A New Era of Climate Medicine — Addressing Heat-Triggered Renal Disease
21-08-2019 – Cecilia Sorensen,Ramon Garcia-Trabanino
Combating EPA Rollbacks — Health Care’s Response to a Retreat on Climate
24-07-2019 – Gina McCarthy,Aaron Bernstein
The Climate Crisis — Health and Care Delivery
21-08-2019 – Renee N. Salas,Caren G. Solomon
Prescription Drug Monitoring Programs — Friend or Folly in Addressing the Opioid-Overdose Crisis?
21-08-2019 – Rebecca L. Haffajee
The Comfort of the Ordinary — On Dying as We’ve Lived
21-08-2019 – Caroline Wellbery
Ambient Particulate Air Pollution and Daily Mortality in 652 Cities
21-08-2019 – Cong Liu,Renjie Chen,Francesco Sera,Ana M. Vicedo-Cabrera,Yuming Guo,Shilu Tong,Micheline S.Z.S. Coelho,Paulo H.N. Saldiva,Eric Lavigne,Patricia Matus,Nicolas Valdes Ortega,Samuel Osorio Garcia,Mathilde Pascal,Massimo Stafoggia,Matteo Scortichini,Masahiro Hashizume,Yasushi Honda,Magali Hurtado-Díaz,Julio Cruz,Baltazar Nunes,João P. Teixeira,Ho Kim,Aurelio Tobias,Carmen Íñiguez,Bertil Forsberg,Christofer Åström,Martina S. Ragettli,Yue-Leon Guo,Bing-Yu Chen,Michelle L. Bell,Caradee Y. Wright,Noah Scovronick,Rebecca M. Garland,Ai Milojevic,Jan Kyselý,Aleš Urban,Hans Orru,Ene Indermitte,Jouni J.K. Jaakkola,Niilo R.I. Ryti,Klea Katsouyanni,Antonis Analitis,Antonella Zanobetti,Joel Schwartz,Jianmin Chen,Tangchun Wu,Aaron Cohen,Antonio Gasparrini,Haidong Kan
Journal Article, Research Support, Non-U.S. Gov’t
The systematic evaluation of the results of time-series studies of air pollution is challenged by differences in model specification and publication bias. We evaluated the associations of inhalable particulate matter (PM) with an aerodynamic diameter of 10 μm or less (PM On average, an increase of 10 μg per cubic meter in the 2-day moving average of PM Our data show independent associations between short-term exposure to PM
Effects of Serelaxin in Patients with Acute Heart Failure
21-08-2019 – Marco Metra,John R. Teerlink,Gad Cotter,Beth A. Davison,G. Michael Felker,Gerasimos Filippatos,Barry H. Greenberg,Peter S. Pang,Piotr Ponikowski,Adriaan A. Voors,Kirkwood F. Adams,Stefan D. Anker,Alexandra Arias-Mendoza,Patricio Avendaño,Fernando Bacal,Michael Böhm,Guillermo Bortman,John G.F. Cleland,Alain Cohen-Solal,Maria G. Crespo-Leiro,Maria Dorobantu,Luis E. Echeverría,Roberto Ferrari,Sorel Goland,Eva Goncalvesová,Assen Goudev,Lars Køber,Juan Lema-Osores,Phillip D. Levy,Kenneth McDonald,Pravin Manga,Béla Merkely,Christian Mueller,Burkert Pieske,Jose Silva-Cardoso,Jindřich Špinar,Iain Squire,Janina Stępińska,Walter Van Mieghem,Dirk von Lewinski,Gerhard Wikström,Mehmet B. Yilmaz,Nicole Hagner,Thomas Holbro,Tsushung A. Hua,Shalini V. Sabarwal,Thomas Severin,Peter Szecsödy,Claudio Gimpelewicz
Journal Article, Research Support, Non-U.S. Gov’t
Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure.
In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 μg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days.
A total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P = 0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P = 0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups.
In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 Clinical
Trials.gov number, NCT01870778.).
Oral Selinexor–Dexamethasone for Triple-Class Refractory Multiple Myeloma
21-08-2019 – Ajai Chari,Dan T. Vogl,Maria Gavriatopoulou,Ajay K. Nooka,Andrew J. Yee,Carol A. Huff,Philippe Moreau,David Dingli,Craig Cole,Sagar Lonial,Meletios Dimopoulos,A. Keith Stewart,Joshua Richter,Ravi Vij,Sascha Tuchman,Marc S. Raab,Katja C. Weisel,Michel Delforge,Robert F. Cornell,David Kaminetzky,James E. Hoffman,Luciano J. Costa,Terri L. Parker,Moshe Levy,Martin Schreder,Nathalie Meuleman,Laurent Frenzel,Mohamad Mohty,Sylvain Choquet,Gary Schiller,Raymond L. Comenzo,Monika Engelhardt,Thomas Illmer,Philip Vlummens,Chantal Doyen,Thierry Facon,Lionel Karlin,Aurore Perrot,Klaus Podar,Michael G. Kauffman,Sharon Shacham,Lingling Li,Shijie Tang,Carla Picklesimer,Jean-Richard Saint-Martin,Marsha Crochiere,Hua Chang,Samir Parekh,Yosef Landesman,Jatin Shah,Paul G. Richardson,Sundar Jagannath
Journal Article, Research Support, Non-U.S. Gov’t
Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options.
We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point.
A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients.
Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM Clinical
Trials.gov number, NCT02336815.).
Myocardial Viability and Long-Term Outcomes in Ischemic Cardiomyopathy
21-08-2019 – Julio A. Panza,Alicia M. Ellis,Hussein R. Al-Khalidi,Thomas A. Holly,Daniel S. Berman,Jae K. Oh,Gerald M. Pohost,George Sopko,Lukasz Chrzanowski,Daniel B. Mark,Tomasz Kukulski,Liliana E. Favaloro,Gerald Maurer,Pedro S. Farsky,Ru-San Tan,Federico M. Asch,Eric J. Velazquez,Jean L. Rouleau,Kerry L. Lee,Robert O. Bonow
Journal Article, Research Support, N.I.H., Extramural
The role of assessment of myocardial viability in identifying patients with ischemic cardiomyopathy who might benefit from surgical revascularization remains controversial. Furthermore, although improvement in left ventricular function is one of the goals of revascularization, its relationship to subsequent outcomes is unclear.
Among 601 patients who had coronary artery disease that was amenable to coronary-artery bypass grafting (CABG) and who had a left ventricular ejection fraction of 35% or lower, we prospectively assessed myocardial viability using single-photon-emission computed tomography, dobutamine echocardiography, or both. Patients were randomly assigned to undergo CABG and receive medical therapy or to receive medical therapy alone. Left ventricular ejection fraction was measured at baseline and after 4 months of follow-up in 318 patients. The primary end point was death from any cause. The median duration of follow-up was 10.4 years.
CABG plus medical therapy was associated with a lower incidence of death from any cause than medical therapy alone (182 deaths among 298 patients in the CABG group vs. 209 deaths among 303 patients in the medical-therapy group; adjusted hazard ratio, 0.73; 95% confidence interval, 0.60 to 0.90). However, no significant interaction was observed between the presence or absence of myocardial viability and the beneficial effect of CABG plus medical therapy over medical therapy alone (P = 0.34 for interaction). An increase in left ventricular ejection fraction was observed only among patients with myocardial viability, irrespective of treatment assignment. There was no association between changes in left ventricular ejection fraction and subsequent death.
The findings of this study do not support the concept that myocardial viability is associated with a long-term benefit of CABG in patients with ischemic cardiomyopathy. The presence of viable myocardium was associated with improvement in left ventricular systolic function, irrespective of treatment, but such improvement was not related to long-term survival. (Funded by the National Institutes of Health; STICH Clinical
Trials.gov number, NCT00023595.).
Drug Effects on the Thyroid
21-08-2019 – Henry B. Burch
Journal Article, Review
Fish Bone Perforation
21-08-2019 – Takafumi Taguchi,Hiroyuki Kitagawa
Case Reports, Journal Article
21-08-2019 – Sondes Mhamdi,Kais Mhamdi
Case Reports, Journal Article
Case 26-2019: A 27-Year-Old Woman with Opioid Use Disorder and Suicidal Ideation
21-08-2019 – Mladen Nisavic,Efren J. Flores,Marilyn Heng,Nicholas J. Kontos,Nadia Quijije
Case Reports, Journal Article
Prioritizing Health in a Changing Climate
21-08-2019 – Renee N. Salas,Debra Malina,Caren G. Solomon
Do We Really Need Another Time-Series Study of the PM2.5–Mortality Association?
21-08-2019 – John R. Balmes
Why Are Physicians So Confused about Acute Heart Failure?
21-08-2019 – Milton Packer
Human Health on an Ailing Planet — Historical Perspectives on Our Future
21-08-2019 – James H. Dunk,David S. Jones,Anthony Capon,Warwick H. Anderson
Fornix-Region Deep Brain Stimulation–Induced Memory Flashbacks in Alzheimer’s Disease
21-08-2019 – Wissam Deeb,Bryan Salvato,Leonardo Almeida,Kelly D. Foote,Robert Amaral,Jurgen Germann,Paul B. Rosenberg,David F. Tang-Wai,David A. Wolk,Anna D. Burke,Stephen Salloway,Marwan N. Sabbagh,M. Mallar Chakravarty,Gwenn S. Smith,Constantine G. Lyketsos,Andres M. Lozano,Michael S. Okun
Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome
21-08-2019 – Geen auteurs bekend
Ibrutinib and Venetoclax for First-Line Treatment of CLL
21-08-2019 – N Jain,V Gandhi,W Wierda
Age of Red Cells for Transfusion and Outcomes in Critically Ill Adults
Toppling the Ethical Balance — Health Care Refusal and the Trump Administration
31-07-2019 – Elizabeth Sepper
Roxadustat and Anemia of Chronic Kidney Disease
24-07-2019 – Joshua Kaplan
Global HIV Treatment — Turning Headwinds to Tailwinds
24-07-2019 – Diane V. Havlir,Meg C. Doherty
Roxadustat for Anemia in Patients with Kidney Disease Not Receiving Dialysis
24-07-2019 – Nan Chen,Chuanming Hao,Xiaomei Peng,Hongli Lin,Aiping Yin,Li Hao,Ye Tao,Xinling Liang,Zhengrong Liu,Changying Xing,Jianghua Chen,Laimin Luo,Li Zuo,Yunhua Liao,Bi-Cheng Liu,Robert Leong,Chunrong Wang,Cameron Liu,Thomas Neff,Lynda Szczech,Kin-Hung P. Yu
Roxadustat (FG-4592) is an oral inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase that stimulates erythropoiesis and regulates iron metabolism. In phase 2 studies involving patients with chronic kidney disease, roxadustat increased levels of endogenous erythropoietin to within or near the physiologic range, along with increasing hemoglobin levels and improving iron homeostasis. Additional data are needed regarding the efficacy and safety of roxadustat for the treatment of anemia in patients with chronic kidney disease who are not undergoing dialysis.
In this phase 3 trial conducted at 29 sites in China, we randomly assigned 154 patients with chronic kidney disease in a 2:1 ratio to receive roxadustat or placebo three times a week for 8 weeks in a double-blind manner. All the patients had a hemoglobin level of 7.0 to 10.0 g per deciliter at baseline. The randomized phase of the trial was followed by an 18-week open-label period in which all the patients received roxadustat; parenteral iron was withheld. The primary end point was the mean change from baseline in the hemoglobin level, averaged over weeks 7 through 9.
During the primary-analysis period, the mean (±SD) change from baseline in the hemoglobin level was an increase of 1.9±1.2 g per deciliter in the roxadustat group and a decrease of 0.4±0.8 g per deciliter in the placebo group (P<0.001). The mean reduction from baseline in the hepcidin level (associated with greater iron availability) was 56.14±63.40 ng per milliliter in the roxadustat group and 15.10±48.06 ng per milliliter in the placebo group. The reduction from baseline in the total cholesterol level was 40.6 mg per deciliter in the roxadustat group and 7.7 mg per deciliter in the placebo group. Hyperkalemia and metabolic acidosis occurred more frequently in the roxadustat group than in the placebo group. The efficacy of roxadustat in hemoglobin correction and maintenance was maintained during the 18-week open-label period.
In Chinese patients with chronic kidney disease who were not undergoing dialysis, those in the roxadustat group had a higher mean hemoglobin level than those in the placebo group after 8 weeks. During the 18-week open-label phase of the trial, roxadustat was associated with continued efficacy. (Funded by Fibro
Gen and Fibro
Gen [China] Medical Technology Development; Clinical
Trials.gov number, NCT02652819.).
Roxadustat Treatment for Anemia in Patients Undergoing Long-Term Dialysis
24-07-2019 – Nan Chen,Chuanming Hao,Bi-Cheng Liu,Hongli Lin,Caili Wang,Changying Xing,Xinling Liang,Gengru Jiang,Zhengrong Liu,Xuemei Li,Li Zuo,Laimin Luo,Jianqin Wang,Ming-hui Zhao,Zhihong Liu,Guang-Yan Cai,Li Hao,Robert Leong,Chunrong Wang,Cameron Liu,Thomas Neff,Lynda Szczech,Kin-Hung P. Yu
Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. Additional data are needed regarding the effectiveness and safety of roxadustat as compared with standard therapy (epoetin alfa) for the treatment of anemia in patients undergoing dialysis.
In a trial conducted in China, we randomly assigned (in a 2:1 ratio) patients who had been undergoing dialysis and erythropoiesis-stimulating agent therapy with epoetin alfa for at least 6 weeks to receive roxadustat or epoetin alfa three times per week for 26 weeks. Parenteral iron was withheld except as rescue therapy. The primary end point was the mean change in hemoglobin level from baseline to the average level during weeks 23 through 27. Noninferiority of roxadustat would be established if the lower boundary of the two-sided 95% confidence interval for the difference between the values in the roxadustat group and epoetin alfa group was greater than or equal to -1.0 g per deciliter. Patients in each group had doses adjusted to reach a hemoglobin level of 10.0 to 12.0 g per deciliter. Safety was assessed by analysis of adverse events and clinical laboratory values.
A total of 305 patients underwent randomization (204 in the roxadustat group and 101 in the epoetin alfa group), and 256 patients (162 and 94, respectively) completed the 26-week treatment period. The mean baseline hemoglobin level was 10.4 g per deciliter. Roxadustat led to a numerically greater mean (±SD) change in hemoglobin level from baseline to weeks 23 through 27 (0.7±1.1 g per deciliter) than epoetin alfa (0.5±1.0 g per deciliter) and was statistically noninferior (difference, 0.2±1.2 g per deciliter; 95% confidence interval [CI], -0.02 to 0.5). As compared with epoetin alfa, roxadustat increased the transferrin level (difference, 0.43 g per liter; 95% CI, 0.32 to 0.53), maintained the serum iron level (difference, 25 μg per deciliter; 95% CI, 17 to 33), and attenuated decreases in the transferrin saturation (difference, 4.2 percentage points; 95% CI, 1.5 to 6.9). At week 27, the decrease in total cholesterol was greater with roxadustat than with epoetin alfa (difference, -22 mg per deciliter; 95% CI, -29 to -16), as was the decrease in low-density lipoprotein cholesterol (difference, -18 mg per deciliter; 95% CI, -23 to -13). Roxadustat was associated with a mean reduction in hepcidin of 30.2 ng per milliliter (95% CI, -64.8 to -13.6), as compared with 2.3 ng per milliliter (95% CI, -51.6 to 6.2) in the epoetin alfa group. Hyperkalemia and upper respiratory infection occurred at a higher frequency in the roxadustat group, and hypertension occurred at a higher frequency in the epoetin alfa group.
Oral roxadustat was noninferior to parenteral epoetin alfa as therapy for anemia in Chinese patients undergoing dialysis. (Funded by Fibro
Gen and Fibro
Gen [China] Medical Technology Development; Clinical
Trials.gov number, NCT02652806.).
Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV
24-07-2019 – Willem D.F. Venter,Michelle Moorhouse,Simiso Sokhela,Lee Fairlie,Nkuli Mashabane,Masebole Masenya,Celicia Serenata,Godspower Akpomiemie,Ambar Qavi,Nomathemba Chandiwana,Shane Norris,Matthew Chersich,Polly Clayden,Elaine Abrams,Natasha Arulappan,Alinda Vos,Kaitlyn McCann,Bryony Simmons,Andrew Hill
Two drugs under consideration for inclusion in antiretroviral therapy (ART) regimens for human immunodeficiency virus (HIV) infection are dolutegravir (DTG) and tenofovir alafenamide fumarate (TAF). There are limited data on their use in low- and middle-income countries.
We conducted a 96-week, phase 3, investigator-led, open-label, randomized trial in South Africa, in which we compared a triple-therapy combination of emtricitabine (FTC) and DTG plus either of two tenofovir prodrugs – TAF (TAF-based group) or tenofovir disoproxil fumarate (TDF) (TDF-based group) – against the local standard-of-care regimen of TDF-FTC-efavirenz (standard-care group). Inclusion criteria included an age of 12 years or older, no receipt of ART in the previous 6 months, a creatinine clearance of more than 60 ml per minute (>80 ml per minute in patients younger than 19 years of age), and an HIV type 1 (HIV-1) RNA level of 500 copies or more per milliliter. The primary end point was the percentage of patients with a 48-week HIV-1 RNA level of less than 50 copies per milliliter (as determined with the Snapshot algorithm from the Food and Drug Administration; noninferiority margin, -10 percentage points). We report the primary (48-week) efficacy and safety data.
A total of 1053 patients underwent randomization from February 2017 through May 2018. More than 99% of the patients were black, and 59% were female. The mean age was 32 years, and the mean CD4 count was 337 cells per cubic millimeter. At week 48, the percentage of patients with an HIV-1 RNA level of less than 50 copies per milliliter was 84% in the TAF-based group, 85% in the TDF-based group, and 79% in the standard-care group, findings that indicate that the DTG-containing regimens were noninferior to the standard-care regimen. The number of patients who discontinued the trial regimen was higher in the standard-care group than in the other two groups. In the per-protocol population, the standard-care regimen had equivalent potency to the other two regimens. The TAF-based regimen had less effect on bone density and renal function than the other regimens. Weight increase (both lean and fat mass) was greatest in the TAF-based group and among female patients (mean increase, 6.4 kg in the TAF-based group, 3.2 kg in the TDF-based group, and 1.7 kg in the standard-care group). No resistance to integrase inhibitors was identified in patients receiving the DTG-containing regimens.
Treatment with DTG combined with either of two tenofovir prodrugs (TAF and TDF) showed noninferior efficacy to treatment with the standard-care regimen. There was significantly more weight gain with the DTG-containing regimens, especially in combination with TAF, than with the standard-care regimen. (ADVANCE Clinical
Trials.gov number, NCT03122262.).
Dolutegravir-Based or Low-Dose Efavirenz–Based Regimen for the Treatment of HIV-1
24-07-2019 – Geen auteurs bekend
An efavirenz-based regimen (with a 600-mg dose of efavirenz, known as EFV600) was the World Health Organization preferred first-line treatment for human immunodeficiency virus type 1 (HIV-1) infection until June 2018. Given concerns about side effects, dolutegravir-based and low-dose efavirenz-based combinations have been considered as first-line treatments for HIV-1 in resource-limited settings.
We conducted an open-label, multicenter, randomized, phase 3 noninferiority trial in Cameroon. Adults with HIV-1 infection who had not received antiretroviral therapy and had an HIV-1 RNA level (viral load) of at least 1000 copies per milliliter were randomly assigned to receive either dolutegravir or the reference treatment of low-dose efavirenz (a 400-mg dose, known as EFV400), combined with tenofovir and lamivudine. The primary end point was the proportion of participants with a viral load of less than 50 copies per milliliter at week 48, on the basis of the Food and Drug Administration snapshot algorithm. The difference between treatment groups was calculated, and noninferiority was tested with a margin of 10 percentage points.
A total of 613 participants received at least one dose of the assigned regimen. At week 48, a viral load of less than 50 copies per milliliter was observed in 231 of 310 participants (74.5%) in the dolutegravir group and in 209 of 303 participants (69.0%) in the EFV400 group, with a difference of 5.5 percentage points (95% confidence interval [CI], -1.6 to 12.7; P1000 copies per milliliter) was observed in 3 participants in the dolutegravir group (with none acquiring drug-resistance mutations) and in 16 participants in the EFV400 group. More weight gain was observed in the dolutegravir group than in the EFV400 group (median weight gain, 5.0 kg vs. 3.0 kg; incidence of obesity, 12.3% vs. 5.4%).
In HIV-1-infected adults in Cameroon, a dolutegravir-based regimen was noninferior to an EFV400-based reference regimen with regard to viral suppression at week 48. Among participants who had a viral load of at least 100,000 copies per milliliter when antiretroviral therapy was initiated, fewer participants than expected had viral suppression. (Funded by Unitaid and the French National Agency for AIDS Research; NAMSAL ANRS 12313 Clinical
Trials.gov number, NCT02777229.).
Health Care Autonomy of Women Living with HIV
24-07-2019 – Robert R. Redfield,Surbhi Modi,Cynthia A. Moore,Augustina Delaney,Margaret A. Honein,Hank L. Tomlinson
Dolutegravir Use at Conception — Additional Surveillance Data from Botswana
22-07-2019 – Mmakgomo M. Raesima,Chibuike M. Ogbuabo,Vasavi Thomas,Sara E. Forhan,Gadzikanani Gokatweng,Eldah Dintwa,Chipo Petlo,Catherine Motswere-Chirwa,Elizabeth M. Rabold,Sarah C. Tinker,Shifawu Odunsi,Sifelani Malima,Omphemetse Mmunyane,Thusoetsile Modise,Kelame Kefitlhile,Kunle Dare,Mpho Letebele,Michelle E. Roland,Cynthia A. Moore,Surbhi Modi,Dhelia M. Williamson
Neural-Tube Defects and Antiretroviral Treatment Regimens in Botswana
22-07-2019 – Rebecca Zash,Lewis Holmes,Modiegi Diseko,Denise L. Jacobson,Sean Brummel,Gloria Mayondi,Arielle Isaacson,Sonya Davey,Judith Mabuta,Mompati Mmalane,Tendani Gaolathe,M. Essex,Shahin Lockman,Joseph Makhema,Roger L. Shapiro
A preliminary safety signal for neural-tube defects was previously reported in association with dolutegravir exposure from the time of conception, which has affected choices of antiretroviral treatment (ART) for human immunodeficiency virus (HIV)-infected women of reproductive potential. The signal can now be evaluated with data from follow-up of additional pregnancies. We conducted birth-outcomes surveillance at hospitals throughout Botswana, expanding from 8 to 18 sites in 2018. Trained midwives performed surface examinations of all live-born and stillborn infants. Research assistants photographed abnormalities after maternal consent was obtained. The prevalence of neural-tube defects and major external structural defects according to maternal HIV infection and ART exposure status was determined. In the primary analyses, we used the Newcombe method to evaluate differences in prevalence with 95% confidence intervals. From August 2014 through March 2019, surveillance captured 119,477 deliveries; 119,033 (99.6%) had an infant surface examination that could be evaluated, and 98 neural-tube defects were identified (0.08% of deliveries). Among 1683 deliveries in which the mother was taking dolutegravir at conception, 5 neural-tube defects were found (0.30% of deliveries); the defects included two instances of myelomeningocele, one of anencephaly, one of encephalocele, and one of iniencephaly. In comparison, 15 neural-tube defects were found among 14,792 deliveries (0.10%) in which the mother was taking any non-dolutegravir ART at conception, 3 among 7959 (0.04%) in which the mother was taking efavirenz at conception, 1 among 3840 (0.03%) in which the mother started dolutegravir treatment during pregnancy, and 70 among 89,372 (0.08%) in HIV-uninfected mothers. The prevalence of neural-tube defects was higher in association with dolutegravir treatment at conception than with non-dolutegravir ART at conception (difference, 0.20 percentage points; 95% confidence interval [CI], 0.01 to 0.59) or with other types of ART exposure. Major external structural defects were found in 0.95% of deliveries among women exposed to dolutegravir at conception and 0.68% of those among women exposed to non-dolutegravir ART at conception (difference, 0.27 percentage points; 95% CI, -0.13 to 0.87). The prevalence of neural-tube defects was slightly higher in association with dolutegravir exposure at conception than with other types of ART exposure at conception (3 per 1000 deliveries vs. 1 per 1000 deliveries). (Funded by the National Institutes of Health.).
Primary Care First — Is It a Step Back?
17-07-2019 – Laura L. Sessums,Sanjay Basu,Bruce E. Landon
Medicaid Work Requirements — Results from the First Year in Arkansas
19-06-2019 – Benjamin D. Sommers,Anna L. Goldman,Robert J. Blendon,E. John Orav,Arnold M. Epstein
Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes
11-06-2019 – Mansoor Husain,Andreas L. Birkenfeld,Morten Donsmark,Kathleen Dungan,Freddy G. Eliaschewitz,Denise R. Franco,Ole K. Jeppesen,Ildiko Lingvay,Ofri Mosenzon,Sue D. Pedersen,Cees J. Tack,Mette Thomsen,Tina Vilsbøll,Mark L. Warren,Stephen C. Bain
Establishing cardiovascular safety of new therapies for type 2 diabetes is important. Safety data are available for the subcutaneous form of the glucagon-like peptide-1 receptor agonist semaglutide but are needed for oral semaglutide.
We assessed cardiovascular outcomes of once-daily oral semaglutide in an event-driven, randomized, double-blind, placebo-controlled trial involving patients at high cardiovascular risk (age of ≥50 years with established cardiovascular or chronic kidney disease, or age of ≥60 years with cardiovascular risk factors only). The primary outcome in a time-to-event analysis was the first occurrence of a major adverse cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The trial was designed to rule out 80% excess cardiovascular risk as compared with placebo (noninferiority margin of 1.8 for the upper boundary of the 95% confidence interval for the hazard ratio for the primary outcome).
A total of 3183 patients were randomly assigned to receive oral semaglutide or placebo. The mean age of the patients was 66 years; 2695 patients (84.7%) were 50 years of age or older and had cardiovascular or chronic kidney disease. The median time in the trial was 15.9 months. Major adverse cardiovascular events occurred in 61 of 1591 patients (3.8%) in the oral semaglutide group and 76 of 1592 (4.8%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.57 to 1.11; P<0.001 for noninferiority). Results for components of the primary outcome were as follows: death from cardiovascular causes, 15 of 1591 patients (0.9%) in the oral semaglutide group and 30 of 1592 (1.9%) in the placebo group (hazard ratio, 0.49; 95% CI, 0.27 to 0.92); nonfatal myocardial infarction, 37 of 1591 patients (2.3%) and 31 of 1592 (1.9%), respectively (hazard ratio, 1.18; 95% CI, 0.73 to 1.90); and nonfatal stroke, 12 of 1591 patients (0.8%) and 16 of 1592 (1.0%), respectively (hazard ratio, 0.74; 95% CI, 0.35 to 1.57). Death from any cause occurred in 23 of 1591 patients (1.4%) in the oral semaglutide group and 45 of 1592 (2.8%) in the placebo group (hazard ratio, 0.51; 95% CI, 0.31 to 0.84). Gastrointestinal adverse events leading to discontinuation of oral semaglutide or placebo were more common with oral semaglutide.
In this trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo. (Funded by Novo Nordisk; PIONEER 6 Clinical
Trials.gov number, NCT02692716.).
Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma
31-05-2019 – Yuan Zhang,Lei Chen,Guo-Qing Hu,Ning Zhang,Xiao-Dong Zhu,Kun-Yu Yang,Feng Jin,Mei Shi,Yu-Pei Chen,Wei-Han Hu,Zhi-Bin Cheng,Si-Yang Wang,Ye Tian,Xi-Cheng Wang,Yan Sun,Jin-Gao Li,Wen-Fei Li,Yu-Hong Li,Ling-Long Tang,Yan-Ping Mao,Guan-Qun Zhou,Rui Sun,Xu Liu,Rui Guo,Guo-Xian Long,Shao-Qiang Liang,Ling Li,Jing Huang,Jin-Hua Long,Jian Zang,Qiao-Dan Liu,Li Zou,Qiong-Fei Su,Bao-Min Zheng,Yun Xiao,Ying Guo,Fei Han,Hao-Yuan Mo,Jia-Wei Lv,Xiao-Jing Du,Cheng Xu,Na Liu,Ying-Qin Li,Melvin L. K. Chua,Fang-Yun Xie,Ying Sun,Jun Ma
Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials.
In a parallel-group, multicenter, randomized, controlled, phase 3 trial, we compared gemcitabine and cisplatin as induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone. Patients with locoregionally advanced nasopharyngeal carcinoma were randomly assigned in a 1:1 ratio to receive gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8) plus cisplatin (80 mg per square meter on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg per square meter every 3 weeks for three cycles plus intensity-modulated radiotherapy) or chemoradiotherapy alone. The primary end point was recurrence-free survival (i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence] or death from any cause) in the intention-to-treat population. Secondary end points included overall survival, treatment adherence, and safety.
A total of 480 patients were included in the trial (242 patients in the induction chemotherapy group and 238 in the standard-therapy group). At a median follow-up of 42.7 months, the 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 to 0.77; P = 0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77). A total of 96.7% of the patients completed three cycles of induction chemotherapy. The incidence of acute adverse events of grade 3 or 4 was 75.7% in the induction chemotherapy group and 55.7% in the standard-therapy group, with a higher incidence of neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy group. The incidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy group and 11.4% in the standard-therapy group.
Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded by the Innovation Team Development Plan of the Ministry of Education and others; Clinical
Trials.gov number, NCT01872962.).
Benralizumab for the Prevention of COPD Exacerbations
20-05-2019 – Gerard J. Criner,Bartolome R. Celli,Christopher E. Brightling,Alvar Agusti,Alberto Papi,Dave Singh,Don D. Sin,Claus F. Vogelmeier,Frank C. Sciurba,Mona Bafadhel,Vibeke Backer,Motokazu Kato,Alejandra Ramírez-Venegas,Yu-Feng Wei,Leif Bjermer,Vivian H. Shih,Maria Jison,Sean O’Quinn,Natalya Makulova,Paul Newbold,Mitchell Goldman,Ubaldo J. Martin
The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known.
In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. <220 per cubic millimeter]) who had frequent exacerbations despite receiving guideline-based inhaled treatment. Patients were randomly assigned to receive benralizumab (30 or 100 mg in GALATHEA; 10, 30, or 100 mg in TERRANOVA) every 8 weeks (every 4 weeks for the first three doses) or placebo. The primary end point was the treatment effect of benralizumab, measured as the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56 in patients with baseline blood eosinophil counts of 220 per cubic millimeter or greater. Safety was also assessed.
In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo.
Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by Astra
Zeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA Clinical
Trials.gov numbers, NCT02138916 and NCT02155660.).