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  • Vaccination of Infants with Meningococcal Group B Vaccine (4CMenB) in England
    N. Engl. J. Med. (IF 70.670) Pub Date : 2020-01-23
    Shamez N. Ladhani; Nick Andrews; Sydel R. Parikh; Helen Campbell; Joanne White; Michael Edelstein; Xilian Bai; Jay Lucidarme; Ray Borrow; Mary E. Ramsay

    Background In September 2015, the United Kingdom introduced the multicomponent meningococcal group B vaccine (4CMenB, Bexsero) into its publicly funded national immunization program at a reduced two-dose priming schedule for infants, with a 12-month booster. Methods Using data from enhanced national surveillance of invasive meningococcal disease in England, we evaluated the effect of vaccination on the incidence of meningococcal group B disease during the first 3 years of the program. The effect of vaccination was assessed by comparing the observed incidence of disease with the expected incidence based on the incidence during the 4-year prevaccination period in equivalent cohorts and with the use of disease trends in cohorts of children younger than 5 years of age who were not eligible to receive the vaccine. Vaccine effectiveness was estimated with the use of the indirect screening method. Results 4CMenB uptake in England remained consistently high; data from the first 3 months of 2018 showed that 92.5% of children had completed the primary immunizations by their first birthday and 87.9% had received all three doses by 2 years. From September 2015 through August 2018, the incidence of meningococcal group B disease in England (average annual birth cohort, approximately 650,000 infants) was significantly lower in vaccine-eligible cohorts than the expected incidence (63 observed cases as compared with 253 expected cases; incidence rate ratio, 0.25; 95% confidence interval [CI], 0.19 to 0.36), with a 75% reduction in age groups that were fully eligible for vaccination. The adjusted vaccine effectiveness against meningococcal group B disease was 52.7% (95% CI, −33.5 to 83.2) with a two-dose priming schedule for infants and 59.1% (95% CI, −31.1 to 87.2) with a two-dose priming schedule plus a booster at 1 year). Over the 3-year period, there were 169 cases of meningococcal group B disease in the vaccine-eligible cohorts, and an estimated 277 cases (95% CI, 236 to 323) were prevented. Conclusions The 4CMenB program was associated with continued positive effect against meningococcal group B disease in children in England, and protection after three doses of the vaccine was sustained for at least 2 years. (Funded by Public Health England.) QUICK TAKE VIDEO SUMMARY Effect of Group B Meningococcal Vaccination  02:04

    更新日期:2020-01-23
  • Meningococcal B Vaccine and Meningococcal Carriage in Adolescents in Australia
    N. Engl. J. Med. (IF 70.670) Pub Date : 2020-01-23
    Helen S. Marshall; Mark McMillan; Ann P. Koehler; Andrew Lawrence; Thomas R. Sullivan; Jenny M. MacLennan; Martin C.J. Maiden; Shamez N. Ladhani; Mary E. Ramsay; Caroline Trotter; Ray Borrow; Adam Finn; Charlene M. Kahler; Jane Whelan; Kumaran Vadivelu; Peter Richmond

    Background The meningococcal group B vaccine 4CMenB is a new, recombinant protein-based vaccine that is licensed to protect against invasive group B meningococcal disease. However, its role in preventing transmission and, therefore, inducing population (herd) protection is uncertain. Methods We used cluster randomization to assign, according to school, students in years 10 to 12 (age, 15 to 18 years) in South Australia to receive 4CMenB vaccination either at baseline (intervention) or at 12 months (control). The primary outcome was oropharyngeal carriage of disease-causing Neisseria meningitidis (group A, B, C, W, X, or Y) in students in years 10 and 11, as identified by polymerase-chain-reaction assays for PorA (encoding porin protein A) and N. meningitidis genogroups. Secondary outcomes included carriage prevalence and acquisition of all N. meningitidis and individual disease-causing genogroups. Risk factors for carriage were assessed at baseline. Results A total of 237 schools participated. During April through June 2017, a total of 24,269 students in years 10 and 11 and 10,220 students in year 12 were enrolled. At 12 months, there was no difference in the prevalence of carriage of disease-causing N. meningitidis between the vaccination group (2.55%; 326 of 12,746) and the control group (2.52%; 291 of 11,523) (adjusted odds ratio, 1.02; 95% confidence interval [CI], 0.80 to 1.31; P=0.85). There were no significant differences in the secondary carriage outcomes. At baseline, the risk factors for carriage of disease-causing N. meningitidis included later year of schooling (adjusted odds ratio for year 12 vs. year 10, 2.75; 95% CI, 2.03 to 3.73), current upper respiratory tract infection (adjusted odds ratio, 1.35; 95% CI, 1.12 to 1.63), cigarette smoking (adjusted odds ratio, 1.91; 95% CI, 1.29 to 2.83), water-pipe smoking (adjusted odds ratio, 1.82; 95% CI, 1.30 to 2.54), attending pubs or clubs (adjusted odds ratio, 1.54; 95% CI, 1.28 to 1.86), and intimate kissing (adjusted odds ratio, 1.65; 95% CI, 1.33 to 2.05). No vaccine safety concerns were identified. Conclusions Among Australian adolescents, the 4CMenB vaccine had no discernible effect on the carriage of disease-causing meningococci, including group B. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT03089086.)

    更新日期:2020-01-23
  • Elagolix for Heavy Menstrual Bleeding in Women with Uterine Fibroids
    N. Engl. J. Med. (IF 70.670) Pub Date : 2020-01-23
    William D. Schlaff; Ronald T. Ackerman; Ayman Al-Hendy; David F. Archer; Kurt T. Barnhart; Linda D. Bradley; Bruce R. Carr; Eve C. Feinberg; Sandra M. Hurtado; JinHee Kim; Ran Liu; R. Garn Mabey; Charlotte D. Owens; Alfred Poindexter; Elizabeth E. Puscheck; Henry Rodriguez-Ginorio; James A. Simon; Ahmed M. Soliman; Elizabeth A. Stewart; Nelson B. Watts; Ozgul Muneyyirci-Delale

    Background Uterine fibroids are hormone-responsive neoplasms that are associated with heavy menstrual bleeding. Elagolix, an oral gonadotropin-releasing hormone antagonist resulting in rapid, reversible suppression of ovarian sex hormones, may reduce fibroid-associated bleeding. Methods We conducted two identical, double-blind, randomized, placebo-controlled, 6-month phase 3 trials (Elaris Uterine Fibroids 1 and 2 [UF-1 and UF-2]) to evaluate the efficacy and safety of elagolix at a dose of 300 mg twice daily with hormonal “add-back” therapy (to replace reduced levels of endogenous hormones; in this case, estradiol, 1 mg, and norethindrone acetate, 0.5 mg, once daily) in women with fibroid-associated bleeding. An elagolix-alone group was included to assess the impact of add-back therapy on the hypoestrogenic effects of elagolix. The primary end point was menstrual blood loss of less than 80 ml during the final month of treatment and at least a 50% reduction in menstrual blood loss from baseline to the final month; missing data were imputed with the use of multiple imputation. Results A total of 412 women in UF-1 and 378 women in UF-2 underwent randomization, received elagolix or placebo, and were included in the analyses. Criteria for the primary end point were met in 68.5% of 206 women in UF-1 and in 76.5% of 189 women in UF-2 who received elagolix plus add-back therapy, as compared with 8.7% of 102 women and 10% of 94 women, respectively, who received placebo (P<0.001 for both trials). Among the women who received elagolix alone, the primary end point was met in 84.1% of 104 women in UF-1 and in 77% of 95 women in UF-2. Hot flushes (in both trials) and metrorrhagia (in UF-1) occurred significantly more commonly with elagolix plus add-back therapy than with placebo. Hypoestrogenic effects of elagolix, especially decreases in bone mineral density, were attenuated with add-back therapy. Conclusions Elagolix with add-back therapy was effective in reducing heavy menstrual bleeding in women with uterine fibroids. (Funded by AbbVie; Elaris UF-1 and Elaris UF-2 ClinicalTrials.gov numbers, NCT02654054 and NCT02691494.)

    更新日期:2020-01-23
  • Teprotumumab for the Treatment of Active Thyroid Eye Disease
    N. Engl. J. Med. (IF 70.670) Pub Date : 2020-01-23
    Raymond S. Douglas; George J. Kahaly; Amy Patel; Saba Sile; Elizabeth H.Z. Thompson; Renee Perdok; James C. Fleming; Brian T. Fowler; Claudio Marcocci; Michele Marinò; Alessandro Antonelli; Roger Dailey; Gerald J. Harris; Anja Eckstein; Jade Schiffman; Rosa Tang; Christine Nelson; Mario Salvi; Sara Wester; Jeffrey W. Sherman; Thomas Vescio; Robert J. Holt; Terry J. Smith

    Background Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition for which no Food and Drug Administration–approved medical therapy is available. Strong evidence has implicated the insulin-like growth factor I receptor (IGF-IR) in the pathogenesis of this disease. Methods In a randomized, double-masked, placebo-controlled, phase 3 multicenter trial, we assigned patients with active thyroid eye disease in a 1:1 ratio to receive intravenous infusions of the IGF-IR inhibitor teprotumumab (10 mg per kilogram of body weight for the first infusion and 20 mg per kilogram for subsequent infusions) or placebo once every 3 weeks for 21 weeks; the last trial visit for this analysis was at week 24. The primary outcome was a proptosis response (a reduction in proptosis of ≥2 mm) at week 24. Prespecified secondary outcomes at week 24 were an overall response (a reduction of ≥2 points in the Clinical Activity Score plus a reduction in proptosis of ≥2 mm), a Clinical Activity Score of 0 or 1 (indicating no or minimal inflammation), the mean change in proptosis across trial visits (from baseline through week 24), a diplopia response (a reduction in diplopia of ≥1 grade), and the mean change in overall score on the Graves’ ophthalmopathy-specific quality-of-life (GO-QOL) questionnaire across trial visits (from baseline through week 24; a mean change of ≥6 points is considered clinically meaningful). Results A total of 41 patients were assigned to the teprotumumab group and 42 to the placebo group. At week 24, the percentage of patients with a proptosis response was higher with teprotumumab than with placebo (83% [34 patients] vs. 10% [4 patients], P<0.001), with a number needed to treat of 1.36. All secondary outcomes were significantly better with teprotumumab than with placebo, including overall response (78% of patients [32] vs. 7% [3]), Clinical Activity Score of 0 or 1 (59% [24] vs. 21% [9]), the mean change in proptosis (−2.82 mm vs. −0.54 mm), diplopia response (68% [19 of 28] vs. 29% [8 of 28]), and the mean change in GO-QOL overall score (13.79 points vs. 4.43 points) (P≤0.001 for all). Reductions in extraocular muscle, orbital fat volume, or both were observed in 6 patients in the teprotumumab group who underwent orbital imaging. Most adverse events were mild or moderate in severity; two serious events occurred in the teprotumumab group, of which one (an infusion reaction) led to treatment discontinuation. Conclusions Among patients with active thyroid eye disease, teprotumumab resulted in better outcomes with respect to proptosis, Clinical Activity Score, diplopia, and quality of life than placebo; serious adverse events were uncommon. (Funded by Horizon Therapeutics; OPTIC ClinicalTrials.gov number, NCT03298867, and EudraCT number, 2017-002763-18.) VISUAL ABSTRACT Teprotumumab for Thyroid Eye Disease

    更新日期:2020-01-23
  • Trial of Anifrolumab in Active Systemic Lupus Erythematosus
    N. Engl. J. Med. (IF 70.670) Pub Date : 2020-01-16
    Eric F. Morand; Richard Furie; Yoshiya Tanaka; Ian N. Bruce; Anca D. Askanase; Christophe Richez; Sang-Cheol Bae; Philip Z. Brohawn; Lilia Pineda; Anna Berglind; Raj Tummala

    Background Anifrolumab, a human monoclonal antibody to type I interferon receptor subunit 1 investigated for the treatment of systemic lupus erythematosus (SLE), did not have a significant effect on the primary end point in a previous phase 3 trial. The current phase 3 trial used a secondary end point from that trial as the primary end point. Methods We randomly assigned patients in a 1:1 ratio to receive intravenous anifrolumab (300 mg) or placebo every 4 weeks for 48 weeks. The primary end point of this trial was a response at week 52 defined with the use of the British Isles Lupus Assessment Group (BILAG)–based Composite Lupus Assessment (BICLA). A BICLA response requires reduction in any moderate-to-severe baseline disease activity and no worsening in any of nine organ systems in the BILAG index, no worsening on the Systemic Lupus Erythematosus Disease Activity Index, no increase of 0.3 points or more in the score on the Physician Global Assessment of disease activity (on a scale from 0 [no disease activity] to 3 [severe disease]), no discontinuation of the trial intervention, and no use of medications restricted by the protocol. Secondary end points included a BICLA response in patients with a high interferon gene signature at baseline; reductions in the glucocorticoid dose, in the severity of skin disease, and in counts of swollen and tender joints; and the annualized flare rate. Results A total of 362 patients received the randomized intervention: 180 received anifrolumab and 182 received placebo. The percentage of patients who had a BICLA response was 47.8% in the anifrolumab group and 31.5% in the placebo group (difference, 16.3 percentage points; 95% confidence interval, 6.3 to 26.3; P=0.001). Among patients with a high interferon gene signature, the percentage with a response was 48.0% in the anifrolumab group and 30.7% in the placebo group; among patients with a low interferon gene signature, the percentage was 46.7% and 35.5%, respectively. Secondary end points with respect to the glucocorticoid dose and the severity of skin disease, but not counts of swollen and tender joints and the annualized flare rate, also showed a significant benefit with anifrolumab. Herpes zoster and bronchitis occurred in 7.2% and 12.2% of the patients, respectively, who received anifrolumab. There was one death from pneumonia in the anifrolumab group. Conclusions Monthly administration of anifrolumab resulted in a higher percentage of patients with a response (as defined by a composite end point) at week 52 than did placebo, in contrast to the findings of a similar phase 3 trial involving patients with SLE that had a different primary end point. The frequency of herpes zoster was higher with anifrolumab than with placebo. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT02446899.) VISUAL ABSTRACT Anifrolumab for Systemic Lupus Erythematosus

    更新日期:2020-01-16
  • A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants
    N. Engl. J. Med. (IF 70.670) Pub Date : 2020-01-16
    Sandra E. Juul; Bryan A. Comstock; Rajan Wadhawan; Dennis E. Mayock; Sherry E. Courtney; Tonya Robinson; Kaashif A. Ahmad; Ellen Bendel-Stenzel; Mariana Baserga; Edmund F. LaGamma; L. Corbin Downey; Raghavendra Rao; Nancy Fahim; Andrea Lampland; Ivan D. Frantz III; Janine Y. Khan; Michael Weiss; Maureen M. Gilmore; Robin K. Ohls; Nishant Srinivasan; Jorge E. Perez; Victor McKay; Phuong T. Vu; Jean Lowe; Karl Kuban; T. Michael O’Shea; Adam L. Hartman; Patrick J. Heagerty

    Background High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established. Methods In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for a total of six doses, followed by a maintenance dose of 400 U per kilogram three times per week by subcutaneous injection through 32 completed weeks of postmenstrual age. Placebo was administered as intravenous saline followed by sham injections. The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. Severe neurodevelopmental impairment was defined as severe cerebral palsy or a composite motor or composite cognitive score of less than 70 (which corresponds to 2 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. Results A total of 741 infants were included in the per-protocol efficacy analysis: 376 received erythropoietin and 365 received placebo. There was no significant difference between the erythropoietin group and the placebo group in the incidence of death or severe neurodevelopmental impairment at 2 years of age (97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence interval, 0.81 to 1.32; P=0.80). There were no significant differences between the groups in the rates of retinopathy of prematurity, intracranial hemorrhage, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in the frequency of serious adverse events. Conclusions High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age. (Funded by the National Institute of Neurological Disorders and Stroke; PENUT ClinicalTrials.gov number, NCT01378273.)

    更新日期:2020-01-16
  • Lipoprotein(a) Reduction in Persons with Cardiovascular Disease
    N. Engl. J. Med. (IF 70.670) Pub Date : 2020-01-16
    Sotirios Tsimikas; Ewa Karwatowska-Prokopczuk; Ioanna Gouni-Berthold; Jean-Claude Tardif; Seth J. Baum; Elizabeth Steinhagen-Thiessen; Michael D. Shapiro; Erik S. Stroes; Patrick M. Moriarty; Børge G. Nordestgaard; Shuting Xia; Jonathan Guerriero; Nicholas J. Viney; Louis O’Dea; Joseph L. Witztum

    Background Lipoprotein(a) levels are genetically determined and, when elevated, are a risk factor for cardiovascular disease and aortic stenosis. There are no approved pharmacologic therapies to lower lipoprotein(a) levels. Methods We conducted a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening lipoprotein(a) levels of at least 60 mg per deciliter (150 nmol per liter). Patients received the hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-LRx, referred to here as APO(a)-LRx (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or saline placebo subcutaneously for 6 to 12 months. The lipoprotein(a) level was measured with an isoform-independent assay. The primary end point was the percent change in lipoprotein(a) level from baseline to month 6 of exposure (week 25 in the groups that received monthly doses and week 27 in the groups that received more frequent doses). Results The median baseline lipoprotein(a) levels in the six groups ranged from 204.5 to 246.6 nmol per liter. Administration of APO(a)-LRx resulted in dose-dependent decreases in lipoprotein(a) levels, with mean percent decreases of 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001). There were no significant differences between any APO(a)-LRx dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions. Conclusions APO(a)-LRx reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease. (Funded by Akcea Therapeutics; ClinicalTrials.gov number, NCT03070782.)

    更新日期:2020-01-16
  • JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency
    N. Engl. J. Med. (IF 70.670) Pub Date : 2020-01-16
    Fahad Alsohime; Marta Martin-Fernandez; Mohamad-Hani Temsah; Majed Alabdulhafid; Tom Le Voyer; Malak Alghamdi; Xueer Qiu; Najla Alotaibi; Areej Alkahtani; Sofija Buta; Emmanuelle Jouanguy; Ayman Al-Eyadhy; Conor Gruber; Gamal M. Hasan; Fahad A. Bashiri; Rabih Halwani; Hamdy H. Hassan; Saleh Al-Muhsen; Nouf Alkhamis; Zobaida Alsum; Jean-Laurent Casanova; Jacinta Bustamante; Dusan Bogunovic; Abdullah A. Alangari

    Deficiency of ubiquitin-specific peptidase 18 (USP18) is a severe type I interferonopathy. USP18 down-regulates type I interferon signaling by blocking the access of Janus-associated kinase 1 (JAK1) to the type I interferon receptor. The absence of USP18 results in unmitigated interferon-mediated inflammation and is lethal during the perinatal period. We describe a neonate who presented with hydrocephalus, necrotizing cellulitis, systemic inflammation, and respiratory failure. Exome sequencing identified a homozygous mutation at an essential splice site on USP18. The encoded protein was expressed but devoid of negative regulatory ability. Treatment with ruxolitinib was followed by a prompt and sustained recovery. (Funded by King Saud University and others.)

    更新日期:2020-01-16
  • Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes
    N. Engl. J. Med. (IF 70.670) Pub Date : 2020-01-09
    Pierre Fenaux; Uwe Platzbecker; Ghulam J. Mufti; Guillermo Garcia-Manero; Rena Buckstein; Valeria Santini; María Díez-Campelo; Carlo Finelli; Mario Cazzola; Osman Ilhan; Mikkael A. Sekeres; José F. Falantes; Beatriz Arrizabalaga; Flavia Salvi; Valentina Giai; Paresh Vyas; David Bowen; Dominik Selleslag; Amy E. DeZern; Joseph G. Jurcic; Ulrich Germing; Katharina S. Götze; Bruno Quesnel; Odile Beyne-Rauzy; Thomas Cluzeau; Maria-Teresa Voso; Dominiek Mazure; Edo Vellenga; Peter L. Greenberg; Eva Hellström-Lindberg; Amer M. Zeidan; Lionel Adès; Amit Verma; Michael R. Savona; Abderrahmane Laadem; Aziz Benzohra; Jennie Zhang; Anita Rampersad; Diana R. Dunshee; Peter G. Linde; Matthew L. Sherman; Rami S. Komrokji; Alan F. List

    Background Patients with anemia and lower-risk myelodysplastic syndromes in whom erythropoiesis-stimulating agent therapy is not effective generally become dependent on red-cell transfusions. Luspatercept, a recombinant fusion protein that binds transforming growth factor β superfamily ligands to reduce SMAD2 and SMAD3 signaling, showed promising results in a phase 2 study. Methods In a double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients with very-low-risk, low-risk, or intermediate-risk myelodysplastic syndromes (defined according to the Revised International Prognostic Scoring System) with ring sideroblasts who had been receiving regular red-cell transfusions to receive either luspatercept (at a dose of 1.0 up to 1.75 mg per kilogram of body weight) or placebo, administered subcutaneously every 3 weeks. The primary end point was transfusion independence for 8 weeks or longer during weeks 1 through 24, and the key secondary end point was transfusion independence for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48. Results Of the 229 patients enrolled, 153 were randomly assigned to receive luspatercept and 76 to receive placebo; the baseline characteristics of the patients were balanced. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in the luspatercept group, as compared with 13% of those in the placebo group (P<0.001). A higher percentage of patients in the luspatercept group than in the placebo group met the key secondary end point (28% vs. 8% for weeks 1 through 24, and 33% vs. 12% for weeks 1 through 48; P<0.001 for both comparisons). The most common luspatercept-associated adverse events (of any grade) included fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of adverse events decreased over time. Conclusions Luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts who had been receiving regular red-cell transfusions and who had disease that was refractory to or unlikely to respond to erythropoiesis-stimulating agents or who had discontinued such agents owing to an adverse event. (Funded by Celgene and Acceleron Pharma; MEDALIST ClinicalTrials.gov number, NCT02631070; EudraCT number, 2015-003454-41.)

    更新日期:2020-01-09
  • A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke
    N. Engl. J. Med. (IF 70.670) Pub Date : 2020-01-02
    Pierre Amarenco; Jong S. Kim; Julien Labreuche; Hugo Charles; Jérémie Abtan; Yannick Béjot; Lucie Cabrejo; Jae-Kwan Cha; Grégory Ducrocq; Maurice Giroud; Celine Guidoux; Cristina Hobeanu; Yong-Jae Kim; Bertrand Lapergue; Philippa C. Lavallée; Byung-Chul Lee; Kyung-Bok Lee; Didier Leys; Marie-Hélène Mahagne; Elena Meseguer; Norbert Nighoghossian; Fernando Pico; Yves Samson; Igor Sibon; P. Gabriel Steg; Sang-Min Sung; Pierre-Jean Touboul; Emmanuel Touzé; Olivier Varenne; Éric Vicaut; Nessima Yelles; Eric Bruckert

    Background The use of intensive lipid-lowering therapy by means of statin medications is recommended after transient ischemic attack (TIA) and ischemic stroke of atherosclerotic origin. The target level for low-density lipoprotein (LDL) cholesterol to reduce cardiovascular events after stroke has not been well studied. Methods In this parallel-group trial conducted in France and South Korea, we randomly assigned patients with ischemic stroke in the previous 3 months or a TIA within the previous 15 days to a target LDL cholesterol level of less than 70 mg per deciliter (1.8 mmol per liter) (lower-target group) or to a target range of 90 mg to 110 mg per deciliter (2.3 to 2.8 mmol per liter) (higher-target group). All the patients had evidence of cerebrovascular or coronary-artery atherosclerosis and received a statin, ezetimibe, or both. The composite primary end point of major cardiovascular events included ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or death from cardiovascular causes. Results A total of 2860 patients were enrolled and followed for a median of 3.5 years; 1430 were assigned to each LDL cholesterol target group. The mean LDL cholesterol level at baseline was 135 mg per deciliter (3.5 mmol per liter), and the mean achieved LDL cholesterol level was 65 mg per deciliter (1.7 mmol per liter) in the lower-target group and 96 mg per deciliter (2.5 mmol per liter) in the higher-target group. The trial was stopped for administrative reasons after 277 of an anticipated 385 end-point events had occurred. The composite primary end point occurred in 121 patients (8.5%) in the lower-target group and in 156 (10.9%) in the higher-target group (adjusted hazard ratio, 0.78; 95% confidence interval, 0.61 to 0.98; P=0.04). The incidence of intracranial hemorrhage and newly diagnosed diabetes did not differ significantly between the two groups. Conclusions After an ischemic stroke or TIA with evidence of atherosclerosis, patients who had a target LDL cholesterol level of less than 70 mg per deciliter had a lower risk of subsequent cardiovascular events than those who had a target range of 90 mg to 110 mg per deciliter. (Funded by the French Ministry of Health and others; Treat Stroke to Target ClinicalTrials.gov number, NCT01252875.) QUICK TAKE VIDEO SUMMARY Lowering the Target for LDL Cholesterol after Stroke  01:43

    更新日期:2020-01-02
  • Alcohol Abstinence in Drinkers with Atrial Fibrillation
    N. Engl. J. Med. (IF 70.670) Pub Date : 2020-01-02
    Aleksandr Voskoboinik; Jonathan M. Kalman; Anurika De Silva; Thomas Nicholls; Benedict Costello; Shane Nanayakkara; Sandeep Prabhu; Dion Stub; Sonia Azzopardi; Donna Vizi; Geoffrey Wong; Chrishan Nalliah; Hariharan Sugumar; Michael Wong; Emily Kotschet; David Kaye; Andrew J. Taylor; Peter M. Kistler

    Background Excessive alcohol consumption is associated with incident atrial fibrillation and adverse atrial remodeling; however, the effect of abstinence from alcohol on secondary prevention of atrial fibrillation is unclear. Methods We conducted a multicenter, prospective, open-label, randomized, controlled trial at six hospitals in Australia. Adults who consumed 10 or more standard drinks (with 1 standard drink containing approximately 12 g of pure alcohol) per week and who had paroxysmal or persistent atrial fibrillation in sinus rhythm at baseline were randomly assigned in a 1:1 ratio to either abstain from alcohol or continue their usual alcohol consumption. The two primary end points were freedom from recurrence of atrial fibrillation (after a 2-week “blanking period”) and total atrial fibrillation burden (proportion of time in atrial fibrillation) during 6 months of follow-up. Results Of 140 patients who underwent randomization (85% men; mean [±SD] age, 62±9 years), 70 were assigned to the abstinence group and 70 to the control group. Patients in the abstinence group reduced their alcohol intake from 16.8±7.7 to 2.1±3.7 standard drinks per week (a reduction of 87.5%), and patients in the control group reduced their alcohol intake from 16.4±6.9 to 13.2±6.5 drinks per week (a reduction of 19.5%). After a 2-week blanking period, atrial fibrillation recurred in 37 of 70 patients (53%) in the abstinence group and in 51 of 70 patients (73%) in the control group. The abstinence group had a longer period before recurrence of atrial fibrillation than the control group (hazard ratio, 0.55; 95% confidence interval, 0.36 to 0.84; P=0.005). The atrial fibrillation burden over 6 months of follow-up was significantly lower in the abstinence group than in the control group (median percentage of time in atrial fibrillation, 0.5% [interquartile range, 0.0 to 3.0] vs. 1.2% [interquartile range, 0.0 to 10.3]; P=0.01). Conclusions Abstinence from alcohol reduced arrhythmia recurrences in regular drinkers with atrial fibrillation. (Funded by the Government of Victoria Operational Infrastructure Support Program and others; Australian New Zealand Clinical Trials Registry number, ACTRN12616000256471.) VISUAL ABSTRACT Alcohol Abstinence for Atrial Fibrillation

    更新日期:2020-01-02
  • Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A
    N. Engl. J. Med. (IF 70.670) Pub Date : 2020-01-02
    K. John Pasi; Savita Rangarajan; Nina Mitchell; Will Lester; Emily Symington; Bella Madan; Michael Laffan; Chris B. Russell; Mingjin Li; Glenn F. Pierce; Wing Y. Wong

    Background Adeno-associated virus (AAV)–mediated gene therapy is under investigation as a therapeutic option for persons with hemophilia A. Efficacy and safety data include 3 years of follow-up after a single administration of AAV5-hFVIII-SQ. Methods We report durable efficacy, long-term safety, and clinical and biologic results in 15 adults with severe hemophilia A (factor VIII level, ≤1 IU per deciliter) who had received a single infusion of AAV5-hFVIII-SQ at various dose levels. We evaluated the factor VIII level, annualized rate of bleeding events, use of factor VIII, safety, expression kinetics, and biologic markers of AAV transduction for up to 3 years. Results Three years after infusion, two participants (one who had received 6×1012 vector genomes [vg] per kilogram of body weight and one who had received 2×1013 vg per kilogram) had factor VIII expression of less than 1 IU per deciliter, as assessed on chromogenic assay. Seven participants (who had received 6×1013 vg per kilogram) had a median factor VIII expression of 20 IU per deciliter; the median number of annualized treated bleeding events was 0, and the median use of exogenous factor VIII was reduced from 138.5 infusions to 0 infusions per year. Bleeding in all target joints (major joints with ≥3 bleeding events within 6 months) in this cohort resolved (≤2 bleeding events within 12 months). Two years after infusion, six participants (who had received 4×1013 vg per kilogram) had a median factor VIII expression of 13 IU per deciliter; the median annualized rate of bleeding events was 0, and the median use of factor VIII was reduced from 155.5 infusions to 0.5 infusions per year. Bleeding in target joints resolved in five of six participants. The factor VIII pharmacodynamic profiles reflected cellular turnover in the blood and molecular events leading to episomal DNA stabilization for persistent expression, findings that are consistent with previous observations in two model systems. Transgene-derived human factor VIII (hFVIII) protein activity mirrored native hFVIII in hemostatic ability. No inhibitor development, thromboses, deaths, or persistent changes in liver-function tests were observed. Conclusions Gene therapy with AAV5-hFVIII-SQ vector in participants with hemophilia A resulted in sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor VIII use in all participants who had received 4×1013 vg per kilogram or 6×1013 vg per kilogram of the gene therapy. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795; EudraCT number, 2014-003880-38.)

    更新日期:2020-01-02
  • Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC
    N. Engl. J. Med. (IF 70.670) Pub Date : 2020-01-02
    Suresh S. Ramalingam; Johan Vansteenkiste; David Planchard; Byoung Chul Cho; Jhanelle E. Gray; Yuichiro Ohe; Caicun Zhou; Thanyanan Reungwetwattana; Ying Cheng; Busyamas Chewaskulyong; Riyaz Shah; Manuel Cobo; Ki Hyeong Lee; Parneet Cheema; Marcello Tiseo; Thomas John; Meng-Chih Lin; Fumio Imamura; Takayasu Kurata; Alexander Todd; Rachel Hodge; Matilde Saggese; Yuri Rukazenkov; Jean-Charles Soria

    Background Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) that selectively inhibits both EGFR-TKI–sensitizing and EGFR T790M resistance mutations. A phase 3 trial compared first-line osimertinib with other EGFR-TKIs in patients with EGFR mutation–positive advanced non–small-cell lung cancer (NSCLC). The trial showed longer progression-free survival with osimertinib than with the comparator EGFR-TKIs (hazard ratio for disease progression or death, 0.46). Data from the final analysis of overall survival have not been reported. Methods In this trial, we randomly assigned 556 patients with previously untreated advanced NSCLC with an EGFR mutation (exon 19 deletion or L858R allele) in a 1:1 ratio to receive either osimertinib (80 mg once daily) or one of two other EGFR-TKIs (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily, with patients receiving these drugs combined in a single comparator group). Overall survival was a secondary end point. Results The median overall survival was 38.6 months (95% confidence interval [CI], 34.5 to 41.8) in the osimertinib group and 31.8 months (95% CI, 26.6 to 36.0) in the comparator group (hazard ratio for death, 0.80; 95.05% CI, 0.64 to 1.00; P=0.046). At 3 years, 79 of 279 patients (28%) in the osimertinib group and 26 of 277 (9%) in the comparator group were continuing to receive a trial regimen; the median exposure was 20.7 months and 11.5 months, respectively. Adverse events of grade 3 or higher were reported in 42% of the patients in the osimertinib group and in 47% of those in the comparator group. Conclusions Among patients with previously untreated advanced NSCLC with an EGFR mutation, those who received osimertinib had longer overall survival than those who received a comparator EGFR-TKI. The safety profile for osimertinib was similar to that of the comparator EGFR-TKIs, despite a longer duration of exposure in the osimertinib group. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125.)

    更新日期:2020-01-02
  • Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-12-26
    Jean-Claude Tardif; Simon Kouz; David D. Waters; Olivier F. Bertrand; Rafael Diaz; Aldo P. Maggioni; Fausto J. Pinto; Reda Ibrahim; Habib Gamra; Ghassan S. Kiwan; Colin Berry; José López-Sendón; Petr Ostadal; Wolfgang Koenig; Denis Angoulvant; Jean C. Grégoire; Marc-André Lavoie; Marie-Pierre Dubé; David Rhainds; Mylène Provencher; Lucie Blondeau; Andreas Orfanos; Philippe L. L’Allier; Marie-Claude Guertin; François Roubille

    Background Experimental and clinical evidence supports the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent antiinflammatory medication that is indicated for the treatment of gout and pericarditis. Methods We performed a randomized, double-blind trial involving patients recruited within 30 days after a myocardial infarction. The patients were randomly assigned to receive either low-dose colchicine (0.5 mg once daily) or placebo. The primary efficacy end point was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. The components of the primary end point and safety were also assessed. Results A total of 4745 patients were enrolled; 2366 patients were assigned to the colchicine group, and 2379 to the placebo group. Patients were followed for a median of 22.6 months. The primary end point occurred in 5.5% of the patients in the colchicine group, as compared with 7.1% of those in the placebo group (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P=0.02). The hazard ratios were 0.84 (95% CI, 0.46 to 1.52) for death from cardiovascular causes, 0.83 (95% CI, 0.25 to 2.73) for resuscitated cardiac arrest, 0.91 (95% CI, 0.68 to 1.21) for myocardial infarction, 0.26 (95% CI, 0.10 to 0.70) for stroke, and 0.50 (95% CI, 0.31 to 0.81) for urgent hospitalization for angina leading to coronary revascularization. Diarrhea was reported in 9.7% of the patients in the colchicine group and in 8.9% of those in the placebo group (P=0.35). Pneumonia was reported as a serious adverse event in 0.9% of the patients in the colchicine group and in 0.4% of those in the placebo group (P=0.03). Conclusions Among patients with a recent myocardial infarction, colchicine at a dose of 0.5 mg daily led to a significantly lower risk of ischemic cardiovascular events than placebo. (Funded by the Government of Quebec and others; COLCOT ClinicalTrials.gov number, NCT02551094.) QUICK TAKE VIDEO SUMMARY Low-Dose Colchicine after Myocardial Infarction  01:41

    更新日期:2019-12-26
  • Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-12-26
    Ronald de Wit; Johann de Bono; Cora N. Sternberg; Karim Fizazi; Bertrand Tombal; Christian Wülfing; Gero Kramer; Jean-Christophe Eymard; Aristotelis Bamias; Joan Carles; Roberto Iacovelli; Bohuslav Melichar; Ásgerður Sverrisdóttir; Christine Theodore; Susan Feyerabend; Carole Helissey; Ayse Ozatilgan; Christine Geffriaud-Ricouard; Daniel Castellano

    Background The efficacy and safety of cabazitaxel, as compared with an androgen-signaling–targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel and had progression within 12 months while receiving the alternative inhibitor (abiraterone or enzalutamide) are unclear. Methods We randomly assigned, in a 1:1 ratio, patients who had previously received docetaxel and an androgen-signaling–targeted inhibitor (abiraterone or enzalutamide) to receive cabazitaxel (at a dose of 25 mg per square meter of body-surface area intravenously every 3 weeks, plus prednisone daily and granulocyte colony-stimulating factor) or the other androgen-signaling–targeted inhibitor (either 1000 mg of abiraterone plus prednisone daily or 160 mg of enzalutamide daily). The primary end point was imaging-based progression-free survival. Secondary end points of survival, response, and safety were assessed. Results A total of 255 patients underwent randomization. After a median follow-up of 9.2 months, imaging-based progression or death was reported in 95 of 129 patients (73.6%) in the cabazitaxel group, as compared with 101 of 126 patients (80.2%) in the group that received an androgen-signaling–targeted inhibitor (hazard ratio, 0.54; 95% confidence interval [CI], 0.40 to 0.73; P<0.001). The median imaging-based progression-free survival was 8.0 months with cabazitaxel and 3.7 months with the androgen-signaling–targeted inhibitor. The median overall survival was 13.6 months with cabazitaxel and 11.0 months with the androgen-signaling–targeted inhibitor (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.89; P=0.008). The median progression-free survival was 4.4 months with cabazitaxel and 2.7 months with an androgen-signaling–targeted inhibitor (hazard ratio for progression or death, 0.52; 95% CI, 0.40 to 0.68; P<0.001), a prostate-specific antigen response occurred in 35.7% and 13.5% of the patients, respectively (P<0.001), and tumor response was noted in 36.5% and 11.5% (P=0.004). Adverse events of grade 3 or higher occurred in 56.3% of patients receiving cabazitaxel and in 52.4% of those receiving an androgen-signaling–targeted inhibitor. No new safety signals were observed. Conclusions Cabazitaxel significantly improved a number of clinical outcomes, as compared with the androgen-signaling–targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who had been previously treated with docetaxel and the alternative androgen-signaling–targeted agent (abiraterone or enzalutamide). (Funded by Sanofi; CARD ClinicalTrials.gov number, NCT02485691.) VISUAL ABSTRACT Cabazitaxel in Metastatic Prostate Cancer

    更新日期:2019-12-26
  • Schistosomiasis — Assessing Progress toward the 2020 and 2025 Global Goals
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-12-26
    Arminder K. Deol; Fiona M. Fleming; Beatriz Calvo-Urbano; Martin Walker; Victor Bucumi; Issah Gnandou; Edridah M. Tukahebwa; Samuel Jemu; Upendo J. Mwingira; Abdulhakeem Alkohlani; Mahamadou Traoré; Eugene Ruberanziza; Seydou Touré; Maria-Gloria Basáñez; Michael D. French; Joanne P. Webster

    With the vision of “a world free of schistosomiasis,” the World Health Organization (WHO) set ambitious goals of control of this debilitating disease and its elimination as a public health problem by 2020 and 2025, respectively. As these milestones become imminent, and if programs are to succeed, it is important to evaluate the WHO programmatic guidelines empirically.

    更新日期:2019-12-26
  • Early High-Dose Vitamin D3 for Critically Ill, Vitamin D–Deficient Patients
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-12-26
    The National Heart

    Background Vitamin D deficiency is a common, potentially reversible contributor to morbidity and mortality among critically ill patients. The potential benefits of vitamin D supplementation in acute critical illness require further study. Methods We conducted a randomized, double-blind, placebo-controlled, phase 3 trial of early vitamin D3 supplementation in critically ill, vitamin D–deficient patients who were at high risk for death. Randomization occurred within 12 hours after the decision to admit the patient to an intensive care unit. Eligible patients received a single enteral dose of 540,000 IU of vitamin D3 or matched placebo. The primary end point was 90-day all-cause, all-location mortality. Results A total of 1360 patients were found to be vitamin D–deficient during point-of-care screening and underwent randomization. Of these patients, 1078 had baseline vitamin D deficiency (25-hydroxyvitamin D level, <20 ng per milliliter [50 nmol per liter]) confirmed by subsequent testing and were included in the primary analysis population. The mean day 3 level of 25-hydroxyvitamin D was 46.9±23.2 ng per milliliter (117±58 nmol per liter) in the vitamin D group and 11.4±5.6 ng per milliliter (28±14 nmol per liter) in the placebo group (difference, 35.5 ng per milliliter; 95% confidence interval [CI], 31.5 to 39.6). The 90-day mortality was 23.5% in the vitamin D group (125 of 531 patients) and 20.6% in the placebo group (109 of 528 patients) (difference, 2.9 percentage points; 95% CI, −2.1 to 7.9; P=0.26). There were no clinically important differences between the groups with respect to secondary clinical, physiological, or safety end points. The severity of vitamin D deficiency at baseline did not affect the association between the treatment assignment and mortality. Conclusions Early administration of high-dose enteral vitamin D3 did not provide an advantage over placebo with respect to 90-day mortality or other, nonfatal outcomes among critically ill, vitamin D–deficient patients. (Funded by the National Heart, Lung, and Blood Institute; VIOLET ClinicalTrials.gov number, NCT03096314.)

    更新日期:2019-12-26
  • Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-12-19
    Antonio González-Martín; Bhavana Pothuri; Ignace Vergote; René DePont Christensen; Whitney Graybill; Mansoor R. Mirza; Colleen McCormick; Domenica Lorusso; Paul Hoskins; Gilles Freyer; Klaus Baumann; Kris Jardon; Andrés Redondo; Richard G. Moore; Christof Vulsteke; Roisin E. O’Cearbhaill; Bente Lund; Floor Backes; Pilar Barretina-Ginesta; Ashley F. Haggerty; Maria J. Rubio-Pérez; Mark S. Shahin; Giorgia Mangili; William H. Bradley; Ilan Bruchim; Kaiming Sun; Izabela A. Malinowska; Yong Li; Divya Gupta; Bradley J. Monk

    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 BRCA 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.) QUICK TAKE VIDEO SUMMARY A PARP Inhibitor for Ovarian Cancer  02:10

    更新日期:2019-12-19
  • Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-12-19
    Robert L. Coleman; Gini F. Fleming; Mark F. Brady; Elizabeth M. Swisher; Karina D. Steffensen; Michael Friedlander; Aikou Okamoto; Kathleen N. Moore; Noa Efrat Ben-Baruch; Theresa L. Werner; Noelle G. Cloven; Ana Oaknin; Paul A. DiSilvestro; Mark A. Morgan; Joo-Hyun Nam; Charles A. Leath; Shibani Nicum; Andrea R. Hagemann; Ramey D. Littell; David Cella; Sally Baron-Hay; Jesus Garcia-Donas; Mika Mizuno; Katherine Bell-McGuinn; Danielle M. Sullivan; Bruce A. Bach; Sudipta Bhattacharya; Christine K. Ratajczak; Peter J. Ansell; Minh H. Dinh; Carol Aghajanian; Michael A. Bookman

    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 BRCA-mutation cohort, the cohort with homologous-recombination deficiency (HRD) (which included the BRCA-mutation cohort), and the intention-to-treat population. Results A total of 1140 patients underwent randomization. In the BRCA-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.)

    更新日期:2019-12-19
  • Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-12-19
    Isabelle Ray-Coquard; Patricia Pautier; Sandro Pignata; David Pérol; Antonio González-Martín; Regina Berger; Keiichi Fujiwara; Ignace Vergote; Nicoletta Colombo; Johanna Mäenpää; Frédéric Selle; Jalid Sehouli; Domenica Lorusso; Eva M. Guerra Alía; Alexander Reinthaller; Shoji Nagao; Claudia Lefeuvre-Plesse; Ulrich Canzler; Giovanni Scambia; Alain Lortholary; Frederik Marmé; Pierre Combe; Nikolaus de Gregorio; Manuel Rodrigues; Paul Buderath; Coraline Dubot; Alexander Burges; Benoît You; Eric Pujade-Lauraine; Philipp Harter

    Background Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a BRCA mutation. The effect of combining maintenance olaparib and bevacizumab in patients regardless of BRCA mutation status is unknown. Methods We conducted a randomized, double-blind, international phase 3 trial. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinum–taxane chemotherapy plus bevacizumab. Patients were eligible regardless of surgical outcome or BRCA mutation status. Patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg twice daily) or placebo for up to 24 months; all the patients received bevacizumab at a dose of 15 mg per kilogram of body weight every 3 weeks for up to 15 months in total. The primary end point was the time from randomization until investigator-assessed disease progression or death. Results Of the 806 patients who underwent randomization, 537 were assigned to receive olaparib and 269 to receive placebo. After a median follow-up of 22.9 months, the median progression-free survival was 22.1 months with olaparib plus bevacizumab and 16.6 months with placebo plus bevacizumab (hazard ratio for disease progression or death, 0.59; 95% confidence interval [CI], 0.49 to 0.72; P<0.001). The hazard ratio (olaparib group vs. placebo group) for disease progression or death was 0.33 (95% CI, 0.25 to 0.45) in patients with tumors positive for homologous-recombination deficiency (HRD), including tumors that had BRCA mutations (median progression-free survival, 37.2 vs. 17.7 months), and 0.43 (95% CI, 0.28 to 0.66) in patients with HRD-positive tumors that did not have BRCA mutations (median progression-free survival, 28.1 vs. 16.6 months). Adverse events were consistent with the established safety profiles of olaparib and bevacizumab. Conclusions In patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a BRCA mutation. (Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644.)

    更新日期:2019-12-19
  • Final Analysis of a Trial of M72/AS01E Vaccine to Prevent Tuberculosis
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-12-19
    Dereck R. Tait; Mark Hatherill; Olivier Van Der Meeren; Ann M. Ginsberg; Elana Van Brakel; Bruno Salaun; Thomas J. Scriba; Elaine J. Akite; Helen M. Ayles; Anne Bollaerts; Marie-Ange Demoitié; Andreas Diacon; Thomas G. Evans; Paul Gillard; Elizabeth Hellström; James C. Innes; Maria Lempicki; Mookho Malahleha; Neil Martinson; Doris Mesia Vela; Monde Muyoyeta; Videlis Nduba; Thierry G. Pascal; Michele Tameris; Friedrich Thienemann; Robert J. Wilkinson; François Roman

    Results of an earlier analysis of a trial of the M72/AS01E candidate vaccine against Mycobacterium tuberculosis showed that in infected adults, the vaccine provided 54.0% protection against active pulmonary tuberculosis disease, without evident safety concerns. We now report the results of the 3-year final analysis of efficacy, safety, and immunogenicity.

    更新日期:2019-12-19
  • A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-12-12
    Sabue Mulangu; Lori E. Dodd; Richard T. Davey; Olivier Tshiani Mbaya; Michael Proschan; Daniel Mukadi; Mariano Lusakibanza Manzo; Didier Nzolo; Antoine Tshomba Oloma; Augustin Ibanda; Rosine Ali; Sinaré Coulibaly; Adam C. Levine; Rebecca Grais; Janet Diaz; H. Clifford Lane; Jean-Jacques Muyembe-Tamfum; the PALM Writing Group

    Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial.

    更新日期:2019-12-13
  • Metoprolol for the Prevention of Acute Exacerbations of COPD
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-12-12
    Mark T. Dransfield; Helen Voelker; Surya P. Bhatt; Keith Brenner; Richard Casaburi; Carolyn E. Come; J. Allen D. Cooper; Gerard J. Criner; Jeffrey L. Curtis; MeiLan K. Han; Umur Hatipoğlu; Erika S. Helgeson; Vipul V. Jain; Ravi Kalhan; David Kaminsky; Robert Kaner; Ken M. Kunisaki; Allison A. Lambert; Matthew R. Lammi; Sarah Lindberg; Barry J. Make; Fernando J. Martinez; Charlene McEvoy; Ralph J. Panos; Robert M. Reed; Paul D. Scanlon; Frank C. Sciurba; Anthony Smith; Peruvemba S. Sriram; William W. Stringer; Jeremy A. Weingarten; J. Michael Wells; Elizabeth Westfall; Stephen C. Lazarus; John E. Connett

    Background Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials. Methods In this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol. Results A total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV1) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P=0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group. Conclusions Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.) VISUAL ABSTRACT Beta-Blockers for COPD Exacerbations

    更新日期:2019-12-13
  • Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-12-12
    Timothy P. Hughes; Michael J. Mauro; Jorge E. Cortes; Hironobu Minami; Delphine Rea; Daniel J. DeAngelo; Massimo Breccia; Yeow-Tee Goh; Moshe Talpaz; Andreas Hochhaus; Philipp le Coutre; Oliver Ottmann; Michael C. Heinrich; Juan L. Steegmann; Michael W.N. Deininger; Jeroen J.W.M. Janssen; Francois-Xavier Mahon; Yosuke Minami; David Yeung; David M. Ross; Martin S. Tallman; Jae H. Park; Brian J. Druker; David Hynds; Yuyan Duan; Christophe Meille; Florence Hourcade-Potelleret; K. Gary Vanasse; Fabian Lang; Dong-Wook Kim

    Background Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome–positive leukemia are unknown. Methods In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months. Results Patients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia. Conclusions Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02081378.)

    更新日期:2019-12-13
  • Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-12-12
    Jean-Baptiste Lascarrou; Hamid Merdji; Amélie Le Gouge; Gwenhael Colin; Guillaume Grillet; Patrick Girardie; Elisabeth Coupez; Pierre-François Dequin; Alain Cariou; Thierry Boulain; Noelle Brule; Jean-Pierre Frat; Pierre Asfar; Nicolas Pichon; Mickael Landais; Gaëtan Plantefeve; Jean-Pierre Quenot; Jean-Charles Chakarian; Michel Sirodot; Stéphane Legriel; Julien Letheulle; Didier Thevenin; Arnaud Desachy; Arnaud Delahaye; Vlad Botoc; Sylvie Vimeux; Frederic Martino; Bruno Giraudeau; Jean Reignier

    Background Moderate therapeutic hypothermia is currently recommended to improve neurologic outcomes in adults with persistent coma after resuscitated out-of-hospital cardiac arrest. However, the effectiveness of moderate therapeutic hypothermia in patients with nonshockable rhythms (asystole or pulseless electrical activity) is debated. Methods We performed an open-label, randomized, controlled trial comparing moderate therapeutic hypothermia (33°C during the first 24 hours) with targeted normothermia (37°C) in patients with coma who had been admitted to the intensive care unit (ICU) after resuscitation from cardiac arrest with nonshockable rhythm. The primary outcome was survival with a favorable neurologic outcome, assessed on day 90 after randomization with the use of the Cerebral Performance Category (CPC) scale (which ranges from 1 to 5, with higher scores indicating greater disability). We defined a favorable neurologic outcome as a CPC score of 1 or 2. Outcome assessment was blinded. Mortality and safety were also assessed. Results From January 2014 through January 2018, a total of 584 patients from 25 ICUs underwent randomization, and 581 were included in the analysis (3 patients withdrew consent). On day 90, a total of 29 of 284 patients (10.2%) in the hypothermia group were alive with a CPC score of 1 or 2, as compared with 17 of 297 (5.7%) in the normothermia group (difference, 4.5 percentage points; 95% confidence interval [CI], 0.1 to 8.9; P=0.04). Mortality at 90 days did not differ significantly between the hypothermia group and the normothermia group (81.3% and 83.2%, respectively; difference, −1.9 percentage points; 95% CI, −8.0 to 4.3). The incidence of prespecified adverse events did not differ significantly between groups. Conclusions Among patients with coma who had been resuscitated from cardiac arrest with nonshockable rhythm, moderate therapeutic hypothermia at 33°C for 24 hours led to a higher percentage of patients who survived with a favorable neurologic outcome at day 90 than was observed with targeted normothermia. (Funded by the French Ministry of Health and others; HYPERION ClinicalTrials.gov number, NCT01994772.)

    更新日期:2019-12-13
  • Total Hip Arthroplasty or Hemiarthroplasty for Hip Fracture
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-12-05
    The HEALTH Investigators

    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.) QUICK TAKE VIDEO SUMMARY Comparing Surgical Options for Hip Fracture  02:00

    更新日期:2019-12-05
  • Phase 3 Efficacy Analysis of a Typhoid Conjugate Vaccine Trial in Nepal
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-12-05
    Mila Shakya; Rachel Colin-Jones; Katherine Theiss-Nyland; Merryn Voysey; Dikshya Pant; Nicola Smith; Xinxue Liu; Susan Tonks; Olga Mazur; Yama G. Farooq; Jenny Clarke; Jennifer Hill; Anup Adhikari; Sabina Dongol; Abhilasha Karkey; Binod Bajracharya; Sarah Kelly; Meeru Gurung; Stephen Baker; Kathleen M. Neuzil; Shrijana Shrestha; Buddha Basnyat; Andrew J. Pollard

    Salmonella Typhi is a major cause of fever in children in low- and middle-income countries. A typhoid conjugate vaccine (TCV) that was recently prequalified by the World Health Organization was shown to be efficacious in a human challenge model, but data from efficacy trials in areas where typhoid is endemic are lacking.

    更新日期:2019-12-05
  • Endoscopic or Surgical Myotomy in Patients with Idiopathic Achalasia
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-12-05
    Yuki B. Werner; Bengt Hakanson; Jan Martinek; Alessandro Repici; Burkhard H.A. von Rahden; Albert J. Bredenoord; Raf Bisschops; Helmut Messmann; Marius C. Vollberg; Tania Noder; Jan F. Kersten; Oliver Mann; Jakob Izbicki; Alexander Pazdro; Uberto Fumagalli; Riccardo Rosati; Christoph-Thomas Germer; Marlies P. Schijven; Alice Emmermann; Daniel von Renteln; Paul Fockens; Guy Boeckxstaens; Thomas Rösch

    Background Pneumatic dilation and laparoscopic Heller’s myotomy (LHM) are established treatments for idiopathic achalasia. Peroral endoscopic myotomy (POEM) is a less invasive therapy with promising early study results. Methods In a multicenter, randomized trial, we compared POEM with LHM plus Dor’s fundoplication in patients with symptomatic achalasia. The primary end point was clinical success, defined as an Eckardt symptom score of 3 or less (range, 0 to 12, with higher scores indicating more severe symptoms of achalasia) without the use of additional treatments, at the 2-year follow-up; a noninferiority margin of −12.5 percentage points was used in the primary analysis. Secondary end points included adverse events, esophageal function, Gastrointestinal Quality of Life Index score (range, 0 to 144, with higher scores indicating better function), and gastroesophageal reflux. Results A total of 221 patients were randomly assigned to undergo either POEM (112 patients) or LHM plus Dor’s fundoplication (109 patients). Clinical success at the 2-year follow-up was observed in 83.0% of patients in the POEM group and 81.7% of patients in the LHM group (difference, 1.4 percentage points; 95% confidence interval [CI], −8.7 to 11.4; P=0.007 for noninferiority). Serious adverse events occurred in 2.7% of patients in the POEM group and 7.3% of patients in the LHM group. Improvement in esophageal function from baseline to 24 months, as assessed by measurement of the integrated relaxation pressure of the lower esophageal sphincter, did not differ significantly between the treatment groups (difference, −0.75 mm Hg; 95% CI, −2.26 to 0.76), nor did improvement in the score on the Gastrointestinal Quality of Life Index (difference, 0.14 points; 95% CI, −4.01 to 4.28). At 3 months, 57% of patients in the POEM group and 20% of patients in the LHM group had reflux esophagitis, as assessed by endoscopy; at 24 months, the corresponding percentages were 44% and 29%. Conclusions In this randomized trial, POEM was noninferior to LHM plus Dor’s fundoplication in controlling symptoms of achalasia at 2 years. Gastroesophageal reflux was more common among patients who underwent POEM than among those who underwent LHM. (Funded by the European Clinical Research Infrastructure Network and others; ClinicalTrials.gov number, NCT01601678.)

    更新日期:2019-12-05
  • Ubrogepant for the Treatment of Migraine
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-12-05
    David W. Dodick; Richard B. Lipton; Jessica Ailani; Kaifeng Lu; Michelle Finnegan; Joel M. Trugman; Armin Szegedi

    Background Ubrogepant is an oral, small-molecule calcitonin gene–related peptide receptor antagonist for acute migraine treatment. Methods We conducted a randomized trial to evaluate the efficacy, safety, and side-effect profile of ubrogepant. We assigned adults with migraine, with or without aura, in a 1:1:1 ratio to receive an initial dose of placebo, ubrogepant at a dose of 50 mg, or ubrogepant at a dose of 100 mg for treatment of a single migraine attack, with the option to take a second dose. The coprimary efficacy end points were freedom from pain at 2 hours after the initial dose and absence of the most bothersome migraine-associated symptom at 2 hours. Secondary end points included pain relief (at 2 hours), sustained pain relief (from 2 to 24 hours), sustained freedom from pain (from 2 to 24 hours), and absence of symptoms associated with migraine (photophobia, phonophobia, and nausea) at 2 hours. Results A total of 1672 participants were enrolled; 559 were assigned to receive placebo, 556 to receive 50 mg of ubrogepant, and 557 to receive 100 mg of ubrogepant. The percentage of participants who had freedom from pain at 2 hours was 11.8% in the placebo group, 19.2% in the 50-mg ubrogepant group (P=0.002, adjusted for multiplicity, for the comparison with placebo), and 21.2% in the 100-mg ubrogepant group (P<0.001). The percentage of participants who had freedom from the most bothersome symptom at 2 hours was 27.8% in the placebo group, 38.6% in the 50-mg ubrogepant group (P=0.002), and 37.7% in the 100-mg ubrogepant group (P=0.002). Adverse events within 48 hours after the initial or optional second dose were reported in 12.8% of participants in the placebo group, in 9.4% in the 50-mg ubrogepant group, and in 16.3% in the 100-mg ubrogepant group. The most common adverse events were nausea, somnolence, and dry mouth (reported in 0.4 to 4.1%); these events were more frequent in the 100-mg ubrogepant group (reported in 2.1 to 4.1%). Serious adverse events reported within 30 days in the ubrogepant groups included appendicitis, spontaneous abortion, pericardial effusion, and seizure; none of the events occurred within 48 hours after the dose. Conclusions A higher percentage of participants who received ubrogepant than of those who received placebo had freedom from pain and absence of the most bothersome symptom at 2 hours after the dose. The most commonly reported adverse events were nausea, somnolence, and dry mouth. Further trials are needed to determine the durability and safety of ubrogepant for acute migraine treatment and to compare it with other drugs for migraine. (Funded by Allergan; ClinicalTrials.gov number, NCT02828020.)

    更新日期:2019-12-05
  • Supplemental MRI Screening for Women with Extremely Dense Breast Tissue
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-11-28
    Marije F. Bakker; Stéphanie V. de Lange; Ruud M. Pijnappel; Ritse M. Mann; Petra H.M. Peeters; Evelyn M. Monninkhof; Marleen J. Emaus; Claudette E. Loo; Robertus H.C. Bisschops; Marc B.I. Lobbes; Matthijn D.F. de Jong; Katya M. Duvivier; Jeroen Veltman; Nico Karssemeijer; Harry J. de Koning; Paul J. van Diest; Willem P.T.M. Mali; Maurice A.A.J. van den Bosch; Wouter B. Veldhuis; Carla H. van Gils

    Background Extremely dense breast tissue is a risk factor for breast cancer and limits the detection of cancer with mammography. Data are needed on the use of supplemental magnetic resonance imaging (MRI) to improve early detection and reduce interval breast cancers in such patients. Methods In this multicenter, randomized, controlled trial in the Netherlands, we assigned 40,373 women between the ages of 50 and 75 years with extremely dense breast tissue and normal results on screening mammography to a group that was invited to undergo supplemental MRI or to a group that received mammography screening only. The groups were assigned in a 1:4 ratio, with 8061 in the MRI-invitation group and 32,312 in the mammography-only group. The primary outcome was the between-group difference in the incidence of interval cancers during a 2-year screening period. Results The interval-cancer rate was 2.5 per 1000 screenings in the MRI-invitation group and 5.0 per 1000 screenings in the mammography-only group, for a difference of 2.5 per 1000 screenings (95% confidence interval [CI], 1.0 to 3.7; P<0.001). Of the women who were invited to undergo MRI, 59% accepted the invitation. Of the 20 interval cancers that were diagnosed in the MRI-invitation group, 4 were diagnosed in the women who actually underwent MRI (0.8 per 1000 screenings) and 16 in those who did not accept the invitation (4.9 per 1000 screenings). The MRI cancer-detection rate among the women who actually underwent MRI screening was 16.5 per 1000 screenings (95% CI, 13.3 to 20.5). The positive predictive value was 17.4% (95% CI, 14.2 to 21.2) for recall for additional testing and 26.3% (95% CI, 21.7 to 31.6) for biopsy. The false positive rate was 79.8 per 1000 screenings. Among the women who underwent MRI, 0.1% had either an adverse event or a serious adverse event during or immediately after the screening. Conclusions The use of supplemental MRI screening in women with extremely dense breast tissue and normal results on mammography resulted in the diagnosis of significantly fewer interval cancers than mammography alone during a 2-year screening period. (Funded by the University Medical Center Utrecht and others; DENSE ClinicalTrials.gov number, NCT01315015.) QUICK TAKE VIDEO SUMMARY MRI Screening for Dense Breasts  01:55

    更新日期:2019-11-28
  • Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-11-28
    Jaideep Kapur; Jordan Elm; James M. Chamberlain; William Barsan; James Cloyd; Daniel Lowenstein; Shlomo Shinnar; Robin Conwit; Caitlyn Meinzer; Hannah Cock; Nathan Fountain; Jason T. Connor; Robert Silbergleit

    Background The choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied. Methods In a randomized, blinded, adaptive trial, we compared the efficacy and safety of three intravenous anticonvulsive agents — levetiracetam, fosphenytoin, and valproate — in children and adults with convulsive status epilepticus that was unresponsive to treatment with benzodiazepines. The primary outcome was absence of clinically evident seizures and improvement in the level of consciousness by 60 minutes after the start of drug infusion, without additional anticonvulsant medication. The posterior probabilities that each drug was the most or least effective were calculated. Safety outcomes included life-threatening hypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence, and death. Results A total of 384 patients were enrolled and randomly assigned to receive levetiracetam (145 patients), fosphenytoin (118), or valproate (121). Reenrollment of patients with a second episode of status epilepticus accounted for 16 additional instances of randomization. In accordance with a prespecified stopping rule for futility of finding one drug to be superior or inferior, a planned interim analysis led to the trial being stopped. Of the enrolled patients, 10% were determined to have had psychogenic seizures. The primary outcome of cessation of status epilepticus and improvement in the level of consciousness at 60 minutes occurred in 68 patients assigned to levetiracetam (47%; 95% credible interval, 39 to 55), 53 patients assigned to fosphenytoin (45%; 95% credible interval, 36 to 54), and 56 patients assigned to valproate (46%; 95% credible interval, 38 to 55). The posterior probability that each drug was the most effective was 0.41, 0.24, and 0.35, respectively. Numerically more episodes of hypotension and intubation occurred in the fosphenytoin group and more deaths occurred in the levetiracetam group than in the other groups, but these differences were not significant. Conclusions In the context of benzodiazepine-refractory convulsive status epilepticus, the anticonvulsant drugs levetiracetam, fosphenytoin, and valproate each led to seizure cessation and improved alertness by 60 minutes in approximately half the patients, and the three drugs were associated with similar incidences of adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ESETT ClinicalTrials.gov number, NCT01960075.) VISUAL ABSTRACT Trial of Three Anticonvulsant Medications for Status Epilepticus

    更新日期:2019-11-28
  • Trial of Satralizumab in Neuromyelitis Optica Spectrum Disorder
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-11-28
    Takashi Yamamura; Ingo Kleiter; Kazuo Fujihara; Jacqueline Palace; Benjamin Greenberg; Beata Zakrzewska-Pniewska; Francesco Patti; Ching-Piao Tsai; Albert Saiz; Hayato Yamazaki; Yuichi Kawata; Padraig Wright; Jerome De Seze

    Background Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system and is associated with autoantibodies to anti–aquaporin-4 (AQP4-IgG) in approximately two thirds of patients. Interleukin-6 is involved in the pathogenesis of the disorder. Satralizumab is a humanized monoclonal antibody targeting the interleukin-6 receptor. The efficacy of satralizumab added to immunosuppressant treatment in patients with NMOSD is unclear. Methods In a phase 3, randomized, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1 ratio, patients with NMOSD who were seropositive or seronegative for AQP4-IgG to receive either satralizumab, at a dose of 120 mg, or placebo, administered subcutaneously at weeks 0, 2, and 4 and every 4 weeks thereafter, added to stable immunosuppressant treatment. The primary end point was the first protocol-defined relapse in a time-to-event analysis. Key secondary end points were the change from baseline to week 24 in the visual-analogue scale (VAS) pain score (range, 0 to 100, with higher scores indicating more pain) and the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) score (range, 0 to 52, with lower scores indicating more fatigue). Safety was also assessed. Results A total of 83 patients were enrolled, with 41 assigned to the satralizumab group and 42 to the placebo group. The median treatment duration with satralizumab in the double-blind period was 107.4 weeks. Relapse occurred in 8 patients (20%) receiving satralizumab and in 18 (43%) receiving placebo (hazard ratio, 0.38; 95% confidence interval [CI], 0.16 to 0.88). Multiple imputation for censored data resulted in hazard ratios ranging from 0.34 to 0.44 (with corresponding P values of 0.01 to 0.04). Among 55 AQP4-IgG–seropositive patients, relapse occurred in 11% of those in the satralizumab group and in 43% of those in the placebo group (hazard ratio, 0.21; 95% CI, 0.06 to 0.75); among 28 AQP4-IgG–seronegative patients, relapse occurred in 36% and 43%, respectively (hazard ratio, 0.66; 95% CI, 0.20 to 2.24). The between-group difference in the change in the mean VAS pain score was 4.08 (95% CI, −8.44 to 16.61); the between-group difference in the change in the mean FACIT-F score was −3.10 (95% CI, −8.38 to 2.18). The rates of serious adverse events and infections did not differ between groups. Conclusions Among patients with NMOSD, satralizumab added to immunosuppressant treatment led to a lower risk of relapse than placebo but did not differ from placebo in its effect on pain or fatigue. (Funded by Chugai Pharmaceutical; ClinicalTrials.gov number, NCT02028884.)

    更新日期:2019-11-28
  • Diagnosis of Pulmonary Embolism with d-Dimer Adjusted to Clinical Probability
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-11-28
    Clive Kearon; Kerstin de Wit; Sameer Parpia; Sam Schulman; Marc Afilalo; Andrew Hirsch; Frederick A. Spencer; Sangita Sharma; Frédérick D’Aragon; Jean-François Deshaies; Gregoire Le Gal; Alejandro Lazo-Langner; Cynthia Wu; Lisa Rudd-Scott; Shannon M. Bates; Jim A. Julian

    Background Retrospective analyses suggest that pulmonary embolism is ruled out by a d-dimer level of less than 1000 ng per milliliter in patients with a low clinical pretest probability (C-PTP) and by a d-dimer level of less than 500 ng per milliliter in patients with a moderate C-PTP. Methods We performed a prospective study in which pulmonary embolism was considered to be ruled out without further testing in outpatients with a low C-PTP and a d-dimer level of less than 1000 ng per milliliter or with a moderate C-PTP and a d-dimer level of less than 500 ng per milliliter. All other patients underwent chest imaging (usually computed tomographic pulmonary angiography). If pulmonary embolism was not diagnosed, patients did not receive anticoagulant therapy. All patients were followed for 3 months to detect venous thromboembolism. Results A total of 2017 patients were enrolled and evaluated, of whom 7.4% had pulmonary embolism on initial diagnostic testing. Of the 1325 patients who had a low C-PTP (1285 patients) or moderate C-PTP (40 patients) and a negative d-dimer test (i.e., <1000 or <500 ng per milliliter, respectively), none had venous thromboembolism during follow-up (95% confidence interval [CI], 0.00 to 0.29%). These included 315 patients who had a low C-PTP and a d-dimer level of 500 to 999 ng per milliliter (95% CI, 0.00 to 1.20%). Of all 1863 patients who did not receive a diagnosis of pulmonary embolism initially and did not receive anticoagulant therapy, 1 patient (0.05%; 95% CI, 0.01 to 0.30) had venous thromboembolism. Our diagnostic strategy resulted in the use of chest imaging in 34.3% of patients, whereas a strategy in which pulmonary embolism is considered to be ruled out with a low C-PTP and a d-dimer level of less than 500 ng per milliliter would result in the use of chest imaging in 51.9% (difference, −17.6 percentage points; 95% CI, −19.2 to −15.9). Conclusions A combination of a low C-PTP and a d-dimer level of less than 1000 ng per milliliter identified a group of patients at low risk for pulmonary embolism during follow-up. (Funded by the Canadian Institutes of Health Research and others; PEGeD ClinicalTrials.gov number, NCT02483442.)

    更新日期:2019-11-28
  • Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-11-21
    John J.V. McMurray; Scott D. Solomon; Silvio E. Inzucchi; Lars Køber; Mikhail N. Kosiborod; Felipe A. Martinez; Piotr Ponikowski; Marc S. Sabatine; Inder S. Anand; Jan Bělohlávek; Michael Böhm; Chern-En Chiang; Vijay K. Chopra; Rudolf A. de Boer; Akshay S. Desai; Mirta Diez; Jaroslaw Drozdz; Andrej Dukát; Junbo Ge; Jonathan G. Howlett; Tzvetana Katova; Masafumi Kitakaze; Charlotta E.A. Ljungman; Béla Merkely; Jose C. Nicolau; Eileen O’Meara; Mark C. Petrie; Pham N. Vinh; Morten Schou; Sergey Tereshchenko; Subodh Verma; Claes Held; David L. DeMets; Kieran F. Docherty; Pardeep S. Jhund; Olof Bengtsson; Mikaela Sjöstrand; Anna-Maria Langkilde

    Background In patients with type 2 diabetes, inhibitors of sodium–glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes. Methods In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death. Results Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups. Conclusions Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. (Funded by AstraZeneca; DAPA-HF ClinicalTrials.gov number, NCT03036124.) QUICK TAKE VIDEO SUMMARY Dapagliflozin in Patients with Heart Failure 01:46

    更新日期:2019-11-21
  • Efficacy of a Tetravalent Dengue Vaccine in Healthy Children and Adolescents
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-11-21
    Shibadas Biswal; Humberto Reynales; Xavier Saez-Llorens; Pio Lopez; Charissa Borja-Tabora; Pope Kosalaraksa; Chukiat Sirivichayakul; Veerachai Watanaveeradej; Luis Rivera; Felix Espinoza; LakKumar Fernando; Reynaldo Dietze; Kleber Luz; Rivaldo Venâncio da Cunha; José Jimeno; Eduardo López-Medina; Astrid Borkowski; Manja Brose; Martina Rauscher; Inge LeFevre; Svetlana Bizjajeva; Lulu Bravo; Derek Wallace

    Dengue, a mosquito-borne viral disease, was designated a World Health Organization top 10 threat to global health in 2019.

    更新日期:2019-11-21
  • Nivolumab plus Ipilimumab in Advanced Non–Small-Cell Lung Cancer
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-11-21
    Matthew D. Hellmann; Luis Paz-Ares; Reyes Bernabe Caro; Bogdan Zurawski; Sang-We Kim; Enric Carcereny Costa; Keunchil Park; Aurelia Alexandru; Lorena Lupinacci; Emmanuel de la Mora Jimenez; Hiroshi Sakai; Istvan Albert; Alain Vergnenegre; Solange Peters; Konstantinos Syrigos; Fabrice Barlesi; Martin Reck; Hossein Borghaei; Julie R. Brahmer; Kenneth J. O’Byrne; William J. Geese; Prabhu Bhagavatheeswaran; Sridhar K. Rabindran; Ravi S. Kasinathan; Faith E. Nathan; Suresh S. Ramalingam

    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.)

    更新日期:2019-11-21
  • Ticagrelor with or without Aspirin in High-Risk Patients after PCI
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-11-21
    Roxana Mehran; Usman Baber; Samin K. Sharma; David J. Cohen; Dominick J. Angiolillo; Carlo Briguori; Jin Y. Cha; Timothy Collier; George Dangas; Dariusz Dudek; Vladimír Džavík; Javier Escaned; Robert Gil; Paul Gurbel; Christian W. Hamm; Timothy Henry; Kurt Huber; Adnan Kastrati; Upendra Kaul; Ran Kornowski; Mitchell Krucoff; Vijay Kunadian; Steven O. Marx; Shamir R. Mehta; David Moliterno; E. Magnus Ohman; Keith Oldroyd; Gennaro Sardella; Samantha Sartori; Richard Shlofmitz; P. Gabriel Steg; Giora Weisz; Bernhard Witzenbichler; Ya-ling Han; Stuart Pocock; C. Michael Gibson

    Background Monotherapy with a P2Y12 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.) VISUAL ABSTRACT Ticagrelor with or without Aspirin after PCI

    更新日期:2019-11-21
  • Drug-Resistant E. coli Bacteremia Transmitted by Fecal Microbiota Transplant
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-11-21
    Zachariah DeFilipp; Patricia P. Bloom; Mariam Torres Soto; Michael K. Mansour; Mohamad R.A. Sater; Miriam H. Huntley; Sarah Turbett; Raymond T. Chung; Yi-Bin Chen; Elizabeth L. Hohmann

    Fecal microbiota transplantation (FMT) is an emerging therapy for recurrent or refractory Clostridioides difficile infection and is being actively investigated for other conditions. We describe two patients in whom extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli bacteremia occurred after they had undergone FMT in two independent clinical trials; both cases were linked to the same stool donor by means of genomic sequencing. One of the patients died. Enhanced donor screening to limit the transmission of microorganisms that could lead to adverse infectious events and continued vigilance to define the benefits and risks of FMT across different patient populations are warranted.

    更新日期:2019-11-21
  • Phase 3 Efficacy Trial of Modified Vaccinia Ankara as a Vaccine against Smallpox
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-11-14
    Phillip R. Pittman; Matthew Hahn; HeeChoon S. Lee; Craig Koca; Nathaly Samy; Darja Schmidt; Joachim Hornung; Heinz Weidenthaler; Christopher R. Heery; Thomas P.H. Meyer; Günter Silbernagl; Jane Maclennan; Paul Chaplin

    Background Many countries have stockpiled vaccines because of concerns about the reemergence of smallpox. Traditional smallpox vaccines are based on replicating vaccinia viruses; these vaccines have considerable side effects. Methods To evaluate the efficacy of modified vaccinia Ankara (MVA) as a potential smallpox vaccine, we randomly assigned 440 participants to receive two doses of MVA followed by one dose of the established replicating-vaccinia vaccine ACAM2000 (the MVA group) or to receive one dose of ACAM2000 (the ACAM2000-only group). The two primary end points were noninferiority of the MVA vaccine to ACAM2000 with respect to the peak serum neutralizing antibody titers and attenuation of the ACAM2000-associated major cutaneous reaction by previous MVA vaccination, measured according to the maximum lesion area and the derived area attenuation ratio. Results A total of 220 and 213 participants were randomly assigned and vaccinated in the MVA group and ACAM2000-only group, respectively, and 208 participants received two MVA vaccinations. At peak visits, MVA vaccination induced a geometric mean titer of neutralizing antibodies of 153.5 at week 6, as compared with 79.3 at week 4 with ACAM2000 (a ratio of 1.94 [95% confidence interval {CI}, 1.56 to 2.40]). At day 14, the geometric mean titer of neutralizing antibodies induced by a single MVA vaccination (16.2) was equal to that induced by ACAM2000 (16.2), and the percentages of participants with seroconversion were similar (90.8% and 91.8%, respectively). The median lesion areas of the major cutaneous reaction were 0 mm2 in the MVA group and 76.0 mm2 in the ACAM2000-only group, resulting in an area attenuation ratio of 97.9% (95% CI, 96.6 to 98.3). There were fewer adverse events or adverse events of grade 3 or higher after both MVA vaccination periods in the MVA group than in the ACAM2000-only group (17 vs. 64 participants with adverse events of grade 3 or higher, P<0.001). Conclusions No safety concerns associated with the MVA vaccine were identified. Immune responses and attenuation of the major cutaneous reaction suggest that this MVA vaccine protected against variola infection. (Funded by the Office of the Assistant Secretary for Preparedness and Response Biomedical Advanced Research and Development Authority of the Department of Health and Human Services and Bavarian Nordic; ClinicalTrials.gov number, NCT01913353.) QUICK TAKE VIDEO SUMMARY A Modified Smallpox Vaccine 02:15

    更新日期:2019-11-14
  • Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-11-14
    Marco V. Perez; Kenneth W. Mahaffey; Haley Hedlin; John S. Rumsfeld; Ariadna Garcia; Todd Ferris; Vidhya Balasubramanian; Andrea M. Russo; Amol Rajmane; Lauren Cheung; Grace Hung; Justin Lee; Peter Kowey; Nisha Talati; Divya Nag; Santosh E. Gummidipundi; Alexis Beatty; Mellanie True Hills; Sumbul Desai; Christopher B. Granger; Manisha Desai; Mintu P. Turakhia

    Background Optical sensors on wearable devices can detect irregular pulses. The ability of a smartwatch application (app) to identify atrial fibrillation during typical use is unknown. Methods Participants without atrial fibrillation (as reported by the participants themselves) used a smartphone (Apple iPhone) app to consent to monitoring. If a smartwatch-based irregular pulse notification algorithm identified possible atrial fibrillation, a telemedicine visit was initiated and an electrocardiography (ECG) patch was mailed to the participant, to be worn for up to 7 days. Surveys were administered 90 days after notification of the irregular pulse and at the end of the study. The main objectives were to estimate the proportion of notified participants with atrial fibrillation shown on an ECG patch and the positive predictive value of irregular pulse intervals with a targeted confidence interval width of 0.10. Results We recruited 419,297 participants over 8 months. Over a median of 117 days of monitoring, 2161 participants (0.52%) received notifications of irregular pulse. Among the 450 participants who returned ECG patches containing data that could be analyzed — which had been applied, on average, 13 days after notification — atrial fibrillation was present in 34% (97.5% confidence interval [CI], 29 to 39) overall and in 35% (97.5% CI, 27 to 43) of participants 65 years of age or older. Among participants who were notified of an irregular pulse, the positive predictive value was 0.84 (95% CI, 0.76 to 0.92) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular pulse notification and 0.71 (97.5% CI, 0.69 to 0.74) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular tachogram. Of 1376 notified participants who returned a 90-day survey, 57% contacted health care providers outside the study. There were no reports of serious app-related adverse events. Conclusions The probability of receiving an irregular pulse notification was low. Among participants who received notification of an irregular pulse, 34% had atrial fibrillation on subsequent ECG patch readings and 84% of notifications were concordant with atrial fibrillation. This siteless (no on-site visits were required for the participants), pragmatic study design provides a foundation for large-scale pragmatic studies in which outcomes or adherence can be reliably assessed with user-owned devices. (Funded by Apple; Apple Heart Study ClinicalTrials.gov number, NCT03335800.)

    更新日期:2019-11-14
  • Trial of Apremilast for Oral Ulcers in Behçet’s Syndrome
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-11-14
    Gülen Hatemi; Alfred Mahr; Yoshiaki Ishigatsubo; Yeong-Wook Song; Mitsuhiro Takeno; Doyoung Kim; Melike Melikoğlu; Sue Cheng; Shannon McCue; Maria Paris; Mindy Chen; Yusuf Yazici

    Background The small-molecule phosphodiesterase 4 inhibitor apremilast modulates cytokines that are up-regulated in Behçet’s syndrome. In a phase 2 trial involving patients with Behçet’s syndrome, apremilast reduced the incidence and severity of oral ulcers. Data on the efficacy and safety of apremilast in patients with Behçet’s syndrome who had active oral ulcers and had not previously received biologic agents are limited. Methods In a phase 3 trial, we randomly assigned, in a 1:1 ratio, patients who had Behçet’s syndrome with active oral ulcers but no major organ involvement to receive either apremilast at a dose of 30 mg or placebo, administered orally, twice daily for 12 weeks, followed by a 52-week extension phase. The primary end point was the area under the curve (AUC) for the total number of oral ulcers during the 12-week placebo-controlled period (with lower values indicating fewer ulcers). There were 13 secondary end points, including complete response of oral ulcers, change from baseline in pain associated with oral ulcers, disease activity, and change from baseline in the Behçet’s Disease Quality of Life score (range, 0 to 30, with higher scores indicating greater impairment in quality of life). Safety was also assessed. Results A total of 207 patients underwent randomization (104 patients to the apremilast group and 103 to the placebo group). The AUC for the number of oral ulcers was 129.5 for apremilast, as compared with 222.1 for placebo (least-squares mean difference, −92.6; 95% confidence interval [CI], −130.6 to −54.6; P<0.001). The change from baseline in the Behçet’s Disease Quality of Life score was −4.3 points in the apremilast group, as compared with −1.2 points in the placebo group (least-squares mean difference, −3.1 points; 95% CI, −4.9 to −1.3). Adverse events with apremilast included diarrhea, nausea, and headache. Conclusions In patients with oral ulcers associated with Behçet’s syndrome, apremilast resulted in a greater reduction in the number of oral ulcers than placebo but was associated with adverse events, including diarrhea, nausea, and headache. (Funded by Celgene; ClinicalTrials.gov number, NCT02307513.) VISUAL ABSTRACT Apremilast for Oral Ulcers in Behçet’s Syndrome

    更新日期:2019-11-14
  • Secondary Surgical Cytoreduction for Recurrent Ovarian Cancer
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-11-14
    Robert L. Coleman; Nick M. Spirtos; Danielle Enserro; Thomas J. Herzog; Paul Sabbatini; Deborah K. Armstrong; Jae-Weon Kim; Sang-Yoon Park; Byoung-Gie Kim; Joo-Hyun Nam; Keiichi Fujiwara; Joan L. Walker; Ann C. Casey; Angeles Alvarez Secord; Steve Rubin; John K. Chan; Paul DiSilvestro; Susan A. Davidson; David E. Cohn; Krishnansu S. Tewari; Karen Basen-Engquist; Helen Q. Huang; Mark F. Brady; Robert S. Mannel

    Background Secondary surgical cytoreduction in women with platinum-sensitive, recurrent epithelial ovarian, primary peritoneal, or fallopian-tube (“ovarian”) cancer is widely practiced but has not been evaluated in phase 3 investigation. Methods We randomly assigned patients with recurrent ovarian cancer who had received one previous therapy, had an interval during which no platinum-based chemotherapy was used (platinum-free interval) of 6 months or more, and had investigator-determined resectable disease (to no macroscopic residual disease) to undergo secondary surgical cytoreduction and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Adjuvant chemotherapy (paclitaxel–carboplatin or gemcitabine–carboplatin) and use of bevacizumab were at the discretion of the investigator. The primary end point was overall survival. Results A total of 485 patients underwent randomization, 240 to secondary cytoreduction before chemotherapy and 245 to chemotherapy alone. The median follow-up was 48.1 months. Complete gross resection was achieved in 67% of the patients assigned to surgery who underwent the procedure. Platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance was administered to 84% of the patients overall and was equally distributed between the two groups. The hazard ratio for death (surgery vs. no surgery) was 1.29 (95% confidence interval [CI], 0.97 to 1.72; P=0.08), which corresponded to a median overall survival of 50.6 months and 64.7 months, respectively. Adjustment for platinum-free interval and chemotherapy choice did not alter the effect. The hazard ratio for disease progression or death (surgery vs. no surgery) was 0.82 (95% CI, 0.66 to 1.01; median progression-free survival, 18.9 months and 16.2 months, respectively). Surgical morbidity at 30 days was 9%; 1 patient (0.4%) died from postoperative complications. Patient-reported quality of life decreased significantly after surgery but did not differ significantly between the two groups after recovery. Conclusions In this trial involving patients with platinum-sensitive, recurrent ovarian cancer, secondary surgical cytoreduction followed by chemotherapy did not result in longer overall survival than chemotherapy alone. (Funded by the National Cancer Institute and others; GOG-0213 ClinicalTrials.gov number, NCT00565851.)

    更新日期:2019-11-14
  • Neurodegenerative Disease Mortality among Former Professional Soccer Players
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-11-07
    Daniel F. Mackay; Emma R. Russell; Katy Stewart; John A. MacLean; Jill P. Pell; William Stewart

    Background Neurodegenerative disorders have been reported in elite athletes who participated in contact sports. The incidence of neurodegenerative disease among former professional soccer players has not been well characterized. Methods We conducted a retrospective cohort study to compare mortality from neurodegenerative disease among 7676 former professional soccer players (identified from databases of Scottish players) with that among 23,028 controls from the general population who were matched to the players on the basis of sex, age, and degree of social deprivation. Causes of death were determined from death certificates. Data on medications dispensed for the treatment of dementia in the two cohorts were also compared. Prescription information was obtained from the national Prescribing Information System. Results Over a median of 18 years, 1180 former soccer players (15.4%) and 3807 controls (16.5%) died. All-cause mortality was lower among former players than among controls up to the age of 70 years and was higher thereafter. Mortality from ischemic heart disease was lower among former players than among controls (hazard ratio, 0.80; 95% confidence interval [CI], 0.66 to 0.97; P=0.02), as was mortality from lung cancer (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.001). Mortality with neurodegenerative disease listed as the primary cause was 1.7% among former soccer players and 0.5% among controls (subhazard ratio [the hazard ratio adjusted for competing risks of death from ischemic heart disease and death from any cancer], 3.45; 95% CI, 2.11 to 5.62; P<0.001). Among former players, mortality with neurodegenerative disease listed as the primary or a contributory cause on the death certificate varied according to disease subtype and was highest among those with Alzheimer’s disease (hazard ratio [former players vs. controls], 5.07; 95% CI, 2.92 to 8.82; P<0.001) and lowest among those with Parkinson’s disease (hazard ratio, 2.15; 95% CI, 1.17 to 3.96; P=0.01). Dementia-related medications were prescribed more frequently to former players than to controls (odds ratio, 4.90; 95% CI, 3.81 to 6.31; P<0.001). Mortality with neurodegenerative disease listed as the primary or a contributory cause did not differ significantly between goalkeepers and outfield players (hazard ratio, 0.73; 95% CI, 0.43 to 1.24; P=0.24), but dementia-related medications were prescribed less frequently to goalkeepers (odds ratio, 0.41; 95% CI, 0.19 to 0.89; P=0.02). Conclusions In this retrospective epidemiologic analysis, mortality from neurodegenerative disease was higher and mortality from other common diseases lower among former Scottish professional soccer players than among matched controls. Dementia-related medications were prescribed more frequently to former players than to controls. These observations need to be confirmed in prospective matched-cohort studies. (Funded by the Football Association and Professional Footballers’ Association.) QUICK TAKE VIDEO SUMMARY Neurodegenerative Disease Mortality and Former Professional Soccer Players 01:47

    更新日期:2019-11-07
  • Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-11-07
    Peter G. Middleton; Marcus A. Mall; Pavel Dřevínek; Larry C. Lands; Edward F. McKone; Deepika Polineni; Bonnie W. Ramsey; Jennifer L. Taylor-Cousar; Elizabeth Tullis; François Vermeulen; Gautham Marigowda; Charlotte M. McKee; Samuel M. Moskowitz; Nitin Nair; Jessica Savage; Christopher Simard; Simon Tian; David Waltz; Fengjuan Xuan; Steven M. Rowe; Raksha Jain

    Background Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del–minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes. Methods We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor–tezacaftor–ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del–minimal function genotypes. Patients were randomly assigned to receive elexacaftor–tezacaftor–ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4. Results A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor–tezacaftor–ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire–Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor–tezacaftor–ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor–tezacaftor–ivacaftor group. Conclusions Elexacaftor–tezacaftor–ivacaftor was efficacious in patients with cystic fibrosis with Phe508del–minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.) VISUAL ABSTRACT Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis

    更新日期:2019-11-07
  • Five-Year Outcomes after PCI or CABG for Left Main Coronary Disease
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-11-07
    Gregg W. Stone; A. Pieter Kappetein; Joseph F. Sabik; Stuart J. Pocock; Marie-Claude Morice; John Puskas; David E. Kandzari; Dimitri Karmpaliotis; W. Morris Brown; Nicholas J. Lembo; Adrian Banning; Béla Merkely; Ferenc Horkay; Piet W. Boonstra; Ad J. van Boven; Imre Ungi; Gabor Bogáts; Samer Mansour; Nicolas Noiseux; Manel Sabaté; Jose Pomar; Mark Hickey; Anthony Gershlick; Pawel E. Buszman; Andrzej Bochenek; Erick Schampaert; Pierre Pagé; Rodrigo Modolo; John Gregson; Charles A. Simonton; Roxana Mehran; Ioanna Kosmidou; Philippe Généreux; Aaron Crowley; Ovidiu Dressler; Patrick W. Serruys

    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.)

    更新日期:2019-11-07
  • Prevention of Early Ventilator-Associated Pneumonia after Cardiac Arrest
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-11-07
    Bruno François; Alain Cariou; Raphaël Clere-Jehl; Pierre-François Dequin; Françoise Renon-Carron; Thomas Daix; Christophe Guitton; Nicolas Deye; Stéphane Legriel; Gaëtan Plantefève; Jean-Pierre Quenot; Arnaud Desachy; Toufik Kamel; Sandrine Bedon-Carte; Jean-Luc Diehl; Nicolas Chudeau; Elias Karam; Isabelle Durand-Zaleski; Bruno Giraudeau; Philippe Vignon; Amélie Le Gouge

    Background Patients who are treated with targeted temperature management after out-of-hospital cardiac arrest with shockable rhythm are at increased risk for ventilator-associated pneumonia. The benefit of preventive short-term antibiotic therapy has not been shown. Methods We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving adult patients (>18 years of age) in intensive care units (ICUs) who were being mechanically ventilated after out-of-hospital cardiac arrest related to initial shockable rhythm and treated with targeted temperature management at 32 to 34°C. Patients with ongoing antibiotic therapy, chronic colonization with multidrug-resistant bacteria, or moribund status were excluded. Either intravenous amoxicillin–clavulanate (at doses of 1 g and 200 mg, respectively) or placebo was administered three times a day for 2 days, starting less than 6 hours after the cardiac arrest. The primary outcome was early ventilator-associated pneumonia (during the first 7 days of hospitalization). An independent adjudication committee determined diagnoses of ventilator-associated pneumonia. Results A total of 198 patients underwent randomization, and 194 were included in the analysis. After adjudication, 60 cases of ventilator-associated pneumonia were confirmed, including 51 of early ventilator-associated pneumonia. The incidence of early ventilator-associated pneumonia was lower with antibiotic prophylaxis than with placebo (19 patients [19%] vs. 32 [34%]; hazard ratio, 0.53; 95% confidence interval, 0.31 to 0.92; P=0.03). No significant differences between the antibiotic group and the control group were observed with respect to the incidence of late ventilator-associated pneumonia (4% and 5%, respectively), the number of ventilator-free days (21 days and 19 days), ICU length of stay (5 days and 8 days if patients were discharged and 7 days and 7 days if patients had died), and mortality at day 28 (41% and 37%). At day 7, no increase in resistant bacteria was identified. Serious adverse events did not differ significantly between the two groups. Conclusions A 2-day course of antibiotic therapy with amoxicillin–clavulanate in patients receiving a 32-to-34°C targeted temperature management strategy after out-of-hospital cardiac arrest with initial shockable rhythm resulted in a lower incidence of early ventilator-associated pneumonia than placebo. No significant between-group differences were observed for other key clinical variables, such as ventilator-free days and mortality at day 28. (Funded by the French Ministry of Health; ANTHARTIC ClinicalTrials.gov number, NCT02186951.)

    更新日期:2019-11-07
  • Six-Month Randomized, Multicenter Trial of Closed-Loop Control in Type 1 Diabetes
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-10-31
    Sue A. Brown; Boris P. Kovatchev; Dan Raghinaru; John W. Lum; Bruce A. Buckingham; Yogish C. Kudva; Lori M. Laffel; Carol J. Levy; Jordan E. Pinsker; R. Paul Wadwa; Eyal Dassau; Francis J. Doyle; Stacey M. Anderson; Mei Mei Church; Vikash Dadlani; Laya Ekhlaspour; Gregory P. Forlenza; Elvira Isganaitis; David W. Lam; Craig Kollman; Roy W. Beck

    Background Closed-loop systems that automate insulin delivery may improve glycemic outcomes in patients with type 1 diabetes. Methods In this 6-month randomized, multicenter trial, patients with type 1 diabetes were assigned in a 2:1 ratio to receive treatment with a closed-loop system (closed-loop group) or a sensor-augmented pump (control group). The primary outcome was the percentage of time that the blood glucose level was within the target range of 70 to 180 mg per deciliter (3.9 to 10.0 mmol per liter), as measured by continuous glucose monitoring. Results A total of 168 patients underwent randomization; 112 were assigned to the closed-loop group, and 56 were assigned to the control group. The age range of the patients was 14 to 71 years, and the glycated hemoglobin level ranged from 5.4 to 10.6%. All 168 patients completed the trial. The mean (±SD) percentage of time that the glucose level was within the target range increased in the closed-loop group from 61±17% at baseline to 71±12% during the 6 months and remained unchanged at 59±14% in the control group (mean adjusted difference, 11 percentage points; 95% confidence interval [CI], 9 to 14; P<0.001). The results with regard to the main secondary outcomes (percentage of time that the glucose level was >180 mg per deciliter, mean glucose level, glycated hemoglobin level, and percentage of time that the glucose level was <70 mg per deciliter or <54 mg per deciliter [3.0 mmol per liter]) all met the prespecified hierarchical criterion for significance, favoring the closed-loop system. The mean difference (closed loop minus control) in the percentage of time that the blood glucose level was lower than 70 mg per deciliter was −0.88 percentage points (95% CI, −1.19 to −0.57; P<0.001). The mean adjusted difference in glycated hemoglobin level after 6 months was −0.33 percentage points (95% CI, −0.53 to −0.13; P=0.001). In the closed-loop group, the median percentage of time that the system was in closed-loop mode was 90% over 6 months. No serious hypoglycemic events occurred in either group; one episode of diabetic ketoacidosis occurred in the closed-loop group. Conclusions In this 6-month trial involving patients with type 1 diabetes, the use of a closed-loop system was associated with a greater percentage of time spent in a target glycemic range than the use of a sensor-augmented insulin pump. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases; iDCL ClinicalTrials.gov number, NCT03563313.) QUICK TAKE VIDEO SUMMARY Closed-Loop Control Systems in Type 1 Diabetes 01:37

    更新日期:2019-11-01
  • Nintedanib in Progressive Fibrosing Interstitial Lung Diseases
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-10-31
    Kevin R. Flaherty; Athol U. Wells; Vincent Cottin; Anand Devaraj; Simon L.F. Walsh; Yoshikazu Inoue; Luca Richeldi; Martin Kolb; Kay Tetzlaff; Susanne Stowasser; Carl Coeck; Emmanuelle Clerisme-Beaty; Bernd Rosenstock; Manuel Quaresma; Thomas Haeufel; Rainer-Georg Goeldner; Rozsa Schlenker-Herceg; Kevin K. Brown

    Background Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the efficacy of nintedanib has been shown in idiopathic pulmonary fibrosis, its efficacy across a broad range of fibrosing lung diseases is unknown. Methods In this double-blind, placebo-controlled, phase 3 trial conducted in 15 countries, we randomly assigned patients with fibrosing lung disease affecting more than 10% of lung volume on high-resolution computed tomography (CT) to receive nintedanib at a dose of 150 mg twice daily or placebo. All the patients met criteria for progression of interstitial lung disease in the past 24 months despite treatment and had a forced vital capacity (FVC) of at least 45% of the predicted value and a diffusing capacity of the lung for carbon monoxide ranging from 30 to less than 80% of the predicted value. Randomization was stratified according to the fibrotic pattern (a pattern of usual interstitial pneumonia [UIP] or other fibrotic patterns) on high-resolution CT. The primary end point was the annual rate of decline in the FVC, as assessed over a 52-week period. The two primary populations for analysis were the overall population and patients with a UIP-like fibrotic pattern. Results A total of 663 patients were treated. In the overall population, the adjusted rate of decline in the FVC was −80.8 ml per year with nintedanib and −187.8 ml per year with placebo, for a between-group difference of 107.0 ml per year (95% confidence interval [CI], 65.4 to 148.5; P<0.001). In patients with a UIP-like fibrotic pattern, the adjusted rate of decline in the FVC was −82.9 ml per year with nintedanib and −211.1 ml per year with placebo, for a difference of 128.2 ml (95% CI, 70.8 to 185.6; P<0.001). Diarrhea was the most common adverse event, as reported in 66.9% and 23.9% of patients treated with nintedanib and placebo, respectively. Abnormalities on liver-function testing were more common in the nintedanib group than in the placebo group. Conclusions In patients with progressive fibrosing interstitial lung diseases, the annual rate of decline in the FVC was significantly lower among patients who received nintedanib than among those who received placebo. Diarrhea was a common adverse event. (Funded by Boehringer Ingelheim; INBUILD ClinicalTrials.gov number, NCT02999178.)

    更新日期:2019-11-01
  • Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-10-31
    Alexander E. Perl; Giovanni Martinelli; Jorge E. Cortes; Andreas Neubauer; Ellin Berman; Stefania Paolini; Pau Montesinos; Maria R. Baer; Richard A. Larson; Celalettin Ustun; Francesco Fabbiano; Harry P. Erba; Antonio Di Stasi; Robert Stuart; Rebecca Olin; Margaret Kasner; Fabio Ciceri; Wen-Chien Chou; Nikolai Podoltsev; Christian Recher; Hisayuki Yokoyama; Naoko Hosono; Sung-Soo Yoon; Je-Hwan Lee; Timothy Pardee; Amir T. Fathi; Chaofeng Liu; Nahla Hasabou; Xuan Liu; Erkut Bahceci; Mark J. Levis

    Background Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML. Methods In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3-mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission. Results Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%). Conclusions Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML. (Funded by Astellas Pharma; ADMIRAL ClinicalTrials.gov number, NCT02421939.) VISUAL ABSTRACT Gilteritinib vs. Salvage Chemotherapy for AML

    更新日期:2019-11-01
  • Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-10-24
    Scott D. Solomon; John J.V. McMurray; Inder S. Anand; Junbo Ge; Carolyn S.P. Lam; Aldo P. Maggioni; Felipe Martinez; Milton Packer; Marc A. Pfeffer; Burkert Pieske; Margaret M. Redfield; Jean L. Rouleau; Dirk J. van Veldhuisen; Faiez Zannad; Michael R. Zile; Akshay S. Desai; Brian Claggett; Pardeep S. Jhund; Sergey A. Boytsov; Josep Comin-Colet; John Cleland; Hans-Dirk Düngen; Eva Goncalvesova; Tzvetana Katova; Jose F. Kerr Saraiva; Małgorzata Lelonek; Bela Merkely; Michele Senni; Sanjiv J. Shah; Jingmin Zhou; Adel R. Rizkala; Jianjian Gong; Victor C. Shi; Martin P. Lefkowitz

    Background The angiotensin receptor–neprilysin inhibitor sacubitril–valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor–neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear. Methods We randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril–valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed. Results There were 894 primary events in 526 patients in the sacubitril–valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P=0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril–valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril–valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% CI, 0.0 to 2.1) higher in the sacubitril–valsartan group. Patients in the sacubitril–valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril–valsartan in patients with lower ejection fraction and in women. Conclusions Sacubitril–valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. (Funded by Novartis; PARAGON-HF ClinicalTrials.gov number, NCT01920711.)

    更新日期:2019-10-24
  • A Genotype-Guided Strategy for Oral P2Y12 Inhibitors in Primary PCI
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-10-24
    Daniel M.F. Claassens; Gerrit J.A. Vos; Thomas O. Bergmeijer; Renicus S. Hermanides; Arnoud W.J. van ’t Hof; Pim van der Harst; Emanuele Barbato; Carmine Morisco; Richard M. Tjon Joe Gin; Folkert W. Asselbergs; Arend Mosterd; Jean-Paul R. Herrman; Willem J.M. Dewilde; Paul W.A. Janssen; Johannes C. Kelder; Maarten J. Postma; Anthonius de Boer; Cornelis Boersma; Vera H.M. Deneer; Jurriën M. ten Berg

    Background It is unknown whether patients undergoing primary percutaneous coronary intervention (PCI) benefit from genotype-guided selection of oral P2Y12 inhibitors. Methods We conducted a randomized, open-label, assessor-blinded trial in which patients undergoing primary PCI with stent implantation were assigned in a 1:1 ratio to receive either a P2Y12 inhibitor on the basis of early CYP2C19 genetic testing (genotype-guided group) or standard treatment with either ticagrelor or prasugrel (standard-treatment group) for 12 months. In the genotype-guided group, carriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles received ticagrelor or prasugrel, and noncarriers received clopidogrel. The two primary outcomes were net adverse clinical events — defined as death from any cause, myocardial infarction, definite stent thrombosis, stroke, or major bleeding defined according to Platelet Inhibition and Patient Outcomes (PLATO) criteria — at 12 months (primary combined outcome; tested for noninferiority, with a noninferiority margin of 2 percentage points for the absolute difference) and PLATO major or minor bleeding at 12 months (primary bleeding outcome). Results For the primary analysis, 2488 patients were included: 1242 in the genotype-guided group and 1246 in the standard-treatment group. The primary combined outcome occurred in 63 patients (5.1%) in the genotype-guided group and in 73 patients (5.9%) in the standard-treatment group (absolute difference, −0.7 percentage points; 95% confidence interval [CI], −2.0 to 0.7; P<0.001 for noninferiority). The primary bleeding outcome occurred in 122 patients (9.8%) in the genotype-guided group and in 156 patients (12.5%) in the standard-treatment group (hazard ratio, 0.78; 95% CI, 0.61 to 0.98; P=0.04). Conclusions In patients undergoing primary PCI, a CYP2C19 genotype–guided strategy for selection of oral P2Y12 inhibitor therapy was noninferior to standard treatment with ticagrelor or prasugrel at 12 months with respect to thrombotic events and resulted in a lower incidence of bleeding. (Funded by the Netherlands Organization for Health Research and Development; POPular Genetics ClinicalTrials.gov number, NCT01761786; Netherlands Trial Register number, NL2872.) QUICK TAKE VIDEO SUMMARY Testing Genotype-Guided Therapy in PCI 02:05

    更新日期:2019-10-24
  • Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-10-24
    Scott Kopetz; Axel Grothey; Rona Yaeger; Eric Van Cutsem; Jayesh Desai; Takayuki Yoshino; Harpreet Wasan; Fortunato Ciardiello; Fotios Loupakis; Yong Sang Hong; Neeltje Steeghs; Tormod K. Guren; Hendrik-Tobias Arkenau; Pilar Garcia-Alfonso; Per Pfeiffer; Sergey Orlov; Sara Lonardi; Elena Elez; Tae-Won Kim; Jan H.M. Schellens; Christina Guo; Asha Krishnan; Jeroen Dekervel; Van Morris; Aitana Calvo Ferrandiz; L.S. Tarpgaard; Michael Braun; Ashwin Gollerkeri; Christopher Keir; Kati Maharry; Michael Pickard; Janna Christy-Bittel; Lisa Anderson; Victor Sandor; Josep Tabernero

    Background Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling. Methods In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E–mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis. Results The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group. Conclusions A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.)

    更新日期:2019-10-24
  • Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-10-24
    Jinkuk Kim; Chunguang Hu; Christelle Moufawad El Achkar; Lauren E. Black; Julie Douville; Austin Larson; Mary K. Pendergast; Sara F. Goldkind; Eunjung A. Lee; Ashley Kuniholm; Aubrie Soucy; Jai Vaze; Nandkishore R. Belur; Kristina Fredriksen; Iva Stojkovska; Alla Tsytsykova; Myriam Armant; Renata L. DiDonato; Jaejoon Choi; Laura Cornelissen; Luis M. Pereira; Erika F. Augustine; Casie A. Genetti; Kira Dies; Brenda Barton; Lucinda Williams; Benjamin D. Goodlett; Bobbie L. Riley; Amy Pasternak; Emily R. Berry; Kelly A. Pflock; Stephen Chu; Chantal Reed; Kimberly Tyndall; Pankaj B. Agrawal; Alan H. Beggs; P. Ellen Grant; David K. Urion; Richard O. Snyder; Susan E. Waisbren; Annapurna Poduri; Peter J. Park; Al Patterson; Alessandra Biffi; Joseph R. Mazzulli; Olaf Bodamer; Charles B. Berde; Timothy W. Yu

    Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an “N-of-1” study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila’s Miracle Foundation and others.)

    更新日期:2019-10-24
  • Randomized Trial of Medical versus Surgical Treatment for Refractory Heartburn
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-10-17
    Stuart J. Spechler; John G. Hunter; Karen M. Jones; Robert Lee; Brian R. Smith; Hiroshi Mashimo; Vivian M. Sanchez; Kerry B. Dunbar; Thai H. Pham; Uma K. Murthy; Taewan Kim; Christian S. Jackson; Jason M. Wallen; Erik C. von Rosenvinge; Jonathan P. Pearl; Loren Laine; Anthony W. Kim; Andrew M. Kaz; Roger P. Tatum; Ziad F. Gellad; Sandhya Lagoo-Deenadayalan; Joel H. Rubenstein; Amir A. Ghaferi; Wai-Kit Lo; Ronald S. Fernando; Bobby S. Chan; Shirley C. Paski; Dawn Provenzale; Donald O. Castell; David Lieberman; Rhonda F. Souza; William D. Chey; Stuart R. Warren; Anne Davis-Karim; Shelby D. Melton; Robert M. Genta; Tracey Serpi; Kousick Biswas; Grant D. Huang

    Background Heartburn that persists despite proton-pump inhibitor (PPI) treatment is a frequent clinical problem with multiple potential causes. Treatments for PPI-refractory heartburn are of unproven efficacy and focus on controlling gastroesophageal reflux with reflux-reducing medication (e.g., baclofen) or antireflux surgery or on dampening visceral hypersensitivity with neuromodulators (e.g., desipramine). Methods Patients who were referred to Veterans Affairs (VA) gastroenterology clinics for PPI-refractory heartburn received 20 mg of omeprazole twice daily for 2 weeks, and those with persistent heartburn underwent endoscopy, esophageal biopsy, esophageal manometry, and multichannel intraluminal impedance–pH monitoring. If patients were found to have reflux-related heartburn, we randomly assigned them to receive surgical treatment (laparoscopic Nissen fundoplication), active medical treatment (omeprazole plus baclofen, with desipramine added depending on symptoms), or control medical treatment (omeprazole plus placebo). The primary outcome was treatment success, defined as a decrease of 50% or more in the Gastroesophageal Reflux Disease (GERD)–Health Related Quality of Life score (range, 0 to 50, with higher scores indicating worse symptoms) at 1 year. Results A total of 366 patients (mean age, 48.5 years; 280 men) were enrolled. Prerandomization procedures excluded 288 patients: 42 had relief of their heartburn during the 2-week omeprazole trial, 70 did not complete trial procedures, 54 were excluded for other reasons, 23 had non-GERD esophageal disorders, and 99 had functional heartburn (not due to GERD or other histopathologic, motility, or structural abnormality). The remaining 78 patients underwent randomization. The incidence of treatment success with surgery (18 of 27 patients, 67%) was significantly superior to that with active medical treatment (7 of 25 patients, 28%; P=0.007) or control medical treatment (3 of 26 patients, 12%; P<0.001). The difference in the incidence of treatment success between the active medical group and the control medical group was 16 percentage points (95% confidence interval, −5 to 38; P=0.17). Conclusions Among patients referred to VA gastroenterology clinics for PPI-refractory heartburn, systematic workup revealed truly PPI-refractory and reflux-related heartburn in a minority of patients. For that highly selected subgroup, surgery was superior to medical treatment. (Funded by the Department of Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT01265550.)

    更新日期:2019-10-17
  • Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-10-17
    Stefanie Schüpke; Franz-Josef Neumann; Maurizio Menichelli; Katharina Mayer; Isabell Bernlochner; Jochen Wöhrle; Gert Richardt; Christoph Liebetrau; Bernhard Witzenbichler; David Antoniucci; Ibrahim Akin; Lorenz Bott-Flügel; Marcus Fischer; Ulf Landmesser; Hugo A. Katus; Dirk Sibbing; Melchior Seyfarth; Marion Janisch; Duino Boncompagni; Raphaela Hilz; Wolfgang Rottbauer; Rainer Okrojek; Helge Möllmann; Willibald Hochholzer; Angela Migliorini; Salvatore Cassese; Pasquale Mollo; Erion Xhepa; Sebastian Kufner; Axel Strehle; Stefan Leggewie; Abdelhakim Allali; Gjin Ndrepepa; Helmut Schühlen; Dominick J. Angiolillo; Christian W. Hamm; Alexander Hapfelmeier; Ralph Tölg; Dietmar Trenk; Heribert Schunkert; Karl-Ludwig Laugwitz; Adnan Kastrati

    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.) QUICK TAKE VIDEO SUMMARY Ticagrelor versus Prasugrel in Acute Coronary Syndromes 01:59

    更新日期:2019-10-17
  • Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-10-17
    James Larkin; Vanna Chiarion-Sileni; Rene Gonzalez; Jean-Jacques Grob; Piotr Rutkowski; Christopher D. Lao; C. Lance Cowey; Dirk Schadendorf; John Wagstaff; Reinhard Dummer; Pier F. Ferrucci; Michael Smylie; David Hogg; Andrew Hill; Ivan Márquez-Rodas; John Haanen; Massimo Guidoboni; Michele Maio; Patrick Schöffski; Matteo S. Carlino; Céleste Lebbé; Grant McArthur; Paolo A. Ascierto; Gregory A. Daniels; Georgina V. Long; Lars Bastholt; Jasmine I. Rizzo; Agnes Balogh; Andriy Moshyk; F. Stephen Hodi; Jedd D. Wolchok

    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.)

    更新日期:2019-10-17
  • 20-Year Follow-up of Statins in Children with Familial Hypercholesterolemia
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-10-17
    Ilse K. Luirink; Albert Wiegman; D. Meeike Kusters; Michel H. Hof; Jaap W. Groothoff; Eric de Groot; John J.P. Kastelein; Barbara A. Hutten

    Background Familial hypercholesterolemia is characterized by severely elevated low-density lipoprotein (LDL) cholesterol levels and premature cardiovascular disease. The short-term efficacy of statin therapy in children is well established, but longer follow-up studies evaluating changes in the risk of cardiovascular disease are scarce. Methods We report a 20-year follow-up study of statin therapy in children. A total of 214 patients with familial hypercholesterolemia (genetically confirmed in 98% of the patients), who were previously participants in a placebo-controlled trial evaluating the 2-year efficacy and safety of pravastatin, were invited for follow-up, together with their 95 unaffected siblings. Participants completed a questionnaire, provided blood samples, and underwent measurements of carotid intima–media thickness. The incidence of cardiovascular disease among the patients with familial hypercholesterolemia was compared with that among their 156 affected parents. Results Of the original cohort, 184 of 214 patients with familial hypercholesterolemia (86%) and 77 of 95 siblings (81%) were seen in follow-up; among the 214 patients, data on cardiovascular events and on death from cardiovascular causes were available for 203 (95%) and 214 (100%), respectively. The mean LDL cholesterol level in the patients had decreased from 237.3 to 160.7 mg per deciliter (from 6.13 to 4.16 mmol per liter) — a decrease of 32% from the baseline level; treatment goals (LDL cholesterol <100 mg per deciliter [2.59 mmol per liter]) were achieved in 37 patients (20%). Mean progression of carotid intima–media thickness over the entire follow-up period was 0.0056 mm per year in patients with familial hypercholesterolemia and 0.0057 mm per year in siblings (mean difference adjusted for sex, −0.0001 mm per year; 95% confidence interval, −0.0010 to 0.0008). The cumulative incidence of cardiovascular events and of death from cardiovascular causes at 39 years of age was lower among the patients with familial hypercholesterolemia than among their affected parents (1% vs. 26% and 0% vs. 7%, respectively). Conclusions In this study, initiation of statin therapy during childhood in patients with familial hypercholesterolemia slowed the progression of carotid intima–media thickness and reduced the risk of cardiovascular disease in adulthood. (Funded by the AMC Foundation.)

    更新日期:2019-10-17
  • Complete Revascularization with Multivessel PCI for Myocardial Infarction
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-10-10
    Shamir R. Mehta; David A. Wood; Robert F. Storey; Roxana Mehran; Kevin R. Bainey; Helen Nguyen; Brandi Meeks; Giuseppe Di Pasquale; Jose López-Sendón; David P. Faxon; Laura Mauri; Sunil V. Rao; Laurent Feldman; P. Gabriel Steg; Álvaro Avezum; Tej Sheth; Natalia Pinilla-Echeverri; Raul Moreno; Gianluca Campo; Benjamin Wrigley; Sasko Kedev; Andrew Sutton; Richard Oliver; Josep Rodés-Cabau; Goran Stanković; Robert Welsh; Shahar Lavi; Warren J. Cantor; Jia Wang; Juliet Nakamya; Shrikant I. Bangdiwala; John A. Cairns

    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.) QUICK TAKE VIDEO SUMMARY Complete Revascularization in Myocardial Infarction 02:22

    更新日期:2019-10-10
  • Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-10-10
    Marin L. Gantner; Kevin Eade; Martina Wallace; Michal K. Handzlik; Regis Fallon; Jennifer Trombley; Roberto Bonelli; Sarah Giles; Sarah Harkins-Perry; Tjebo F.C. Heeren; Lydia Sauer; Yoichiro Ideguchi; Michelle Baldini; Lea Scheppke; Michael I. Dorrell; Maki Kitano; Barbara J. Hart; Carolyn Cai; Takayuki Nagasaki; Mehmet G. Badur; Mali Okada; Sasha M. Woods; Catherine Egan; Mark Gillies; Robyn Guymer; Florian Eichler; Melanie Bahlo; Marcus Fruttiger; Rando Allikmets; Paul S. Bernstein; Christian M. Metallo; Martin Friedlander

    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 SPTLC1 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 SPTLC1 or SPTLC2 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.)

    更新日期:2019-10-10
  • Controlled Trial of Two Incremental Milk-Feeding Rates in Preterm Infants
    N. Engl. J. Med. (IF 70.670) Pub Date : 2019-10-10
    Jon Dorling; Jane Abbott; Janet Berrington; Beth Bosiak; Ursula Bowler; Elaine Boyle; Nicholas Embleton; Oliver Hewer; Samantha Johnson; Edmund Juszczak; Alison Leaf; Louise Linsell; Kenny McCormick; William McGuire; Omar Omar; Christopher Partlett; Mehali Patel; Tracy Roberts; Ben Stenson; John Townend

    Background Observational data have shown that slow advancement of enteral feeding volumes in preterm infants is associated with a reduced risk of necrotizing enterocolitis but an increased risk of late-onset sepsis. However, data from randomized trials are limited. Methods We randomly assigned very preterm or very-low-birth-weight infants to daily milk increments of 30 ml per kilogram of body weight (faster increment) or 18 ml per kilogram (slower increment) until reaching full feeding volumes. The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months. Secondary outcomes included components of the primary outcome, confirmed or suspected late-onset sepsis, necrotizing enterocolitis, and cerebral palsy. Results Among 2804 infants who underwent randomization, the primary outcome could be assessed in 1224 (87.4%) assigned to the faster increment and 1246 (88.7%) assigned to the slower increment. Survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 of 1224 infants (65.5%) assigned to the faster increment and 848 of 1246 (68.1%) assigned to the slower increment (adjusted risk ratio, 0.96; 95% confidence interval [CI], 0.92 to 1.01; P=0.16). Late-onset sepsis occurred in 414 of 1389 infants (29.8%) in the faster-increment group and 434 of 1397 (31.1%) in the slower-increment group (adjusted risk ratio, 0.96; 95% CI, 0.86 to 1.07). Necrotizing enterocolitis occurred in 70 of 1394 infants (5.0%) in the faster-increment group and 78 of 1399 (5.6%) in the slower-increment group (adjusted risk ratio, 0.88; 95% CI, 0.68 to 1.16). Conclusions There was no significant difference in survival without moderate or severe neurodevelopmental disability at 24 months in very preterm or very-low-birth-weight infants with a strategy of advancing milk feeding volumes in daily increments of 30 ml per kilogram as compared with 18 ml per kilogram. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; SIFT Current Controlled Trials number, ISRCTN76463425.)

    更新日期:2019-10-10
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