Democratizing Evidence Production — A 51-Year-Old Man with Sudden Onset of Dense Hemiparesis
16-10-2019 – Shaheen Chowdhury,Timothy Laux,Michelle Morse,Angela Jenks,Scott Stonington,Yogesh Jain
The Cost of Applying to Medical School — A Barrier to Diversifying the Profession
16-10-2019 – Lorena Millo,Noelani Ho,Peter A. Ubel
Unplugging the Pipeline — A Call for Term Limits in Academic Medicine
16-10-2019 – Whitney H. Beeler,Christina Mangurian,Reshma Jagsi
Randomized Trial of Medical versus Surgical Treatment for Refractory Heartburn
16-10-2019 – 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
Journal Article, Research Support, U.S. Gov’t, Non-P.H.S.
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).
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-p
H 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. 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). 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; Clinical
Trials.gov number, NCT01265550.).
Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes
01-09-2019 – 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
Journal Article, Research Support, Non-U.S. Gov’t
The relative merits of ticagrelor as compared with prasugrel in patients with acute coronary syndromes for whom invasive evaluation is planned are uncertain.
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.
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).
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 Clinical
Trials.gov number, NCT01944800.).
Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma
28-09-2019 – 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
Journal Article, Research Support, Non-U.S. Gov’t
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.
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.
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.
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; Check
Mate 067 Clinical
Trials.gov number, NCT01844505.).
20-Year Follow-up of Statins in Children with Familial Hypercholesterolemia
16-10-2019 – Ilse K. Luirink,Albert Wiegman,D. Meeike Kusters,Michel H. Hof,Jaap W. Groothoff,Eric de Groot,John J.P. Kastelein,Barbara A. Hutten
Journal Article, Research Support, Non-U.S. Gov’t
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. 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. 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). 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.).
Lipid Management for the Prevention of Atherosclerotic Cardiovascular Disease
16-10-2019 – Erin D. Michos,John W. McEvoy,Roger S. Blumenthal
Journal Article, Review
16-10-2019 – Andrew N. Robinson,John S.P. Loh
Case Reports, Journal Article
Calcinosis in Juvenile Dermatomyositis
16-10-2019 – Jianguo Li,Zhixuan Zhou
Case Reports, Journal Article
Case 32-2019: A 70-Year-Old Woman with Rapidly Progressive Ataxia
16-10-2019 – Bart K. Chwalisz,Bradley R. Buchbinder,Jeremy D. Schmahmann,Wesley R. Samore
Case Reports, Journal Article
Think First, Cut Last — Lessons from a Clinical Trial of Refractory Heartburn
16-10-2019 – Nicholas J. Talley
Ticagrelor or Prasugrel in Acute Coronary Syndromes — The Winner Takes It All?
16-10-2019 – Hani Jneid
16-10-2019 – Brendan M. Reilly
More about Factor H Autoantibodies in Membranous Nephropathy
16-10-2019 – Elisabetta Valoti,Marina Noris,Giuseppe Remuzzi
Ribociclib and Endocrine Therapy in Breast Cancer
16-10-2019 – SA Im,YS Lu,D Tripathy
Erdafitinib in Urothelial Carcinoma
16-10-2019 – Y Loriot,A Necchi,AO Siefker-Radtke
Nintedanib for Systemic Sclerosis–Associated Interstitial Lung Disease
16-10-2019 – O Distler,M Gahlemann,TM Maher
New Guidelines for Statistical Reporting
16-10-2019 – D Harrington
Electrolyte and Acid–Base Disturbances in Patients with Diabetes Mellitus
Journal Article, Published Erratum
Toward Automated Insulin Delivery
16-10-2019 – Daniela Bruttomesso
Six-Month Randomized, Multicenter Trial of Closed-Loop Control in Type 1 Diabetes
16-10-2019 – 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
Closed-loop systems that automate insulin delivery may improve glycemic outcomes in patients with type 1 diabetes.
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.
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; P180 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.
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; i
Trials.gov number, NCT03563313.).
Will Emergency Holds Reduce Opioid Overdose Deaths?
16-10-2019 – Elizabeth A. Samuels,Otis U. Warren,Corey S. Davis,Paul P. Christopher
Everolimus-Eluting Stents or Bypass Surgery for Left Main Coronary Artery Disease
Conservative Oxygen Therapy during Mechanical Ventilation in the ICU
14-10-2019 – Geen auteurs bekend
Patients who are undergoing mechanical ventilation in the intensive care unit (ICU) often receive a high fraction of inspired oxygen (Fio We randomly assigned 1000 adult patients who were anticipated to require mechanical ventilation beyond the day after recruitment in the ICU to receive conservative or usual oxygen therapy. In the two groups, the default lower limit for oxygen saturation as measured by pulse oximetry (Spo The number of ventilator-free days did not differ significantly between the conservative-oxygen group and the usual-oxygen group, with a median duration of 21.3 days (interquartile range, 0 to 26.3) and 22.1 days (interquartile range, 0 to 26.2), respectively, for an absolute difference of -0.3 days (95% confidence interval [CI], -2.1 to 1.6; P = 0.80). The conservative-oxygen group spent more time in the ICU with an Fio In adults undergoing mechanical ventilation in the ICU, the use of conservative oxygen therapy, as compared with usual oxygen therapy, did not significantly affect the number of ventilator-free days. (Funded by the New Zealand Health Research Council; ICU-ROX Australian and New Zealand Clinical Trials Registry number, ACTRN12615000957594.).
Drug Regulation in the Era of Individualized Therapies
09-10-2019 – Janet Woodcock,Peter Marks
Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease
09-10-2019 – 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.).
Tennessee’s Opening Bid for a Medicaid Block Grant
09-10-2019 – Melinda B. Buntin
Pathology of Vaping-Associated Lung Injury
02-10-2019 – Yasmeen M. Butt,Maxwell L. Smith,Henry D. Tazelaar,Laszlo T. Vaszar,Karen L. Swanson,Matthew J. Cecchini,Jennifer M. Boland,Melanie C. Bois,James H. Boyum,Adam T. Froemming,Andras Khoor,Isabel Mira-Avendano,Aiyub Patel,Brandon T. Larsen
Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm
02-10-2019 – 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
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.
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.
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.
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 Clinical
Trials.gov number, NCT01994772.).
Medical Deferred Action — Living on Borrowed Time
02-10-2019 – Lakshmi Ganapathi,Adolfo Caldas,Jacqueline Miranda,Julia R. Köhler,Gary Visner,Gregory Sawicki
Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer
30-09-2019 – 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
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.
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.
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.
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 Clinical
Trials.gov number, NCT02485691.).
Understanding Progressive Fibrosing Interstitial Lung Disease through Therapeutic Trials
29-09-2019 – Hilary J. Goldberg
Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer
30-09-2019 – 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
Patients with metastatic colorectal cancer with the In this open-label, phase 3 trial, we enrolled 665 patients with 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. 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
Nintedanib in Progressive Fibrosing Interstitial Lung Diseases
29-09-2019 – 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
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.
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.
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.
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 Clinical
Trials.gov number, NCT02999178.).
Five-Year Outcomes after PCI or CABG for Left Main Coronary Disease
28-09-2019 – 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
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.
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.
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).
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 Clinical
Trials.gov number, NCT01205776.).
Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer
28-09-2019 – 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
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.
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
A total of 1140 patients underwent randomization. In the
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 Abb
Vie; VELIA/GOG-3005 Clinical
Trials.gov number, NCT02470585.).
Nivolumab plus Ipilimumab in Advanced Non–Small-Cell Lung Cancer
28-09-2019 – 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
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.
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.
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.
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; Check
Mate 227 Clinical
Trials.gov number, NCT02477826.).
Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer
28-09-2019 – 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
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
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.
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.
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 Glaxo
Kline; PRIMA/ENGOT-OV26/GOG-3012 Clinical
Trials.gov number, NCT02655016.).
Total Hip Arthroplasty or Hemiarthroplasty for Hip Fracture
26-09-2019 – Geen auteurs bekend
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.
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.
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 Mc
Master 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. 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; Clinical
Trials.gov number, NCT00556842.).
Ticagrelor with or without Aspirin in High-Risk Patients after PCI
26-09-2019 – 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
Monotherapy with a P2Y
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.
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).
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 Astra
Zeneca; TWILIGHT Clinical
Trials.gov number, NCT02270242.).
Real-Time Digital Surveillance of Vaping-Induced Pulmonary Disease
20-09-2019 – Yulin Hswen,John S. Brownstein
Heart-Failure Therapy — New Drugs but Old Habits?
19-09-2019 – James C. Fang
Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction
19-09-2019 – 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
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.
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.
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.
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 Astra
Zeneca; DAPA-HF Clinical
Trials.gov number, NCT03036124.).
Vaping-Induced Lung Injury
06-09-2019 – David C. Christiani
Pulmonary Illness Related to E-Cigarette Use in Illinois and Wisconsin — Preliminary Report
06-09-2019 – Jennifer E. Layden,Isaac Ghinai,Ian Pray,Anne Kimball,Mark Layer,Mark Tenforde,Livia Navon,Brooke Hoots,Phillip P. Salvatore,Megan Elderbrook,Thomas Haupt,Jeffrey Kanne,Megan T. Patel,Lori Saathoff-Huber,Brian A. King,Josh G. Schier,Christina A. Mikosz,Jonathan Meiman
E-cigarettes are battery-operated devices that heat a liquid and deliver an aerosolized product to the user. Pulmonary illnesses related to e-cigarette use have been reported, but no large series has been described. In July 2019, the Wisconsin Department of Health Services and the Illinois Department of Public Health received reports of pulmonary disease associated with the use of e-cigarettes (also called vaping) and launched a coordinated public health investigation. We defined case patients as persons who reported use of e-cigarette devices and related products in the 90 days before symptom onset and had pulmonary infiltrates on imaging and whose illnesses were not attributed to other causes. Medical record abstraction and case patient interviews were conducted with the use of standardized tools. There were 53 case patients, 83% of whom were male; the median age of the patients was 19 years. The majority of patients presented with respiratory symptoms (98%), gastrointestinal symptoms (81%), and constitutional symptoms (100%). All case patients had bilateral infiltrates on chest imaging (which was part of the case definition). A total of 94% of the patients were hospitalized, 32% underwent intubation and mechanical ventilation, and one death was reported. A total of 84% of the patients reported having used tetrahydrocannabinol products in e-cigarette devices, although a wide variety of products and devices was reported. Syndromic surveillance data from Illinois showed that the mean monthly rate of visits related to severe respiratory illness in June through August of 2019 was twice the rate that was observed in the same months in 2018. Case patients presented with similar clinical characteristics. Although the features of e-cigarette use that were responsible for injury have not been identified, this cluster of illnesses represents an emerging clinical syndrome or syndromes. Additional work is needed to characterize the pathophysiology and to identify the definitive causes.
A Genotype-Guided Strategy for Oral P2Y12 Inhibitors in Primary PCI
03-09-2019 – 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
It is unknown whether patients undergoing primary percutaneous coronary intervention (PCI) benefit from genotype-guided selection of oral P2Y 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 P2Y 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). In patients undergoing primary PCI, a
Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction
01-09-2019 – 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
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.
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.
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.
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 Clinical
Trials.gov number, NCT01920711.).