference, -0.52 [95% CI, -1.94 to 0.89]; P = .15). At 12 months, opioid discontinuation occurred in 65 of 225 participants (29%) in the intervention group and 15 of 208 participants (7%) in the usual care group (odds ratio, 5.55 [95% CI, 2.80 to 10.99]; absolute difference, 21.7% [95% CI, 14.8% to 28.6%]; P < .001). Serious adverse events occurred in 8% (25/305) of the participants in the intervention group and 5% (16/303) of the participants in the usual care group. The most common serious adverse events were gastrointestinal (2% in the intervention group and 0% in the usual care group) and locomotor/musculoskeletal (2% in the intervention group and 1% in the usual care group). Four people (1%) in the intervention group received additional medical care for possible or probable symptoms of opioid withdrawal (shortness of breath, hot flushes, fever and pain, small intestinal bleed, and an overdose suicide attempt).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />In people with chronic pain due to nonmalignant causes, compared with usual care, a group-based educational intervention that included group and individual support and skill-based learning significantly reduced patient-reported use of opioids, but had no effect on perceived pain interference with daily life activities.<br /><b>Trial registration</b><br />isrctn.org Identifier: ISRCTN49470934.<br /><br /><br /><br /><small>JAMA: 23 May 2023; 329:1745-1756</small></div>
Sandhu HK, Booth K, Furlan AD, Shaw J, ... Eldabe S, Underwood M
JAMA: 23 May 2023; 329:1745-1756 | PMID: 37219554
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<div><h4>Intervention to Promote Communication About Goals of Care for Hospitalized Patients With Serious Illness: A Randomized Clinical Trial.</h4><i>Curtis JR, Lee RY, Brumback LC, Kross EK, ... Abedini NC, Engelberg RA</i><br /><b>Importance</b><br />Discussions about goals of care are important for high-quality palliative care yet are often lacking for hospitalized older patients with serious illness.<br /><b>Objective</b><br />To evaluate a communication-priming intervention to promote goals-of-care discussions between clinicians and hospitalized older patients with serious illness.<br /><b>Design, setting, and participants</b><br />A pragmatic, randomized clinical trial of a clinician-facing communication-priming intervention vs usual care was conducted at 3 US hospitals within 1 health care system, including a university, county, and community hospital. Eligible hospitalized patients were aged 55 years or older with any of the chronic illnesses used by the Dartmouth Atlas project to study end-of-life care or were aged 80 years or older. Patients with documented goals-of-care discussions or a palliative care consultation between hospital admission and eligibility screening were excluded. Randomization occurred between April 2020 and March 2021 and was stratified by study site and history of dementia.<br /><b>Intervention</b><br />Physicians and advance practice clinicians who were treating the patients randomized to the intervention received a 1-page, patient-specific intervention (Jumpstart Guide) to prompt and guide goals-of-care discussions.<br /><b>Main outcomes and measures</b><br />The primary outcome was the proportion of patients with electronic health record-documented goals-of-care discussions within 30 days. There was also an evaluation of whether the effect of the intervention varied by age, sex, history of dementia, minoritized race or ethnicity, or study site.<br /><b>Results</b><br />Of 3918 patients screened, 2512 were enrolled (mean age, 71.7 [SD, 10.8] years and 42% were women) and randomized (1255 to the intervention group and 1257 to the usual care group). The patients were American Indian or Alaska Native (1.8%), Asian (12%), Black (13%), Hispanic (6%), Native Hawaiian or Pacific Islander (0.5%), non-Hispanic (93%), and White (70%). The proportion of patients with electronic health record-documented goals-of-care discussions within 30 days was 34.5% (433 of 1255 patients) in the intervention group vs 30.4% (382 of 1257 patients) in the usual care group (hospital- and dementia-adjusted difference, 4.1% [95% CI, 0.4% to 7.8%]). The analyses of the treatment effect modifiers suggested that the intervention had a larger effect size among patients with minoritized race or ethnicity. Among 803 patients with minoritized race or ethnicity, the hospital- and dementia-adjusted proportion with goals-of-care discussions was 10.2% (95% CI, 4.0% to 16.5%) higher in the intervention group than in the usual care group. Among 1641 non-Hispanic White patients, the adjusted proportion with goals-of-care discussions was 1.6% (95% CI, -3.0% to 6.2%) higher in the intervention group than in the usual care group. There was no evidence of differential treatment effects of the intervention on the primary outcome by age, sex, history of dementia, or study site.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Among hospitalized older adults with serious illness, a pragmatic clinician-facing communication-priming intervention significantly improved documentation of goals-of-care discussions in the electronic health record, with a greater effect size in racially or ethnically minoritized patients.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT04281784.<br /><br /><br /><br /><small>JAMA: 21 May 2023; epub ahead of print</small></div>
Curtis JR, Lee RY, Brumback LC, Kross EK, ... Abedini NC, Engelberg RA
JAMA: 21 May 2023; epub ahead of print | PMID: 37210665
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<div><h4>Airway-Occluding Mucus Plugs and Mortality in Patients With Chronic Obstructive Pulmonary Disease.</h4><i>Diaz AA, Orejas JL, Grumley S, Nath HP, ... Cho M, San José Estépar R</i><br /><b>Importance</b><br />Airway mucus plugs are common in patients with chronic obstructive pulmonary disease (COPD); however, the association of airway mucus plugging and mortality in patients with COPD is unknown.<br /><b>Objective</b><br />To determine whether airway mucus plugs identified on chest computed tomography (CT) were associated with increased all-cause mortality.<br /><b>Design, setting, and participants</b><br />Observational retrospective analysis of prospectively collected data of patients with a diagnosis of COPD in the Genetic Epidemiology of COPD cohort. Participants were non-Hispanic Black or White individuals, aged 45 to 80 years, who smoked at least 10 pack-years. Participants were enrolled at 21 centers across the US between November 2007 and April 2011 and were followed up through August 31, 2022.<br /><b>Exposures</b><br />Mucus plugs that completely occluded airways on chest CT scans, identified in medium- to large-sized airways (ie, approximately 2- to 10-mm lumen diameter) and categorized as affecting 0, 1 to 2, or 3 or more lung segments.<br /><b>Main outcomes and measures</b><br />The primary outcome was all-cause mortality, assessed with proportional hazard regression analysis. Models were adjusted for age, sex, race and ethnicity, body mass index, pack-years smoked, current smoking status, forced expiratory volume in the first second of expiration, and CT measures of emphysema and airway disease.<br /><b>Results</b><br />Among the 4483 participants with COPD, 4363 were included in the primary analysis (median age, 63 years [IQR, 57-70 years]; 44% were women). A total of 2585 (59.3%), 953 (21.8%), and 825 (18.9%) participants had mucus plugs in 0, 1 to 2, and 3 or more lung segments, respectively. During a median 9.5-year follow-up, 1769 participants (40.6%) died. The mortality rates were 34.0% (95% CI, 32.2%-35.8%), 46.7% (95% CI, 43.5%-49.9%), and 54.1% (95% CI, 50.7%-57.4%) in participants who had mucus plugs in 0, 1 to 2, and 3 or more lung segments, respectively. The presence of mucus plugs in 1 to 2 vs 0 and 3 or more vs 0 lung segments was associated with an adjusted hazard ratio of death of 1.15 (95% CI, 1.02-1.29) and 1.24 (95% CI, 1.10-1.41), respectively.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />In participants with COPD, the presence of mucus plugs that obstructed medium- to large-sized airways was associated with higher all-cause mortality compared with patients without mucus plugging on chest CT scans.<br /><br /><br /><br /><small>JAMA: 21 May 2023; epub ahead of print</small></div>
Diaz AA, Orejas JL, Grumley S, Nath HP, ... Cho M, San José Estépar R
JAMA: 21 May 2023; epub ahead of print | PMID: 37210745
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<div><h4>The Economic Burden of Racial, Ethnic, and Educational Health Inequities in the US.</h4><i>LaVeist TA, Pérez-Stable EJ, Richard P, Anderson A, ... Assenov A, Gaskin DJ</i><br /><b>Importance</b><br />Health inequities exist for racial and ethnic minorities and persons with lower educational attainment due to differential exposure to economic, social, structural, and environmental health risks and limited access to health care.<br /><b>Objective</b><br />To estimate the economic burden of health inequities for racial and ethnic minority populations (American Indian and Alaska Native, Asian, Black, Latino, and Native Hawaiian and Other Pacific Islander) and adults 25 years and older with less than a 4-year college degree in the US. Outcomes include the sum of excess medical care expenditures, lost labor market productivity, and the value of excess premature death (younger than 78 years) by race and ethnicity and the highest level of educational attainment compared with health equity goals.<br /><b>Evidence review</b><br />Analysis of 2016-2019 data from the Medical Expenditure Panel Survey (MEPS) and state-level Behavioral Risk Factor Surveillance System (BRFSS) and 2016-2018 mortality data from the National Vital Statistics System and 2018 IPUMS American Community Survey. There were 87 855 survey respondents to MEPS, 1 792 023 survey respondents to the BRFSS, and 8 416 203 death records from the National Vital Statistics System.<br /><b>Findings</b><br />In 2018, the estimated economic burden of racial and ethnic health inequities was $421 billion (using MEPS) or $451 billion (using BRFSS data) and the estimated burden of education-related health inequities was $940 billion (using MEPS) or $978 billion (using BRFSS). Most of the economic burden was attributable to the poor health of the Black population; however, the burden attributable to American Indian or Alaska Native and Native Hawaiian or Other Pacific Islander populations was disproportionately greater than their share of the population. Most of the education-related economic burden was incurred by adults with a high school diploma or General Educational Development equivalency credential. However, adults with less than a high school diploma accounted for a disproportionate share of the burden. Although they make up only 9% of the population, they bore 26% of the costs.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />The economic burden of racial and ethnic and educational health inequities is unacceptably high. Federal, state, and local policy makers should continue to invest resources to develop research, policies, and practices to eliminate health inequities in the US.<br /><br /><br /><br /><small>JAMA: 16 May 2023; 329:1682-1692</small></div>
LaVeist TA, Pérez-Stable EJ, Richard P, Anderson A, ... Assenov A, Gaskin DJ
JAMA: 16 May 2023; 329:1682-1692 | PMID: 37191700
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<div><h4>Excess Mortality and Years of Potential Life Lost Among the Black Population in the US, 1999-2020.</h4><i>Caraballo C, Massey DS, Ndumele CD, Haywood T, ... Faust JS, Krumholz HM</i><br /><b>Importance</b><br />Amid efforts in the US to promote health equity, there is a need to assess recent progress in reducing excess deaths and years of potential life lost among the Black population compared with the White population.<br /><b>Objective</b><br />To evaluate trends in excess mortality and years of potential life lost among the Black population compared with the White population.<br /><b>Design, setting, and participants</b><br />Serial cross-sectional study using US national data from the Centers for Disease Control and Prevention from 1999 through 2020. We included data from non-Hispanic White and non-Hispanic Black populations across all age groups.<br /><b>Exposures</b><br />Race as documented in the death certificates.<br /><b>Main outcomes and measures</b><br />Excess age-adjusted all-cause mortality, cause-specific mortality, age-specific mortality, and years of potential life lost rates (per 100 000 individuals) among the Black population compared with the White population.<br /><b>Results</b><br />From 1999 to 2011, the age-adjusted excess mortality rate declined from 404 to 211 excess deaths per 100 000 individuals among Black males (P for trend <.001). However, the rate plateaued from 2011 through 2019 (P for trend = .98) and increased in 2020 to 395-rates not seen since 2000. Among Black females, the rate declined from 224 excess deaths per 100 000 individuals in 1999 to 87 in 2015 (P for trend <.001). There was no significant change between 2016 and 2019 (P for trend = .71) and in 2020 rates increased to 192-levels not seen since 2005. The trends in rates of excess years of potential life lost followed a similar pattern. From 1999 to 2020, the disproportionately higher mortality rates in Black males and females resulted in 997 623 and 628 464 excess deaths, respectively, representing a loss of more than 80 million years of life. Heart disease had the highest excess mortality rates, and the excess years of potential life lost rates were largest among infants and middle-aged adults.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Over a recent 22-year period, the Black population in the US experienced more than 1.63 million excess deaths and more than 80 million excess years of life lost when compared with the White population. After a period of progress in reducing disparities, improvements stalled, and differences between the Black population and the White population worsened in 2020.<br /><br /><br /><br /><small>JAMA: 16 May 2023; 329:1662-1670</small></div>
Caraballo C, Massey DS, Ndumele CD, Haywood T, ... Faust JS, Krumholz HM
JAMA: 16 May 2023; 329:1662-1670 | PMID: 37191702
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<div><h4>Association of a Housing Mobility Program With Childhood Asthma Symptoms and Exacerbations.</h4><i>Pollack CE, Roberts LC, Peng RD, Cimbolic P, ... Keet CA, Matsui EC</i><br /><b>Importance</b><br />Structural racism has been implicated in the disproportionally high asthma morbidity experienced by children living in disadvantaged, urban neighborhoods. Current approaches designed to reduce asthma triggers have modest impact.<br /><b>Objective</b><br />To examine whether participation in a housing mobility program that provided housing vouchers and assistance moving to low-poverty neighborhoods was associated with reduced asthma morbidity among children and to explore potential mediating factors.<br /><b>Design, setting, and participants</b><br />Cohort study of 123 children aged 5 to 17 years with persistent asthma whose families participated in the Baltimore Regional Housing Partnership housing mobility program from 2016 to 2020. Children were matched to 115 children enrolled in the Urban Environment and Childhood Asthma (URECA) birth cohort using propensity scores.<br /><b>Exposure</b><br />Moving to a low-poverty neighborhood.<br /><b>Main outcomes</b><br />Caregiver-reported asthma exacerbations and symptoms.<br /><b>Results</b><br />Among 123 children enrolled in the program, median age was 8.4 years, 58 (47.2%) were female, and 120 (97.6%) were Black. Prior to moving, 89 of 110 children (81%) lived in a high-poverty census tract (>20% of families below the poverty line); after moving, only 1 of 106 children with after-move data (0.9%) lived in a high-poverty tract. Among this cohort, 15.1% (SD, 35.8) had at least 1 exacerbation per 3-month period prior to moving vs 8.5% (SD, 28.0) after moving, an adjusted difference of -6.8 percentage points (95% CI, -11.9% to -1.7%; P = .009). Maximum symptom days in the past 2 weeks were 5.1 (SD, 5.0) before moving and 2.7 (SD, 3.8) after moving, an adjusted difference of -2.37 days (95% CI, -3.14 to -1.59; P < .001). Results remained significant in propensity score-matched analyses with URECA data. Measures of stress, including social cohesion, neighborhood safety, and urban stress, all improved with moving and were estimated to mediate between 29% and 35% of the association between moving and asthma exacerbations.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Children with asthma whose families participated in a program that helped them move into low-poverty neighborhoods experienced significant improvements in asthma symptom days and exacerbations. This study adds to the limited evidence suggesting that programs to counter housing discrimination can reduce childhood asthma morbidity.<br /><br /><br /><br /><small>JAMA: 16 May 2023; 329:1671-1681</small></div>
Pollack CE, Roberts LC, Peng RD, Cimbolic P, ... Keet CA, Matsui EC
JAMA: 16 May 2023; 329:1671-1681 | PMID: 37191703
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<div><h4>Global Variations in Heart Failure Etiology, Management, and Outcomes.</h4><i>G-CHF Investigators, Joseph P, Roy A, Lonn E, ... Probstfield J, Yusuf S</i><br /><b>Importance</b><br />Most epidemiological studies of heart failure (HF) have been conducted in high-income countries with limited comparable data from middle- or low-income countries.<br /><b>Objective</b><br />To examine differences in HF etiology, treatment, and outcomes between groups of countries at different levels of economic development.<br /><b>Design, setting, and participants</b><br />Multinational HF registry of 23 341 participants in 40 high-income, upper-middle-income, lower-middle-income, and low-income countries, followed up for a median period of 2.0 years.<br /><b>Main outcomes and measures</b><br />HF cause, HF medication use, hospitalization, and death.<br /><b>Results</b><br />Mean (SD) age of participants was 63.1 (14.9) years, and 9119 (39.1%) were female. The most common cause of HF was ischemic heart disease (38.1%) followed by hypertension (20.2%). The proportion of participants with HF with reduced ejection fraction taking the combination of a β-blocker, renin-angiotensin system inhibitor, and mineralocorticoid receptor antagonist was highest in upper-middle-income (61.9%) and high-income countries (51.1%), and it was lowest in low-income (45.7%) and lower-middle-income countries (39.5%) (P < .001). The age- and sex- standardized mortality rate per 100 person-years was lowest in high-income countries (7.8 [95% CI, 7.5-8.2]), 9.3 (95% CI, 8.8-9.9) in upper-middle-income countries, 15.7 (95% CI, 15.0-16.4) in lower-middle-income countries, and it was highest in low-income countries (19.1 [95% CI, 17.6-20.7]). Hospitalization rates were more frequent than death rates in high-income countries (ratio = 3.8) and in upper-middle-income countries (ratio = 2.4), similar in lower-middle-income countries (ratio = 1.1), and less frequent in low-income countries (ratio = 0.6). The 30-day case-fatality rate after first hospital admission was lowest in high-income countries (6.7%), followed by upper-middle-income countries (9.7%), then lower-middle-income countries (21.1%), and highest in low-income countries (31.6%). The proportional risk of death within 30 days of a first hospital admission was 3- to 5-fold higher in lower-middle-income countries and low-income countries compared with high-income countries after adjusting for patient characteristics and use of long-term HF therapies.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />This study of HF patients from 40 different countries and derived from 4 different economic levels demonstrated differences in HF etiologies, management, and outcomes. These data may be useful in planning approaches to improve HF prevention and treatment globally.<br /><br /><br /><br /><small>JAMA: 16 May 2023; 329:1650-1661</small></div>
G-CHF Investigators, Joseph P, Roy A, Lonn E, ... Probstfield J, Yusuf S
JAMA: 16 May 2023; 329:1650-1661 | PMID: 37191704
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<div><h4>Diagnosis and Management of Cirrhosis and Its Complications: A Review.</h4><i>Tapper EB, Parikh ND</i><br /><b>Importance</b><br />Cirrhosis affects approximately 2.2 million adults in the US. From 2010 to 2021, the annual age-adjusted mortality of cirrhosis increased from 14.9 per 100 000 to 21.9 per 100 000 people.<br /><b>Observations</b><br />The most common causes of cirrhosis in the US, which can overlap, include alcohol use disorder (approximately 45% of all cases of cirrhosis), nonalcoholic fatty liver disease (26%), and hepatitis C (41%). Patients with cirrhosis experience symptoms including muscle cramps (approximately 64% prevalence), pruritus (39%), poor-quality sleep (63%), and sexual dysfunction (53%). Cirrhosis can be diagnosed by liver biopsy but may also be diagnosed noninvasively. Elastography, a noninvasive assessment of liver stiffness measured in kilopascals, can typically confirm cirrhosis at levels of 15 kPa or greater. Approximately 40% of people with cirrhosis are diagnosed when they present with complications such as hepatic encephalopathy or ascites. The median survival time following onset of hepatic encephalopathy and ascites is 0.92 and 1.1 years, respectively. Among people with ascites, the annual incidence of spontaneous bacterial peritonitis is 11% and of hepatorenal syndrome is 8%; the latter is associated with a median survival of less than 2 weeks. Approximately 1% to 4% of patients with cirrhosis develop hepatocellular carcinoma each year, which is associated with a 5-year survival of approximately 20%. In a 3-year randomized clinical trial of 201 patients with portal hypertension, nonselective β-blockers (carvedilol or propranolol) reduced the risk of decompensation or death compared with placebo (16% vs 27%). Compared with sequential initiation, combination aldosterone antagonist and loop diuretics were more likely to resolve ascites (76% vs 56%) with lower rates of hyperkalemia (4% vs 18%). In meta-analyses of randomized trials, lactulose was associated with reduced mortality relative to placebo (8.5% vs 14%) in randomized trials involving 705 patients and reduced risk of recurrent overt hepatic encephalopathy (25.5% vs 46.8%) in randomized trials involving 1415 patients. In a randomized clinical trial of 300 patients, terlipressin improved the rate of reversal of hepatorenal syndrome from 39% to 18%. Trials addressing symptoms of cirrhosis have demonstrated efficacy for hydroxyzine in improving sleep dysfunction, pickle brine and taurine for reducing muscle cramps, and tadalafil for improving sexual dysfunction in men.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Approximately 2.2 million US adults have cirrhosis. Many symptoms, such as muscle cramps, poor-quality sleep, pruritus, and sexual dysfunction, are common and treatable. First-line therapies include carvedilol or propranolol to prevent variceal bleeding, lactulose for hepatic encephalopathy, combination aldosterone antagonists and loop diuretics for ascites, and terlipressin for hepatorenal syndrome.<br /><br /><br /><br /><small>JAMA: 09 May 2023; 329:1589-1602</small></div>
Tapper EB, Parikh ND
JAMA: 09 May 2023; 329:1589-1602 | PMID: 37159031
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<div><h4>Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis: The ISABELA 1 and 2 Randomized Clinical Trials.</h4><i>Maher TM, Ford P, Brown KK, Costabel U, ... Wijsenbeek MS, ISABELA 1 and 2 Investigators</i><br /><b>Importance</b><br />There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF).<br /><b>Objective</b><br />To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF.<br /><b>Design, setting, and participants</b><br />The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2.<br /><b>Interventions</b><br />Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks.<br /><b>Main outcomes and measures</b><br />The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George\'s Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life).<br /><b>Results</b><br />At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was -124.6 mL (95% CI, -178.0 to -71.2 mL) with 600 mg of ziritaxestat vs -147.3 mL (95% CI, -199.8 to -94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, -52.3 to 97.6 mL]), and -173.9 mL (95% CI, -225.7 to -122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, -26.7 mL [95% CI, -100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was -173.8 mL (95% CI, -209.2 to -138.4 mL) with 600 mg of ziritaxestat vs -176.6 mL (95% CI, -211.4 to -141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, -46.9 to 52.4 mL]) and -174.9 mL (95% CI, -209.5 to -140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, -47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444.<br /><br /><br /><br /><small>JAMA: 09 May 2023; 329:1567-1578</small></div>
Maher TM, Ford P, Brown KK, Costabel U, ... Wijsenbeek MS, ISABELA 1 and 2 Investigators
JAMA: 09 May 2023; 329:1567-1578 | PMID: 37159034
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<div><h4>Effect of Prophylactic Antibiotics on Mortality in Severe Alcohol-Related Hepatitis: A Randomized Clinical Trial.</h4><i>Louvet A, Labreuche J, Dao T, Thévenot T, ... Duhamel A, Mathurin P</i><br /><b>Importance</b><br />The benefits of prophylactic antibiotics for hospitalized patients with severe alcohol-related hepatitis are unclear.<br /><b>Objective</b><br />To determine the efficacy of amoxicillin-clavulanate, compared with placebo, on mortality in patients hospitalized with severe alcohol-related hepatitis and treated with prednisolone.<br /><b>Design, setting, and participants</b><br />Multicenter, randomized, double-blind clinical trial among patients with biopsy-proven severe alcohol-related hepatitis (Maddrey function score ≥32 and Model for End-stage Liver Disease [MELD] score ≥21) from June 13, 2015, to May 24, 2019, in 25 centers in France and Belgium. All patients were followed up for 180 days. Final follow-up occurred on November 19, 2019.<br /><b>Intervention</b><br />Patients were randomly assigned (1:1 allocation) to receive prednisolone combined with amoxicillin-clavulanate (n = 145) or prednisolone combined with placebo (n = 147).<br /><b>Main outcome and measures</b><br />The primary outcome was all-cause mortality at 60 days. Secondary outcomes were all-cause mortality at 90 and 180 days; incidence of infection, incidence of hepatorenal syndrome, and proportion of participants with a MELD score less than 17 at 60 days; and proportion of patients with a Lille score less than 0.45 at 7 days.<br /><b>Results</b><br />Among 292 randomized patients (mean age, 52.8 [SD, 9.2] years; 80 [27.4%] women) 284 (97%) were analyzed. There was no significant difference in 60-day mortality between participants randomized to amoxicillin-clavulanate and those randomized to placebo (17.3% in the amoxicillin-clavulanate group and 21.3% in the placebo group [P = .33]; between-group difference, -4.7% [95% CI, -14.0% to 4.7%]; hazard ratio, 0.77 [95% CI, 0.45-1.31]). Infection rates at 60 days were significantly lower in the amoxicillin-clavulanate group (29.7% vs 41.5%; mean difference, -11.8% [95% CI, -23.0% to -0.7%]; subhazard ratio, 0.62; [95% CI, 0.41-0.91]; P = .02). There were no significant differences in any of the remaining 3 secondary outcomes. The most common serious adverse events were related to liver failure (25 in the amoxicillin-clavulanate group and 20 in the placebo group), infections (23 in the amoxicillin-clavulanate group and 46 in the placebo group), and gastrointestinal disorders (15 in the amoxicillin-clavulanate group and 21 in the placebo group).<br /><br /><b>Conclusion:</b><br/>and relevance</b><br />In patients hospitalized with severe alcohol-related hepatitis, amoxicillin-clavulanate combined with prednisolone did not improve 2-month survival compared with prednisolone alone. These results do not support prophylactic antibiotics to improve survival in patients hospitalized with severe alcohol-related hepatitis.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT02281929.<br /><br /><br /><br /><small>JAMA: 09 May 2023; 329:1558-1566</small></div>
Louvet A, Labreuche J, Dao T, Thévenot T, ... Duhamel A, Mathurin P
JAMA: 09 May 2023; 329:1558-1566 | PMID: 37159035
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<div><h4>Screening for Latent Tuberculosis Infection in Adults: US Preventive Services Task Force Recommendation Statement.</h4><i>US Preventive Services Task Force, Mangione CM, Barry MJ, Nicholson WK, ... Underwood SM, Wong JB</i><br /><b>Importance</b><br />In the US, tuberculosis remains an important preventable disease, including active tuberculosis, which may be infectious, and latent tuberculosis infection (LTBI), which is asymptomatic and not infectious but can later progress to active disease. The precise prevalence rate of LTBI in the US is difficult to determine; however, estimated prevalence is about 5.0%, or up to 13 million persons. Incidence of tuberculosis varies by geography and living accommodations, suggesting an association with social determinants of health.<br /><b>Objective</b><br />To update its 2016 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on LTBI screening and treatment in asymptomatic adults seen in primary care, as well as the accuracy of LTBI screening tests.<br /><b>Population</b><br />Asymptomatic adults 18 years or older at increased risk for tuberculosis.<br /><b>Evidence assessment</b><br />The USPSTF concludes with moderate certainty that there is a moderate net benefit in preventing active tuberculosis disease by screening for LTBI in persons at increased risk for tuberculosis infection.<br /><b>Recommendation</b><br />The USPSTF recommends screening for LTBI in populations at increased risk. (B recommendation).<br /><br /><br /><br /><small>JAMA: 02 May 2023; 329:1487-1494</small></div>
US Preventive Services Task Force, Mangione CM, Barry MJ, Nicholson WK, ... Underwood SM, Wong JB
JAMA: 02 May 2023; 329:1487-1494 | PMID: 37129649
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<div><h4>Screening for Latent Tuberculosis Infection in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.</h4><i>Jonas DE, Riley SR, Lee LC, Coffey CP, ... Voisin CE, Kahwati LC</i><br /><b>Importance</b><br />Latent tuberculosis infection (LTBI) can progress to active tuberculosis disease, causing morbidity and mortality.<br /><b>Objective</b><br />To review the evidence on benefits and harms of screening for and treatment of LTBI in adults to inform the US Preventive Services Task Force (USPSTF).<br /><b>Data sources</b><br />PubMed/MEDLINE, Cochrane Library, and trial registries through December 3, 2021; references; experts; literature surveillance through January 20, 2023.<br /><b>Study selection</b><br />English-language studies of LTBI screening, LTBI treatment, or accuracy of the tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). Studies of LTBI screening and treatment for public health surveillance or disease management were excluded.<br /><b>Data extraction and synthesis</b><br />Dual review of abstracts, full-text articles, and study quality; qualitative synthesis of findings; meta-analyses conducted when a sufficient number of similar studies were available.<br /><b>Main outcomes and measures</b><br />Screening test accuracy; development of active tuberculosis disease, transmission, quality of life, mortality, and harms.<br /><b>Results</b><br />A total of 113 publications were included (112 studies; N = 69 009). No studies directly evaluated the benefits and harms of screening. Pooled estimates for sensitivity of the TST were 0.80 (95% CI, 0.74-0.87) at the 5-mm induration threshold, 0.81 (95% CI, 0.76-0.87) at the 10-mm threshold, and 0.60 (95% CI, 0.46-0.74) at the 15-mm threshold. Pooled estimates for sensitivity of IGRA tests ranged from 0.81 (95% CI, 0.79-0.84) to 0.90 (95% CI, 0.87-0.92). Pooled estimates for specificity of screening tests ranged from 0.95 to 0.99. For treatment of LTBI, a large (n = 27 830), good-quality randomized clinical trial found a relative risk (RR) for progression to active tuberculosis at 5 years of 0.35 (95% CI, 0.24-0.52) for 24 weeks of isoniazid compared with placebo (number needed to treat, 112) and an increase in hepatotoxicity (RR, 4.59 [95% CI, 2.03-10.39]; number needed to harm, 279). A previously published meta-analysis reported that multiple regimens were efficacious compared with placebo or no treatment. Meta-analysis found greater risk for hepatotoxicity with isoniazid than with rifampin (pooled RR, 4.22 [95% CI, 2.21-8.06]; n = 7339).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />No studies directly evaluated the benefits and harms of screening for LTBI compared with no screening. TST and IGRAs were moderately sensitive and highly specific. Treatment of LTBI with recommended regimens reduced the risk of progression to active tuberculosis. Isoniazid was associated with higher rates of hepatotoxicity than placebo or rifampin.<br /><br /><br /><br /><small>JAMA: 02 May 2023; 329:1495-1509</small></div>
Jonas DE, Riley SR, Lee LC, Coffey CP, ... Voisin CE, Kahwati LC
JAMA: 02 May 2023; 329:1495-1509 | PMID: 37129650
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<div><h4>Prednisone vs Placebo and Live Birth in Patients With Recurrent Implantation Failure Undergoing In Vitro Fertilization: A Randomized Clinical Trial.</h4><i>Sun Y, Cui L, Lu Y, Tan J, ... Zhang H, Chen ZJ</i><br /><b>Importance</b><br />Implantation failure remains a critical barrier to in vitro fertilization. Prednisone, as an immune-regulatory agent, is widely used to improve the probability of implantation and pregnancy, although the evidence for efficacy is inadequate.<br /><b>Objective</b><br />To determine the efficacy of 10 mg of prednisone compared with placebo on live birth among women with recurrent implantation failure.<br /><b>Design, setting, and participants</b><br />A double-blind, placebo-controlled, randomized clinical trial conducted at 8 fertility centers in China. Eligible women who had a history of 2 or more unsuccessful embryo transfer cycles, were younger than 38 years when oocytes were retrieved, and were planning to undergo frozen-thawed embryo transfer with the availability of good-quality embryos were enrolled from November 2018 to August 2020 (final follow-up August 2021).<br /><b>Interventions</b><br />Participants were randomized (1:1) to receive oral pills containing either 10 mg of prednisone (n = 357) or matching placebo (n = 358) once daily, from the day at which they started endometrial preparation for frozen-thawed embryo transfer through early pregnancy.<br /><b>Main outcomes and measures</b><br />The primary outcome was live birth, defined as the delivery of any number of neonates born at 28 or more weeks\' gestation with signs of life.<br /><b>Results</b><br />Among 715 women randomized (mean age, 32 years), 714 (99.9%) had data available on live birth outcomes and were included in the primary analysis. Live birth occurred among 37.8% of women (135 of 357) in the prednisone group vs 38.8% of women (139 of 358) in the placebo group (absolute difference, -1.0% [95% CI, -8.1% to 6.1%]; relative ratio [RR], 0.97 [95% CI, 0.81 to 1.17]; P = .78). The rates of biochemical pregnancy loss were 17.3% in the prednisone group and 9.9% in the placebo group (absolute difference, 7.5% [95% CI, 0.6% to 14.3%]; RR, 1.75 [95% CI, 1.03 to 2.99]; P = .04). Of those in the prednisone group, preterm delivery occurred among 11.8% and of those in the placebo group, 5.5% of pregnancies (absolute difference, 6.3% [95% CI, 0.2% to 12.4%]; RR, 2.14 [95% CI, 1.00 to 4.58]; P = .04). There were no statistically significant between-group differences in the rates of biochemical pregnancy, clinical pregnancy, implantation, neonatal complications, congenital anomalies, other adverse events, or mean birthweights.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Among patients with recurrent implantation failure, treatment with prednisone did not improve live birth rate compared with placebo. Data suggested that the use of prednisone may increase the risk of preterm delivery and biochemical pregnancy loss. Our results challenge the value of prednisone use in clinical practice for the treatment of recurrent implantation failure.<br /><b>Trial registration</b><br />Chinese Clinical Trial Registry Identifier: ChiCTR1800018783.<br /><br /><br /><br /><small>JAMA: 02 May 2023; 329:1460-1468</small></div>
Sun Y, Cui L, Lu Y, Tan J, ... Zhang H, Chen ZJ
JAMA: 02 May 2023; 329:1460-1468 | PMID: 37129654
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<div><h4>National Trends in Mental Health-Related Emergency Department Visits Among Youth, 2011-2020.</h4><i>Bommersbach TJ, McKean AJ, Olfson M, Rhee TG</i><br /><b>Importance</b><br />There has been increasing concern about the burden of mental health problems among youth, especially since the COVID-19 pandemic. Trends in mental health-related emergency department (ED) visits are an important indicator of unmet outpatient mental health needs.<br /><b>Objective</b><br />To estimate annual trends in mental health-related ED visits among US children, adolescents, and young adults between 2011 and 2020.<br /><b>Design, setting, and participants</b><br />Data from 2011 to 2020 in the National Hospital Ambulatory Medical Care Survey, an annual cross-sectional national probability sample survey of EDs, was used to examine mental health-related visits for youths aged 6 to 24 years (unweighted = 49 515).<br /><b>Main outcomes and measures</b><br />Mental health-related ED visits included visits associated with psychiatric or substance use disorders and were identified by International Classification of Diseases-Ninth Revision, Clinical Modification (ICD-9-CM; 2011-2015) and ICD-10-CM (2016-2020) discharge diagnosis codes or by reason-for-visit (RFV) codes. We estimated the annual proportion of mental health-related pediatric ED visits from 2011 to 2020. Subgroup analyses were performed by demographics and broad psychiatric diagnoses. Multivariable-adjusted logistic regression analyses estimated factors independently associated with mental health-related ED visits controlling for period effects.<br /><b>Results</b><br />From 2011 to 2020, the weighted number of pediatric mental health-related visits increased from 4.8 million (7.7% of all pediatric ED visits) to 7.5 million (13.1% of all ED visits) with an average annual percent change of 8.0% (95% CI, 6.1%-10.1%; P < .001). Significant linearly increasing trends were seen among children, adolescents, and young adults, with the greatest increase among adolescents and across sex and race and ethnicity. While all types of mental health-related visits significantly increased, suicide-related visits demonstrated the greatest increase from 0.9% to 4.2% of all pediatric ED visits (average annual percent change, 23.1% [95% CI, 19.0%-27.5%]; P < .001).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Over the last 10 years, the proportion of pediatric ED visits for mental health reasons has approximately doubled, including a 5-fold increase in suicide-related visits. These findings underscore an urgent need to improve crisis and emergency mental health service capacity for young people, especially for children experiencing suicidal symptoms.<br /><br /><br /><br /><small>JAMA: 02 May 2023; 329:1469-1477</small></div>
Bommersbach TJ, McKean AJ, Olfson M, Rhee TG
JAMA: 02 May 2023; 329:1469-1477 | PMID: 37129655
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<div><h4>Community Health Workers in Early Childhood Well-Child Care for Medicaid-Insured Children: A Randomized Clinical Trial.</h4><i>Coker TR, Liljenquist K, Lowry SJ, Fiscella K, ... Guerra LJS, Szilagyi PG</i><br /><b>Importance</b><br />An intervention model (the Parent-focused Redesign for Encounters, Newborns to Toddlers; the PARENT intervention) for well-child care that integrates a community health worker into preventive care services may enhance early childhood well-child care.<br /><b>Objective</b><br />To examine the effectiveness of the PARENT intervention vs usual care for parents with children younger than 2 years of age.<br /><b>Design, setting, and participants</b><br />A cluster randomized clinical trial was conducted between March 2019 and July 2022. Of the 1283 parents with a child younger than 2 years of age presenting for a well-child visit at 1 of the 10 clinic sites (2 federally qualified health centers in California and Washington) approached for trial participation, 937 were enrolled.<br /><b>Intervention</b><br />Five clinics implemented the PARENT intervention, which is a team-based approach to care that uses a community health worker in the role of a coach (ie, health educator) as part of the well-child care team to provide comprehensive preventive services, and 5 clinics provided usual care.<br /><b>Main outcomes and measures</b><br />There were 2 primary outcomes: score for parent-reported receipt of recommended anticipatory guidance during well-child visits (score range, 0-100) and emergency department (ED) use (proportion with ≥2 ED visits). The secondary outcomes included psychosocial screening, developmental screening, health care use, and parent-reported experiences of care.<br /><b>Results</b><br />Of the 937 parents who were enrolled, 914 remained eligible to participate (n = 438 in the intervention group and n = 476 in the usual care group; 95% were mothers, 73% reported Latino ethnicity, and 63% reported an annual income <$30 000). The majority (855/914; 94%) of the children (mean age, 4.4 months at parental enrollment) were insured by Medicaid. Of the 914 parents who remained eligible and enrolled, 785 (86%) completed the 12-month follow-up interview. Parents of children treated at the intervention clinics (n = 375) reported receiving more anticipatory guidance than the parents of children treated at the usual care clinics (n = 407) (mean score, 73.9 [SD, 23.4] vs 63.3 [SD, 27.8], respectively; adjusted absolute difference, 11.01 [95% CI, 6.44 to 15.59]). There was no difference in ED use (proportion with ≥2 ED visits) between the intervention group (n = 376) and the usual care group (n = 407) (37.2% vs 36.1%, respectively; adjusted absolute difference, 1.2% [95% CI, -5.5% to 8.0%]). The effects of the intervention on the secondary outcomes included a higher amount of psychosocial assessments performed, a greater number of parents who had developmental or behavioral concerns elicited and addressed, increased attendance at well-child visits, and greater parental experiences with the care received (helpfulness of care).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />The intervention resulted in improvements in the receipt of preventive care services vs usual care for children insured by Medicaid by incorporating community health workers in a team-based approach to early childhood well-child care.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT03797898.<br /><br /><br /><br /><small>JAMA: 30 Apr 2023; epub ahead of print</small></div>
Coker TR, Liljenquist K, Lowry SJ, Fiscella K, ... Guerra LJS, Szilagyi PG
JAMA: 30 Apr 2023; epub ahead of print | PMID: 37120800
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<div><h4>Diagnosis and Management of Pituitary Adenomas: A Review.</h4><i>Tritos NA, Miller KK</i><br /><b>Importance</b><br />Pituitary adenomas are neoplasms of the pituitary adenohypophyseal cell lineage and include functioning tumors, characterized by the secretion of pituitary hormones, and nonfunctioning tumors. Clinically evident pituitary adenomas occur in approximately 1 in 1100 persons.<br /><b>Observations</b><br />Pituitary adenomas are classified as either macroadenomas (≥10 mm) (48% of tumors) or microadenomas (<10 mm). Macroadenomas may cause mass effect, such as visual field defects, headache, and/or hypopituitarism, which occur in about 18% to 78%, 17% to 75%, and 34% to 89% of patients, respectively. Thirty percent of pituitary adenomas are nonfunctioning adenomas, which do not produce hormones. Functioning tumors are those that produce an excess of normally produced hormones and include prolactinomas, somatotropinomas, corticotropinomas, and thyrotropinomas, which produce prolactin, growth hormone, corticotropin, and thyrotropin, respectively. Approximately 53% of pituitary adenomas are prolactinomas, which can cause hypogonadism, infertility, and/or galactorrhea. Twelve percent are somatotropinomas, which cause acromegaly in adults and gigantism in children, and 4% are corticotropinomas, which secrete corticotropin autonomously, resulting in hypercortisolemia and Cushing disease. All patients with pituitary tumors require endocrine evaluation for hormone hypersecretion. Patients with macroadenomas additionally require evaluation for hypopituitarism, and patients with tumors compressing the optic chiasm should be referred to an ophthalmologist for formal visual field testing. For those requiring treatment, first-line therapy is usually transsphenoidal pituitary surgery, except for prolactinomas, for which medical therapy, either bromocriptine or cabergoline, is usually first line.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Clinically manifest pituitary adenomas affect approximately 1 in 1100 people and can be complicated by syndromes of hormone excess as well as visual field defects and hypopituitarism from mass effect in larger tumors. First-line therapy for prolactinomas consists of bromocriptine or cabergoline, and transsphenoidal pituitary surgery is first-line therapy for other pituitary adenomas requiring treatment.<br /><br /><br /><br /><small>JAMA: 25 Apr 2023; 329:1386-1398</small></div>
Tritos NA, Miller KK
JAMA: 25 Apr 2023; 329:1386-1398 | PMID: 37097352
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<div><h4>Emulation of Randomized Clinical Trials With Nonrandomized Database Analyses: Results of 32 Clinical Trials.</h4><i>Wang SV, Schneeweiss S, RCT-DUPLICATE Initiative, Franklin JM, ... Paraoan D, Quinto K</i><br /><b>Importance</b><br />Nonrandomized studies using insurance claims databases can be analyzed to produce real-world evidence on the effectiveness of medical products. Given the lack of baseline randomization and measurement issues, concerns exist about whether such studies produce unbiased treatment effect estimates.<br /><b>Objective</b><br />To emulate the design of 30 completed and 2 ongoing randomized clinical trials (RCTs) of medications with database studies using observational analogues of the RCT design parameters (population, intervention, comparator, outcome, time [PICOT]) and to quantify agreement in RCT-database study pairs.<br /><b>Design, setting, and participants</b><br />New-user cohort studies with propensity score matching using 3 US claims databases (Optum Clinformatics, MarketScan, and Medicare). Inclusion-exclusion criteria for each database study were prespecified to emulate the corresponding RCT. RCTs were explicitly selected based on feasibility, including power, key confounders, and end points more likely to be emulated with real-world data. All 32 protocols were registered on ClinicalTrials.gov before conducting analyses. Emulations were conducted from 2017 through 2022.<br /><b>Exposures</b><br />Therapies for multiple clinical conditions were included.<br /><b>Main outcomes and measures</b><br />Database study emulations focused on the primary outcome of the corresponding RCT. Findings of database studies were compared with RCTs using predefined metrics, including Pearson correlation coefficients and binary metrics based on statistical significance agreement, estimate agreement, and standardized difference.<br /><b>Results</b><br />In these highly selected RCTs, the overall observed agreement between the RCT and the database emulation results was a Pearson correlation of 0.82 (95% CI, 0.64-0.91), with 75% meeting statistical significance, 66% estimate agreement, and 75% standardized difference agreement. In a post hoc analysis limited to 16 RCTs with closer emulation of trial design and measurements, concordance was higher (Pearson r, 0.93; 95% CI, 0.79-0.97; 94% meeting statistical significance, 88% estimate agreement, 88% standardized difference agreement). Weaker concordance occurred among 16 RCTs for which close emulation of certain design elements that define the research question (PICOT) with data from insurance claims was not possible (Pearson r, 0.53; 95% CI, 0.00-0.83; 56% meeting statistical significance, 50% estimate agreement, 69% standardized difference agreement).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Real-world evidence studies can reach similar conclusions as RCTs when design and measurements can be closely emulated, but this may be difficult to achieve. Concordance in results varied depending on the agreement metric. Emulation differences, chance, and residual confounding can contribute to divergence in results and are difficult to disentangle.<br /><br /><br /><br /><small>JAMA: 25 Apr 2023; 329:1376-1385</small></div>
Wang SV, Schneeweiss S, RCT-DUPLICATE Initiative, Franklin JM, ... Paraoan D, Quinto K
JAMA: 25 Apr 2023; 329:1376-1385 | PMID: 37097356
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<div><h4>Piperacillin-Tazobactam Compared With Cefoxitin as Antimicrobial Prophylaxis for Pancreatoduodenectomy: A Randomized Clinical Trial.</h4><i>D\'Angelica MI, Ellis RJ, Liu JB, Brajcich BC, ... Pitt HA, Ko CY</i><br /><b>Importance</b><br />Despite improvements in perioperative mortality, the incidence of postoperative surgical site infection (SSI) remains high after pancreatoduodenectomy. The effect of broad-spectrum antimicrobial surgical prophylaxis in reducing SSI is poorly understood.<br /><b>Objective</b><br />To define the effect of broad-spectrum perioperative antimicrobial prophylaxis on postoperative SSI incidence compared with standard care antibiotics.<br /><b>Design, setting, and participants</b><br />Pragmatic, open-label, multicenter, randomized phase 3 clinical trial at 26 hospitals across the US and Canada. Participants were enrolled between November 2017 and August 2021, with follow-up through December 2021. Adults undergoing open pancreatoduodenectomy for any indication were eligible. Individuals were excluded if they had allergies to study medications, active infections, chronic steroid use, significant kidney dysfunction, or were pregnant or breastfeeding. Participants were block randomized in a 1:1 ratio and stratified by the presence of a preoperative biliary stent. Participants, investigators, and statisticians analyzing trial data were unblinded to treatment assignment.<br /><b>Intervention</b><br />The intervention group received piperacillin-tazobactam (3.375 or 4 g intravenously) as perioperative antimicrobial prophylaxis, while the control group received cefoxitin (2 g intravenously; standard care).<br /><b>Main outcomes and measures</b><br />The primary outcome was development of postoperative SSI within 30 days. Secondary end points included 30-day mortality, development of clinically relevant postoperative pancreatic fistula, and sepsis. All data were collected as part of the American College of Surgeons National Surgical Quality Improvement Program.<br /><b>Results</b><br />The trial was terminated at an interim analysis on the basis of a predefined stopping rule. Of 778 participants (378 in the piperacillin-tazobactam group [median age, 66.8 y; 233 {61.6%} men] and 400 in the cefoxitin group [median age, 68.0 y; 223 {55.8%} men]), the percentage with SSI at 30 days was lower in the perioperative piperacillin-tazobactam vs cefoxitin group (19.8% vs 32.8%; absolute difference, -13.0% [95% CI, -19.1% to -6.9%]; P < .001). Participants treated with piperacillin-tazobactam, vs cefoxitin, had lower rates of postoperative sepsis (4.2% vs 7.5%; difference, -3.3% [95% CI, -6.6% to 0.0%]; P = .02) and clinically relevant postoperative pancreatic fistula (12.7% vs 19.0%; difference, -6.3% [95% CI, -11.4% to -1.2%]; P = .03). Mortality rates at 30 days were 1.3% (5/378) among participants treated with piperacillin-tazobactam and 2.5% (10/400) among those receiving cefoxitin (difference, -1.2% [95% CI, -3.1% to 0.7%]; P = .32).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />In participants undergoing open pancreatoduodenectomy, use of piperacillin-tazobactam as perioperative prophylaxis reduced postoperative SSI, pancreatic fistula, and multiple downstream sequelae of SSI. The findings support the use of piperacillin-tazobactam as standard care for open pancreatoduodenectomy.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT03269994.<br /><br /><br /><br /><small>JAMA: 20 Apr 2023; epub ahead of print</small></div>
D'Angelica MI, Ellis RJ, Liu JB, Brajcich BC, ... Pitt HA, Ko CY
JAMA: 20 Apr 2023; epub ahead of print | PMID: 37078771
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<div><h4>Screening for Skin Cancer: US Preventive Services Task Force Recommendation Statement.</h4><i>US Preventive Services Task Force, Mangione CM, Barry MJ, Nicholson WK, ... Underwood SM, Wong JB</i><br /><b>Importance</b><br />Skin cancer is the most commonly diagnosed cancer in the US. There are different types of skin cancer varying in disease incidence and severity. Basal and squamous cell carcinomas are the most common types of skin cancer but infrequently lead to death or substantial morbidity. Melanomas represent about 1% of skin cancer and cause the most skin cancer deaths. Melanoma is about 30 times more common in White persons than in Black persons. However, persons with darker skin color are often diagnosed at later stages, when skin cancer is more difficult to treat.<br /><b>Objective</b><br />To update its 2016 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on the benefits and harms of screening for skin cancer in asymptomatic adolescents and adults.<br /><b>Population</b><br />Asymptomatic adolescents and adults who do not have a history of premalignant or malignant skin lesions.<br /><b>Evidence assessment</b><br />The USPSTF concludes that the evidence is insufficient to determine the balance of benefits and harms of visual skin examination by a clinician to screen for skin cancer in asymptomatic adolescents and adults.<br /><b>Recommendation</b><br />The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of visual skin examination by a clinician to screen for skin cancer in adolescents and adults. (I statement).<br /><br /><br /><br /><small>JAMA: 18 Apr 2023; 329:1290-1295</small></div>
US Preventive Services Task Force, Mangione CM, Barry MJ, Nicholson WK, ... Underwood SM, Wong JB
JAMA: 18 Apr 2023; 329:1290-1295 | PMID: 37071089
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<div><h4>Skin Cancer Screening: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.</h4><i>Henrikson NB, Ivlev I, Blasi PR, Nguyen MB, ... Perdue LA, Lin JS</i><br /><b>Importance</b><br />Skin cancer is the most common cancer type and is a major cause of morbidity.<br /><b>Objective</b><br />To systematically review the benefits and harms of screening for skin cancer to inform the US Preventive Services Task Force.<br /><b>Data sources</b><br />MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from June 1, 2015, through January 7, 2022; surveillance through December 16, 2022.<br /><b>Study selection</b><br />English-language studies conducted in asymptomatic populations 15 years or older.<br /><b>Data extraction and synthesis</b><br />Two reviewers independently appraised the articles and extracted relevant data from fair- or good-quality studies; results were narratively summarized.<br /><b>Main outcomes and measures</b><br />Morbidity; mortality; skin cancer stage, precursor lesions, or lesion thickness at detection; harms of screening.<br /><b>Results</b><br />Twenty studies in 29 articles were included (N = 6 053 411). Direct evidence on screening effectiveness was from 3 nonrandomized analyses of 2 population-based skin cancer screening programs in Germany (n = 1 791 615) and suggested no melanoma mortality benefit at the population level over 4 to 10 years\' follow-up. Six studies (n = 2 935 513) provided inconsistent evidence on the association between clinician skin examination and lesion thickness or stage at diagnosis. Compared with usual care, routine clinician skin examination was not associated with increased detection of skin cancer or precursor lesions (5 studies) or stage at melanoma detection (3 studies). Evidence on the association between clinician skin examination and lesion thickness at detection was inconsistent (3 studies). Nine studies (n = 1 326 051) found a consistent positive association between more advanced stage at melanoma detection and increasing risk of melanoma-associated and all-cause mortality. Two studies (n = 232) found little to no persistent cosmetic or psychosocial harms associated with screening.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />A substantial nonrandomized evidence base suggests a clear association between earlier stage at skin cancer detection and decreased mortality risk. However, nonrandomized studies suggest little to no melanoma mortality benefit associated with skin cancer screening with visual skin examination in adolescents or adults and no association between routine clinician skin examination and earlier stage at melanoma detection. Evidence is inconsistent regarding whether clinician skin examination is associated with thinner melanoma lesions at detection.<br /><br /><br /><br /><small>JAMA: 18 Apr 2023; 329:1296-1307</small></div>
Henrikson NB, Ivlev I, Blasi PR, Nguyen MB, ... Perdue LA, Lin JS
JAMA: 18 Apr 2023; 329:1296-1307 | PMID: 37071090
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<div><h4>Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer: A Randomized Clinical Trial.</h4><i>Watanabe J, Muro K, Shitara K, Yamazaki K, ... Tsuchihara K, Yoshino T</i><br /><b>Importance</b><br />For patients with RAS wild-type metastatic colorectal cancer, adding anti-epidermal growth factor receptor (anti-EGFR) or anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibodies to first-line doublet chemotherapy is routine, but the optimal targeted therapy has not been defined.<br /><b>Objective</b><br />To evaluate the effect of adding panitumumab (an anti-EGFR monoclonal antibody) vs bevacizumab (an anti-VEGF monoclonal antibody) to standard first-line chemotherapy for treatment of RAS wild-type, left-sided, metastatic colorectal cancer.<br /><b>Design, setting, and participants</b><br />Randomized, open-label, phase 3 clinical trial at 197 sites in Japan in May 2015-January 2022 among 823 patients with chemotherapy-naive RAS wild-type, unresectable metastatic colorectal cancer (final follow-up, January 14, 2022).<br /><b>Interventions</b><br />Panitumumab (n = 411) or bevacizumab (n = 412) plus modified fluorouracil, l-leucovorin, and oxaliplatin (mFOLFOX6) every 14 days.<br /><b>Main outcomes and measures</b><br />The primary end point, overall survival, was tested first in participants with left-sided tumors, then in the overall population. Secondary end points were progression-free survival, response rate, duration of response, and curative (defined as R0 status) resection rate.<br /><b>Results</b><br />In the as-treated population (n = 802; median age, 66 years; 282 [35.2%] women), 604 (75.3%) had left-sided tumors. Median follow-up was 61 months. Median overall survival was 37.9 months with panitumumab vs 34.3 months with bevacizumab in participants with left-sided tumors (hazard ratio [HR] for death, 0.82; 95.798% CI, 0.68-0.99; P = .03) and 36.2 vs 31.3 months, respectively, in the overall population (HR, 0.84; 95% CI, 0.72-0.98; P = .03). Median progression-free survival for panitumumab vs bevacizumab was 13.1 vs 11.9 months, respectively, for those with left-sided tumors (HR, 1.00; 95% CI, 0.83-1.20) and 12.2 vs 11.4 months overall (HR, 1.05; 95% CI, 0.90-1.24). Response rates with panitumumab vs bevacizumab were 80.2% vs 68.6%, respectively, for left-sided tumors (difference, 11.2%; 95% CI, 4.4%-17.9%) and 74.9% vs 67.3% overall (difference, 7.7%; 95% CI, 1.5%-13.8%). Median duration of response with panitumumab vs bevacizumab was 13.1 vs 11.2 months for left-sided tumors (HR, 0.86; 95% CI, 0.70-1.10) and 11.9 vs 10.7 months overall (HR, 0.89; 95% CI, 0.74-1.06). Curative resection rates with panitumumab vs bevacizumab were 18.3% vs 11.6% for left-sided tumors; (difference, 6.6%; 95% CI, 1.0%-12.3%) and 16.5% vs 10.9% overall (difference, 5.6%; 95% CI, 1.0%-10.3%). Common treatment-emergent adverse events were acneiform rash (panitumumab: 74.8%; bevacizumab: 3.2%), peripheral sensory neuropathy (panitumumab: 70.8%; bevacizumab: 73.7%), and stomatitis (panitumumab: 61.6%; bevacizumab: 40.5%).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Among patients with RAS wild-type metastatic colorectal cancer, adding panitumumab, compared with bevacizumab, to standard first-line chemotherapy significantly improved overall survival in those with left-sided tumors and in the overall population.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT02394795.<br /><br /><br /><br /><small>JAMA: 18 Apr 2023; 329:1271-1282</small></div>
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<div><h4>Added Therapeutic Benefit of Top-Selling Brand-name Drugs in Medicare.</h4><i>Egilman AC, Rome BN, Kesselheim AS</i><br /><b>Importance</b><br />The Inflation Reduction Act of 2022 authorizes Medicare to negotiate prices of top-selling drugs based on several factors, including therapeutic benefit compared with existing treatment options.<br /><b>Objective</b><br />To determine the added therapeutic benefit of the 50 top-selling brand-name drugs in Medicare in 2020, as assessed by health technology assessment (HTA) organizations in Canada, France, and Germany.<br /><b>Design, setting, and participants</b><br />In this cross-sectional study, publicly available therapeutic benefit ratings, US Food and Drug Administration documents, and the Medicare Part B and Part D prescription drug spending dashboards were used to determine the 50 top-selling single-source drugs used in Medicare in 2020 and to assess their added therapeutic benefit ratings through 2021.<br /><b>Main outcomes and measures</b><br />Ratings from HTA bodies in Canada, France, and Germany were categorized as high (moderate or greater) or low (minor or no) added benefit. Each drug was rated based on its most favorable rating across countries, indications, subpopulations, and dosage forms. We compared the use and prerebate and postrebate (ie, net) Medicare spending between drugs with high vs low added benefit.<br /><b>Results</b><br />Forty-nine drugs (98%) received an HTA rating by at least 1 country; 22 of 36 drugs (61%) received a low added benefit rating in Canada, 34 of 47 in France (72%), and 17 of 29 in Germany (59%). Across countries, 27 drugs (55%) had a low added therapeutic rating, accounting for $19.3 billion in annual estimated net spending, or 35% of Medicare net spending on the 50 top-selling single-source drugs and 11% of total Medicare net prescription drug spending in 2020. Compared with those with high added benefit, drugs with a low added therapeutic rating were used by more Medicare beneficiaries (median 387 149 vs 44 869) and had lower net spending per beneficiary (median $992 vs $32 287).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Many top-selling Medicare drugs received low added benefit ratings by the national HTA organizations of Canada, France, and Germany. When negotiating prices for these drugs, Medicare should ensure they are not priced higher than reasonable therapeutic alternatives.<br /><br /><br /><br /><small>JAMA: 18 Apr 2023; 329:1283-1289</small></div>
Egilman AC, Rome BN, Kesselheim AS
JAMA: 18 Apr 2023; 329:1283-1289 | PMID: 37071095
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<div><h4>VE303, a Defined Bacterial Consortium, for Prevention of Recurrent Clostridioides difficile Infection: A Randomized Clinical Trial.</h4><i>Louie T, Golan Y, Khanna S, Bobilev D, ... Silber JL, Pardi DS</i><br /><b>Importance</b><br />The effect of rationally defined nonpathogenic, nontoxigenic, commensal strains of Clostridia on prevention of Clostridioides difficile infection (CDI) is unknown.<br /><b>Objective</b><br />To determine the efficacy of VE303, a defined bacterial consortium of 8 strains of commensal Clostridia, in adults at high risk for CDI recurrence. The primary objective was to determine the recommended VE303 dosing for a phase 3 trial.<br /><b>Design, setting, and participants</b><br />Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study conducted from February 2019 to September 2021 at 27 sites in the US and Canada. The study included 79 participants aged 18 years or older who were diagnosed with laboratory-confirmed CDI with 1 or more prior CDI episodes in the last 6 months and those with primary CDI at high risk for recurrence (defined as aged ≥75 years or ≥65 years with ≥1 risk factors: creatinine clearance <60 mL/min/1.73 m2, proton pump inhibitor use, remote [>6 months earlier] CDI history).<br /><b>Interventions</b><br />Participants were randomly assigned to high-dose VE303 (8.0 × 109 colony-forming units [CFUs]) (n = 30), low-dose VE303 (1.6 × 109 CFUs) (n = 27), or placebo capsules (n = 22) orally once daily for 14 days.<br /><b>Main outcomes and measures</b><br />The primary efficacy end point was the proportion of participants with CDI recurrence at 8 weeks using a combined clinical and laboratory definition. The primary efficacy end point was analyzed in 3 prespecified analyses, using successively broader definitions for an on-study CDI recurrence: (1) diarrhea consistent with CDI plus a toxin-positive stool sample; (2) diarrhea consistent with CDI plus a toxin-positive, polymerase chain reaction-positive, or toxigenic culture-positive stool sample; and (3) diarrhea consistent with CDI plus laboratory confirmation or (in the absence of a stool sample) treatment with a CDI-targeted antibiotic.<br /><b>Results</b><br />Baseline characteristics were similar across the high-dose VE303 (n = 29; 1 additional participant excluded from efficacy analysis), low-dose VE303 (n = 27), and placebo (n = 22) groups. The participants\' median age was 63.5 years (range, 24-96); 70.5% were female; and 1.3% were Asian, 1.3% Black, 2.6% Hispanic, and 96.2% White. CDI recurrence rates through week 8 (using the efficacy analysis 3 definition) were 13.8% (4/29) for high-dose VE303, 37.0% (10/27) for low-dose VE303, and 45.5% (10/22) for placebo (P = .006, high-dose VE303 vs placebo).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Among adults with laboratory-confirmed CDI with 1 or more prior CDI episodes in the last 6 months and those with primary CDI at high risk for recurrence, high-dose VE303 prevented recurrent CDI compared with placebo. A larger, phase 3 study is needed to confirm these findings.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT03788434.<br /><br /><br /><br /><small>JAMA: 15 Apr 2023; epub ahead of print</small></div>
Louie T, Golan Y, Khanna S, Bobilev D, ... Silber JL, Pardi DS
JAMA: 15 Apr 2023; epub ahead of print | PMID: 37060545
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<div><h4>Diagnosis and Management of Prediabetes: A Review.</h4><i>Echouffo-Tcheugui JB, Perreault L, Ji L, Dagogo-Jack S</i><br /><b>Importance</b><br />Prediabetes, an intermediate stage between normal glucose regulation and diabetes, affects 1 in 3 adults in the US and approximately 720 million individuals worldwide.<br /><b>Observations</b><br />Prediabetes is defined by a fasting glucose level of 100 to 125 mg/dL, a glucose level of 140 to 199 mg/dL measured 2 hours after a 75-g oral glucose load, or glycated hemoglobin level (HbA1C) of 5.7% to 6.4% or 6.0% to 6.4%. In the US, approximately 10% of people with prediabetes progress to having diabetes each year. A meta-analysis found that prediabetes at baseline was associated with increased mortality and increased cardiovascular event rates (excess absolute risk, 7.36 per 10 000 person-years for mortality and 8.75 per 10 000 person-years for cardiovascular disease during 6.6 years). Intensive lifestyle modification, consisting of calorie restriction, increased physical activity (≥150 min/wk), self-monitoring, and motivational support, decreased the incidence of diabetes by 6.2 cases per 100 person-years during a 3-year period. Metformin decreased the risk of diabetes among individuals with prediabetes by 3.2 cases per 100 person-years during 3 years. Metformin is most effective for women with prior gestational diabetes and for individuals younger than 60 years with body mass index of 35 or greater, fasting plasma glucose level of 110 mg/dL or higher, or HbA1c level of 6.0% or higher.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Prediabetes is associated with increased risk of diabetes, cardiovascular events, and mortality. First-line therapy for prediabetes is lifestyle modification that includes weight loss and exercise or metformin. Lifestyle modification is associated with a larger benefit than metformin.<br /><br /><br /><br /><small>JAMA: 11 Apr 2023; 329:1206-1216</small></div>
Echouffo-Tcheugui JB, Perreault L, Ji L, Dagogo-Jack S
JAMA: 11 Apr 2023; 329:1206-1216 | PMID: 37039787
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<div><h4>Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support-Free Days in Patients Hospitalized With COVID-19: A Randomized Clinical Trial.</h4><i>Writing Committee for the REMAP-CAP Investigators, Lawler PR, Derde LPG, van de Veerdonk FL, ... McArthur CJ, Webb SA</i><br /><b>Importance</b><br />Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19.<br /><b>Objective</b><br />To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19.<br /><b>Design, setting, and participants</b><br />In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022).<br /><b>Interventions</b><br />Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days.<br /><b>Main outcomes and measures</b><br />The primary outcome was organ support-free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes.<br /><b>Results</b><br />On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support-free days among critically ill patients was 10 (-1 to 16) in the ACE inhibitor group (n = 231), 8 (-1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support-free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT02735707.<br /><br /><br /><br /><small>JAMA: 11 Apr 2023; 329:1183-1196</small></div>
Writing Committee for the REMAP-CAP Investigators, Lawler PR, Derde LPG, van de Veerdonk FL, ... McArthur CJ, Webb SA
JAMA: 11 Apr 2023; 329:1183-1196 | PMID: 37039790
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<div><h4>Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials.</h4><i>Self WH, Shotwell MS, Gibbs KW, de Wit M, ... Collins SP, ACTIV-4 Host Tissue Investigators</i><br /><b>Importance</b><br />Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology.<br /><b>Objective</b><br />To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II.<br /><b>Design, setting, and participants</b><br />Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022.<br /><b>Interventions</b><br />A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo.<br /><b>Main outcomes and measures</b><br />The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient\'s status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension.<br /><b>Results</b><br />Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT04924660.<br /><br /><br /><br /><small>JAMA: 11 Apr 2023; 329:1170-1182</small></div>
Self WH, Shotwell MS, Gibbs KW, de Wit M, ... Collins SP, ACTIV-4 Host Tissue Investigators
JAMA: 11 Apr 2023; 329:1170-1182 | PMID: 37039791
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<div><h4>Heterogeneity in Blood Pressure Response to 4 Antihypertensive Drugs: A Randomized Clinical Trial.</h4><i>Sundström J, Lind L, Nowrouzi S, Hagström E, ... Marttala K, Östlund O</i><br /><b>Importance</b><br />Hypertension is the leading risk factor for premature death worldwide. Multiple blood pressure-lowering therapies are available but the potential for maximizing benefit by personalized targeting of drug classes is unknown.<br /><b>Objective</b><br />To investigate and quantify the potential for targeting specific drugs to specific individuals to maximize blood pressure effects.<br /><b>Design, setting, and participants</b><br />A randomized, double-blind, repeated crossover trial in men and women with grade 1 hypertension at low risk for cardiovascular events at an outpatient research clinic in Sweden. Mixed-effects models were used to assess the extent to which individuals responded better to one treatment than another and to estimate the additional blood pressure lowering achievable by personalized treatment.<br /><b>Interventions</b><br />Each participant was scheduled for treatment in random order with 4 different classes of blood pressure-lowering drugs (lisinopril [angiotensin-converting enzyme inhibitor], candesartan [angiotensin-receptor blocker], hydrochlorothiazide [thiazide], and amlodipine [calcium channel blocker]), with repeated treatments for 2 classes.<br /><b>Main outcomes and measures</b><br />Ambulatory daytime systolic blood pressure, measured at the end of each treatment period.<br /><b>Results</b><br />There were 1468 completed treatment periods (median length, 56 days) recorded in 270 of the 280 randomized participants (54% men; mean age, 64 years). The blood pressure response to different treatments varied considerably between individuals (P < .001), specifically for the choices of lisinopril vs hydrochlorothiazide, lisinopril vs amlodipine, candesartan vs hydrochlorothiazide, and candesartan vs amlodipine. Large differences were excluded for the choices of lisinopril vs candesartan and hydrochlorothiazide vs amlodipine. On average, personalized treatment had the potential to provide an additional 4.4 mm Hg-lower systolic blood pressure.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />These data reveal substantial heterogeneity in blood pressure response to drug therapy for hypertension, findings that may have implications for personalized therapy.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT02774460.<br /><br /><br /><br /><small>JAMA: 11 Apr 2023; 329:1160-1169</small></div>
Sundström J, Lind L, Nowrouzi S, Hagström E, ... Marttala K, Östlund O
JAMA: 11 Apr 2023; 329:1160-1169 | PMID: 37039792
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<div><h4>Operative Hysteroscopy vs Vacuum Aspiration for Incomplete Spontaneous Abortion: A Randomized Clinical Trial.</h4><i>Huchon C, Drioueche H, Koskas M, Agostini A, ... Bussières L, Fauconnier A</i><br /><b>Importance</b><br />Vacuum aspiration is commonly used to remove retained products of conception in patients with incomplete spontaneous abortion. Scarring of the uterine cavity may occur, potentially impairing future fertility. A procedural alternative, operative hysteroscopy, has gained popularity with a presumption of better future fertility.<br /><b>Objective</b><br />To assess the superiority of hysteroscopy to vacuum aspiration for subsequent pregnancy in patients with incomplete spontaneous abortion who intend to have future pregnancy.<br /><b>Design, setting, and participants</b><br />The HY-PER randomized, controlled, single-blind trial included 574 patients between November 6, 2014, and May 3, 2017, with a 2-year duration of follow-up. This multicenter trial recruited patients in 15 French hospitals. Individuals aged 18 to 44 years and planned for surgery for an incomplete spontaneous abortion with plans to subsequently conceive were randomized in a 1:1 ratio.<br /><b>Interventions</b><br />Surgical treatment by hysteroscopy (n = 288) or vacuum aspiration (n = 286).<br /><b>Main outcomes and measures</b><br />The primary outcome was a pregnancy of at least 22 weeks\' duration during 2-year follow-up.<br /><b>Results</b><br />The intention-to-treat analyses included 563 women (mean [SD] age, 32.6 [5.4] years). All aspiration procedures were completed. The hysteroscopic procedure could not be completed for 19 patients (7%), 18 of which were converted to vacuum aspiration (8 with inability to completely resect, 7 with insufficient visualization, 2 with anesthetic complications that required a shortened procedure, 1 with equipment failure). One hysteroscopy failed due to a false passage during cervical dilatation. During the 2-year follow-up, 177 patients (62.8%) in the hysteroscopy group and 190 (67.6%) in the vacuum aspiration (control) group achieved the primary outcome (difference, -4.8% [95% CI, -13% to 3.0%]; P = .23). The time-to-event analyses showed no statistically significant difference between groups for the primary outcome (hazard ratio, 0.87 [95% CI, 0.71 to 1.07]). Duration of surgery and hospitalization were significantly longer for hysteroscopy. Rates of new miscarriages, ectopic pregnancies, Clavien-Dindo surgical complications of grade 3 or above (requiring surgical, endoscopic, or radiological intervention or life-threatening event or death), and reinterventions to remove remaining products of conception did not differ between groups.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Surgical management by hysteroscopy of incomplete spontaneous abortions in patients intending to conceive again was not associated with more subsequent births or a better safety profile than vacuum aspiration. Moreover, operative hysteroscopy was not feasible in all cases.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT02201732.<br /><br /><br /><br /><small>JAMA: 11 Apr 2023; 329:1197-1205</small></div>
Huchon C, Drioueche H, Koskas M, Agostini A, ... Bussières L, Fauconnier A
JAMA: 11 Apr 2023; 329:1197-1205 | PMID: 37039805
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<div><h4>Population-Level Health Effects of Involuntary Displacement of People Experiencing Unsheltered Homelessness Who Inject Drugs in US Cities.</h4><i>Barocas JA, Nall SK, Axelrath S, Pladsen C, ... Mosites E, NHBS Study Group</i><br /><b>Importance</b><br />At least 500 000 people in the US experience homelessness nightly. More than 30% of people experiencing homelessness also have a substance use disorder. Involuntary displacement is a common practice in responding to unsheltered people experiencing homelessness. Understanding the health implications of displacement (eg, \"sweeps,\" \"clearings,\" \"cleanups\") is important, especially as they relate to key substance use disorder outcomes.<br /><b>Objective</b><br />To estimate the long-term health effects of involuntary displacement of people experiencing homelessness who inject drugs in 23 US cities.<br /><b>Design, setting, and participants</b><br />A closed cohort microsimulation model that simulates the natural history of injection drug use and health outcomes among people experiencing homelessness who inject drugs in 23 US cities. The model was populated with city-level data from the Centers for Disease Control and Prevention\'s National HIV Behavioral Surveillance system and published data to make representative cohorts of people experiencing homelessness who inject drugs in those cities.<br /><b>Main outcomes and measures</b><br />Projected outcomes included overdose mortality, serious injection-related infections and mortality related to serious injection-related infections, hospitalizations, initiations of medications for opioid use disorder, and life-years lived over a 10-year period for 2 scenarios: \"no displacement\" and \"continual involuntary displacement.\" The population-attributable fraction of continual displacement to mortality was estimated among this population.<br /><b>Results</b><br />Models estimated between 974 and 2175 additional overdose deaths per 10 000 people experiencing homelessness at 10 years in scenarios in which people experiencing homelessness who inject drugs were continually involuntarily displaced compared with no displacement. Between 611 and 1360 additional people experiencing homelessness who inject drugs per 10 000 people were estimated to be hospitalized with continual involuntary displacement, and there will be an estimated 3140 to 8812 fewer initiations of medications for opioid use disorder per 10 000 people. Continual involuntary displacement may contribute to between 15.6% and 24.4% of additional deaths among unsheltered people experiencing homelessness who inject drugs over a 10-year period.<br /><br /><b>Conclusion:</b><br/>and relevance</b><br />Involuntary displacement of people experiencing homelessness may substantially increase drug-related morbidity and mortality. These findings have implications for the practice of involuntary displacement, as well as policies such as access to housing and supportive services, that could mitigate these harms.<br /><br /><br /><br /><small>JAMA: 10 Apr 2023; epub ahead of print</small></div>
Barocas JA, Nall SK, Axelrath S, Pladsen C, ... Mosites E, NHBS Study Group
JAMA: 10 Apr 2023; epub ahead of print | PMID: 37036716
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<div><h4>Diagnosis and Treatment of Acute Myocarditis: A Review.</h4><i>Ammirati E, Moslehi JJ</i><br /><b>Importance</b><br />Acute myocarditis, defined as a sudden inflammatory injury to the myocardium, affects approximately 4 to 14 people per 100 000 each year globally and is associated with a mortality rate of approximately 1% to 7%.<br /><b>Observations</b><br />The most common causes of myocarditis are viruses, such as influenza and coronavirus; systemic autoimmune disorders, such as systemic lupus erythematosus; drugs, such as immune checkpoint inhibitors; and vaccines, including smallpox and mRNA COVID-19 vaccines. Approximately 82% to 95% of adult patients with acute myocarditis present with chest pain, while 19% to 49% present with dyspnea, and 5% to 7% with syncope. The diagnosis of myocarditis can be suggested by presenting symptoms, elevated biomarkers such as troponins, electrocardiographic changes of ST segments, and echocardiographic wall motion abnormalities or wall thickening. Cardiac magnetic resonance imaging or endomyocardial biopsy are required for definitive diagnosis. Treatment depends on acuity, severity, clinical presentation, and etiology. Approximately 75% of patients admitted with myocarditis have an uncomplicated course, with a mortality rate of approximately 0%. In contrast, acute myocarditis that is complicated by acute heart failure or ventricular arrhythmias is associated with a 12% rate of either in-hospital mortality or need for heart transplant. Approximately 2% to 9% of patients have hemodynamic instability, characterized by inability to maintain adequate end-organ perfusion, and require inotropic agents, or mechanical circulatory devices, such as extracorporeal life support, to facilitate functional recovery. These patients have an approximately 28% rate of mortality or heart transplant at 60 days. Immunosuppression (eg, corticosteroids) is appropriate for patients who have myocarditis characterized by eosinophilic or giant cell myocardial infiltrations or due to systemic autoimmune disorders. However, the specific immune cells that should be targeted to improve outcomes in patients with myocarditis remain unclear.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Acute myocarditis affects approximately 4 to 14 per 100 000 people per year. First-line therapy depends on acuity, severity, clinical presentation, and etiology and includes supportive care. While corticosteroids are often used for specific forms of myocarditis (eg, eosinophilic or giant cell infiltrations), this practice is based on anecdotal evidence, and randomized clinical trials of optimal therapeutic interventions for acute myocarditis are needed.<br /><br /><br /><br /><small>JAMA: 04 Apr 2023; 329:1098-1113</small></div>
Ammirati E, Moslehi JJ
JAMA: 04 Apr 2023; 329:1098-1113 | PMID: 37014337
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<div><h4>Differences in Treatment Patterns and Outcomes of Acute Myocardial Infarction for Low- and High-Income Patients in 6 Countries.</h4><i>Landon BE, Hatfield LA, Bakx P, Banerjee A, ... Weinreb G, Cram P</i><br /><b>Importance</b><br />Differences in the organization and financing of health systems may produce more or less equitable outcomes for advantaged vs disadvantaged populations. We compared treatments and outcomes of older high- and low-income patients across 6 countries.<br /><b>Objective</b><br />To determine whether treatment patterns and outcomes for patients presenting with acute myocardial infarction differ for low- vs high-income individuals across 6 countries.<br /><b>Design, setting, and participants</b><br />Serial cross-sectional cohort study of all adults aged 66 years or older hospitalized with acute myocardial infarction from 2013 through 2018 in the US, Canada, England, the Netherlands, Taiwan, and Israel using population-representative administrative data.<br /><b>Exposures</b><br />Being in the top and bottom quintile of income within and across countries.<br /><b>Main outcomes and measures</b><br />Thirty-day and 1-year mortality; secondary outcomes included rates of cardiac catheterization and revascularization, length of stay, and readmission rates.<br /><b>Results</b><br />We studied 289 376 patients hospitalized with ST-segment elevation myocardial infarction (STEMI) and 843 046 hospitalized with non-STEMI (NSTEMI). Adjusted 30-day mortality generally was 1 to 3 percentage points lower for high-income patients. For instance, 30-day mortality among patients admitted with STEMI in the Netherlands was 10.2% for those with high income vs 13.1% for those with low income (difference, -2.8 percentage points [95% CI, -4.1 to -1.5]). One-year mortality differences for STEMI were even larger than 30-day mortality, with the highest difference in Israel (16.2% vs 25.3%; difference, -9.1 percentage points [95% CI, -16.7 to -1.6]). In all countries, rates of cardiac catheterization and percutaneous coronary intervention were higher among high- vs low-income populations, with absolute differences ranging from 1 to 6 percentage points (eg, 73.6% vs 67.4%; difference, 6.1 percentage points [95% CI, 1.2 to 11.0] for percutaneous intervention in England for STEMI). Rates of coronary artery bypass graft surgery for patients with STEMI in low- vs high-income strata were similar but for NSTEMI were generally 1 to 2 percentage points higher among high-income patients (eg, 12.5% vs 11.0% in the US; difference, 1.5 percentage points [95% CI, 1.3 to 1.8 ]). Thirty-day readmission rates generally also were 1 to 3 percentage points lower and hospital length of stay generally was 0.2 to 0.5 days shorter for high-income patients.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />High-income individuals had substantially better survival and were more likely to receive lifesaving revascularization and had shorter hospital lengths of stay and fewer readmissions across almost all countries. Our results suggest that income-based disparities were present even in countries with universal health insurance and robust social safety net systems.<br /><br /><br /><br /><small>JAMA: 04 Apr 2023; 329:1088-1097</small></div>
Landon BE, Hatfield LA, Bakx P, Banerjee A, ... Weinreb G, Cram P
JAMA: 04 Apr 2023; 329:1088-1097 | PMID: 37014339
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<div><h4>Does This Child With High Blood Pressure Have Secondary Hypertension?: The Rational Clinical Examination Systematic Review.</h4><i>Nugent JT, Jiang K, Funaro MC, Saran I, ... Wilson FP, Greenberg JH</i><br /><b>Importance</b><br />Guidelines recommend that all children and adolescents with hypertension undergo evaluation for secondary causes. Identifying clinical factors associated with secondary hypertension may decrease unnecessary testing for those with primary hypertension.<br /><b>Objective</b><br />To determine the utility of the clinical history, physical examination, and 24-hour ambulatory blood pressure monitoring for differentiating primary hypertension from secondary hypertension in children and adolescents (aged ≤21 years).<br /><b>Data sources and study selection</b><br />The databases of MEDLINE, PubMed Central, Embase, Web of Science, and Cochrane Library were searched from inception to January 2022 without language limits. Two authors identified studies describing clinical characteristics in children and adolescents with primary and secondary hypertension.<br /><b>Data extraction and synthesis</b><br />For each clinical finding in each study, a 2 × 2 table was created that included the number of patients with and without the finding who had primary vs secondary hypertension. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool.<br /><b>Main outcomes and measures</b><br />Random-effects modeling was used to calculate sensitivity, specificity, and likelihood ratios (LRs).<br /><b>Results</b><br />Of 3254 unique titles and abstracts screened, 30 studies met inclusion criteria for the meta-analysis and 23 (N = 4210 children and adolescents) were used for pooling in the meta-analysis. In the 3 studies conducted at primary care clinics or school-based screening clinics, the prevalence of secondary hypertension was 9.0% (95% CI, 4.5%-15.0%). In the 20 studies conducted at subspecialty clinics, the prevalence of secondary hypertension was 44% (95% CI, 36%-53%). The demographic findings most strongly associated with secondary hypertension were family history of secondary hypertension (sensitivity, 0.46; specificity, 0.90; LR, 4.7 [95% CI, 2.9-7.6]), weight in the 10th percentile or lower for age and sex (sensitivity, 0.27; specificity, 0.94; LR, 4.5 [95% CI, 1.2-18]), history of prematurity (sensitivity range, 0.17-0.33; specificity range, 0.86-0.94; LR range, 2.3-2.8), and age of 6 years or younger (sensitivity range, 0.25-0.36; specificity range, 0.86-0.88; LR range, 2.2-2.6). Laboratory studies most associated with secondary hypertension were microalbuminuria (sensitivity, 0.13; specificity, 0.99; LR, 13 [95% CI, 3.1-53]) and serum uric acid concentration of 5.5 mg/dL or lower (sensitivity range, 0.70-0.73; specificity range, 0.65-0.89; LR range, 2.1-6.3). Increased daytime diastolic blood pressure load combined with increased nocturnal systolic blood pressure load on 24-hour ambulatory blood pressure monitoring was associated with secondary hypertension (sensitivity, 0.40; specificity, 0.82; LR, 4.8 [95% CI, 1.2-20]). Findings associated with a decreased likelihood of secondary hypertension were asymptomatic presentation (LR range, 0.19-0.36), obesity (LR, 0.34 [95% CI, 0.13-0.90]), and family history of any hypertension (LR, 0.42 [95% CI, 0.30-0.57]). Hypertension stage, headache, and left ventricular hypertrophy did not distinguish secondary from primary hypertension.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Family history of secondary hypertension, younger age, lower body weight, and increased blood pressure load using 24-hour ambulatory blood pressure monitoring were associated with a higher likelihood of secondary hypertension. No individual sign or symptom definitively differentiates secondary hypertension from primary hypertension.<br /><br /><br /><br /><small>JAMA: 28 Mar 2023; 329:1012-1021</small></div>
Nugent JT, Jiang K, Funaro MC, Saran I, ... Wilson FP, Greenberg JH
JAMA: 28 Mar 2023; 329:1012-1021 | PMID: 36976276
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<div><h4>Pediatric Mental Health Hospitalizations at Acute Care Hospitals in the US, 2009-2019.</h4><i>Arakelyan M, Freyleue S, Avula D, McLaren JL, O\'Malley AJ, Leyenaar JK</i><br /><b>Importance</b><br />Approximately 1 in 6 youth in the US have a mental health condition, and suicide is a leading cause of death among this population. Recent national statistics describing acute care hospitalizations for mental health conditions are lacking.<br /><b>Objectives</b><br />To describe national trends in pediatric mental health hospitalizations between 2009 and 2019, to compare utilization among mental health and non-mental health hospitalizations, and to characterize variation in utilization across hospitals.<br /><b>Design, setting, and participants</b><br />Retrospective analysis of the 2009, 2012, 2016, and 2019 Kids\' Inpatient Database, a nationally representative database of US acute care hospital discharges. Analysis included 4 767 840 weighted hospitalizations among children 3 to 17 years of age.<br /><b>Exposures</b><br />Hospitalizations with primary mental health diagnoses were identified using the Child and Adolescent Mental Health Disorders Classification System, which classified mental health diagnoses into 30 mutually exclusive disorder types.<br /><b>Main outcomes and measures</b><br />Measures included number and proportion of hospitalizations with a primary mental health diagnosis and with attempted suicide, suicidal ideation, or self-injury; number and proportion of hospital days and interfacility transfers attributable to mental health hospitalizations; mean lengths of stay (days) and transfer rates among mental health and non-mental health hospitalizations; and variation in these measures across hospitals.<br /><b>Results</b><br />Of 201 932 pediatric mental health hospitalizations in 2019, 123 342 (61.1% [95% CI, 60.3%-61.9%]) were in females, 100 038 (49.5% [95% CI, 48.3%-50.7%]) were in adolescents aged 15 to 17 years, and 103 456 (51.3% [95% CI, 48.6%-53.9%]) were covered by Medicaid. Between 2009 and 2019, the number of pediatric mental health hospitalizations increased by 25.8%, and these hospitalizations accounted for a significantly higher proportion of pediatric hospitalizations (11.5% [95% CI, 10.2%-12.8%] vs 19.8% [95% CI, 17.7%-21.9%]), hospital days (22.2% [95% CI, 19.1%-25.3%] vs 28.7% [95% CI, 24.4%-33.0%]), and interfacility transfers (36.9% [95% CI, 33.2%-40.5%] vs 49.3% [95% CI, 45.9%-52.7%]). The percentage of mental health hospitalizations with attempted suicide, suicidal ideation, or self-injury diagnoses increased significantly from 30.7% (95% CI, 28.6%-32.8%) in 2009 to 64.2% (95% CI, 62.3%-66.2%) in 2019. Length of stay and interfacility transfer rates varied significantly across hospitals. Across all years, mental health hospitalizations had significantly longer mean lengths of stay and higher transfer rates compared with non-mental health hospitalizations.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Between 2009 and 2019, the number and proportion of pediatric acute care hospitalizations due to mental health diagnoses increased significantly. The majority of mental health hospitalizations in 2019 included a diagnosis of attempted suicide, suicidal ideation, or self-injury, underscoring the increasing importance of this concern.<br /><br /><br /><br /><small>JAMA: 28 Mar 2023; 329:1000-1011</small></div>
Arakelyan M, Freyleue S, Avula D, McLaren JL, O'Malley AJ, Leyenaar JK
JAMA: 28 Mar 2023; 329:1000-1011 | PMID: 36976279
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<div><h4>Diagnosis and Treatment of Chronic Lymphocytic Leukemia: A Review.</h4><i>Shadman M</i><br /><b>Importance</b><br />Chronic lymphocytic leukemia (CLL), defined by a minimum of 5 × 109/L monoclonal B cells in the blood, affects more than 200 000 people and is associated with approximately 4410 deaths in the US annually. CLL is associated with an immunocompromised state and an increased rate of complications from infections.<br /><b>Observations</b><br />At the time of diagnosis, the median age of patients with CLL is 70 years, and an estimated 95% of patients have at least 1 medical comorbidity. Approximately 70% to 80% of patients with CLL are asymptomatic at the time of diagnosis, and one-third will never require treatment for CLL. Prognostic models have been developed to estimate the time to first treatment and the overall survival, but for patients who are asymptomatic, irrespective of disease risk category, clinical observation is the standard of care. Patients with symptomatic disease who have bulky or progressive lymphadenopathy or hepatosplenomegaly and those with a low neutrophil count, anemia, or thrombocytopenia and/or symptoms of fever, drenching night sweats, and weight loss (B symptoms) should be offered treatment. For these patients, first-line treatment consists of a regimen containing either a covalent Bruton tyrosine kinase (BTK) inhibitor (acalabrutinib, zanubrutinib, or ibrutinib) or a B-cell leukemia/lymphoma 2 (BCL2) inhibitor (venetoclax). There is no evidence that starting either class before the other improves outcomes. The covalent BTK inhibitors are typically used indefinitely. Survival rates are approximately 88% at 4 years for acalabrutinib, 94% at 2 years for zanubrutinib, and 78% at 7 years for ibrutinib. Venetoclax is prescribed in combination with obinutuzumab, a monoclonal anti-CD20 antibody, in first-line treatment for 1 year (overall survival, 82% at 5-year follow-up). A noncovalent BTK inhibitor, pitobrutinib, has shown an overall response rate of more than 70% after failure of covalent BTK inhibitors and venetoclax. Phosphoinositide 3\'-kinase (PI3K) inhibitors (idelalisib and duvelisib) can be prescribed for disease that progresses with BTK inhibitors and venetoclax, but patients require close monitoring for adverse events such as autoimmune conditions and infections. In patients with multiple relapses, chimeric antigen receptor T-cell (CAR-T) therapy with lisocabtagene maraleucel was associated with a 45% complete response rate. The only potential cure for CLL is allogeneic hematopoietic cell transplant, which remains an option after use of targeted agents.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />More than 200 000 people in the US are living with a CLL diagnosis, and CLL causes approximately 4410 deaths each year in the US. Approximately two-thirds of patients eventually need treatment. Highly effective novel targeted agents include BTK inhibitors such as acalabrutinib, zanubrutinib, ibrutinib, and pirtobrutinib or BCL2 inhibitors such as venetoclax.<br /><br /><br /><br /><small>JAMA: 21 Mar 2023; 329:918-932</small></div>
Shadman M
JAMA: 21 Mar 2023; 329:918-932 | PMID: 36943212
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<div><h4>Early vs Interval Postpartum Intrauterine Device Placement: A Randomized Clinical Trial.</h4><i>Averbach S, Kully G, Hinz E, Dey A, ... Haider S, Hofler LG</i><br /><b>Importance</b><br />The early postpartum period, 2 to 4 weeks after birth, may be a convenient time for intrauterine device (IUD) placement; the placement could then coincide with early postpartum or well-baby visits.<br /><b>Objective</b><br />To determine expulsion rates for IUDs placed early postpartum compared with those placed at the standard interval 6-week visit.<br /><b>Design, setting, and participants</b><br />In this randomized noninferiority trial, people who had a vaginal or cesarean birth were randomly assigned to undergo early (14-28 days) or interval (42-56 days) postpartum IUD placement. Clinicians blinded to participant study group used transvaginal ultrasonography to confirm IUD presence and position at the 6-month postpartum follow-up. The study assessed 642 postpartum people from 4 US medical centers, enrolled a consecutive sample of 404 participants from March 2018 to July 2021, and followed up each participant for 6 months postpartum.<br /><b>Interventions</b><br />Early postpartum IUD placement, at 2 to 4 weeks postpartum, vs standard interval placement 6 to 8 weeks postpartum.<br /><b>Main outcomes and measures</b><br />The primary outcome was complete IUD expulsion by 6 months postpartum; the prespecified noninferiority margin was 6%. Secondary outcomes were partial IUD expulsion, IUD removal, pelvic infection, patient satisfaction, uterine perforation, pregnancy, and IUD use at 6 months postpartum. IUD malposition was an exploratory outcome.<br /><b>Results</b><br />Among 404 enrolled participants, 203 participants were randomly assigned to undergo early IUD placement and 201 to undergo interval IUD placement (mean [SD] age, 29.9 [5.4] years; 46 [11.4%] were Black, 228 [56.4%] were White, and 175 [43.3%] were Hispanic). By 6 months postpartum, 53 participants (13%) never had an IUD placed and 57 (14%) were lost to follow-up. Among the 294 participants (73%) who received an IUD and completed 6-month follow-up, complete expulsion rates were 3 of 149 (2.0% [95% CI, 0.4%-5.8%]) in the early placement group and 0 of 145 (0% [95% CI, 0.0%-2.5%]) in the interval placement group (between-group difference, 2.0 [95% CI, -0.5 to 5.7] percentage points). Partial expulsion occurred in 14 (9.4% [95% CI, 5.2%-15.3%]) participants in the early placement group and 11 (7.6% [95% CI, 3.9%-13.2%]) participants in the interval placement group (between-group difference, 1.8 [95% CI, -4.8 to 8.6] percentage points). IUD use at 6 months was similar between the groups: 141 (69.5% [95% CI, 62.6%-75.7%]) participants in the early group vs 139 (67.2% [95% CI, 60.2%-73.6%]) in the interval group.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Early IUD placement at 2 to 4 weeks postpartum compared with 6 to 8 weeks postpartum was noninferior for complete expulsion, but not partial expulsion. Understanding the risk of expulsion at these time points may help patients and clinicians make informed choices about the timing of IUD placement.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT03462758.<br /><br /><br /><br /><small>JAMA: 21 Mar 2023; 329:910-917</small></div>
Averbach S, Kully G, Hinz E, Dey A, ... Haider S, Hofler LG
JAMA: 21 Mar 2023; 329:910-917 | PMID: 36943214
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<div><h4>Efficacy and Safety of Early Administration of 4-Factor Prothrombin Complex Concentrate in Patients With Trauma at Risk of Massive Transfusion: The PROCOAG Randomized Clinical Trial.</h4><i>Bouzat P, Charbit J, Abback PS, Huet-Garrigue D, ... Payen JF, PROCOAG Study Group</i><br /><b>Importance</b><br />Optimal transfusion strategies in traumatic hemorrhage are unknown. Reports suggest a beneficial effect of 4-factor prothrombin complex concentrate (4F-PCC) on blood product consumption.<br /><b>Objective</b><br />To investigate the efficacy and safety of 4F-PCC administration in patients at risk of massive transfusion.<br /><b>Design, setting, and participants</b><br />Double-blind, randomized, placebo-controlled superiority trial in 12 French designated level I trauma centers from December 29, 2017, to August 31, 2021, involving consecutive patients with trauma at risk of massive transfusion. Follow-up was completed on August 31, 2021.<br /><b>Interventions</b><br />Intravenous administration of 1 mL/kg of 4F-PCC (25 IU of factor IX/kg) vs 1 mL/kg of saline solution (placebo). Patients, investigators, and data analysts were blinded to treatment assignment. All patients received early ratio-based transfusion (packed red blood cells:fresh frozen plasma ratio of 1:1 to 2:1) and were treated according to European traumatic hemorrhage guidelines.<br /><b>Main outcomes and measures</b><br />The primary outcome was 24-hour all blood product consumption (efficacy); arterial or venous thromboembolic events were a secondary outcome (safety).<br /><b>Results</b><br />Of 4313 patients with the highest trauma level activation, 350 were eligible for emergency inclusion, 327 were randomized, and 324 were analyzed (164 in the 4F-PCC group and 160 in the placebo group). The median (IQR) age of participants was 39 (27-56) years, Injury Severity Score was 36 (26-50 [major trauma]), and admission blood lactate level was 4.6 (2.8-7.4) mmol/L; prehospital arterial systolic blood pressure was less than 90 mm Hg in 179 of 324 patients (59%), 233 patients (73%) were men, and 226 (69%) required expedient hemorrhage control. There was no statistically or clinically significant between-group difference in median (IQR) total 24-hour blood product consumption (12 [5-19] U in the 4F-PCC group vs 11 [6-19] U in the placebo group; absolute difference, 0.2 U [95% CI, -2.99 to 3.33]; P = .72). In the 4F-PCC group, 56 patients (35%) presented with at least 1 thromboembolic event vs 37 patients (24%) in the placebo group (absolute difference, 11% [95% CI, 1%-21%]; relative risk, 1.48 [95% CI, 1.04-2.10]; P = .03).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Among patients with trauma at risk of massive transfusion, there was no significant reduction of 24-hour blood product consumption after administration of 4F-PCC, but thromboembolic events were more common. These findings do not support systematic use of 4F-PCC in patients at risk of massive transfusion.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT03218722.<br /><br /><br /><br /><small>JAMA: 21 Mar 2023; epub ahead of print</small></div>
Bouzat P, Charbit J, Abback PS, Huet-Garrigue D, ... Payen JF, PROCOAG Study Group
JAMA: 21 Mar 2023; epub ahead of print | PMID: 36942533
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<div><h4>Heterogeneous Treatment Effects of Therapeutic-Dose Heparin in Patients Hospitalized for COVID-19.</h4><i>Goligher EC, Lawler PR, Jensen TP, Talisa V, ... ATTACC, and ACTIV-4a Investigators</i><br /><b>Importance</b><br />Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making.<br /><b>Objective</b><br />To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE.<br /><b>Design, setting, and participants</b><br />Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial.<br /><b>Exposures</b><br />Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis.<br /><b>Main outcomes and measures</b><br />Organ support-free days, assigning a value of -1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival.<br /><b>Results</b><br />Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support-free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support-free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI <30) vs higher BMI groups (BMI ≥30; posterior probability of difference in ORs >90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT04372589.<br /><br /><br /><br /><small>JAMA: 21 Mar 2023; epub ahead of print</small></div>
Goligher EC, Lawler PR, Jensen TP, Talisa V, ... ATTACC, and ACTIV-4a Investigators
JAMA: 21 Mar 2023; epub ahead of print | PMID: 36942550
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<div><h4>Heart Failure With Preserved Ejection Fraction: A Review.</h4><i>Redfield MM, Borlaug BA</i><br /><b>Importance</b><br />Heart failure with preserved ejection fraction (HFpEF), defined as HF with an EF of 50% or higher at diagnosis, affects approximately 3 million people in the US and up to 32 million people worldwide. Patients with HFpEF are hospitalized approximately 1.4 times per year and have an annual mortality rate of approximately 15%.<br /><b>Observations</b><br />Risk factors for HFpEF include older age, hypertension, diabetes, dyslipidemia, and obesity. Approximately 65% of patients with HFpEF present with dyspnea and physical examination, chest radiographic, echocardiographic, or invasive hemodynamic evidence of HF with overt congestion (volume overload) at rest. Approximately 35% of patients with HFpEF present with \"unexplained\" dyspnea on exertion, meaning they do not have clear physical, radiographic, or echocardiographic signs of HF. These patients have elevated atrial pressures with exercise as measured with invasive hemodynamic stress testing or estimated with Doppler echocardiography stress testing. In unselected patients presenting with unexplained dyspnea, the H2FPEF score incorporating clinical (age, hypertension, obesity, atrial fibrillation status) and resting Doppler echocardiographic (estimated pulmonary artery systolic pressure or left atrial pressure) variables can assist with diagnosis (H2FPEF score range, 0-9; score >5 indicates more than 95% probability of HFpEF). Specific causes of the clinical syndrome of HF with normal EF other than HFpEF should be identified and treated, such as valvular, infiltrative, or pericardial disease. First-line pharmacologic therapy consists of sodium-glucose cotransporter type 2 inhibitors, such as dapagliflozin or empagliflozin, which reduced HF hospitalization or cardiovascular death by approximately 20% compared with placebo in randomized clinical trials. Compared with usual care, exercise training and diet-induced weight loss produced clinically meaningful increases in functional capacity and quality of life in randomized clinical trials. Diuretics (typically loop diuretics, such as furosemide or torsemide) should be prescribed to patients with overt congestion to improve symptoms. Education in HF self-care (eg, adherence to medications and dietary restrictions, monitoring of symptoms and vital signs) can help avoid HF decompensation.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Approximately 3 million people in the US have HFpEF. First-line therapy consists of sodium-glucose cotransporter type 2 inhibitors, exercise, HF self-care, loop diuretics as needed to maintain euvolemia, and weight loss for patients with obesity and HFpEF.<br /><br /><br /><br /><small>JAMA: 14 Mar 2023; 329:827-838</small></div>
Redfield MM, Borlaug BA
JAMA: 14 Mar 2023; 329:827-838 | PMID: 36917048
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<div><h4>Association Between California\'s State Insurance Gender Nondiscrimination Act and Utilization of Gender-Affirming Surgery.</h4><i>Schoenbrunner A, Beckmeyer A, Kunnath N, Ibrahim A, ... Kuzon WM, Diaz A</i><br /><b>Importance</b><br />Gender-affirming surgery is often beneficial for gender-diverse or -dysphoric patients. Access to gender-affirming surgery is often limited through restrictive legislation and insurance policies.<br /><b>Objective</b><br />To investigate the association between California\'s 2013 implementation of the Insurance Gender Nondiscrimination Act, which prohibits insurers and health plans from limiting benefits based on a patient\'s sex, gender, gender identity, or gender expression, and utilization of gender-affirming surgery among California residents.<br /><b>Design, setting, and participants</b><br />Population epidemiology study of transgender and gender-diverse patients undergoing gender-affirming surgery (facial, chest, and genital surgery) between 2005 and 2019. Utilization of gender-affirming surgery in California before and after implementation of the Insurance Gender Nondiscrimination Act in July 2013 was compared with utilization in Washington and Arizona, control states chosen because of geographic similarity and because they expanded Medicaid on the same date as California-January 1, 2014. The date of last follow-up was December 31, 2019.<br /><b>Exposures</b><br />California\'s Insurance Gender Nondiscrimination Act, implemented on July 9, 2013.<br /><b>Main outcomes and measures</b><br />Receipt of gender-affirming surgery, defined as undergoing at least 1 facial, chest, or genital procedure.<br /><b>Results</b><br />A total of 25 252 patients (California: n = 17 934 [71%]; control: n = 7328 [29%]) had a diagnosis of gender dysphoria. Median ages were 34.0 years in California (with or without gender-affirming surgery), 39 years (IQR, 28-49 years) among those undergoing gender-affirming surgery in control states, and 36 years (IQR, 22-56 years) among those not undergoing gender-affirming surgery in control states. Patients underwent at least 1 gender-affirming surgery within the study period in 2918 (11.6%) admissions-2715 (15.1%) in California vs 203 (2.8%) in control states. There was a statistically significant increase in gender-affirming surgery in the third quarter of July 2013 in California vs control states, coinciding with the timing of the Insurance Gender Nondiscrimination Act (P < .001). Implementation of the policy was associated with an absolute 12.1% (95% CI, 10.3%-13.9%; P < .001) increase in the probability of undergoing gender-affirming surgery in California vs control states observed in the subset of insured patients (13.4% [95% CI, 11.5%-15.4%]; P < .001) but not self-pay patients (-22.6% [95% CI, -32.8% to -12.5%]; P < .001).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Implementation in California of its Insurance Gender Nondiscrimination Act was associated with a significant increase in utilization of gender-affirming surgery in California compared with the control states Washington and Arizona. These data might inform state legislative efforts to craft policies preventing discrimination in health coverage for state residents, including transgender and gender-diverse patients.<br /><br /><br /><br /><small>JAMA: 14 Mar 2023; 329:819-826</small></div>
Schoenbrunner A, Beckmeyer A, Kunnath N, Ibrahim A, ... Kuzon WM, Diaz A
JAMA: 14 Mar 2023; 329:819-826 | PMID: 36917051
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<div><h4>Medicare Advantage Enrollment Among Beneficiaries With End-Stage Renal Disease in the First Year of the 21st Century Cures Act.</h4><i>Nguyen KH, Oh EG, Meyers DJ, Kim D, Mehrotra R, Trivedi AN</i><br /><b>Importance</b><br />Before 2021, most Medicare beneficiaries with end-stage renal disease (ESRD) were unable to enroll in private Medicare Advantage (MA) plans. The 21st Century Cures Act permitted these beneficiaries to enroll in MA plans effective January 2021.<br /><b>Objective</b><br />To examine changes in MA enrollment among Medicare beneficiaries with ESRD after enactment of the 21st Century Cures Act overall and by race or ethnicity and dual-eligible status.<br /><b>Design, setting, and participants</b><br />This cross-sectional time-trend study used data from Medicare beneficiaries with ESRD (both kidney transplant recipients and those undergoing dialysis) between January 2019 and December 2021. Data were analyzed between June and October 2022.<br /><b>Exposures</b><br />21st Century Cures Act.<br /><b>Main outcomes and measures</b><br />Primary outcomes were the proportion of Medicare beneficiaries with prevalent ESRD who switched from traditional Medicare to MA between 2020 and 2021 and those with incident ESRD who newly enrolled in MA in 2021. Individuals who stayed in traditional Medicare were enrolled in 2020 and 2021 and those who switched to MA were enrolled in traditional Medicare in 2020 and MA in 2021.<br /><b>Results</b><br />Among 575 797 beneficiaries with ESRD in 2020 or 2021 (mean [SD] age, 64.7 [14.2] years, 42.2% female, 34.0% Black, and 7.7% Hispanic or Latino), the proportion of beneficiaries enrolled in MA increased from 24.8% (December 2020) to 37.4% (December 2021), a relative change of 50.8%. The largest relative increases in MA enrollment were among Black (72.8% relative increase), Hispanic (44.8%), and dual-eligible beneficiaries with ESRD (73.6%). Among 359 617 beneficiaries with TM and prevalent ESRD in 2020, 17.6% switched to MA in 2021. Compared with individuals who stayed in traditional Medicare, those who switched to MA had modestly more chronic conditions (6.3 vs 6.1; difference, 0.12 conditions [95% CI, 0.10-0.16]) and similar nondrug spending in 2020 (difference, $509 [95% CI, -$58 to $1075]) but were more likely to be Black (difference, 19.5 percentage points [95% CI, 19.1-19.9]) and have dual Medicare-Medicaid eligibility (difference, 20.8 percentage points [95% CI, 20.4-21.2]). Among beneficiaries who were newly eligible for Medicare ESRD benefits in 2021, 35.2% enrolled in MA.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Results suggest that increases in MA enrollment among Medicare beneficiaries with ESRD were substantial the first year after the 21st Century Cures Act, particularly among Black, Hispanic, and dual-eligible individuals. Policy makers and MA plans may need to assess network adequacy, disenrollment, and equity of care for beneficiaries who enrolled in MA.<br /><br /><br /><br /><small>JAMA: 14 Mar 2023; 329:810-818</small></div>
Nguyen KH, Oh EG, Meyers DJ, Kim D, Mehrotra R, Trivedi AN
JAMA: 14 Mar 2023; 329:810-818 | PMID: 36917063
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<div><h4>DNA Sequencing to Detect Residual Disease in Adults With Acute Myeloid Leukemia Prior to Hematopoietic Cell Transplant.</h4><i>Dillon LW, Gui G, Page KM, Ravindra N, ... Weisdorf DJ, Hourigan CS</i><br /><b>Importance</b><br />Preventing relapse for adults with acute myeloid leukemia (AML) in first remission is the most common indication for allogeneic hematopoietic cell transplant. The presence of AML measurable residual disease (MRD) has been associated with higher relapse rates, but testing is not standardized.<br /><b>Objective</b><br />To determine whether DNA sequencing to identify residual variants in the blood of adults with AML in first remission before allogeneic hematopoietic cell transplant identifies patients at increased risk of relapse and poorer overall survival compared with those without these DNA variants.<br /><b>Design, setting, and participants</b><br />In this retrospective observational study, DNA sequencing was performed on pretransplant blood from patients aged 18 years or older who had undergone their first allogeneic hematopoietic cell transplant during first remission for AML associated with variants in FLT3, NPM1, IDH1, IDH2, or KIT at 1 of 111 treatment sites from 2013 through 2019. Clinical data were collected, through May 2022, by the Center for International Blood and Marrow Transplant Research.<br /><b>Exposure</b><br />Centralized DNA sequencing of banked pretransplant remission blood samples.<br /><b>Main outcomes and measures</b><br />The primary outcomes were overall survival and relapse. Day of transplant was considered day 0. Hazard ratios were reported using Cox proportional hazards regression models.<br /><b>Results</b><br />Of 1075 patients tested, 822 had FLT3 internal tandem duplication (FLT3-ITD) and/or NPM1 mutated AML (median age, 57.1 years, 54% female). Among 371 patients in the discovery cohort, the persistence of NPM1 and/or FLT3-ITD variants in the blood of 64 patients (17.3%) in remission before undergoing transplant was associated with worse outcomes after transplant (2013-2017). Similarly, of the 451 patients in the validation cohort who had undergone transplant in 2018-2019, 78 patients (17.3%) with residual NPM1 and/or FLT3-ITD variants had higher rates of relapse at 3 years (68% vs 21%; difference, 47% [95% CI, 26% to 69%]; HR, 4.32 [95% CI, 2.98 to 6.26]; P < .001) and decreased survival at 3 years (39% vs 63%; difference, -24% [2-sided 95% CI, -39% to -9%]; HR, 2.43 [95% CI, 1.71 to 3.45]; P < .001).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Among patients with acute myeloid leukemia in first remission prior to allogeneic hematopoietic cell transplant, the persistence of FLT3 internal tandem duplication or NPM1 variants in the blood at an allele fraction of 0.01% or higher was associated with increased relapse and worse survival compared with those without these variants. Further study is needed to determine whether routine DNA-sequencing testing for residual variants can improve outcomes for patients with acute myeloid leukemia.<br /><br /><br /><br /><small>JAMA: 07 Mar 2023; 329:745-755</small></div>
Dillon LW, Gui G, Page KM, Ravindra N, ... Weisdorf DJ, Hourigan CS
JAMA: 07 Mar 2023; 329:745-755 | PMID: 36881031
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<div><h4>Effect of Induction Therapy With Olamkicept vs Placebo on Clinical Response in Patients With Active Ulcerative Colitis: A Randomized Clinical Trial.</h4><i>Zhang S, Chen B, Wang B, Chen H, ... Schreiber S, Chen M</i><br /><b>Importance</b><br />Olamkicept, a soluble gp130-Fc-fusion-protein, selectively inhibits interleukin 6 (IL-6) trans-signaling by binding the soluble IL-6 receptor/IL-6 complex. It has anti-inflammatory activities in inflammatory murine models without immune suppression.<br /><b>Objective</b><br />To assess the effect of olamkicept as induction therapy in patients with active ulcerative colitis.<br /><b>Design, setting, and participants</b><br />Randomized, double-blind, placebo-controlled phase 2 trial of olamkicept in 91 adults with active ulcerative colitis (full Mayo score ≥5, rectal bleeding score ≥1, endoscopy score ≥2) and an inadequate response to conventional therapy. The study was conducted at 22 clinical study sites in East Asia. Patients were recruited beginning in February 2018. Final follow-up occurred in December 2020.<br /><b>Interventions</b><br />Eligible patients were randomized 1:1:1 to receive a biweekly intravenous infusion of olamkicept 600 mg (n = 30) or 300 mg (n = 31) or placebo (n = 30) for 12 weeks.<br /><b>Main outcomes and measures</b><br />The primary end point was clinical response at week 12 (defined as ≥3 and ≥30% decrease from baseline total Mayo score; range, 0-12 [worst] with ≥1 decrease and ≤1 in rectal bleeding [range, 0-3 {worst}]). There were 25 secondary efficacy outcomes, including clinical remission and mucosal healing at week 12.<br /><b>Results</b><br />Ninety-one patients (mean age, 41 years; 25 women [27.5%]) were randomized; 79 (86.8%) completed the trial. At week 12, more patients receiving olamkicept 600 mg (17/29 [58.6%]) or 300 mg (13/30 [43.3%]) achieved clinical response than placebo (10/29 [34.5%]), with adjusted difference vs placebo of 26.6% (90% CI, 6.2% to 47.1%; P = .03) for 600 mg and 8.3% (90% CI, -12.6% to 29.1%; P = .52) for 300 mg. Among patients randomized to receive 600 mg olamkicept, 16 of 25 secondary outcomes were statistically significant compared with placebo. Among patients randomized to receive 300 mg, 6 of 25 secondary outcomes were statistically significant compared with placebo. Treatment-related adverse events occurred in 53.3% (16/30) of patients receiving 600 mg olamkicept, 58.1% (18/31) receiving 300 mg olamkicept, and 50% (15/30) receiving placebo. The most common drug-related adverse events were bilirubin presence in the urine, hyperuricemia, and increased aspartate aminotransferase levels, and all were more common in the olamkicept groups compared with placebo.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Among patients with active ulcerative colitis, biweekly infusion of olamkicept 600 mg, but not 300 mg, resulted in a greater likelihood of clinical response at 12 weeks compared with placebo. Further research is needed for replication and to assess longer-term efficacy and safety.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT03235752.<br /><br /><br /><br /><small>JAMA: 07 Mar 2023; 329:725-734</small></div>
Zhang S, Chen B, Wang B, Chen H, ... Schreiber S, Chen M
JAMA: 07 Mar 2023; 329:725-734 | PMID: 36881032
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<div><h4>Association of FDA Mandate Limiting Acetaminophen (Paracetamol) in Prescription Combination Opioid Products and Subsequent Hospitalizations and Acute Liver Failure.</h4><i>Orandi BJ, McLeod MC, MacLennan PA, Lee WM, ... Locke JE, US Acute Liver Failure Study Group</i><br /><b>Importance</b><br />In January 2011, the US Food and Drug Administration (FDA) announced a mandate to limit acetaminophen (paracetamol) to 325 mg/tablet in combination acetaminophen and opioid medications, with manufacturer compliance required by March 2014.<br /><b>Objective</b><br />To assess the odds of hospitalization and the proportion of acute liver failure (ALF) cases with acetaminophen and opioid toxicity prior to and after the mandate.<br /><b>Design, setting, and participants</b><br />This interrupted time-series analysis used hospitalization data from 2007-2019 involving ICD-9/ICD-10 codes consistent with both acetaminophen and opioid toxicity from the National Inpatient Sample (NIS), a large US hospitalization database, and ALF cases from 1998-2019 involving acetaminophen and opioid products from the Acute Liver Failure Study Group (ALFSG), a cohort of 32 US medical centers. For comparison, hospitalizations and ALF cases consistent with acetaminophen toxicity alone were extracted from the NIS and ALFSG.<br /><b>Exposures</b><br />Time prior to and after the FDA mandate limiting acetaminophen to 325 mg in combination acetaminophen and opioid products.<br /><b>Main outcomes and measures</b><br />Odds of hospitalization involving acetaminophen and opioid toxicity and percentage of ALF cases from acetaminophen and opioid products prior to and after the mandate.<br /><b>Results</b><br />In the NIS, among 474 047 585 hospitalizations from Q1 2007 through Q4 2019, there were 39 606 hospitalizations involving acetaminophen and opioid toxicity; 66.8% of cases were among women; median age, 42.2 (IQR, 28.4-54.1). In the ALFSG, from Q1 1998 through Q3 2019, there were a total of 2631 ALF cases, of which 465 involved acetaminophen and opioid toxicity; 85.4% women; median age, 39.0 (IQR, 32.0-47.0). The predicted incidence of hospitalizations 1 day prior to the FDA announcement was 12.2 cases/100 000 hospitalizations (95% CI, 11.0-13.4); by Q4 2019, it was 4.4/100 000 hospitalizations (95% CI, 4.1-4.7) (absolute difference, 7.8/100 000 [95% CI, 6.6-9.0]; P < .001). The odds of hospitalizations with acetaminophen and opioid toxicity increased 11%/y prior to the announcement (odds ratio [OR], 1.11 [95% CI, 1.06-1.15]) and decreased 11%/y after the announcement (OR, 0.89 [95% CI, 0.88-0.90]). The predicted percentage of ALF cases involving acetaminophen and opioid toxicity 1 day prior to the FDA announcement was 27.4% (95% CI, 23.3%-31.9%); by Q3 2019, it was 5.3% (95% CI, 3.1%-8.8%) (absolute difference, 21.8% [95% CI, 15.5%-32.4%]; P < .001). The percentage of ALF cases involving acetaminophen and opioid toxicity increased 7% per year prior to the announcement (OR, 1.07 [95% CI, 1.03-1.1]; P < .001) and decreased 16% per year after the announcement (OR, 0.84 [95% CI, 0.77-0.92]; P < .001). Sensitivity analyses confirmed these findings.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />The FDA mandate limiting acetaminophen dosage to 325 mg/tablet in prescription acetaminophen and opioid products was associated with a statistically significant decrease in the yearly rate of hospitalizations and proportion per year of ALF cases involving acetaminophen and opioid toxicity.<br /><br /><br /><br /><small>JAMA: 07 Mar 2023; 329:735-744</small></div>
Orandi BJ, McLeod MC, MacLennan PA, Lee WM, ... Locke JE, US Acute Liver Failure Study Group
JAMA: 07 Mar 2023; 329:735-744 | PMID: 36881033
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<div><h4>Effect of Intrapartum Azithromycin vs Placebo on Neonatal Sepsis and Death: A Randomized Clinical Trial.</h4><i>Roca A, Camara B, Bognini JD, Nakakana UN, ... D\'Alessandro U, PregnAnZI-2 Working Group</i><br /><b>Importance</b><br />Neonatal sepsis is a leading cause of neonatal mortality. New interventions are needed to decrease neonatal sepsis and mortality in regions with highest burden.<br /><b>Objective</b><br />To evaluate the efficacy of intrapartum azithromycin to reduce neonatal sepsis or mortality, as well as neonatal and maternal infections.<br /><b>Design, setting, and participants</b><br />This double-blind, placebo-controlled, randomized clinical trial enrolled and followed up birthing parents and their infants at 10 health facilities in The Gambia and Burkina Faso, West Africa, between October 2017 and May 2021.<br /><b>Interventions</b><br />Participants were assigned at random to receive oral azithromycin (2 g) or placebo (ratio 1:1) during labor.<br /><b>Main outcomes and measures</b><br />The primary outcome was a composite of neonatal sepsis or mortality, with the former defined based on microbiologic or clinical criteria. Secondary outcomes were neonatal infections (skin, umbilical, eye and ear infections), malaria, and fever; postpartum infections (puerperal sepsis, mastitis), fever, and malaria; and use of antibiotics during 4-week follow-up.<br /><b>Results</b><br />The trial randomized 11 983 persons in labor (median age, 29.9 years). Overall, 225 newborns (1.9% of 11 783 live births) met the primary end point. The incidence of neonatal mortality or sepsis was similar in the azithromycin and placebo groups (2.0% [115/5889] vs 1.9% [110/5894]; risk difference [RD], 0.09 [95% CI, -0.39 to 0.57]), as was the incidence of neonatal mortality (0.8% vs 0.8%; RD, 0.04 [95% CI, -0.27 to 0.35]) and neonatal sepsis (1.3% vs 1.3%; RD, 0.02 [95% CI, -0.38 to 0.43]). Newborns in the azithromycin group compared with the placebo group had lower incidence of skin infections (0.8% vs 1.7%; RD, -0.90 [95% CI, -1.30 to -0.49]) and need for antibiotics (6.2% vs 7.8%; RD, -1.58 [95% CI, -2.49 to -0.67]). Postpartum parents in the azithromycin group had lower incidence of mastitis (0.3% vs 0.5%; RD, -0.24 [95% CI, -0.47 to -0.01]) and puerperal fever (0.1% vs 0.3%; RD, -0.19 [95% CI, -0.36 to -0.01]).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Azithromycin administered orally during labor did not reduce neonatal sepsis or mortality. These results do not support routine introduction of oral intrapartum azithromycin for this purpose.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT03199547.<br /><br /><br /><br /><small>JAMA: 07 Mar 2023; 329:716-724</small></div>
Roca A, Camara B, Bognini JD, Nakakana UN, ... D'Alessandro U, PregnAnZI-2 Working Group
JAMA: 07 Mar 2023; 329:716-724 | PMID: 36881034
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<div><h4>Coordinated Care to Optimize Cardiovascular Preventive Therapies in Type 2 Diabetes: A Randomized Clinical Trial.</h4><i>Pagidipati NJ, Nelson AJ, Kaltenbach LA, Leyva M, ... Granger CB, COORDINATE–Diabetes Site Investigators</i><br /><b>Importance</b><br />Evidence-based therapies to reduce atherosclerotic cardiovascular disease risk in adults with type 2 diabetes are underused in clinical practice.<br /><b>Objective</b><br />To assess the effect of a coordinated, multifaceted intervention of assessment, education, and feedback vs usual care on the proportion of adults with type 2 diabetes and atherosclerotic cardiovascular disease prescribed all 3 groups of recommended, evidence-based therapies (high-intensity statins, angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers [ARBs], and sodium-glucose cotransporter 2 [SGLT2] inhibitors and/or glucagon-like peptide 1 receptor agonists [GLP-1RAs]).<br /><b>Design, setting, and participants</b><br />Cluster randomized clinical trial with 43 US cardiology clinics recruiting participants from July 2019 through May 2022 and follow-up through December 2022. The participants were adults with type 2 diabetes and atherosclerotic cardiovascular disease not already taking all 3 groups of evidence-based therapies.<br /><b>Interventions</b><br />Assessing local barriers, developing care pathways, coordinating care, educating clinicians, reporting data back to the clinics, and providing tools for participants (n = 459) vs usual care per practice guidelines (n = 590).<br /><b>Main outcomes and measures</b><br />The primary outcome was the proportion of participants prescribed all 3 groups of recommended therapies at 6 to 12 months after enrollment. The secondary outcomes included changes in atherosclerotic cardiovascular disease risk factors and a composite outcome of all-cause death or hospitalization for myocardial infarction, stroke, decompensated heart failure, or urgent revascularization (the trial was not powered to show these differences).<br /><b>Results</b><br />Of 1049 participants enrolled (459 at 20 intervention clinics and 590 at 23 usual care clinics), the median age was 70 years and there were 338 women (32.2%), 173 Black participants (16.5%), and 90 Hispanic participants (8.6%). At the last follow-up visit (12 months for 97.3% of participants), those in the intervention group were more likely to be prescribed all 3 therapies (173/457 [37.9%]) vs the usual care group (85/588 [14.5%]), which is a difference of 23.4% (adjusted odds ratio [OR], 4.38 [95% CI, 2.49 to 7.71]; P < .001) and were more likely to be prescribed each of the 3 therapies (change from baseline in high-intensity statins from 66.5% to 70.7% for intervention vs from 58.2% to 56.8% for usual care [adjusted OR, 1.73; 95% CI, 1.06-2.83]; ACEIs or ARBs: from 75.1% to 81.4% for intervention vs from 69.6% to 68.4% for usual care [adjusted OR, 1.82; 95% CI, 1.14-2.91]; SGLT2 inhibitors and/or GLP-1RAs: from 12.3% to 60.4% for intervention vs from 14.5% to 35.5% for usual care [adjusted OR, 3.11; 95% CI, 2.08-4.64]). The intervention was not associated with changes in atherosclerotic cardiovascular disease risk factors. The composite secondary outcome occurred in 23 of 457 participants (5%) in the intervention group vs 40 of 588 participants (6.8%) in the usual care group (adjusted hazard ratio, 0.79 [95% CI, 0.46 to 1.33]).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />A coordinated, multifaceted intervention increased prescription of 3 groups of evidence-based therapies in adults with type 2 diabetes and atherosclerotic cardiovascular disease.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT03936660.<br /><br /><br /><br /><small>JAMA: 06 Mar 2023; epub ahead of print</small></div>
Pagidipati NJ, Nelson AJ, Kaltenbach LA, Leyva M, ... Granger CB, COORDINATE–Diabetes Site Investigators
JAMA: 06 Mar 2023; epub ahead of print | PMID: 36877177
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<div><h4>Treat-to-Target or High-Intensity Statin in Patients With Coronary Artery Disease: A Randomized Clinical Trial.</h4><i>Hong SJ, Lee YJ, Lee SJ, Hong BK, ... Hong MK, LODESTAR Investigators</i><br /><b>Importance</b><br />In patients with coronary artery disease, some guidelines recommend initial statin treatment with high-intensity statins to achieve at least a 50% reduction in low-density lipoprotein cholesterol (LDL-C). An alternative approach is to begin with moderate-intensity statins and titrate to a specific LDL-C goal. These alternatives have not been compared head-to-head in a clinical trial involving patients with known coronary artery disease.<br /><b>Objective</b><br />To assess whether a treat-to-target strategy is noninferior to a strategy of high-intensity statins for long-term clinical outcomes in patients with coronary artery disease.<br /><b>Design, setting, and participants</b><br />A randomized, multicenter, noninferiority trial in patients with a coronary disease diagnosis treated at 12 centers in South Korea (enrollment: September 9, 2016, through November 27, 2019; final follow-up: October 26, 2022).<br /><b>Interventions</b><br />Patients were randomly assigned to receive either the LDL-C target strategy, with an LDL-C level between 50 and 70 mg/dL as the target, or high-intensity statin treatment, which consisted of rosuvastatin, 20 mg, or atorvastatin, 40 mg.<br /><b>Main outcomes and measures</b><br />Primary end point was a 3-year composite of death, myocardial infarction, stroke, or coronary revascularization with a noninferiority margin of 3.0 percentage points.<br /><b>Results</b><br />Among 4400 patients, 4341 patients (98.7%) completed the trial (mean [SD] age, 65.1 [9.9] years; 1228 females [27.9%]). In the treat-to-target group (n = 2200), which had 6449 person-years of follow-up, moderate-intensity and high-intensity dosing were used in 43% and 54%, respectively. The mean (SD) LDL-C level for 3 years was 69.1 (17.8) mg/dL in the treat-to-target group and 68.4 (20.1) mg/dL in the high-intensity statin group (n = 2200) (P = .21, compared with the treat-to-target group). The primary end point occurred in 177 patients (8.1%) in the treat-to-target group and 190 patients (8.7%) in the high-intensity statin group (absolute difference, -0.6 percentage points [upper boundary of the 1-sided 97.5% CI, 1.1 percentage points]; P < .001 for noninferiority).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Among patients with coronary artery disease, a treat-to-target LDL-C strategy of 50 to 70 mg/dL as the goal was noninferior to a high-intensity statin therapy for the 3-year composite of death, myocardial infarction, stroke, or coronary revascularization. These findings provide additional evidence supporting the suitability of a treat-to-target strategy that may allow a tailored approach with consideration for individual variability in drug response to statin therapy.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT02579499.<br /><br /><br /><br /><small>JAMA: 06 Mar 2023; epub ahead of print</small></div>
Hong SJ, Lee YJ, Lee SJ, Hong BK, ... Hong MK, LODESTAR Investigators
JAMA: 06 Mar 2023; epub ahead of print | PMID: 36877807
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<div><h4>Cardiovascular Risk Factor Prevalence, Treatment, and Control in US Adults Aged 20 to 44 Years, 2009 to March 2020.</h4><i>Aggarwal R, Yeh RW, Joynt Maddox KE, Wadhera RK</i><br /><b>Importance</b><br />Declines in cardiovascular mortality have stagnated in the US over the past decade, in part related to worsening risk factor control in older adults. Little is known about how the prevalence, treatment, and control of cardiovascular risk factors have changed among young adults aged 20 to 44 years.<br /><b>Objective</b><br />To determine if the prevalence of cardiovascular risk factors (hypertension, diabetes, hyperlipidemia, obesity, and tobacco use), treatment rates, and control changed among adults aged 20 to 44 years from 2009 through March 2020, overall and by sex and race and ethnicity.<br /><b>Design, setting, and participants</b><br />Serial cross-sectional analysis of adults aged 20 to 44 years in the US participating in the National Health and Nutrition Examination Survey (2009-2010 to 2017-March 2020).<br /><b>Main outcomes and measures</b><br />National trends in the prevalence of hypertension, diabetes, hyperlipidemia, obesity, and smoking history; treatment rates for hypertension and diabetes; and blood pressure and glycemic control in those receiving treatment.<br /><b>Results</b><br />Among 12 924 US adults aged 20 to 44 years (mean age, 31.8 years; 50.6% women), the prevalence of hypertension was 9.3% (95% CI, 8.1%-10.5%) in 2009-2010 and 11.5% (95% CI, 9.6%-13.4%) in 2017-2020. The prevalence of diabetes (from 3.0% [95% CI, 2.2%-3.7%] to 4.1% [95% CI, 3.5%-4.7%]) and obesity (from 32.7% [95% CI, 30.1%-35.3%] to 40.9% [95% CI, 37.5%-44.3%]) increased from 2009-2010 to 2017-2020, while the prevalence of hyperlipidemia decreased (from 40.5% [95% CI, 38.6%-42.3%] to 36.1% [95% CI, 33.5%-38.7%]). Black adults had high rates of hypertension across the study period (2009-2010: 16.2% [95% CI, 14.0%-18.4%]; 2017-2020: 20.1% [95% CI, 16.8%-23.3%]), and significant increases in hypertension were observed among Mexican American adults (from 6.5% [95% CI, 5.0%-8.0%] to 9.5% [95% CI, 7.3%-11.7%]) and other Hispanic adults (from 4.4% [95% CI, 2.1%-6.8%] to 10.5% [95% CI, 6.8%-14.3%]), while Mexican American adults had a significant rise in diabetes (from 4.3% [95% CI, 2.3%-6.2%] to 7.5% [95% CI, 5.4%-9.6%]). The percentage of young adults treated for hypertension who achieved blood pressure control did not significantly change (from 65.0% [95% CI, 55.8%-74.2%] in 2009-2010 to 74.8% [95% CI, 67.5%-82.1%] in 2017-2020], while glycemic control among young adults receiving treatment for diabetes remained suboptimal throughout the study period (2009-2010: 45.5% [95% CI, 27.7%-63.3%]) to 2017-2020: 56.6% [95% CI, 39.2%-73.9%]).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />In the US, diabetes and obesity increased among young adults from 2009 to March 2020, while hypertension did not change and hyperlipidemia declined. There was variation in trends by race and ethnicity.<br /><br /><br /><br /><small>JAMA: 05 Mar 2023; epub ahead of print</small></div>
Aggarwal R, Yeh RW, Joynt Maddox KE, Wadhera RK
JAMA: 05 Mar 2023; epub ahead of print | PMID: 36871237
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<div><h4>Rate-Adaptive Atrial Pacing for Heart Failure With Preserved Ejection Fraction: The RAPID-HF Randomized Clinical Trial.</h4><i>Reddy YNV, Koepp KE, Carter R, Win S, ... Redfield MM, Borlaug BA</i><br /><b>Importance</b><br />Reduced heart rate during exercise is common and associated with impaired aerobic capacity in heart failure with preserved ejection fraction (HFpEF), but it remains unknown if restoring exertional heart rate through atrial pacing would be beneficial.<br /><b>Objective</b><br />To determine if implanting and programming a pacemaker for rate-adaptive atrial pacing would improve exercise performance in patients with HFpEF and chronotropic incompetence.<br /><b>Design, setting, and participants</b><br />Single-center, double-blind, randomized, crossover trial testing the effects of rate-adaptive atrial pacing in patients with symptomatic HFpEF and chronotropic incompetence at a tertiary referral center (Mayo Clinic) in Rochester, Minnesota. Patients were recruited between 2014 and 2022 with 16-week follow-up (last date of follow-up, May 9, 2022). Cardiac output during exercise was measured by the acetylene rebreathe technique.<br /><b>Interventions</b><br />A total of 32 patients were recruited; of these, 29 underwent pacemaker implantation and were randomized to atrial rate responsive pacing or no pacing first for 4 weeks, followed by a 4-week washout period and then crossover for an additional 4 weeks.<br /><b>Main outcomes and measures</b><br />The primary end point was oxygen consumption (V̇o2) at anaerobic threshold (V̇o2,AT); secondary end points were peak V̇o2, ventilatory efficiency (V̇e/V̇co2 slope), patient-reported health status by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS), and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels.<br /><b>Results</b><br />Of the 29 patients randomized, the mean age was 66 years (SD, 9.7) and 13 (45%) were women. In the absence of pacing, peak V̇o2 and V̇o2 at anaerobic threshold (V̇o2,AT) were both correlated with peak exercise heart rate (r = 0.46-0.51, P < .02 for both). Pacing increased heart rate during low-level and peak exercise (16/min [95% CI, 10 to 23], P < .001; 14/min [95% CI, 7 to 21], P < .001), but there was no significant change in V̇o2,AT (pacing off, 10.4 [SD, 2.9] mL/kg/min; pacing on, 10.7 [SD, 2.6] mL/kg/min; absolute difference, 0.3 [95% CI, -0.5 to 1.0] mL/kg/min; P = .46), peak V̇o2, minute ventilation (V̇e)/carbon dioxide production (V̇co2) slope, KCCQ-OSS, or NT-proBNP level. Despite the increase in heart rate, atrial pacing had no significant effect on cardiac output with exercise, owing to a decrease in stroke volume (-24 mL [95% CI, -43 to -5 mL]; P = .02). Adverse events judged to be related to the pacemaker device were observed in 6 of 29 participants (21%).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />In patients with HFpEF and chronotropic incompetence, implantation of a pacemaker to enhance exercise heart rate did not result in an improvement in exercise capacity and was associated with increased adverse events.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT02145351.<br /><br /><br /><br /><small>JAMA: 05 Mar 2023; epub ahead of print</small></div>
Reddy YNV, Koepp KE, Carter R, Win S, ... Redfield MM, Borlaug BA
JAMA: 05 Mar 2023; epub ahead of print | PMID: 36871285
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This program is still in alpha version.