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    10 years of health-care reform in China: progress and gaps in Universal Health Coverage. Yip Winnie,Fu Hongqiao,Chen Angela T,Zhai Tiemin,Jian Weiyan,Xu Roman,Pan Jay,Hu Min,Zhou Zhongliang,Chen Qiulin,Mao Wenhui,Sun Qiang,Chen Wen Lancet (London, England) In 2009, China launched a major health-care reform and pledged to provide all citizens with equal access to basic health care with reasonable quality and financial risk protection. The government has since quadrupled its funding for health. The reform's first phase (2009-11) emphasised expanding social health insurance coverage for all and strengthening infrastructure. The second phase (2012 onwards) prioritised reforming its health-care delivery system through: (1) systemic reform of public hospitals by removing mark-up for drug sales, adjusting fee schedules, and reforming provider payment and governance structures; and (2) overhaul of its hospital-centric and treatment-based delivery system. In the past 10 years, China has made substantial progress in improving equal access to care and enhancing financial protection, especially for people of a lower socioeconomic status. However, gaps remain in quality of care, control of non-communicable diseases (NCDs), efficiency in delivery, control of health expenditures, and public satisfaction. To meet the needs of China's ageing population that is facing an increased NCD burden, we recommend leveraging strategic purchasing, information technology, and local pilots to build a primary health-care (PHC)-based integrated delivery system by aligning the incentives and governance of hospitals and PHC systems, improving the quality of PHC providers, and educating the public on the value of prevention and health maintenance. 10.1016/S0140-6736(19)32136-1
    Single inhaler extrafine triple therapy in uncontrolled asthma (TRIMARAN and TRIGGER): two double-blind, parallel-group, randomised, controlled phase 3 trials. Virchow Johann Christian,Kuna Piotr,Paggiaro Pierluigi,Papi Alberto,Singh Dave,Corre Sandrine,Zuccaro Florence,Vele Andrea,Kots Maxim,Georges George,Petruzzelli Stefano,Canonica Giorgio Walter Lancet (London, England) BACKGROUND:To date, no studies have assessed the efficacy of single-inhaler triple therapy in asthma. Here we report on two studies that compared the single-inhaler extrafine combination of beclometasone dipropionate (BDP; inhaled corticosteroid), formoterol fumarate (FF; long-acting β agonist), and glycopyrronium (G; long-acting muscarinic antagonist) with the combination of BDP with FF. METHODS:Two parallel-group, double-blind, randomised, active-controlled, phase 3 trials (Triple in Asthma With Uncontrolled Patients on Medium Strength of ICS + LABA [TRIMARAN] and Triple in Asthma High Strength Versus ICS/LABA HS and Tiotropium [TRIGGER]) recruited patients from 171 sites across 16 countries (TRIMARAN), and from 221 sites across 17 countries (TRIGGER). The sites were a mixture of secondary and tertiary care centres and specialised investigation units. Eligible patients were adults (aged 18-75 years) with uncontrolled asthma, a history of one or more exacerbations in the previous year, and previously treated with inhaled corticosteroid (TRIMARAN: medium dose; TRIGGER: high dose) plus a long-acting β agonist. Enrolled patients were initially treated with BDP/FF (TRIMARAN: 100 μg BDP and 6 μg FF; TRIGGER: 200 μg BDP and 6 μg FF) for 2 weeks, then randomly assigned to treatment using an interactive response technology system with a balanced block randomisation scheme stratified by country. Patients, investigators, site staff, and sponsor staff were masked to BDP/FF/G and BDP/FF assignment. In TRIMARAN, patients were randomly assigned (1:1) to 52 weeks of BDP/FF/G (100 μg BDP, 6 μg FF, and 10 μg G) or BDP/FF (100 μg BDP and 6 μg FF), two inhalations twice daily. In TRIGGER, patients were randomly assigned (2:2:1) to 52 weeks of BDP/FF/G (200 μg BDP, 6 μg FF, and 10 μg G) or BDP/FF (200 BDP and 6 μg FF), both two inhalations twice daily, or open-label BDP/FF (200 μg BDP and 6 μg FF) two inhalations twice daily plus tiotropium 2·5 μg two inhalations once daily. Coprimary endpoints for both trials (BDP/FF/G vs BDP/FF) were pre-dose forced expiratory volume in 1 s (FEV) at week 26 and rate of moderate and severe exacerbations over 52 weeks. Safety was assessed in all patients who received at least one dose of study treatment. These trials were registered with ClinicalTrials.gov, NCT02676076 (TRIMARAN), NCT02676089 (TRIGGER). FINDINGS:Between Feb 17, 2016, and May 17, 2018, 1155 patients in TRIMARAN were given BDP/FF/G (n=579) or BDP/FF (n=576). Between April 6, 2016, and May 28, 2018, 1437 patients in TRIGGER were given BDP/FF/G (n=573), BDP/FF (n=576), or BDP/FF plus tiotropium (n=288). Compared with the BDP/FF group, week 26 predose FEV improved in the BDP/FF/G group by 57 mL (95% CI 15-99; p=0·0080) in TRIMARAN and by 73 mL (26-120; p=0·0025) in TRIGGER, with reductions in the rate of moderate and severe exacerbations of 15% (rate ratio 0·85, 95% CI 0·73-0·99; p=0·033) in TRIMARAN and 12% (0·88, 0·75-1·03; p=0·11) in TRIGGER. Four patients had treatment-related serious adverse events, one in TRIMARAN in the BDP/FF/G group and three in TRIGGER-one in the BDP/FF/G and two in the BDP/FF group. Three patients in the BDP/FF/G group in TRIMARAN and two patients in TRIGGER-one in the BDP/FF/G group and one in the BDP/FF group-had adverse events leading to death. None of the deaths were considered as related to treatment. INTERPRETATION:In uncontrolled asthma, addition of a long-acting muscarinic antagonist to inhaled corticosteroid plus long-acting β-agonist therapy improves lung function and reduces exacerbations. FUNDING:Chiesi Farmaceutici. 10.1016/S0140-6736(19)32215-9
    Biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents in patients with ST-segment elevation myocardial infarction (BIOSTEMI): a single-blind, prospective, randomised superiority trial. Iglesias Juan F,Muller Olivier,Heg Dik,Roffi Marco,Kurz David J,Moarof Igal,Weilenmann Daniel,Kaiser Christoph,Tapponnier Maxime,Stortecky Stefan,Losdat Sylvain,Eeckhout Eric,Valgimigli Marco,Odutayo Ayodele,Zwahlen Marcel,Jüni Peter,Windecker Stephan,Pilgrim Thomas Lancet (London, England) BACKGROUND:Newer-generation drug-eluting stents that combine ultrathin strut metallic platforms with biodegradable polymers might facilitate vascular healing and improve clinical outcomes in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention (PCI) compared with contemporary thin strut second-generation drug-eluting stents. We did a randomised clinical trial to investigate the safety and efficacy of ultrathin strut biodegradable polymer sirolimus-eluting stents versus thin strut durable polymer everolimus-eluting stents in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI. METHODS:The BIOSTEMI trial was an investigator-initiated, multicentre, prospective, single-blind, randomised superiority trial at ten hospitals in Switzerland. Patients aged 18 years or older with acute STEMI who were referred for primary PCI were eligible to participate. Patients were randomly allocated (1:1) to either biodegradable polymer sirolimus-eluting stents or durable polymer everolimus-eluting stents. Central randomisation was done based on a computer-generated allocation sequence with variable block sizes of 2, 4, and 6, which was stratified by centre, diabetes status, and presence or absence of multivessel coronary artery disease, and concealed using a secure web-based system. Patients and treating physicians were aware of group allocations, whereas outcome assessors were masked to the allocated stent. The experimental stent (Orsiro; Biotronik; Bülach, Switzerland) consisted of an ultrathin strut cobalt-chromium metallic stent platform releasing sirolimus from a biodegradable polymer. The control stent (Xience Xpedition/Alpine; Abbott Vascular, Abbott Park, IL, USA) consisted of a thin strut cobalt-chromium stent platform that releases everolimus from a durable polymer. The primary endpoint was target lesion failure, a composite of cardiac death, target vessel myocardial reinfarction (Q-wave and non-Q-wave), and clinically-indicated target lesion revascularisation, within 12 months of the index procedure. All analyses were done with the individual participant as the unit of analysis and according to the intention-to-treat principle. The trial was registered with ClinicalTrials.gov, number NCT02579031. FINDINGS:Between April 26, 2016, and March 9, 2018, we randomly assigned 1300 patients (1623 lesions) with acute myocardial infarction to treatment with biodegradable polymer sirolimus-eluting stents (649 patients and 816 lesions) or durable polymer everolimus-eluting stents (651 patients and 806 lesions). At 12 months, follow-up data were available for 614 (95%) patients treated with biodegradable polymer sirolimus-eluting stents and 626 (96%) patients treated with durable polymer everolimus-eluting stents. The primary composite endpoint of target lesion failure occurred in 25 (4%) of 649 patients treated with biodegradable polymer sirolimus-eluting stents and 36 (6%) of 651 patients treated with durable polymer everolimus-eluting stents (difference -1·6 percentage points; rate ratio 0·59, 95% Bayesian credibility interval 0·37-0·94; posterior probability of superiority 0·986). Cardiac death, target vessel myocardial reinfarction, clinically-indicated target lesion revascularisation, and definite stent thrombosis were similar between the two treatment groups in the 12 months of follow-up. INTERPRETATION:In patients with acute STEMI undergoing primary PCI, biodegradable polymer sirolimus-eluting stents were superior to durable polymer everolimus-eluting stents with respect to target lesion failure at 1 year. This difference was driven by reduced ischaemia-driven target lesion revascularisation in patients treated with biodegradable polymer sirolimus-eluting stents compared with durable polymer everolimus-eluting stents. FUNDING:Biotronik. 10.1016/S0140-6736(19)31877-X
    Advances in technology for management of type 1 diabetes. Beck Roy W,Bergenstal Richard M,Laffel Lori M,Pickup John C Lancet (London, England) Technological advances have had a major effect on the management of type 1 diabetes. In addition to blood glucose meters, devices used by people with type 1 diabetes include insulin pumps, continuous glucose monitors, and, most recently, systems that combine both a pump and a monitor for algorithm-driven automation of insulin delivery. In the next 5 years, as many advances are expected in technology for the management of diabetes as there have been in the past 5 years, with improvements in continuous glucose monitoring and more available choices of systems that automate insulin delivery. Expansion of the use of technology will be needed beyond endocrinology practices to primary-care settings and broader populations of patients. Tools to support decision making will also need to be developed to help patients and health-care providers to use the output of these devices to optimise diabetes management. 10.1016/S0140-6736(19)31142-0
    Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial. Cree Bruce A C,Bennett Jeffrey L,Kim Ho Jin,Weinshenker Brian G,Pittock Sean J,Wingerchuk Dean M,Fujihara Kazuo,Paul Friedemann,Cutter Gary R,Marignier Romain,Green Ari J,Aktas Orhan,Hartung Hans-Peter,Lublin Fred D,Drappa Jorn,Barron Gerard,Madani Soraya,Ratchford John N,She Dewei,Cimbora Daniel,Katz Eliezer, Lancet (London, England) BACKGROUND:No approved therapies exist for neuromyelitis optica spectrum disorder (NMOSD), a rare, relapsing, autoimmune, inflammatory disease of the CNS that causes blindness and paralysis. We aimed to assess the efficacy and safety of inebilizumab, an anti-CD19, B cell-depleting antibody, in reducing the risk of attacks and disability in NMOSD. METHODS:We did a multicentre, double-blind, randomised placebo-controlled phase 2/3 study at 99 outpatient specialty clinics or hospitals in 25 countries. Eligible participants were adults (≥18 years old) with a diagnosis of NMOSD, an Expanded Disability Status Scale score of 8·0 or less, and a history of at least one attack requiring rescue therapy in the year before screening or at least two attacks requiring rescue therapy in the 2 years before screening. Participants were randomly allocated (3:1) to 300 mg intravenous inebilizumab or placebo with a central interactive voice response system or interactive web response system and permuted block randomisation. Inebilizumab or placebo was administered on days 1 and 15. Participants, investigators, and all clinical staff were masked to the treatments, and inebilizumab and placebo were indistinguishable in appearance. The primary endpoint was time to onset of an NMOSD attack, as determined by the adjudication committee. Efficacy endpoints were assessed in all randomly allocated patients who received at least one dose of study intervention, and safety endpoints were assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT02200770. FINDINGS:Between Jan 6, 2015, and Sept 24, 2018, 230 participants were randomly assigned to treatment and dosed, with 174 participants receiving inebilizumab and 56 receiving placebo. The randomised controlled period was stopped before complete enrolment, as recommended by the independent data-monitoring committee, because of a clear demonstration of efficacy. 21 (12%) of 174 participants receiving inebilizumab had an attack versus 22 (39%) of 56 participants receiving placebo (hazard ratio 0·272 [95% CI 0·150-0·496]; p<0·0001). Adverse events occurred in 125 (72%) of 174 participants receiving inebilizumab and 41 (73%) of 56 participants receiving placebo. Serious adverse events occurred in eight (5%) of 174 participants receiving inebilizumab and five (9%) of 56 participants receiving placebo. INTERPRETATION:Compared with placebo, inebilizumab reduced the risk of an NMOSD attack. Inebilizumab has potential application as an evidence-based treatment for patients with NMOSD. FUNDING:MedImmune and Viela Bio. 10.1016/S0140-6736(19)31817-3
    Ticagrelor in Patients with Stable Coronary Disease and Diabetes. Steg P Gabriel,Bhatt Deepak L,Simon Tabassome,Fox Kim,Mehta Shamir R,Harrington Robert A,Held Claes,Andersson Marielle,Himmelmann Anders,Ridderstråle Wilhelm,Leonsson-Zachrisson Maria,Liu Yuyin,Opolski Grzegorz,Zateyshchikov Dmitry,Ge Junbo,Nicolau José C,Corbalán Ramón,Cornel Jan H,Widimský Petr,Leiter Lawrence A, The New England journal of medicine BACKGROUND:Patients with stable coronary artery disease and diabetes mellitus who have not had a myocardial infarction or stroke are at high risk for cardiovascular events. Whether adding ticagrelor to aspirin improves outcomes in this population is unclear. METHODS:In this randomized, double-blind trial, we assigned patients who were 50 years of age or older and who had stable coronary artery disease and type 2 diabetes mellitus to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with previous myocardial infarction or stroke were excluded. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria. RESULTS:A total of 19,220 patients underwent randomization. The median follow-up was 39.9 months. Permanent treatment discontinuation was more frequent with ticagrelor than placebo (34.5% vs. 25.4%). The incidence of ischemic cardiovascular events (the primary efficacy outcome) was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; hazard ratio, 0.90; 95% confidence interval [CI], 0.81 to 0.99; P = 0.04), whereas the incidence of TIMI major bleeding was higher (2.2% vs. 1.0%; hazard ratio, 2.32; 95% CI, 1.82 to 2.94; P<0.001), as was the incidence of intracranial hemorrhage (0.7% vs. 0.5%; hazard ratio, 1.71; 95% CI, 1.18 to 2.48; P = 0.005). There was no significant difference in the incidence of fatal bleeding (0.2% vs. 0.1%; hazard ratio, 1.90; 95% CI, 0.87 to 4.15; P = 0.11). The incidence of an exploratory composite outcome of irreversible harm (death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was similar in the ticagrelor group and the placebo group (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86 to 1.02). CONCLUSIONS:In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, those who received ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin. (Funded by AstraZeneca; THEMIS ClinicalTrials.gov number, NCT01991795.). 10.1056/NEJMoa1908077
    Complete Revascularization with Multivessel PCI for Myocardial Infarction. Mehta Shamir R,Wood David A,Storey Robert F,Mehran Roxana,Bainey Kevin R,Nguyen Helen,Meeks Brandi,Di Pasquale Giuseppe,López-Sendón Jose,Faxon David P,Mauri Laura,Rao Sunil V,Feldman Laurent,Steg P Gabriel,Avezum Álvaro,Sheth Tej,Pinilla-Echeverri Natalia,Moreno Raul,Campo Gianluca,Wrigley Benjamin,Kedev Sasko,Sutton Andrew,Oliver Richard,Rodés-Cabau Josep,Stanković Goran,Welsh Robert,Lavi Shahar,Cantor Warren J,Wang Jia,Nakamya Juliet,Bangdiwala Shrikant I,Cairns John A, The New England journal of medicine BACKGROUND:In patients with ST-segment elevation myocardial infarction (STEMI), percutaneous coronary intervention (PCI) of the culprit lesion reduces the risk of cardiovascular death or myocardial infarction. Whether PCI of nonculprit lesions further reduces the risk of such events is unclear. METHODS:We randomly assigned patients with STEMI and multivessel coronary artery disease who had undergone successful culprit-lesion PCI to a strategy of either complete revascularization with PCI of angiographically significant nonculprit lesions or no further revascularization. Randomization was stratified according to the intended timing of nonculprit-lesion PCI (either during or after the index hospitalization). The first coprimary outcome was the composite of cardiovascular death or myocardial infarction; the second coprimary outcome was the composite of cardiovascular death, myocardial infarction, or ischemia-driven revascularization. RESULTS:At a median follow-up of 3 years, the first coprimary outcome had occurred in 158 of the 2016 patients (7.8%) in the complete-revascularization group as compared with 213 of the 2025 patients (10.5%) in the culprit-lesion-only PCI group (hazard ratio, 0.74; 95% confidence interval [CI], 0.60 to 0.91; P = 0.004). The second coprimary outcome had occurred in 179 patients (8.9%) in the complete-revascularization group as compared with 339 patients (16.7%) in the culprit-lesion-only PCI group (hazard ratio, 0.51; 95% CI, 0.43 to 0.61; P<0.001). For both coprimary outcomes, the benefit of complete revascularization was consistently observed regardless of the intended timing of nonculprit-lesion PCI (P = 0.62 and P = 0.27 for interaction for the first and second coprimary outcomes, respectively). CONCLUSIONS:Among patients with STEMI and multivessel coronary artery disease, complete revascularization was superior to culprit-lesion-only PCI in reducing the risk of cardiovascular death or myocardial infarction, as well as the risk of cardiovascular death, myocardial infarction, or ischemia-driven revascularization. (Funded by the Canadian Institutes of Health Research and others; COMPLETE ClinicalTrials.gov number, NCT01740479.). 10.1056/NEJMoa1907775
    Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes. Schüpke Stefanie,Neumann Franz-Josef,Menichelli Maurizio,Mayer Katharina,Bernlochner Isabell,Wöhrle Jochen,Richardt Gert,Liebetrau Christoph,Witzenbichler Bernhard,Antoniucci David,Akin Ibrahim,Bott-Flügel Lorenz,Fischer Marcus,Landmesser Ulf,Katus Hugo A,Sibbing Dirk,Seyfarth Melchior,Janisch Marion,Boncompagni Duino,Hilz Raphaela,Rottbauer Wolfgang,Okrojek Rainer,Möllmann Helge,Hochholzer Willibald,Migliorini Angela,Cassese Salvatore,Mollo Pasquale,Xhepa Erion,Kufner Sebastian,Strehle Axel,Leggewie Stefan,Allali Abdelhakim,Ndrepepa Gjin,Schühlen Helmut,Angiolillo Dominick J,Hamm Christian W,Hapfelmeier Alexander,Tölg Ralph,Trenk Dietmar,Schunkert Heribert,Laugwitz Karl-Ludwig,Kastrati Adnan, The New England journal of medicine BACKGROUND:The relative merits of ticagrelor as compared with prasugrel in patients with acute coronary syndromes for whom invasive evaluation is planned are uncertain. METHODS:In this multicenter, randomized, open-label trial, we randomly assigned patients who presented with acute coronary syndromes and for whom invasive evaluation was planned to receive either ticagrelor or prasugrel. The primary end point was the composite of death, myocardial infarction, or stroke at 1 year. A major secondary end point (the safety end point) was bleeding. RESULTS:A total of 4018 patients underwent randomization. A primary end-point event occurred in 184 of 2012 patients (9.3%) in the ticagrelor group and in 137 of 2006 patients (6.9%) in the prasugrel group (hazard ratio, 1.36; 95% confidence interval [CI], 1.09 to 1.70; P = 0.006). The respective incidences of the individual components of the primary end point in the ticagrelor group and the prasugrel group were as follows: death, 4.5% and 3.7%; myocardial infarction, 4.8% and 3.0%; and stroke, 1.1% and 1.0%. Definite or probable stent thrombosis occurred in 1.3% of patients assigned to ticagrelor and 1.0% of patients assigned to prasugrel, and definite stent thrombosis occurred in 1.1% and 0.6%, respectively. Major bleeding (as defined by the Bleeding Academic Research Consortium scale) was observed in 5.4% of patients in the ticagrelor group and in 4.8% of patients in the prasugrel group (hazard ratio, 1.12; 95% CI, 0.83 to 1.51; P = 0.46). CONCLUSIONS:Among patients who presented with acute coronary syndromes with or without ST-segment elevation, the incidence of death, myocardial infarction, or stroke was significantly lower among those who received prasugrel than among those who received ticagrelor, and the incidence of major bleeding was not significantly different between the two groups. (Funded by the German Center for Cardiovascular Research and Deutsches Herzzentrum München; ISAR-REACT 5 ClinicalTrials.gov number, NCT01944800.). 10.1056/NEJMoa1908973
    Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy. Gantner Marin L,Eade Kevin,Wallace Martina,Handzlik Michal K,Fallon Regis,Trombley Jennifer,Bonelli Roberto,Giles Sarah,Harkins-Perry Sarah,Heeren Tjebo F C,Sauer Lydia,Ideguchi Yoichiro,Baldini Michelle,Scheppke Lea,Dorrell Michael I,Kitano Maki,Hart Barbara J,Cai Carolyn,Nagasaki Takayuki,Badur Mehmet G,Okada Mali,Woods Sasha M,Egan Catherine,Gillies Mark,Guymer Robyn,Eichler Florian,Bahlo Melanie,Fruttiger Marcus,Allikmets Rando,Bernstein Paul S,Metallo Christian M,Friedlander Martin The New England journal of medicine BACKGROUND:Identifying mechanisms of diseases with complex inheritance patterns, such as macular telangiectasia type 2, is challenging. A link between macular telangiectasia type 2 and altered serine metabolism has been established previously. METHODS:Through exome sequence analysis of a patient with macular telangiectasia type 2 and his family members, we identified a variant in encoding a subunit of serine palmitoyltransferase (SPT). Because mutations affecting SPT are known to cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), we examined 10 additional persons with HSAN1 for ophthalmologic disease. We assayed serum amino acid and sphingoid base levels, including levels of deoxysphingolipids, in patients who had macular telangiectasia type 2 but did not have HSAN1 or pathogenic variants affecting SPT. We characterized mice with low serine levels and tested the effects of deoxysphingolipids on human retinal organoids. RESULTS:Two variants known to cause HSAN1 were identified as causal for macular telangiectasia type 2: of 11 patients with HSAN1, 9 also had macular telangiectasia type 2. Circulating deoxysphingolipid levels were 84.2% higher among 125 patients with macular telangiectasia type 2 who did not have pathogenic variants affecting SPT than among 94 unaffected controls. Deoxysphingolipid levels were negatively correlated with serine levels, which were 20.6% lower than among controls. Reduction of serine levels in mice led to increases in levels of retinal deoxysphingolipids and compromised visual function. Deoxysphingolipids caused photoreceptor-cell death in retinal organoids, but not in the presence of regulators of lipid metabolism. CONCLUSIONS:Elevated levels of atypical deoxysphingolipids, caused by variant or or by low serine levels, were risk factors for macular telangiectasia type 2, as well as for peripheral neuropathy. (Funded by the Lowy Medical Research Institute and others.). 10.1056/NEJMoa1815111
    Medications to Reduce Breast Cancer Risk. Jin Jill JAMA 10.1001/jama.2019.12858
    Use of fenofibrate on cardiovascular outcomes in statin users with metabolic syndrome: propensity matched cohort study. Kim Nam Hoon,Han Ki Hoon,Choi Jimi,Lee Juneyoung,Kim Sin Gon BMJ (Clinical research ed.) OBJECTIVE:To investigate whether fenofibrate as add-on to statin treatment reduce persistent cardiovascular risk in adults with metabolic syndrome in a real world setting. DESIGN:Propensity matched cohort study. SETTING:Population based cohort in Korea. PARTICIPANTS:29 771 adults with metabolic syndrome (≥40 years) receiving statin treatment. 2156 participants receiving combined treatment (statin plus fenofibrate) were weighted based on propensity score in a 1:5 ratio with 8549 participants using statin only treatment. MAIN OUTCOME MEASURE:Primary outcome was composite cardiovascular events including incident coronary heart disease, ischaemic stroke, and death from cardiovascular causes. RESULTS:The incidence rate per 1000 person years of composite cardiovascular events was 17.7 (95% confidence interval 14.4 to 21.8) in the combined treatment group and 22.0 (20.1 to 24.1) in the statin group. The risk of composite cardiovascular events was significantly reduced in the combined treatment group compared with statin group (adjusted hazard ratio 0.74, 95% confidence interval 0.58 to 0.93; P=0.01). The significance was maintained in the on-treatment analysis (hazard ratio 0.63, 95% confidence interval 0.44 to 0.92; P=0.02). The risk of incident coronary heart disease, ischaemic stroke, and cardiovascular death was lower in the combined treatment group than statin group but was not significant. Participant characteristics did not appear to be associated with the low risk of composite cardiovascular events with combined treatment. CONCLUSION:In this propensity weighted cohort study of adults with metabolic syndrome, the risk of major cardiovascular events was significantly lower with fenofibrate as add-on to statin treatment than with statin treatment alone. 10.1136/bmj.l5125
    Whole body MRI is effective for identifying metastatic disease in colorectal cancer patients. Cook Rob,Davidson Peter,Martin Rosie, BMJ (Clinical research ed.) The studyTaylor S, Mallett S, Beare S et al. Diagnostic accuracy of whole-body MRI versus standard imaging pathways for metastatic disease in newly diagnosed colorectal cancer: the prospective Streamline C trial. 2019;4:529-37.This project was funded by the NIHR Health Technology Assessment Programme (project number 10/68/01).To read the full NIHR Signal, go to https://discover.dc.nihr.ac.uk/content/signal-000797/identifying-metastatic-disease-in-colorectal-cancer-with-whole-body-mri. 10.1136/bmj.l5453
    Ticagrelor with or without Aspirin in High-Risk Patients after PCI. Mehran Roxana,Baber Usman,Sharma Samin K,Cohen David J,Angiolillo Dominick J,Briguori Carlo,Cha Jin Y,Collier Timothy,Dangas George,Dudek Dariusz,Džavík Vladimír,Escaned Javier,Gil Robert,Gurbel Paul,Hamm Christian W,Henry Timothy,Huber Kurt,Kastrati Adnan,Kaul Upendra,Kornowski Ran,Krucoff Mitchell,Kunadian Vijay,Marx Steven O,Mehta Shamir R,Moliterno David,Ohman E Magnus,Oldroyd Keith,Sardella Gennaro,Sartori Samantha,Shlofmitz Richard,Steg P Gabriel,Weisz Giora,Witzenbichler Bernhard,Han Ya-Ling,Pocock Stuart,Gibson C Michael The New England journal of medicine BACKGROUND:Monotherapy with a P2Y inhibitor after a minimum period of dual antiplatelet therapy is an emerging approach to reduce the risk of bleeding after percutaneous coronary intervention (PCI). METHODS:In a double-blind trial, we examined the effect of ticagrelor alone as compared with ticagrelor plus aspirin with regard to clinically relevant bleeding among patients who were at high risk for bleeding or an ischemic event and had undergone PCI. After 3 months of treatment with ticagrelor plus aspirin, patients who had not had a major bleeding event or ischemic event continued to take ticagrelor and were randomly assigned to receive aspirin or placebo for 1 year. The primary end point was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. We also evaluated the composite end point of death from any cause, nonfatal myocardial infarction, or nonfatal stroke, using a noninferiority hypothesis with an absolute margin of 1.6 percentage points. RESULTS:We enrolled 9006 patients, and 7119 underwent randomization after 3 months. Between randomization and 1 year, the incidence of the primary end point was 4.0% among patients randomly assigned to receive ticagrelor plus placebo and 7.1% among patients assigned to receive ticagrelor plus aspirin (hazard ratio, 0.56; 95% confidence interval [CI], 0.45 to 0.68; P<0.001). The difference in risk between the groups was similar for BARC type 3 or 5 bleeding (incidence, 1.0% among patients receiving ticagrelor plus placebo and 2.0% among patients receiving ticagrelor plus aspirin; hazard ratio, 0.49; 95% CI, 0.33 to 0.74). The incidence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke was 3.9% in both groups (difference, -0.06 percentage points; 95% CI, -0.97 to 0.84; hazard ratio, 0.99; 95% CI, 0.78 to 1.25; P<0.001 for noninferiority). CONCLUSIONS:Among high-risk patients who underwent PCI and completed 3 months of dual antiplatelet therapy, ticagrelor monotherapy was associated with a lower incidence of clinically relevant bleeding than ticagrelor plus aspirin, with no higher risk of death, myocardial infarction, or stroke. (Funded by AstraZeneca; TWILIGHT ClinicalTrials.gov number, NCT02270242.). 10.1056/NEJMoa1908419
    Total Hip Arthroplasty or Hemiarthroplasty for Hip Fracture. ,Bhandari Mohit,Einhorn Thomas A,Guyatt Gordon,Schemitsch Emil H,Zura Robert D,Sprague Sheila,Frihagen Frede,Guerra-Farfán Ernesto,Kleinlugtenbelt Ydo V,Poolman Rudolf W,Rangan Amar,Bzovsky Sofia,Heels-Ansdell Diane,Thabane Lehana,Walter Stephen D,Devereaux P J The New England journal of medicine BACKGROUND:Globally, hip fractures are among the top 10 causes of disability in adults. For displaced femoral neck fractures, there remains uncertainty regarding the effect of a total hip arthroplasty as compared with hemiarthroplasty. METHODS:We randomly assigned 1495 patients who were 50 years of age or older and had a displaced femoral neck fracture to undergo either total hip arthroplasty or hemiarthroplasty. All enrolled patients had been able to ambulate without the assistance of another person before the fracture occurred. The trial was conducted in 80 centers in 10 countries. The primary end point was a secondary hip procedure within 24 months of follow-up. Secondary end points included death, serious adverse events, hip-related complications, health-related quality of life, function, and overall health end points. RESULTS:The primary end point occurred in 57 of 718 patients (7.9%) who were randomly assigned to total hip arthroplasty and 60 of 723 patients (8.3%) who were randomly assigned to hemiarthroplasty (hazard ratio, 0.95; 95% confidence interval [CI], 0.64 to 1.40; P = 0.79). Hip instability or dislocation occurred in 34 patients (4.7%) assigned to total hip arthroplasty and 17 patients (2.4%) assigned to hemiarthroplasty (hazard ratio, 2.00; 99% CI, 0.97 to 4.09). Function, as measured with the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score, pain score, stiffness score, and function score, modestly favored total hip arthroplasty over hemiarthroplasty. Mortality was similar in the two treatment groups (14.3% among the patients assigned to total hip arthroplasty and 13.1% among those assigned to hemiarthroplasty, P = 0.48). Serious adverse events occurred in 300 patients (41.8%) assigned to total hip arthroplasty and in 265 patients (36.7%) assigned to hemiarthroplasty. CONCLUSIONS:Among independently ambulating patients with displaced femoral neck fractures, the incidence of secondary procedures did not differ significantly between patients who were randomly assigned to undergo total hip arthroplasty and those who were assigned to undergo hemiarthroplasty, and total hip arthroplasty provided a clinically unimportant improvement over hemiarthroplasty in function and quality of life over 24 months. (Funded by the Canadian Institutes of Health Research and others; ClinicalTrials.gov number, NCT00556842.). 10.1056/NEJMoa1906190
    Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. Hellmann Matthew D,Paz-Ares Luis,Bernabe Caro Reyes,Zurawski Bogdan,Kim Sang-We,Carcereny Costa Enric,Park Keunchil,Alexandru Aurelia,Lupinacci Lorena,de la Mora Jimenez Emmanuel,Sakai Hiroshi,Albert Istvan,Vergnenegre Alain,Peters Solange,Syrigos Konstantinos,Barlesi Fabrice,Reck Martin,Borghaei Hossein,Brahmer Julie R,O'Byrne Kenneth J,Geese William J,Bhagavatheeswaran Prabhu,Rabindran Sridhar K,Kasinathan Ravi S,Nathan Faith E,Ramalingam Suresh S The New England journal of medicine BACKGROUND:In an early-phase study involving patients with advanced non-small-cell lung cancer (NSCLC), the response rate was better with nivolumab plus ipilimumab than with nivolumab monotherapy, particularly among patients with tumors that expressed programmed death ligand 1 (PD-L1). Data are needed to assess the long-term benefit of nivolumab plus ipilimumab in patients with NSCLC. METHODS:In this open-label, phase 3 trial, we randomly assigned patients with stage IV or recurrent NSCLC and a PD-L1 expression level of 1% or more in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. The patients who had a PD-L1 expression level of less than 1% were randomly assigned in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone. All the patients had received no previous chemotherapy. The primary end point reported here was overall survival with nivolumab plus ipilimumab as compared with chemotherapy in patients with a PD-L1 expression level of 1% or more. RESULTS:Among the patients with a PD-L1 expression level of 1% or more, the median duration of overall survival was 17.1 months (95% confidence interval [CI], 15.0 to 20.1) with nivolumab plus ipilimumab and 14.9 months (95% CI, 12.7 to 16.7) with chemotherapy (P = 0.007), with 2-year overall survival rates of 40.0% and 32.8%, respectively. The median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy. The overall survival benefit was also observed in patients with a PD-L1 expression level of less than 1%, with a median duration of 17.2 months (95% CI, 12.8 to 22.0) with nivolumab plus ipilimumab and 12.2 months (95% CI, 9.2 to 14.3) with chemotherapy. Among all the patients in the trial, the median duration of overall survival was 17.1 months (95% CI, 15.2 to 19.9) with nivolumab plus ipilimumab and 13.9 months (95% CI, 12.2 to 15.1) with chemotherapy. The percentage of patients with grade 3 or 4 treatment-related adverse events in the overall population was 32.8% with nivolumab plus ipilimumab and 36.0% with chemotherapy. CONCLUSIONS:First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level. No new safety concerns emerged with longer follow-up. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 227 ClinicalTrials.gov number, NCT02477826.). 10.1056/NEJMoa1910231
    Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. Larkin James,Chiarion-Sileni Vanna,Gonzalez Rene,Grob Jean-Jacques,Rutkowski Piotr,Lao Christopher D,Cowey C Lance,Schadendorf Dirk,Wagstaff John,Dummer Reinhard,Ferrucci Pier F,Smylie Michael,Hogg David,Hill Andrew,Márquez-Rodas Ivan,Haanen John,Guidoboni Massimo,Maio Michele,Schöffski Patrick,Carlino Matteo S,Lebbé Céleste,McArthur Grant,Ascierto Paolo A,Daniels Gregory A,Long Georgina V,Bastholt Lars,Rizzo Jasmine I,Balogh Agnes,Moshyk Andriy,Hodi F Stephen,Wolchok Jedd D The New England journal of medicine BACKGROUND:Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial. METHODS:We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group. RESULTS:At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted. CONCLUSIONS:Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.). 10.1056/NEJMoa1910836
    Five-Year Outcomes after PCI or CABG for Left Main Coronary Disease. Stone Gregg W,Kappetein A Pieter,Sabik Joseph F,Pocock Stuart J,Morice Marie-Claude,Puskas John,Kandzari David E,Karmpaliotis Dimitri,Brown W Morris,Lembo Nicholas J,Banning Adrian,Merkely Béla,Horkay Ferenc,Boonstra Piet W,van Boven Ad J,Ungi Imre,Bogáts Gabor,Mansour Samer,Noiseux Nicolas,Sabaté Manel,Pomar Jose,Hickey Mark,Gershlick Anthony,Buszman Pawel E,Bochenek Andrzej,Schampaert Erick,Pagé Pierre,Modolo Rodrigo,Gregson John,Simonton Charles A,Mehran Roxana,Kosmidou Ioanna,Généreux Philippe,Crowley Aaron,Dressler Ovidiu,Serruys Patrick W, The New England journal of medicine BACKGROUND:Long-term outcomes after percutaneous coronary intervention (PCI) with contemporary drug-eluting stents, as compared with coronary-artery bypass grafting (CABG), in patients with left main coronary artery disease are not clearly established. METHODS:We randomly assigned 1905 patients with left main coronary artery disease of low or intermediate anatomical complexity (according to assessment at the participating centers) to undergo either PCI with fluoropolymer-based cobalt-chromium everolimus-eluting stents (PCI group, 948 patients) or CABG (CABG group, 957 patients). The primary outcome was a composite of death, stroke, or myocardial infarction. RESULTS:At 5 years, a primary outcome event had occurred in 22.0% of the patients in the PCI group and in 19.2% of the patients in the CABG group (difference, 2.8 percentage points; 95% confidence interval [CI], -0.9 to 6.5; P = 0.13). Death from any cause occurred more frequently in the PCI group than in the CABG group (in 13.0% vs. 9.9%; difference, 3.1 percentage points; 95% CI, 0.2 to 6.1). In the PCI and CABG groups, the incidences of definite cardiovascular death (5.0% and 4.5%, respectively; difference, 0.5 percentage points; 95% CI, -1.4 to 2.5) and myocardial infarction (10.6% and 9.1%; difference, 1.4 percentage points; 95% CI, -1.3 to 4.2) were not significantly different. All cerebrovascular events were less frequent after PCI than after CABG (3.3% vs. 5.2%; difference, -1.9 percentage points; 95% CI, -3.8 to 0), although the incidence of stroke was not significantly different between the two groups (2.9% and 3.7%; difference, -0.8 percentage points; 95% CI, -2.4 to 0.9). Ischemia-driven revascularization was more frequent after PCI than after CABG (16.9% vs. 10.0%; difference, 6.9 percentage points; 95% CI, 3.7 to 10.0). CONCLUSIONS:In patients with left main coronary artery disease of low or intermediate anatomical complexity, there was no significant difference between PCI and CABG with respect to the rate of the composite outcome of death, stroke, or myocardial infarction at 5 years. (Funded by Abbott Vascular; EXCEL ClinicalTrials.gov number, NCT01205776.). 10.1056/NEJMoa1909406
    Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. González-Martín Antonio,Pothuri Bhavana,Vergote Ignace,DePont Christensen René,Graybill Whitney,Mirza Mansoor R,McCormick Colleen,Lorusso Domenica,Hoskins Paul,Freyer Gilles,Baumann Klaus,Jardon Kris,Redondo Andrés,Moore Richard G,Vulsteke Christof,O'Cearbhaill Roisin E,Lund Bente,Backes Floor,Barretina-Ginesta Pilar,Haggerty Ashley F,Rubio-Pérez Maria J,Shahin Mark S,Mangili Giorgia,Bradley William H,Bruchim Ilan,Sun Kaiming,Malinowska Izabela A,Li Yong,Gupta Divya,Monk Bradley J, The New England journal of medicine BACKGROUND:Niraparib, an inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), has been associated with significantly increased progression-free survival among patients with recurrent ovarian cancer after platinum-based chemotherapy, regardless of the presence or absence of mutations. The efficacy of niraparib in patients with newly diagnosed advanced ovarian cancer after a response to first-line platinum-based chemotherapy is unknown. METHODS:In this randomized, double-blind, phase 3 trial, we randomly assigned patients with newly diagnosed advanced ovarian cancer in a 2:1 ratio to receive niraparib or placebo once daily after a response to platinum-based chemotherapy. The primary end point was progression-free survival in patients who had tumors with homologous-recombination deficiency and in those in the overall population, as determined on hierarchical testing. A prespecified interim analysis for overall survival was conducted at the time of the primary analysis of progression-free survival. RESULTS:Of the 733 patients who underwent randomization, 373 (50.9%) had tumors with homologous-recombination deficiency. Among the patients in this category, the median progression-free survival was significantly longer in the niraparib group than in the placebo group (21.9 months vs. 10.4 months; hazard ratio for disease progression or death, 0.43; 95% confidence interval [CI], 0.31 to 0.59; P<0.001). In the overall population, the corresponding progression-free survival was 13.8 months and 8.2 months (hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P<0.001). At the 24-month interim analysis, the rate of overall survival was 84% in the niraparib group and 77% in the placebo group (hazard ratio, 0.70; 95% CI, 0.44 to 1.11). The most common adverse events of grade 3 or higher were anemia (in 31.0% of the patients), thrombocytopenia (in 28.7%), and neutropenia (in 12.8%). No treatment-related deaths occurred. CONCLUSIONS:Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival than those who received placebo, regardless of the presence or absence of homologous-recombination deficiency. (Funded by GlaxoSmithKline; PRIMA/ENGOT-OV26/GOG-3012 ClinicalTrials.gov number, NCT02655016.). 10.1056/NEJMoa1910962
    Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer. Coleman Robert L,Fleming Gini F,Brady Mark F,Swisher Elizabeth M,Steffensen Karina D,Friedlander Michael,Okamoto Aikou,Moore Kathleen N,Efrat Ben-Baruch Noa,Werner Theresa L,Cloven Noelle G,Oaknin Ana,DiSilvestro Paul A,Morgan Mark A,Nam Joo-Hyun,Leath Charles A,Nicum Shibani,Hagemann Andrea R,Littell Ramey D,Cella David,Baron-Hay Sally,Garcia-Donas Jesus,Mizuno Mika,Bell-McGuinn Katherine,Sullivan Danielle M,Bach Bruce A,Bhattacharya Sudipta,Ratajczak Christine K,Ansell Peter J,Dinh Minh H,Aghajanian Carol,Bookman Michael A The New England journal of medicine BACKGROUND:Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma. METHODS:In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). Cytoreductive surgery could be performed before initiation or after 3 cycles of trial treatment. Combination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles. The primary end point was investigator-assessed progression-free survival in the veliparib-throughout group as compared with the control group, analyzed sequentially in the -mutation cohort, the cohort with homologous-recombination deficiency (HRD) (which included the -mutation cohort), and the intention-to-treat population. RESULTS:A total of 1140 patients underwent randomization. In the -mutation cohort, the median progression-free survival was 34.7 months in the veliparib-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.28 to 0.68; P<0.001); in the HRD cohort, it was 31.9 months and 20.5 months, respectively (hazard ratio, 0.57; 95 CI, 0.43 to 0.76; P<0.001); and in the intention-to-treat population, it was 23.5 months and 17.3 months (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). Veliparib led to a higher incidence of anemia and thrombocytopenia when combined with chemotherapy as well as of nausea and fatigue overall. CONCLUSIONS:Across all trial populations, a regimen of carboplatin, paclitaxel, and veliparib induction therapy followed by veliparib maintenance therapy led to significantly longer progression-free survival than carboplatin plus paclitaxel induction therapy alone. The independent value of adding veliparib during induction therapy without veliparib maintenance was less clear. (Funded by AbbVie; VELIA/GOG-3005 ClinicalTrials.gov number, NCT02470585.). 10.1056/NEJMoa1909707
    Association of Change in N-Terminal Pro-B-Type Natriuretic Peptide Following Initiation of Sacubitril-Valsartan Treatment With Cardiac Structure and Function in Patients With Heart Failure With Reduced Ejection Fraction. Januzzi James L,Prescott Margaret F,Butler Javed,Felker G Michael,Maisel Alan S,McCague Kevin,Camacho Alexander,Piña Ileana L,Rocha Ricardo A,Shah Amil M,Williamson Kristin M,Solomon Scott D, JAMA Importance:In patients with heart failure and reduced ejection fraction (HFrEF), treatment with sacubitril-valsartan reduces N-terminal pro-b-type natriuretic peptide (NT-proBNP) concentrations. The effect of sacubitril-valsartan on cardiac remodeling is uncertain. Objective:To determine whether NT-proBNP changes in patients with HFrEF treated with sacubitril-valsartan correlate with changes in measures of cardiac volume and function. Design, Setting, and Participants:Prospective, 12-month, single-group, open-label study of patients with HFrEF enrolled in 78 outpatient sites in the United States. Sacubitril-valsartan was initiated and the dose adjusted. Enrollment commenced on October 25, 2016, and follow-up was completed on October 22, 2018. Exposures:NT-proBNP concentrations among patients treated with sacubitril-valsartan. Main Outcomes and Measures:The primary outcome was the correlation between changes in log2-NT-proBNP concentrations and left ventricular (LV) EF, LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), left atrial volume index (LAVI), and ratio of early transmitral Doppler velocity/early diastolic annular velocity (E/e') at 12 months. Results:Among 794 patients (mean age, 65.1 years; 226 women [28.5%]; mean LVEF = 28.2%), 654 (82.4%) completed the study. The median NT-proBNP concentration at baseline was 816 pg/mL (interquartile range [IQR], 332-1822) and 455 pg/mL (IQR, 153-1090) at 12 months (difference, P < .001). At 12 months, the change in log2-NT-proBNP concentration was correlated with changes in LVEF (r = -0.381 [IQR, -0.448 to -0.310]; P < .001), LVEDVI (r = 0.320 [IQR, 0.246 to 0.391]; P < .001), LVESVI (r = 0.405 [IQR, 0.335 to 0.470]; P < .001), LAVI (r = 0.263 [IQR, 0.186 to 0.338]; P < .001), and E/e' (r = 0.269 [IQR, 0.182 to 0.353]; P < .001). At 12 months, LVEF increased from 28.2% to 37.8% (difference, 9.4% [95% CI, 8.8% to 9.9%]; P < .001), while LVEDVI decreased from 86.93 to 74.15 mL/m2 (difference, -12.25 mL/m2 [IQR, -12.92 to -11.58]; P < .001) and LVESVI decreased from 61.68 to 45.46 mL/m2 (difference, -15.29 mL/m2 [95% CI, -16.03 to -14.55]; P < .001). LAVI and E/e' ratio also decreased significantly. The most frequent adverse events were hypotension (17.6%), dizziness (16.8%), hyperkalemia (13.2%), and worsening kidney function (12.3%). Conclusions and Relevance:In this exploratory study of patients with HFrEF treated with sacubitril-valsartan, reduction in NT-proBNP concentration was weakly yet significantly correlated with improvements in markers of cardiac volume and function at 12 months. The observed reverse cardiac remodeling may provide a mechanistic explanation for the effects of sacubitril-valsartan in patients with HFrEF. Trial Registration:ClinicalTrials.gov Identifier: NCT02887183. 10.1001/jama.2019.12821
    Effect of Sacubitril-Valsartan vs Enalapril on Aortic Stiffness in Patients With Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. Desai Akshay S,Solomon Scott D,Shah Amil M,Claggett Brian L,Fang James C,Izzo Joseph,McCague Kevin,Abbas Cheryl A,Rocha Ricardo,Mitchell Gary F, JAMA Importance:Compared with enalapril, sacubitril-valsartan reduces cardiovascular mortality and heart failure hospitalization in patients with heart failure and reduced ejection fraction (HFrEF). These benefits may be related to effects on hemodynamics and cardiac remodeling. Objective:To determine whether treatment of HFrEF with sacubitril-valsartan improves central aortic stiffness and cardiac remodeling compared with enalapril. Design, Setting, and Participants:Randomized, double-blind clinical trial of 464 participants with heart failure and ejection fraction of 40% or less enrolled across 85 US sites between August 17, 2016, and June 28, 2018. Follow-up was completed on January 26, 2019. Interventions:Randomization (1:1) to sacubitril-valsartan (n = 231; target dosage, 97/103 mg twice daily) vs enalapril (n = 233; target dosage, 10 mg twice daily) for 12 weeks. Main Outcomes and Measures:The primary outcome was change from baseline to week 12 in aortic characteristic impedance (Zc), a measure of central aortic stiffness. Prespecified secondary outcomes included change from baseline to week 12 in N-terminal pro-B-type natriuretic peptide, ejection fraction, global longitudinal strain, mitral annular relaxation velocity, mitral E/e' ratio, left ventricular end-systolic and end-diastolic volume indexes (LVESVI and LVEDVI), left atrial volume index, and ventricular-vascular coupling ratio. Results:Of 464 validly randomized participants (mean age, 67.3 [SD, 9.1] years; 23.5% women), 427 completed the study. At 12 weeks, Zc decreased from 223.8 to 218.9 dyne × s/cm5 in the sacubitril-valsartan group and increased from 213.2 to 214.4 dyne × s/cm5 in the enalapril group (treatment difference, -2.2 [95% CI, -17.6 to 13.2] dyne × s/cm5; P = .78). Of 9 prespecified secondary end points, no significant between-group difference in change from baseline was seen in 4, including left ventricular ejection fraction (34%-36% with sacubitril-valsartan vs 33 to 35% with enalapril; treatment difference, 0.6% [95% CI, -0.4% to 1.7%]; P = .24). However, greater reductions from baseline were seen with sacubitril-valsartan than with enalapril in all others, including left atrial volume (from 30.4 mL/m2 to 28.2 mL/m2 vs from 29.8 mL/m2 to 30.5 mL/m2; treatment difference, -2.8 mL/m2 [95% CI, -4.0 to -1.6 mL/m2]; P < .001), LVEDVI (from 75.1 mL/m2 to 70.3 mL/m2 vs from 79.1 mL/m2 to 75.6 mL/m2; treatment difference, -2.0 mL/m2 [95% CI, -3.7 to 0.3 mL/m2]; P = .02), LVESVI (from 50.8 mL/m2 to 46.3 mL/m2 vs from 54.1 to 50.6 mL/m2; treatment difference, -1.6 mL/m2 [95% CI, -3.1 to -0.03 mL/m2]; P = .045), and mitral E/e' ratio (from 13.8 to 12.3 vs from 13.4 to 13.8; treatment difference, -1.8 [95% CI, -2.8 to -0.8]; P = .001). Rates of adverse events including hypotension (1.7% vs 3.9%) were similar in both groups. Conclusions and Relevance:Treatment of HFrEF with sacubitril-valsartan, compared with enalapril, did not significantly reduce central aortic stiffness. The study findings may provide insight into mechanisms underlying the effects of sacubitril-valsartan in HFrEF. Trial Registration:ClinicalTrials.gov Identifier: NCT02874794. 10.1001/jama.2019.12843
    Association of Metabolic Surgery With Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes and Obesity. Aminian Ali,Zajichek Alexander,Arterburn David E,Wolski Kathy E,Brethauer Stacy A,Schauer Philip R,Kattan Michael W,Nissen Steven E JAMA Importance:Although metabolic surgery (defined as procedures that influence metabolism by inducing weight loss and altering gastrointestinal physiology) significantly improves cardiometabolic risk factors, the effect on cardiovascular outcomes has been less well characterized. Objective:To investigate the relationship between metabolic surgery and incident major adverse cardiovascular events (MACE) in patients with type 2 diabetes and obesity. Design, Setting, and Participants:Of 287 438 adult patients with diabetes in the Cleveland Clinic Health System in the United States between 1998 and 2017, 2287 patients underwent metabolic surgery. In this retrospective cohort study, these patients were matched 1:5 to nonsurgical patients with diabetes and obesity (body mass index [BMI] ≥30), resulting in 11 435 control patients, with follow-up through December 2018. Exposures:Metabolic gastrointestinal surgical procedures vs usual care for type 2 diabetes and obesity. Main Outcomes and Measures:The primary outcome was the incidence of extended MACE (composite of 6 outcomes), defined as first occurrence of all-cause mortality, coronary artery events, cerebrovascular events, heart failure, nephropathy, and atrial fibrillation. Secondary end points included 3-component MACE (myocardial infarction, ischemic stroke, and mortality) and the 6 individual components of the primary end point. Results:Among the 13 722 study participants, the distribution of baseline covariates was balanced between the surgical group and the nonsurgical group, including female sex (65.5% vs 64.2%), median age (52.5 vs 54.8 years), BMI (45.1 vs 42.6), and glycated hemoglobin level (7.1% vs 7.1%). The overall median follow-up duration was 3.9 years (interquartile range, 1.9-6.1 years). At the end of the study period, 385 patients in the surgical group and 3243 patients in the nonsurgical group experienced a primary end point (cumulative incidence at 8-years, 30.8% [95% CI, 27.6%-34.0%] in the surgical group and 47.7% [95% CI, 46.1%-49.2%] in the nonsurgical group [P < .001]; absolute 8-year risk difference [ARD], 16.9% [95% CI, 13.1%-20.4%]; adjusted hazard ratio [HR], 0.61 [95% CI, 0.55-0.69]). All 7 prespecified secondary outcomes showed statistically significant differences in favor of metabolic surgery, including mortality. All-cause mortality occurred in 112 patients in the metabolic surgery group and 1111 patients in the nonsurgical group (cumulative incidence at 8 years, 10.0% [95% CI, 7.8%-12.2%] and 17.8% [95% CI, 16.6%-19.0%]; ARD, 7.8% [95% CI, 5.1%-10.2%]; adjusted HR, 0.59 [95% CI, 0.48-0.72]). Conclusions and Relevance:Among patients with type 2 diabetes and obesity, metabolic surgery, compared with nonsurgical management, was associated with a significantly lower risk of incident MACE. The findings from this observational study must be confirmed in randomized clinical trials. Trial Registration:ClinicalTrials.gov Identifier: NCT03955952. 10.1001/jama.2019.14231
    Association of Genetic Variants Related to Combined Exposure to Lower Low-Density Lipoproteins and Lower Systolic Blood Pressure With Lifetime Risk of Cardiovascular Disease. Ference Brian A,Bhatt Deepak L,Catapano Alberico L,Packard Chris J,Graham Ian,Kaptoge Stephen,Ference Thatcher B,Guo Qi,Laufs Ulrich,Ruff Christian T,Cupido Arjen,Hovingh G Kees,Danesh John,Holmes Michael V,Smith George Davey,Ray Kausik K,Nicholls Stephen J,Sabatine Marc S JAMA Importance:The relationship between exposure to lower low-density lipoprotein cholesterol (LDL-C) and lower systolic blood pressure (SBP) with the risk of cardiovascular disease has not been reliably quantified. Objective:To assess the association of lifetime exposure to the combination of both lower LDL-C and lower SBP with the lifetime risk of cardiovascular disease. Design, Setting, and Participants:Among 438 952 participants enrolled in the UK Biobank between 2006 and 2010 and followed up through 2018, genetic LDL-C and SBP scores were used as instruments to divide participants into groups with lifetime exposure to lower LDL-C, lower SBP, or both. Differences in plasma LDL-C, SBP, and cardiovascular event rates between the groups were compared to estimate associations with lifetime risk of cardiovascular disease. Exposures:Differences in plasma LDL-C and SBP compared with participants with both genetic scores below the median. Genetic risk scores higher than the median were associated with lower LDL-C and lower SBP. Main Outcomes and Measures:Odds ratio (OR) for major coronary events, defined as coronary death, nonfatal myocardial infarction, or coronary revascularization. Results:The mean age of the 438 952 participants was 65.2 years (range, 40.4-80.0 years), 54.1% were women, and 24 980 experienced a first major coronary event. Compared with the reference group, participants with LDL-C genetic scores higher than the median had 14.7-mg/dL lower LDL-C levels and an OR of 0.73 for major coronary events (95% CI, 0.70-0.75; P < .001). Participants with SBP genetic scores higher than the median had 2.9-mm Hg lower SBP and an OR of 0.82 for major coronary events (95% CI, 0.79-0.85, P < .001). Participants in the group with both genetic scores higher than the median had 13.9-mg/dL lower LDL-C, 3.1-mm Hg lower SBP, and an OR of 0.61 for major coronary events (95% CI, 0.59-0.64; P < .001). In a 4 × 4 factorial analysis, exposure to increasing genetic risk scores and lower LDL-C levels and SBP was associated with dose-dependent lower risks of major coronary events. In a meta-regression analysis, combined exposure to 38.67-mg/dL lower LDL-C and 10-mm Hg lower SBP was associated with an OR of 0.22 for major coronary events (95% CI, 0.17-0.26; P < .001), and 0.32 for cardiovascular death (95% CI, 0.25-0.40; P < .001). Conclusions and Relevance:Lifelong genetic exposure to lower levels of low-density lipoprotein cholesterol and lower systolic blood pressure was associated with lower cardiovascular risk. However, these findings cannot be assumed to represent the magnitude of benefit achievable from treatment of these risk factors. 10.1001/jama.2019.14120
    Trends in Use of Medical Imaging in US Health Care Systems and in Ontario, Canada, 2000-2016. Smith-Bindman Rebecca,Kwan Marilyn L,Marlow Emily C,Theis Mary Kay,Bolch Wesley,Cheng Stephanie Y,Bowles Erin J A,Duncan James R,Greenlee Robert T,Kushi Lawrence H,Pole Jason D,Rahm Alanna K,Stout Natasha K,Weinmann Sheila,Miglioretti Diana L JAMA Importance:Medical imaging increased rapidly from 2000 to 2006, but trends in recent years have not been analyzed. Objective:To evaluate recent trends in medical imaging. Design, Setting, and Participants:Retrospective cohort study of patterns of medical imaging between 2000 and 2016 among 16 million to 21 million patients enrolled annually in 7 US integrated and mixed-model insurance health care systems and for individuals receiving care in Ontario, Canada. Exposures:Calendar year and country (United States vs Canada). Main Outcomes and Measures:Use of computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and nuclear medicine imaging. Annual and relative imaging rates by imaging modality, country, and age (children [<18 years], adults [18-64 years], and older adults [≥65 years]). Results:Overall, 135 774 532 imaging examinations were included; 5 439 874 (4%) in children, 89 635 312 (66%) in adults, and 40 699 346 (30%) in older adults. Among adults and older adults, imaging rates were significantly higher in 2016 vs 2000 for all imaging modalities other than nuclear medicine. For example, among older adults, CT imaging rates were 428 per 1000 person-years in 2016 vs 204 per 1000 in 2000 in US health care systems and 409 per 1000 vs 161 per 1000 in Ontario; for MRI, 139 per 1000 vs 62 per 1000 in the United States and 89 per 1000 vs 13 per 1000 in Ontario; and for ultrasound, 495 per 1000 vs 324 per 1000 in the United States and 580 per 1000 vs 332 per 1000 in Ontario. Annual growth in imaging rates among US adults and older adults slowed over time for CT (from an 11.6% annual percentage increase among adults and 9.5% among older adults in 2000-2006 to 3.7% among adults in 2013-2016 and 5.2% among older adults in 2014-2016) and for MRI (from 11.4% in 2000-2004 in adults and 11.3% in 2000-2005 in older adults to 1.3% in 2007-2016 in adults and 2.2% in 2005-2016 in older adults). Patterns in Ontario were similar. Among children, annual growth for CT stabilized or declined (United States: from 10.1% in 2000-2005 to 0.8% in 2013-2016; Ontario: from 3.3% in 2000-2006 to -5.3% in 2006-2016), but patterns for MRI were similar to adults. Changes in annual growth in ultrasound were smaller among adults and children in the United States and Ontario compared with CT and MRI. Nuclear medicine imaging declined in adults and children after 2006. Conclusions and Relevance:From 2000 to 2016 in 7 US integrated and mixed-model health care systems and in Ontario, rates of CT and MRI use continued to increase among adults, but at a slower pace in more recent years. In children, imaging rates continued to increase except for CT, which stabilized or declined in more recent periods. Whether the observed imaging utilization was appropriate or was associated with improved patient outcomes is unknown. 10.1001/jama.2019.11456
    N95 Respirators vs Medical Masks for Preventing Influenza Among Health Care Personnel: A Randomized Clinical Trial. Radonovich Lewis J,Simberkoff Michael S,Bessesen Mary T,Brown Alexandria C,Cummings Derek A T,Gaydos Charlotte A,Los Jenna G,Krosche Amanda E,Gibert Cynthia L,Gorse Geoffrey J,Nyquist Ann-Christine,Reich Nicholas G,Rodriguez-Barradas Maria C,Price Connie Savor,Perl Trish M, JAMA Importance:Clinical studies have been inconclusive about the effectiveness of N95 respirators and medical masks in preventing health care personnel (HCP) from acquiring workplace viral respiratory infections. Objective:To compare the effect of N95 respirators vs medical masks for prevention of influenza and other viral respiratory infections among HCP. Design, Setting, and Participants:A cluster randomized pragmatic effectiveness study conducted at 137 outpatient study sites at 7 US medical centers between September 2011 and May 2015, with final follow-up in June 2016. Each year for 4 years, during the 12-week period of peak viral respiratory illness, pairs of outpatient sites (clusters) within each center were matched and randomly assigned to the N95 respirator or medical mask groups. Interventions:Overall, 1993 participants in 189 clusters were randomly assigned to wear N95 respirators (2512 HCP-seasons of observation) and 2058 in 191 clusters were randomly assigned to wear medical masks (2668 HCP-seasons) when near patients with respiratory illness. Main Outcomes and Measures:The primary outcome was the incidence of laboratory-confirmed influenza. Secondary outcomes included incidence of acute respiratory illness, laboratory-detected respiratory infections, laboratory-confirmed respiratory illness, and influenzalike illness. Adherence to interventions was assessed. Results:Among 2862 randomized participants (mean [SD] age, 43 [11.5] years; 2369 [82.8%]) women), 2371 completed the study and accounted for 5180 HCP-seasons. There were 207 laboratory-confirmed influenza infection events (8.2% of HCP-seasons) in the N95 respirator group and 193 (7.2% of HCP-seasons) in the medical mask group (difference, 1.0%, [95% CI, -0.5% to 2.5%]; P = .18) (adjusted odds ratio [OR], 1.18 [95% CI, 0.95-1.45]). There were 1556 acute respiratory illness events in the respirator group vs 1711 in the mask group (difference, -21.9 per 1000 HCP-seasons [95% CI, -48.2 to 4.4]; P = .10); 679 laboratory-detected respiratory infections in the respirator group vs 745 in the mask group (difference, -8.9 per 1000 HCP-seasons, [95% CI, -33.3 to 15.4]; P = .47); 371 laboratory-confirmed respiratory illness events in the respirator group vs 417 in the mask group (difference, -8.6 per 1000 HCP-seasons [95% CI, -28.2 to 10.9]; P = .39); and 128 influenzalike illness events in the respirator group vs 166 in the mask group (difference, -11.3 per 1000 HCP-seasons [95% CI, -23.8 to 1.3]; P = .08). In the respirator group, 89.4% of participants reported "always" or "sometimes" wearing their assigned devices vs 90.2% in the mask group. Conclusions and Relevance:Among outpatient health care personnel, N95 respirators vs medical masks as worn by participants in this trial resulted in no significant difference in the incidence of laboratory-confirmed influenza. Trial Registration:ClinicalTrials.gov Identifier: NCT01249625. 10.1001/jama.2019.11645
    Effect of Low-Intensity vs Standard-Intensity Warfarin Prophylaxis on Venous Thromboembolism or Death Among Patients Undergoing Hip or Knee Arthroplasty: A Randomized Clinical Trial. Gage Brian F,Bass Anne R,Lin Hannah,Woller Scott C,Stevens Scott M,Al-Hammadi Noor,Anderson Jeffrey L,Li Juan,Rodriguez Tomás,Miller J Philip,McMillin Gwendolyn A,Pendleton Robert C,Jaffer Amir K,King Cristi R,Whipple Brandi,Porche-Sorbet Rhonda,Napoli Lynnae,Merritt Kerri,Thompson Anna M,Hyun Gina,Hollomon Wesley,Barrack Robert L,Nunley Ryan M,Moskowitz Gerard,Dávila-Román Victor,Eby Charles S JAMA Importance:The optimal international normalized ratio (INR) to prevent venous thromboembolism (VTE) in warfarin-treated patients with recent arthroplasty is unknown. Objective:To determine the safety and efficacy of a target INR of 1.8 vs 2.5 for VTE prophylaxis after orthopedic surgery. Design, Setting, and Participants:The randomized Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis enrolled 1650 patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016. Interventions:In a 2 × 2 factorial design, participants were randomized to a target INR of 1.8 (n = 823) or 2.5 (n = 827) and to either genotype-guided or clinically guided warfarin dosing. For the first 11 days of therapy, open-label warfarin dosing was guided by a web application. Main Outcomes and Measures:The primary outcome was the composite of VTE (within 60 days) or death (within 30 days). Participants underwent screening duplex ultrasound postoperatively. The hypothesis was that an INR target of 1.8 would be noninferior to an INR target of 2.5, using a noninferiority margin of 3% for the absolute risk of VTE. Secondary end points were bleeding and INR values of 4 or more. Results:Among 1650 patients who were randomized (mean age, 72.1 years; 1049 women [63.6%]; 1502 white [91.0%]), 1597 (96.8%) received at least 1 dose of warfarin and were included in the primary analysis. The rate of the primary composite outcome of VTE or death was 5.1% (41 of 804) in the low-intensity-warfarin group (INR target, 1.8) vs 3.8% (30 of 793) in the standard-treatment-warfarin group (INR target, 2.5), for a difference of 1.3% (1-sided 95% CI, -∞ to 3.05%, P = .06 for noninferiority). Major bleeding occurred in 0.4% of patients in the low-intensity group and 0.9% of patients in the standard-intensity group, for a difference of -0.5% (95% CI, -1.6% to 0.4%). The INR values of 4 or more occurred in 4.5% of patients in the low-intensity group and 12.2% of the standard-intensity group, for a difference of -7.8% (95% CI, -10.5% to -5.1%). Conclusions and Relevance:Among older patients undergoing hip or knee arthroplasty and receiving warfarin prophylaxis, an international normalized ratio goal of 1.8 compared with 2.5 did not meet the criterion for noninferiority for risk of the composite outcome of VTE or death. However, the trial may have been underpowered to meet this criterion and further research may be warranted. Trial Registration:ClinicalTrials.gov Identifier: NCT01006733. 10.1001/jama.2019.12085
    Medication Use for the Risk Reduction of Primary Breast Cancer in Women: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. Nelson Heidi D,Fu Rongwei,Zakher Bernadette,Pappas Miranda,McDonagh Marian JAMA Importance:Medications to reduce risk of breast cancer are effective for women at increased risk but also cause adverse effects. Objective:To update the 2013 US Preventive Services Task Force systematic review on medications to reduce risk of primary (first diagnosis) invasive breast cancer in women. Data Sources:Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, EMBASE, and MEDLINE (January 1, 2013, to February 1, 2019); manual review of reference lists. Study Selection:Discriminatory accuracy studies of breast cancer risk assessment methods; randomized clinical trials of tamoxifen, raloxifene, and aromatase inhibitors for primary breast cancer prevention; studies of medication adverse effects. Data Extraction and Synthesis:Investigators abstracted data on methods, participant characteristics, eligibility criteria, outcome ascertainment, and follow-up. Results of individual trials were combined by using a profile likelihood random-effects model. Main Outcomes and Measures:Probability of breast cancer in individuals (area under the receiver operating characteristic curve [AUC]); incidence of breast cancer, fractures, thromboembolic events, coronary heart disease events, stroke, endometrial cancer, and cataracts; and mortality. Results:A total of 46 studies (82 articles [>5 million participants]) were included. Eighteen risk assessment methods in 25 studies reported low accuracy in predicting the probability of breast cancer in individuals (AUC, 0.55-0.65). In placebo-controlled trials, tamoxifen (risk ratio [RR], 0.69 [95% CI, 0.59-0.84]; 4 trials [n = 28 421]), raloxifene (RR, 0.44 [95% CI, 0.24-0.80]; 2 trials [n = 17 806]), and the aromatase inhibitors exemestane and anastrozole (RR, 0.45 [95% CI, 0.26-0.70]; 2 trials [n = 8424]) were associated with a lower incidence of invasive breast cancer. Risk for invasive breast cancer was higher for raloxifene than tamoxifen in 1 trial after long-term follow-up (RR, 1.24 [95% CI, 1.05-1.47]; n = 19 747). Raloxifene was associated with lower risk for vertebral fractures (RR, 0.61 [95% CI, 0.53-0.73]; 2 trials [n = 16 929]) and tamoxifen was associated with lower risk for nonvertebral fractures (RR, 0.66 [95% CI, 0.45-0.98]; 1 trial [n = 13 388]) compared with placebo. Tamoxifen and raloxifene were associated with increased thromboembolic events compared with placebo; tamoxifen was associated with more events than raloxifene. Tamoxifen was associated with higher risk of endometrial cancer and cataracts compared with placebo. Symptomatic effects (eg, vasomotor, musculoskeletal) varied by medication. Conclusions and Relevance:Tamoxifen, raloxifene, and aromatase inhibitors were associated with lower risk of primary invasive breast cancer in women but also were associated with adverse effects that differed between medications. Risk stratification methods to identify patients with increased breast cancer risk demonstrated low accuracy. 10.1001/jama.2019.5780
    Medication Use to Reduce Risk of Breast Cancer: US Preventive Services Task Force Recommendation Statement. ,Owens Douglas K,Davidson Karina W,Krist Alex H,Barry Michael J,Cabana Michael,Caughey Aaron B,Doubeni Chyke A,Epling John W,Kubik Martha,Landefeld C Seth,Mangione Carol M,Pbert Lori,Silverstein Michael,Tseng Chien-Wen,Wong John B JAMA Importance:Breast cancer is the most common nonskin cancer among women in the United States and the second leading cause of cancer death. The median age at diagnosis is 62 years, and an estimated 1 in 8 women will develop breast cancer at some point in their lifetime. African American women are more likely to die of breast cancer compared with women of other races. Objective:To update the 2013 US Preventive Services Task Force (USPSTF) recommendation on medications for risk reduction of primary breast cancer. Evidence Review:The USPSTF reviewed evidence on the accuracy of risk assessment methods to identify women who could benefit from risk-reducing medications for breast cancer, as well as evidence on the effectiveness, adverse effects, and subgroup variations of these medications. The USPSTF reviewed evidence from randomized trials, observational studies, and diagnostic accuracy studies of risk stratification models in women without preexisting breast cancer or ductal carcinoma in situ. Findings:The USPSTF found convincing evidence that risk assessment tools can predict the number of cases of breast cancer expected to develop in a population. However, these risk assessment tools perform modestly at best in discriminating between individual women who will or will not develop breast cancer. The USPSTF found convincing evidence that risk-reducing medications (tamoxifen, raloxifene, or aromatase inhibitors) provide at least a moderate benefit in reducing risk for invasive estrogen receptor-positive breast cancer in postmenopausal women at increased risk for breast cancer. The USPSTF found that the benefits of taking tamoxifen, raloxifene, and aromatase inhibitors to reduce risk for breast cancer are no greater than small in women not at increased risk for the disease. The USPSTF found convincing evidence that tamoxifen and raloxifene and adequate evidence that aromatase inhibitors are associated with small to moderate harms. Overall, the USPSTF determined that the net benefit of taking medications to reduce risk of breast cancer is larger in women who have a greater risk for developing breast cancer. Conclusions and Recommendation:The USPSTF recommends that clinicians offer to prescribe risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women who are at increased risk for breast cancer and at low risk for adverse medication effects. (B recommendation) The USPSTF recommends against the routine use of risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, in women who are not at increased risk for breast cancer. (D recommendation) This recommendation applies to asymptomatic women 35 years and older, including women with previous benign breast lesions on biopsy (such as atypical ductal or lobular hyperplasia and lobular carcinoma in situ). This recommendation does not apply to women who have a current or previous diagnosis of breast cancer or ductal carcinoma in situ. 10.1001/jama.2019.11885
    Effect of Corticosteroid-Sparing Treatment With Mycophenolate Mofetil vs Methotrexate on Inflammation in Patients With Uveitis: A Randomized Clinical Trial. Rathinam S R,Gonzales John A,Thundikandy Radhika,Kanakath Anuradha,Murugan S Bala,Vedhanayaki R,Lim Lyndell L,Suhler Eric B,Al-Dhibi Hassan A,Doan Thuy,Keenan Jeremy D,Rao Maya M,Ebert Caleb D,Nguyen Hieu H,Kim Eric,Porco Travis C,Acharya Nisha R, JAMA Importance:Methotrexate and mycophenolate mofetil are commonly used immunomodulatory therapies for achieving corticosteroid-sparing control of noninfectious uveitis, but there is uncertainty about which drug is more effective. Objective:To compare the effect of methotrexate and mycophenolate for achieving corticosteroid-sparing control of noninfectious intermediate uveitis, posterior uveitis, and panuveitis. Design, Setting, and Participants:The First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial screened 265 adults with noninfectious uveitis requiring corticosteroid-sparing immunosuppressive therapy from 9 referral eye centers in India, the United States, Australia, Saudi Arabia, and Mexico between August 22, 2013, and August 16, 2017. Follow-up ended on August 20, 2018. Interventions:Patients were randomized to receive oral methotrexate, 25 mg weekly (n = 107), or oral mycophenolate mofetil, 3 g daily (n = 109). Main Outcomes and Measures:The primary outcome was treatment success at 6 months, which was defined as having control of inflammation in both eyes, no more than 7.5 mg prednisone daily and less than or equal to 2 drops of prednisolone acetate 1%, and no treatment failure due to safety or intolerability. Patients underwent follow-up to 12 months while receiving the same treatment or switched to the other antimetabolite, depending on their 6-month outcome. Results:Among 216 patients who were randomized (median age, 38 years; 135 (62.5%) women), 194 (89.8%) completed follow-up through 6 months. Treatment success occurred in 64 (66.7%) patients in the methotrexate group vs 56 (57.1%) in the mycophenolate group (difference, 9.5% [95% CI, -5.3% to 21.8%]; odds ratio [OR], 1.50 [95% CI, 0.81 to 2.81]; P = .20). Among patients with posterior uveitis or panuveitis, treatment success was achieved in 58 (74.4%) in the methotrexate group vs 42 (55.3%) in the mycophenolate group (difference, 19.1% [95% CI, 3.6% to 30.6%]; OR, 2.35 [95% CI, 1.16 to 4.90]; P = .02); whereas among patients with intermediate uveitis treatment success occurred in 6 (33.3%) in the methotrexate group vs 14 (63.6%) in the mycophenolate group (difference, -30.3% [95% CI, -51.6% to 1.1%]; OR, 0.29 [95% CI, 0.08 to 1.05]; P = .07; P for interaction = .004). Elevated liver enzymes were the most common nonserious laboratory adverse event, occurring in 14 patients (13.0%) in the methotrexate group and 8 patients (7.4%) in the mycophenolate group. Conclusions and Relevance:Among adults with noninfectious uveitis, the use of mycophenolate mofetil compared with methotrexate as first-line corticosteroid-sparing treatment did not result in superior control of inflammation. Further research is needed to determine if either drug is more effective based on the anatomical subtype of uveitis. Trial Registration:ClinicalTrials.gov Identifier: NCT01829295. 10.1001/jama.2019.12618
    Association Between Dialysis Facility Ownership and Access to Kidney Transplantation. Gander Jennifer C,Zhang Xingyu,Ross Katherine,Wilk Adam S,McPherson Laura,Browne Teri,Pastan Stephen O,Walker Elizabeth,Wang Zhensheng,Patzer Rachel E JAMA Importance:For-profit (vs nonprofit) dialysis facilities have historically had lower kidney transplantation rates, but it is unknown if the pattern holds for living donor and deceased donor kidney transplantation, varies by facility ownership, or has persisted over time in a nationally representative population. Objective:To determine the association between dialysis facility ownership and placement on the deceased donor kidney transplantation waiting list, receipt of a living donor kidney transplant, or receipt of a deceased donor kidney transplant. Design, Setting, and Participants:Retrospective cohort study that included 1 478 564 patients treated at 6511 US dialysis facilities. Adult patients with incident end-stage kidney disease from the US Renal Data System (2000-2016) were linked with facility ownership (Dialysis Facility Compare) and characteristics (Dialysis Facility Report). Exposures:The primary exposure was dialysis facility ownership, which was categorized as nonprofit small chains, nonprofit independent facilities, for-profit large chains (>1000 facilities), for-profit small chains (<1000 facilities), and for-profit independent facilities. Main Outcomes and Measures:Access to kidney transplantation was defined as time from initiation of dialysis to placement on the deceased donor kidney transplantation waiting list, receipt of a living donor kidney transplant, or receipt of a deceased donor kidney transplant. Cumulative incidence differences and multivariable Cox models assessed the association between dialysis facility ownership and each outcome. Results:Among 1 478 564 patients, the median age was 66 years (interquartile range, 55-76 years), with 55.3% male, and 28.1% non-Hispanic black patients. Eighty-seven percent of patients received care at a for-profit dialysis facility. A total of 109 030 patients (7.4%) received care at 435 nonprofit small chain facilities; 78 287 (5.3%) at 324 nonprofit independent facilities; 483 988 (32.7%) at 2239 facilities of large for-profit chain 1; 482 689 (32.6%) at 2082 facilities of large for-profit chain 2; 225 890 (15.3%) at 997 for-profit small chain facilities; and 98 680 (6.7%) at 434 for-profit independent facilities. During the study period, 121 680 patients (8.2%) were placed on the deceased donor waiting list, 23 762 (1.6%) received a living donor kidney transplant, and 49 290 (3.3%) received a deceased donor kidney transplant. For-profit facilities had lower 5-year cumulative incidence differences for each outcome vs nonprofit facilities (deceased donor waiting list: -13.2% [95% CI, -13.4% to -13.0%]; receipt of a living donor kidney transplant: -2.3% [95% CI, -2.4% to -2.3%]; and receipt of a deceased donor kidney transplant: -4.3% [95% CI, -4.4% to -4.2%]). Adjusted Cox analyses showed lower relative rates for each outcome among patients treated at all for-profit vs all nonprofit dialysis facilities: deceased donor waiting list (hazard ratio [HR], 0.36 [95% CI, 0.35 to 0.36]); receipt of a living donor kidney transplant (HR, 0.52 [95% CI, 0.51 to 0.54]); and receipt of a deceased donor kidney transplant (HR, 0.44 [95% CI, 0.44 to 0.45]). Conclusions and Relevance:Among US patients with end-stage kidney disease, receiving dialysis at for-profit facilities compared with nonprofit facilities was associated with a lower likelihood of accessing kidney transplantation. Further research is needed to understand the mechanisms behind this association. 10.1001/jama.2019.12803
    Effect of a Multicomponent Home-Based Physical Therapy Intervention on Ambulation After Hip Fracture in Older Adults: The CAP Randomized Clinical Trial. Magaziner Jay,Mangione Kathleen K,Orwig Denise,Baumgarten Mona,Magder Laurence,Terrin Michael,Fortinsky Richard H,Gruber-Baldini Ann L,Beamer Brock A,Tosteson Anna N A,Kenny Anne M,Shardell Michelle,Binder Ellen F,Koval Kenneth,Resnick Barbara,Miller Ram,Forman Sandra,McBride Ruth,Craik Rebecca L JAMA Importance:Disability persists after hip fracture in older persons. Current rehabilitation may not be sufficient to restore ability to walk in the community. Objective:To compare a multicomponent home-based physical therapy intervention (training) with an active control on ability to walk in the community. Design, Setting, and Participants:Parallel, 2-group randomized clinical trial conducted at 3 US clinical centers (Arcadia University, University of Connecticut Health Center, and University of Maryland, Baltimore). Randomization began on September 16, 2013, and ended on June 20, 2017; follow-up ended on October 17, 2017. Patients aged 60 years and older were enrolled after nonpathologic, minimal trauma hip fracture, if they were living in the community and walking without human assistance before the fracture, were assessed within 26 weeks of hospitalization, and were not able to walk during daily activities at the time of enrollment. A total of 210 participants were randomized and reassessed 16 and 40 weeks later. Interventions:The training intervention (active treatment) (n = 105) included aerobic, strength, balance, and functional training. The active control group (n = 105) received transcutaneous electrical nerve stimulation and active range-of-motion exercises. Both groups received 2 to 3 home visits from a physical therapist weekly for 16 weeks; nutritional counseling; and daily vitamin D (2000 IU), calcium (600 mg), and multivitamins. Main Outcomes and Measures:The primary outcome (community ambulation) was defined as walking 300 m or more in 6 minutes at 16 weeks after randomization. The study was designed to test a 1-sided hypothesis of superiority of training compared with active control. Results:Among 210 randomized participants (mean age, 80.8 years; 161 women [76.7%]), 197 (93.8%) completed the trial (187 [89.0%] by completing the 6-minute walk test at 16 weeks and 10 [4.8%] by adjudication of the primary outcome). Among these, 22 of 96 training participants (22.9%) and 18 of 101 active control participants (17.8%) (difference, 5.1% [1-sided 97.5% CI, -∞ to 16.3%]; 1-sided P = .19) became community ambulators. Seventeen training participants (16.2%) and 15 control participants (14.3%) had 1 or more reportable adverse events during the intervention period. The most common reportable adverse events reported were falls (training: 6 [5.7%], control: 4 [3.8%]), femur/hip fracture (2 in each group), pneumonia (training: 2, control: 0), urinary tract infection (training: 2, control: 0), dehydration (training: 0, control: 2), and dyspnea (training: 0, control: 2). Conclusions and Relevance:Among older adults with a hip fracture, a multicomponent home-based physical therapy intervention compared with an active control that included transcutaneous electrical nerve stimulation and active range-of-motion exercises did not result in a statistically significant improvement in the ability to walk 300 m or more in 6 minutes after 16 weeks. Trial Registration:ClinicalTrials.gov Identifier: NCT01783704. 10.1001/jama.2019.12964
    Effect of Behavioral and Pelvic Floor Muscle Therapy Combined With Surgery vs Surgery Alone on Incontinence Symptoms Among Women With Mixed Urinary Incontinence: The ESTEEM Randomized Clinical Trial. Sung Vivian W,Borello-France Diane,Newman Diane K,Richter Holly E,Lukacz Emily S,Moalli Pamela,Weidner Alison C,Smith Ariana L,Dunivan Gena,Ridgeway Beri,Nguyen John N,Mazloomdoost Donna,Carper Benjamin,Gantz Marie G, JAMA Importance:Mixed urinary incontinence, including both stress and urgency incontinence, has adverse effects on a woman's quality of life. Studies evaluating treatments to simultaneously improve both components are lacking. Objective:To determine whether combining behavioral and pelvic floor muscle therapy with midurethral sling is more effective than sling alone for improving mixed urinary incontinence symptoms. Design, Setting, and Participants:Randomized clinical trial involving women 21 years or older with moderate or severe stress and urgency urinary incontinence symptoms for at least 3 months, and at least 1 stress and 1 urgency incontinence episode on a 3-day bladder diary. The trial was conducted across 9 sites in the United States, enrollment between October 2013 and April 2016; final follow-up October 2017. Interventions:Behavioral and pelvic floor muscle therapy (included 1 preoperative and 5 postoperative sessions through 6 months) combined with midurethral sling (n = 209) vs sling alone (n = 207). Main Outcomes and Measures:The primary outcome was change between baseline and 12 months in mixed incontinence symptoms measured by the Urogenital Distress Inventory (UDI) long form; range, 0 to 300 points; minimal clinically important difference, 35 points, with higher scores indicating worse symptoms. Results:Among 480 women randomized (mean [SD] age, 54.0 years [10.7]), 464 were eligible and 416 (86.7%) had postbaseline outcome data and were included in primary analyses. The UDI score in the combined group significantly decreased from 178.0 points at baseline to 30.7 points at 12 months, adjusted mean change -128.1 points (95% CI, -146.5 to -109.8). The UDI score in the sling-only group significantly decreased from 176.8 to 34.5 points, adjusted mean change -114.7 points (95% CI, -133.3 to -96.2). The model-estimated between-group difference (-13.4 points; 95% CI, -25.9 to -1.0; P = .04) did not meet the minimal clinically important difference threshold. Related and unrelated serious adverse events occurred in 10.2% of the participants (8.7% combined and 11.8% sling only). Conclusions and Relevance:Among women with mixed urinary incontinence, behavioral and pelvic floor muscle therapy combined with midurethral sling surgery compared with surgery alone resulted in a small statistically significant difference in urinary incontinence symptoms at 12 months that did not meet the prespecified threshold for clinical importance. Trial Registration:ClinicalTrials.gov Identifier: NCT01959347. 10.1001/jama.2019.12467
    Effect of Vaginal Mesh Hysteropexy vs Vaginal Hysterectomy With Uterosacral Ligament Suspension on Treatment Failure in Women With Uterovaginal Prolapse: A Randomized Clinical Trial. Nager Charles W,Visco Anthony G,Richter Holly E,Rardin Charles R,Rogers Rebecca G,Harvie Heidi S,Zyczynski Halina M,Paraiso Marie Fidela R,Mazloomdoost Donna,Grey Scott,Sridhar Amaanti,Wallace Dennis, JAMA Importance:Vaginal hysterectomy with suture apical suspension is commonly performed for uterovaginal prolapse. Transvaginal mesh hysteropexy is an alternative option. Objective:To compare the efficacy and adverse events of vaginal hysterectomy with suture apical suspension and transvaginal mesh hysteropexy. Design, Setting, Participants:At 9 clinical sites in the US Pelvic Floor Disorders Network, 183 postmenopausal women with symptomatic uterovaginal prolapse were enrolled in a randomized superiority clinical trial between April 2013 and February 2015. The study was designed for primary analysis when the last randomized participant reached 3 years of follow-up in February 2018. Interventions:Ninety-three women were randomized to undergo vaginal mesh hysteropexy and 90 were randomized to undergo vaginal hysterectomy with uterosacral ligament suspension. Main Outcomes and Measures:The primary treatment failure composite outcome (re-treatment of prolapse, prolapse beyond the hymen, or prolapse symptoms) was evaluated with survival models. Secondary outcomes included operative outcomes and adverse events, and were evaluated with longitudinal models or contingency tables as appropriate. Results:A total of 183 participants (mean age, 66 years) were randomized, 175 were included in the trial, and 169 (97%) completed the 3-year follow-up. The primary outcome was not significantly different among women who underwent hysteropexy vs hysterectomy through 48 months (adjusted hazard ratio, 0.62 [95% CI, 0.38-1.02]; P = .06; 36-month adjusted failure incidence, 26% vs 38%). Mean (SD) operative time was lower in the hysteropexy group vs the hysterectomy group (111.5 [39.7] min vs 156.7 [43.9] min; difference, -45.2 [95% CI, -57.7 to -32.7]; P = <.001). Adverse events in the hysteropexy vs hysterectomy groups included mesh exposure (8% vs 0%), ureteral kinking managed intraoperatively (0% vs 7%), granulation tissue after 12 weeks (1% vs 11%), and suture exposure after 12 weeks (3% vs 21%). Conclusions and Relevance:Among women with symptomatic uterovaginal prolapse undergoing vaginal surgery, vaginal mesh hysteropexy compared with vaginal hysterectomy with uterosacral ligament suspension did not result in a significantly lower rate of the composite prolapse outcome after 3 years. However, imprecision in study results precludes a definitive conclusion, and further research is needed to assess whether vaginal mesh hysteropexy is more effective than vaginal hysterectomy with uterosacral ligament suspension. Trial Registration:ClinicalTrials.gov Identifier: NCT01802281. 10.1001/jama.2019.12812
    Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial. Rosenstock Julio,Kahn Steven E,Johansen Odd Erik,Zinman Bernard,Espeland Mark A,Woerle Hans J,Pfarr Egon,Keller Annett,Mattheus Michaela,Baanstra David,Meinicke Thomas,George Jyothis T,von Eynatten Maximilian,McGuire Darren K,Marx Nikolaus, JAMA Importance:Type 2 diabetes is associated with increased cardiovascular risk. In placebo-controlled cardiovascular safety trials, the dipeptidyl peptidase-4 inhibitor linagliptin demonstrated noninferiority, but it has not been tested against an active comparator. Objective:This trial assessed cardiovascular outcomes of linagliptin vs glimepiride (sulfonylurea) in patients with relatively early type 2 diabetes and risk factors for or established atherosclerotic cardiovascular disease. Design, Setting, and Participants:Randomized, double-blind, active-controlled, noninferiority trial, with participant screening from November 2010 to December 2012, conducted at 607 hospital and primary care sites in 43 countries involving 6042 participants. Adults with type 2 diabetes, glycated hemoglobin of 6.5% to 8.5%, and elevated cardiovascular risk were eligible for inclusion. Elevated cardiovascular risk was defined as documented atherosclerotic cardiovascular disease, multiple cardiovascular risk factors, aged at least 70 years, and evidence of microvascular complications. Follow-up ended in August 2018. Interventions:Patients were randomized to receive 5 mg of linagliptin once daily (n = 3023) or 1 to 4 mg of glimepiride once daily (n = 3010) in addition to usual care. Investigators were encouraged to intensify glycemic treatment, primarily by adding or adjusting metformin, α-glucosidase inhibitors, thiazolidinediones, or insulin, according to clinical need. Main Outcomes and Measures:The primary outcome was time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with the aim to establish noninferiority of linagliptin vs glimepiride, defined by the upper limit of the 2-sided 95.47% CI for the hazard ratio (HR) of linagliptin relative to glimepiride of less than 1.3. Results:Of 6042 participants randomized, 6033 (mean age, 64.0 years; 2414 [39.9%] women; mean glycated hemoglobin, 7.2%; median duration of diabetes, 6.3 years; 42% with macrovascular disease; 59% had undergone metformin monotherapy) were treated and analyzed. The median duration of follow-up was 6.3 years. The primary outcome occurred in 356 of 3023 participants (11.8%) in the linagliptin group and 362 of 3010 (12.0%) in the glimepiride group (HR, 0.98 [95.47% CI, 0.84-1.14]; P < .001 for noninferiority), meeting the noninferiority criterion but not superiority (P = .76). Adverse events occurred in 2822 participants (93.4%) in the linagliptin group and 2856 (94.9%) in the glimepiride group, with 15 participants (0.5%) in the linagliptin group vs 16 (0.5%) in the glimepiride group with adjudicated-confirmed acute pancreatitis. At least 1 episode of hypoglycemic adverse events occurred in 320 (10.6%) participants in the linagliptin group and 1132 (37.7%) in the glimepiride group (HR, 0.23 [95% CI, 0.21-0.26]). Conclusions and Relevance:Among adults with relatively early type 2 diabetes and elevated cardiovascular risk, the use of linagliptin compared with glimepiride over a median 6.3 years resulted in a noninferior risk of a composite cardiovascular outcome. Trial Registration:ClinicalTrials.gov Identifier: NCT01243424. 10.1001/jama.2019.13772
    Association of Treatment With Metformin vs Sulfonylurea With Major Adverse Cardiovascular Events Among Patients With Diabetes and Reduced Kidney Function. Roumie Christianne L,Chipman Jonathan,Min Jea Young,Hackstadt Amber J,Hung Adriana M,Greevy Robert A,Grijalva Carlos G,Elasy Tom,Griffin Marie R JAMA Importance:Before 2016, safety concerns limited metformin use in patients with kidney disease; however, the effectiveness of metformin on clinical outcomes in patients with reduced kidney function remains unknown. Objective:To compare major adverse cardiovascular events (MACE) among patients with diabetes and reduced kidney function who continued treatment with metformin or a sulfonylurea. Design, Setting, and Participants:Retrospective cohort study of US veterans receiving care within the national Veterans Health Administration, with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2001 through 2016. There were 174 882 persistent new users of metformin and sulfonylureas who reached a reduced kidney function threshold (estimated glomerular filtration rate <60 mL/min/1.73 m2 or creatinine ≥1.4 mg/dL for women or ≥1.5 mg/dL for men). Patients were followed up from reduced kidney function threshold until MACE, treatment change, loss to follow-up, death, or study end (December 2016). Exposures:New users of metformin or sulfonylurea monotherapy who continued treatment with their glucose-lowering medication after reaching reduced kidney function. Main Outcomes and Measures:MACE included hospitalization for acute myocardial infarction, stroke, transient ischemic attack, or cardiovascular death. The analyses used propensity score weighting to compare the cause-specific hazard of MACE between treatments and estimate cumulative risk accounting for the competing risks of changing therapy or noncardiovascular death. Results:There were 67 749 metformin and 28 976 sulfonylurea persistent monotherapy users; the weighted cohort included 24 679 metformin and 24 799 sulfonylurea users (median age, 70 years [interquartile range {IQR}, 62.8-77.8]; 48 497 men [98%]; and 40 476 white individuals [82%], with median estimated glomerular filtration rate of 55.8 mL/min/1.73 m2 [IQR, 51.6-58.2] and hemoglobin A1c level of 6.6% [IQR, 6.1%-7.2%] at cohort entry). During follow-up (median, 1.0 year for metformin vs 1.2 years for sulfonylurea), there were 1048 MACE outcomes (23.0 per 1000 person-years) among metformin users and 1394 events (29.2 per 1000 person-years) among sulfonylurea users. The cause-specific adjusted hazard ratio of MACE for metformin was 0.80 (95% CI, 0.75-0.86) compared with sulfonylureas, yielding an adjusted rate difference of 5.8 (95% CI, 4.1-7.3) fewer events per 1000 person-years of metformin use compared with sulfonylurea use. Conclusions and Relevance:Among patients with diabetes and reduced kidney function persisting with monotherapy, treatment with metformin, compared with a sulfonylurea, was associated with a lower risk of MACE. 10.1001/jama.2019.13206
    Trends in Dietary Carbohydrate, Protein, and Fat Intake and Diet Quality Among US Adults, 1999-2016. Shan Zhilei,Rehm Colin D,Rogers Gail,Ruan Mengyuan,Wang Dong D,Hu Frank B,Mozaffarian Dariush,Zhang Fang Fang,Bhupathiraju Shilpa N JAMA Importance:Changes in the economy, nutrition policies, and food processing methods can affect dietary macronutrient intake and diet quality. It is essential to evaluate trends in dietary intake, food sources, and diet quality to inform policy makers. Objective:To investigate trends in dietary macronutrient intake, food sources, and diet quality among US adults. Design, Setting, and Participants:Serial cross-sectional analysis of the US nationally representative 24-hour dietary recall data from 9 National Health and Nutrition Examination Survey cycles (1999-2016) among adults aged 20 years or older. Exposure:Survey cycle. Main Outcomes and Measures:Dietary intake of macronutrients and their subtypes, food sources, and the Healthy Eating Index 2015 (range, 0-100; higher scores indicate better diet quality; a minimal clinically important difference has not been defined). Results:There were 43 996 respondents (weighted mean age, 46.9 years; 51.9% women). From 1999 to 2016, the estimated energy from total carbohydrates declined from 52.5% to 50.5% (difference, -2.02%; 95% CI, -2.41% to -1.63%), whereas that of total protein and total fat increased from 15.5% to 16.4% (difference, 0.82%; 95% CI, 0.67%-0.97%) and from 32.0% to 33.2% (difference, 1.20%; 95% CI, 0.84%-1.55%), respectively (all P < .001 for trend). Estimated energy from low-quality carbohydrates decreased by 3.25% (95% CI, 2.74%-3.75%; P < .001 for trend) from 45.1% to 41.8%. Increases were observed in estimated energy from high-quality carbohydrates (by 1.23% [95% CI, 0.84%-1.61%] from 7.42% to 8.65%), plant protein (by 0.38% [95% CI, 0.28%-0.49%] from 5.38% to 5.76%), saturated fatty acids (by 0.36% [95% CI, 0.20%-0.51%] from 11.5% to 11.9%), and polyunsaturated fatty acids (by 0.65% [95% CI, 0.56%-0.74%] from 7.58% to 8.23%) (all P < .001 for trend). The estimated overall Healthy Eating Index 2015 increased from 55.7 to 57.7 (difference, 2.01; 95% CI, 0.86-3.16; P < .001 for trend). Trends in high- and low-quality carbohydrates primarily reflected higher estimated energy from whole grains (0.65%) and reduced estimated energy from added sugars (-2.00%), respectively. Trends in plant protein were predominantly due to higher estimated intake of whole grains (0.12%) and nuts (0.09%). Conclusions and Relevance:From 1999 to 2016, US adults experienced a significant decrease in percentage of energy intake from low-quality carbohydrates and significant increases in percentage of energy intake from high-quality carbohydrates, plant protein, and polyunsaturated fat. Despite improvements in macronutrient composition and diet quality, continued high intake of low-quality carbohydrates and saturated fat remained. 10.1001/jama.2019.13771
    Screening for Asymptomatic Bacteriuria in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. Henderson Jillian T,Webber Elizabeth M,Bean Sarah I JAMA Importance:Screening for asymptomatic bacteriuria can identify patients for whom treatment might be beneficial for preventing symptomatic infection and other health outcomes. Objective:To systematically review benefits and harms of asymptomatic bacteriuria screening and treatment in adults, including during pregnancy, to inform the US Preventive Services Task Force. Data Sources:MEDLINE, PubMed (publisher-supplied records), and Cochrane Collaboration Central Registry of Controlled Trials; surveillance through May 24, 2019. Study Selection:Randomized clinical trials (RCTs) and observational studies on benefits and harms of screening for asymptomatic bacteriuria; RCTs on benefits and harms of asymptomatic bacteriuria treatment. Eligible populations included unselected, asymptomatic individuals without known urinary tract conditions. Data Extraction and Synthesis:Independent critical appraisal and data abstraction by 2 reviewers. Random-effects meta-analysis was conducted to estimate benefits of the interventions. Main Outcomes and Measures:Symptomatic infection; function, morbidity, mortality; pregnancy complications and birth outcomes. Results:Nineteen studies (N = 8443) meeting inclusion criteria were identified. Two cohort studies (n = 5289) found fewer cases of pyelonephritis in the cohorts of screened pregnant women (0.5%) than within retrospective comparisons of unscreened cohorts (2.2% and 1.8%); the larger study estimated a statistically significant relative risk of 0.30 (95% CI, 0.15-0.60). No studies examined screening in nonpregnant populations. Among 12 trials of asymptomatic bacteriuria screening and treatment during pregnancy (n = 2377; 1 conducted within past 30 years), there were reduced rates of pyelonephritis (range, 0%-16.5% for the intervention group and 2.2%-36.4% for the control group; pooled risk ratio [RR], 0.24 [95% CI, 0.14-0.40]; 12 trials) and low birth weight (range, 2.5%-14.8% for the intervention group and 6.7%-21.4% for the control group; pooled RR, 0.64 [95% CI, 0.46-0.90]; 7 trials). There was no significant difference in infant mortality (pooled RR, 0.98 [95% CI, 0.29-3.26]; 6 trials). Five RCTs of asymptomatic bacteriuria treatment in nonpregnant adults (n = 777) did not report any significant differences in risk of infection, mobility, or mortality. Limited evidence on harms of screening or treatment was available, and no statistically significant differences were identified. Conclusions and Relevance:Screening and treatment for asymptomatic bacteriuria during pregnancy was associated with reduced rates of pyelonephritis and low birth weights, but the available evidence was not current, with only 1 study conducted in the past 30 years. Benefits of asymptomatic bacteriuria treatment in nonpregnant adult populations were not found. Trial evidence on harms of asymptomatic bacteriuria antibiotic treatment was limited. 10.1001/jama.2019.10060
    Screening for Asymptomatic Bacteriuria in Adults: US Preventive Services Task Force Recommendation Statement. ,Owens Douglas K,Davidson Karina W,Krist Alex H,Barry Michael J,Cabana Michael,Caughey Aaron B,Doubeni Chyke A,Epling John W,Kubik Martha,Landefeld C Seth,Mangione Carol M,Pbert Lori,Silverstein Michael,Simon Melissa A,Tseng Chien-Wen,Wong John B JAMA Importance:Among the general adult population, women (across all ages) have the highest prevalence of asymptomatic bacteriuria, although rates increase with age among both men and women. Asymptomatic bacteriuria is present in an estimated 1% to 6% of premenopausal women and an estimated 2% to 10% of pregnant women and is associated with pyelonephritis, one of the most common nonobstetric reasons for hospitalization in pregnant women. Among pregnant persons, pyelonephritis is associated with perinatal complications including septicemia, respiratory distress, low birth weight, and spontaneous preterm birth. Objective:To update its 2008 recommendation, the USPSTF commissioned a review of the evidence on potential benefits and harms of screening for and treatment of asymptomatic bacteriuria in adults, including pregnant persons. Population:This recommendation applies to community-dwelling adults 18 years and older and pregnant persons of any age without signs and symptoms of a urinary tract infection. Evidence Assessment:Based on a review of the evidence, the USPSTF concludes with moderate certainty that screening for and treatment of asymptomatic bacteriuria in pregnant persons has moderate net benefit in reducing perinatal complications. There is adequate evidence that pyelonephritis in pregnancy is associated with negative maternal outcomes and that treatment of screen-detected asymptomatic bacteriuria can reduce the incidence of pyelonephritis in pregnant persons. The USPSTF found adequate evidence of harms associated with treatment of asymptomatic bacteriuria (including adverse effects of antibiotic treatment and changes in the microbiome) to be at least small in magnitude. The USPSTF concludes with moderate certainty that screening for and treatment of asymptomatic bacteriuria in nonpregnant adults has no net benefit. The known harms associated with treatment include adverse effects of antibiotic use and changes to the microbiome. Based on these known harms, the USPSTF determined the overall harms to be at least small in this group. Recommendations:The USPSTF recommends screening pregnant persons for asymptomatic bacteriuria using urine culture. (B recommendation) The USPSTF recommends against screening for asymptomatic bacteriuria in nonpregnant adults. (D recommendation). 10.1001/jama.2019.13069
    Oral Lefamulin vs Moxifloxacin for Early Clinical Response Among Adults With Community-Acquired Bacterial Pneumonia: The LEAP 2 Randomized Clinical Trial. Alexander Elizabeth,Goldberg Lisa,Das Anita F,Moran Gregory J,Sandrock Christian,Gasink Leanne B,Spera Patricia,Sweeney Carolyn,Paukner Susanne,Wicha Wolfgang W,Gelone Steven P,Schranz Jennifer JAMA Importance:New antibacterials are needed to treat community-acquired bacterial pneumonia (CABP) because of growing antibacterial resistance and safety concerns with standard care. Objective:To evaluate the efficacy and adverse events of a 5-day oral lefamulin regimen in patients with CABP. Design, Setting, and Participants:A phase 3, noninferiority randomized clinical trial conducted at 99 sites in 19 countries that included adults aged 18 years or older with a Pneumonia Outcomes Research Team (PORT) risk class of II, III, or IV; radiographically documented pneumonia; acute illness; 3 or more CABP symptoms; and 2 or more vital sign abnormalities. The first patient visit was on August 30, 2016, and patients were followed up for 30 days; the final follow-up visit was on January 2, 2018. Interventions:Patients were randomized 1:1 to receive oral lefamulin (600 mg every 12 hours for 5 days; n = 370) or moxifloxacin (400 mg every 24 hours for 7 days; n = 368). Main Outcomes and Measures:The US Food and Drug Administration (FDA) primary end point was early clinical response at 96 hours (within a 24-hour window) after the first dose of either study drug in the intent-to-treat (ITT) population (all randomized patients). Responders were defined as alive, showing improvement in 2 or more of the 4 CABP symptoms, having no worsening of any CABP symptoms, and not receiving any nonstudy antibacterial drug for current CABP episode. The European Medicines Agency coprimary end points (FDA secondary end points) were investigator assessment of clinical response at test of cure (5-10 days after last dose) in the modified ITT population and in the clinically evaluable population. The noninferiority margin was 10% for early clinical response and investigator assessment of clinical response. Results:Among 738 randomized patients (mean age, 57.5 years; 351 women [47.6%]; 360 had a PORT risk class of III or IV [48.8%]), 707 (95.8%) completed the trial. Early clinical response rates were 90.8% with lefamulin and 90.8% with moxifloxacin (difference, 0.1% [1-sided 97.5% CI, -4.4% to ∞]). Rates of investigator assessment of clinical response success were 87.5% with lefamulin and 89.1% with moxifloxacin in the modified ITT population (difference, -1.6% [1-sided 97.5% CI, -6.3% to ∞]) and 89.7% and 93.6%, respectively, in the clinically evaluable population (difference, -3.9% [1-sided 97.5% CI, -8.2% to ∞]) at test of cure. The most frequently reported treatment-emergent adverse events were gastrointestinal (diarrhea: 45/368 [12.2%] in lefamulin group and 4/368 [1.1%] in moxifloxacin group; nausea: 19/368 [5.2%] in lefamulin group and 7/368 [1.9%] in moxifloxacin group). Conclusions and Relevance:Among patients with CABP, 5-day oral lefamulin was noninferior to 7-day oral moxifloxacin with respect to early clinical response at 96 hours after first dose. Trial Registrations:ClinicalTrials.gov Identifier: NCT02813694; European Clinical Trials Identifier: 2015-004782-92. 10.1001/jama.2019.15468