Showing papers on "Randomized controlled trial published in 2018"
Adrian F. Hernandez1, Jennifer B. Green1, Salim Janmohamed2, Ralph B. D'Agostino3 +795 more•Institutions (7)
TL;DR: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events, and evidence-based glucagon-like peptide 1 receptor agonists should be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events.
1,064 citations
TL;DR: Rivaroxaban was associated with relatively low VTE recurrence but higher CRNMB compared with dalteparin, and safety was assessed by major bleeding and clinically relevant nonmajor bleeding (CRNMB).
Abstract: PurposeVenous thromboembolism (VTE) is common in patients with cancer. Long-term daily subcutaneous low molecular weight heparin has been standard treatment for such patients. The purpose of this study was to assess if an oral factor Xa inhibitor, rivaroxaban, would offer an alternative treatment for VTE in patients with cancer.Patient and MethodsIn this multicenter, randomized, open-label, pilot trial in the United Kingdom, patients with active cancer who had symptomatic pulmonary embolism (PE), incidental PE, or symptomatic lower-extremity proximal deep vein thrombosis (DVT) were recruited. Allocation was to dalteparin (200 IU/kg daily during month 1, then 150 IU/kg daily for months 2-6) or rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily for a total of 6 months). The primary outcome was VTE recurrence over 6 months. Safety was assessed by major bleeding and clinically relevant nonmajor bleeding (CRNMB). A sample size of 400 patients would provide estimates of VTE recurrence to within ±...
902 citations
TL;DR: Randomized Controlled Trials (RCTs) are increasingly popular in the social sciences, not only in medicine as discussed by the authors, and they can play a role in building scientific knowledge and useful predictions but they can only do so as part of a cumulative program, combining with other methods, including conceptual and theoretical development, to discover not 'what works', but 'why things work'.
874 citations
TL;DR: Among men with nonmetastatic castration‐resistant prostate cancer, metastasis‐free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo.
Abstract: Background Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis. Methods We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen-deprivation therapy. The primary end point was metastasis-free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death. Results A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after ...
863 citations
TL;DR: It is shown that high bTMB is a clinically actionable biomarker for atezolizumab in NSCLC, and a blood-based DNA sequencing assay to infer tumor mutational burden in the absence of tumor biopsy predicts response to PD-L1 blockade in patients with non-small-cell lung cancer.
Abstract: Although programmed death-ligand 1–programmed death 1 (PD-L1–PD-1) inhibitors are broadly efficacious, improved outcomes have been observed in patients with high PD-L1 expression or high tumor mutational burden (TMB). PD-L1 testing is required for checkpoint inhibitor monotherapy in front-line non-small-cell lung cancer (NSCLC). However, obtaining adequate tumor tissue for molecular testing in patients with advanced disease can be challenging. Thus, an unmet medical need exists for diagnostic approaches that do not require tissue to identify patients who may benefit from immunotherapy. Here, we describe a novel, technically robust, blood-based assay to measure TMB in plasma (bTMB) that is distinct from tissue-based approaches. Using a retrospective analysis of two large randomized trials as test and validation studies, we show that bTMB reproducibly identifies patients who derive clinically significant improvements in progression-free survival from atezolizumab (an anti-PD-L1) in second-line and higher NSCLC. Collectively, our data show that high bTMB is a clinically actionable biomarker for atezolizumab in NSCLC. A blood-based DNA sequencing assay to infer tumor mutational burden in the absence of tumor biopsy predicts response to PD-L1 blockade in patients with non-small-cell lung cancer.
816 citations
TL;DR: The use of balanced crystalloids for intravenous fluid administration resulted in a lower rate of the composite outcome of death from any cause, new renal‐replacement therapy, or persistent renal dysfunction than the use of saline among critically ill adults.
Abstract: Background Both balanced crystalloids and saline are used for intravenous fluid administration in critically ill adults, but it is not known which results in better clinical outcomes. Methods In a pragmatic, cluster-randomized, multiple-crossover trial conducted in five intensive care units at an academic center, we assigned 15,802 adults to receive saline (0.9% sodium chloride) or balanced crystalloids (lactated Ringer’s solution or Plasma-Lyte A) according to the randomization of the unit to which they were admitted. The primary outcome was a major adverse kidney event within 30 days — a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction (defined as an elevation of the creatinine level to ≥200% of baseline) — all censored at hospital discharge or 30 days, whichever occurred first. Results Among the 7942 patients in the balanced-crystalloids group, 1139 (14.3%) had a major adverse kidney event, as compared with 1211 of 7860 patients (15.4%) in the s...
791 citations
TL;DR: The use of CTA in addition to standard care in patients with stable chest pain resulted in a significantly lower rate of death from coronary heart disease or nonfatal myocardial infarction at 5 years than standard care alone, without resulting in a significant higher rate of coronary angiography or coronary revascularization.
Abstract: Background:
Although coronary computed tomographic angiography (CTA) improves diagnostic certainty in the assessment of patients with stable chest pain, its effect on 5-year clinical outcomes is unknown.
Methods:
In an open-label, multicenter, parallel-group trial, we randomly assigned 4146 patients with stable chest pain who had been referred to a cardiology clinic for evaluation to standard care plus CTA (2073 patients) or to standard care alone (2073 patients). Investigations, treatments, and clinical outcomes were assessed over 3 to 7 years of follow-up. The primary end point was death from coronary heart disease or nonfatal myocardial infarction at 5 years.
Results:
The median duration of follow-up was 4.8 years, which yielded 20,254 patient-years of follow-up. The 5-year rate of the primary end point was lower in the CTA group than in the standard-care group (2.3% [48 patients] vs. 3.9% [81 patients]; hazard ratio, 0.59; 95% confidence interval [CI], 0.41 to 0.84; P=0.004). Although the rates of invasive coronary angiography and coronary revascularization were higher in the CTA group than in the standard-care group in the first few months of follow-up, overall rates were similar at 5 years: invasive coronary angiography was performed in 491 patients in the CTA group and in 502 patients in the standard-care group (hazard ratio, 1.00; 95% CI, 0.88 to 1.13), and coronary revascularization was performed in 279 patients in the CTA group and in 267 in the standard-care group (hazard ratio, 1.07; 95% CI, 0.91 to 1.27). However, more preventive therapies were initiated in patients in the CTA group (odds ratio, 1.40; 95% CI, 1.19 to 1.65), as were more antianginal therapies (odds ratio, 1.27; 95% CI, 1.05 to 1.54). There were no significant between-group differences in the rates of cardiovascular or noncardiovascular deaths or deaths from any cause.
Conclusions:
In this trial, the use of CTA in addition to standard care in patients with stable chest pain resulted in a significantly lower rate of death from coronary heart disease or nonfatal myocardial infarction at 5 years than standard care alone, without resulting in a significantly higher rate of coronary angiography or coronary revascularization. (Funded by the Scottish Government Chief Scientist Office and others; SCOT-HEART ClinicalTrials.gov number, NCT01149590).
790 citations
TL;DR: Overall results indicate equivalence, but there have been few studies of the individual psychiatric and somatic conditions so far, and for the majority, guided ICBT has not been compared against face-to-face treatment.
Abstract: During the last two decades, Internet-delivered cognitive behavior therapy (ICBT) has been tested in hundreds of randomized controlled trials, often with promising results. However, the control gro...
775 citations
TL;DR: Considering that oncogenic activation of the PI3K–AKT–mTOR pathway often occurs alongside pro-tumorigenic aberrations in other signalling networks, rational combinations are also needed to optimize the effectiveness of treatment.
Abstract: The PI3K-AKT-mTOR pathway is one of the most frequently dysregulated pathways in cancer and, consequently, more than 40 compounds that target key components of this signalling network have been tested in clinical trials involving patients with a range of different cancers. The clinical development of many of these agents, however, has not advanced to late-phase randomized trials, and the antitumour activity of those that have been evaluated in comparative prospective studies has typically been limited, or toxicities were found to be prohibitive. Nevertheless, the mTOR inhibitors temsirolimus and everolimus and the PI3K inhibitors idelalisib and copanlisib have been approved by the FDA for clinical use in the treatment of a number of different cancers. Novel compounds with greater potency and selectivity, as well as improved therapeutic indices owing to reduced risks of toxicity, are clearly required. In addition, biomarkers that are predictive of a response, such as PIK3CA mutations for inhibitors of the PI3K catalytic subunit α isoform, must be identified and analytically and clinically validated. Finally, considering that oncogenic activation of the PI3K-AKT-mTOR pathway often occurs alongside pro-tumorigenic aberrations in other signalling networks, rational combinations are also needed to optimize the effectiveness of treatment. Herein, we review the current experience with anticancer therapies that target the PI3K-AKT-mTOR pathway.
702 citations
TL;DR: There is increased risk of death following application of paclitaxel‐coated balloons and stents in the femoropopliteal artery of the lower limbs.
Abstract: Background Several randomized controlled trials (RCTs) have already shown that paclitaxel‐coated balloons and stents significantly reduce the rates of vessel restenosis and target lesion revascular...
702 citations
TL;DR: Treatment with opioids was not superior to treatment with nonopioid medications for improving pain-related function over 12 months and results do not support initiation of opioid therapy for moderate to severe chronic back pain or hip or knee osteoarthritis pain.
Abstract: Importance Limited evidence is available regarding long-term outcomes of opioids compared with nonopioid medications for chronic pain. Objective To compare opioid vs nonopioid medications over 12 months on pain-related function, pain intensity, and adverse effects. Design, Setting, and Participants Pragmatic, 12-month, randomized trial with masked outcome assessment. Patients were recruited from Veterans Affairs primary care clinics from June 2013 through December 2015; follow-up was completed December 2016. Eligible patients had moderate to severe chronic back pain or hip or knee osteoarthritis pain despite analgesic use. Of 265 patients enrolled, 25 withdrew prior to randomization and 240 were randomized. Interventions Both interventions (opioid and nonopioid medication therapy) followed a treat-to-target strategy aiming for improved pain and function. Each intervention had its own prescribing strategy that included multiple medication options in 3 steps. In the opioid group, the first step was immediate-release morphine, oxycodone, or hydrocodone/acetaminophen. For the nonopioid group, the first step was acetaminophen (paracetamol) or a nonsteroidal anti-inflammatory drug. Medications were changed, added, or adjusted within the assigned treatment group according to individual patient response. Main Outcomes and Measures The primary outcome was pain-related function (Brief Pain Inventory [BPI] interference scale) over 12 months and the main secondary outcome was pain intensity (BPI severity scale). For both BPI scales (range, 0-10; higher scores = worse function or pain intensity), a 1-point improvement was clinically important. The primary adverse outcome was medication-related symptoms (patient-reported checklist; range, 0-19). Results Among 240 randomized patients (mean age, 58.3 years; women, 32 [13.0%]), 234 (97.5%) completed the trial. Groups did not significantly differ on pain-related function over 12 months (overallP = .58); mean 12-month BPI interference was 3.4 for the opioid group and 3.3 for the nonopioid group (difference, 0.1 [95% CI, −0.5 to 0.7]). Pain intensity was significantly better in the nonopioid group over 12 months (overallP = .03); mean 12-month BPI severity was 4.0 for the opioid group and 3.5 for the nonopioid group (difference, 0.5 [95% CI, 0.0 to 1.0]). Adverse medication-related symptoms were significantly more common in the opioid group over 12 months (overallP = .03); mean medication-related symptoms at 12 months were 1.8 in the opioid group and 0.9 in the nonopioid group (difference, 0.9 [95% CI, 0.3 to 1.5]). Conclusions and Relevance Treatment with opioids was not superior to treatment with nonopioid medications for improving pain-related function over 12 months. Results do not support initiation of opioid therapy for moderate to severe chronic back pain or hip or knee osteoarthritis pain. Trial Registration clinicaltrials.gov Identifier:NCT01583985
TL;DR: In patients with medically treated angina and severe coronary stenosis, PCI did not increase exercise time by more than the effect of a placebo procedure, and the primary endpoint was difference in exercise time increment between groups.
Northwestern University1, George Washington University2, National Institutes of Health3, University of Alabama at Birmingham4, University of Utah5, Stanford University6, Columbia University7, Brown University8, University of Texas Medical Branch9, University of North Carolina at Chapel Hill10, University of Texas Health Science Center at Houston11, Ohio State University12, MetroHealth13, University of Texas Southwestern Medical Center14, University of Colorado Denver15, University of Pennsylvania16, Duke University17, University of Pittsburgh18, Washington University in St. Louis19
TL;DR: Induction of labor at 39 weeks in low‐risk nulliparous women did not result in a significantly lower frequency of a composite adverse perinatal outcome, but it did result in less frequency of cesarean delivery.
Abstract: Background The perinatal and maternal consequences of induction of labor at 39 weeks among low-risk nulliparous women are uncertain. Methods In this multicenter trial, we randomly assigned...
University of Wisconsin-Madison1, Harvard University2, Eastern Cooperative Oncology Group3, Johns Hopkins University4, NorthShore University HealthSystem5, Northwestern University6, University of Virginia7, Mayo Clinic8, Fox Chase Cancer Center9, Washington University in St. Louis10, University Hospitals of Cleveland11, Cleveland Clinic12, University of Kentucky13
TL;DR: The clinical benefit from chemohormonal therapy in prolonging OS was confirmed for patients with high-volume disease; however, for patientsWith low- volume disease, no OS benefit was discerned.
Abstract: Purpose Docetaxel added to androgen-deprivation therapy (ADT) significantly increases the longevity of some patients with metastatic hormone-sensitive prostate cancer. Herein, we present the outcomes of the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial with more mature follow-up and focus on tumor volume. Patients and Methods In this phase III study, 790 patients with metastatic hormone-sensitive prostate cancer were equally randomly assigned to receive either ADT in combination with docetaxel 75 mg/m2 for up to six cycles or ADT alone. The primary end point of the study was overall survival (OS). Additional analyses of the prospectively defined low- and high-volume disease subgroups were performed. High-volume disease was defined as presence of visceral metastases and/or ≥ four bone metastases with at least one outside of the vertebral column and pelvis. Results At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2 months for ADT alone (hazard ratio [HR], 0.72; 95% CI, 0.59 to 0.89; P = .0018). For patients with high-volume disease (n = 513), the median OS was 51.2 months with chemohormonal therapy versus 34.4 months with ADT alone (HR, 0.63; 95% CI, 0.50 to 0.79; P < .001). For those with low-volume disease (n = 277), no OS benefit was observed (HR, 1.04; 95% CI, 0.70 to 1.55; P = .86). Conclusion The clinical benefit from chemohormonal therapy in prolonging OS was confirmed for patients with high-volume disease; however, for patients with low-volume disease, no OS benefit was discerned.
TL;DR: Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated.
TL;DR: In this article, a review of the current knowledge of lifestyle-related risk factors and results from novel trials aiming to prevent cognitive decline and dementia is presented, including the World Wide FINGERS network, which aims to harmonize studies on dementia prevention, generate high-quality scientific evidence and promote its implementation.
Abstract: Research into dementia prevention is of paramount importance if the dementia epidemic is to be halted. Observational studies have identified several potentially modifiable risk factors for dementia, including hypertension, dyslipidaemia and obesity at midlife, diabetes mellitus, smoking, physical inactivity, depression and low levels of education. Randomized clinical trials are needed that investigate whether interventions targeting these risk factors can reduce the risk of cognitive decline and dementia in elderly adults, but such trials are methodologically challenging. To date, most preventive interventions have been tested in small groups, have focused on a single lifestyle factor and have yielded negative or modest results. Given the multifactorial aetiology of dementia and late-onset Alzheimer disease, multidomain interventions that target several risk factors and mechanisms simultaneously might be necessary for an optimal preventive effect. In the past few years, three large multidomain trials (FINGER, MAPT and PreDIVA) have been completed. The FINGER trial showed that a multidomain lifestyle intervention can benefit cognition in elderly people with an elevated risk of dementia. The primary results from the other trials did not show a statistically significant benefit of preventive interventions, but additional analyses among participants at risk of dementia showed beneficial effects of intervention. Overall, results from these three trials suggest that targeting of preventive interventions to at-risk individuals is an effective strategy. This Review discusses the current knowledge of lifestyle-related risk factors and results from novel trials aiming to prevent cognitive decline and dementia. Global initiatives are presented, including the World Wide FINGERS network, which aims to harmonize studies on dementia prevention, generate high-quality scientific evidence and promote its implementation.
TL;DR: Among patients with morbid obesity, there was no significant difference in excess BMI loss between Laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass at 5 years of follow-up after surgery.
Abstract: Importance Sleeve gastrectomy is increasingly used in the treatment of morbid obesity, but its long-term outcome vs the standard Roux-en-Y gastric bypass procedure is unknown. Objective To determine whether there are differences between sleeve gastrectomy and Roux-en-Y gastric bypass in terms of weight loss, changes in comorbidities, increase in quality of life, and adverse events. Design, Setting, and Participants The Swiss Multicenter Bypass or Sleeve Study (SM-BOSS), a 2-group randomized trial, was conducted from January 2007 until November 2011 (last follow-up in March 2017). Of 3971 morbidly obese patients evaluated for bariatric surgery at 4 Swiss bariatric centers, 217 patients were enrolled and randomly assigned to sleeve gastrectomy or Roux-en-Y gastric bypass with a 5-year follow-up period. Interventions Patients were randomly assigned to undergo laparoscopic sleeve gastrectomy (n = 107) or laparoscopic Roux-en-Y gastric bypass (n = 110). Main Outcomes and Measures The primary end point was weight loss, expressed as percentage excess body mass index (BMI) loss. Exploratory end points were changes in comorbidities and adverse events. Results Among the 217 patients (mean age, 45.5 years; 72% women; mean BMI, 43.9) 205 (94.5%) completed the trial. Excess BMI loss was not significantly different at 5 years: for sleeve gastrectomy, 61.1%, vs Roux-en-Y gastric bypass, 68.3% (absolute difference, −7.18%; 95% CI, −14.30% to −0.06%; P = .22 after adjustment for multiple comparisons). Gastric reflux remission was observed more frequently after Roux-en-Y gastric bypass (60.4%) than after sleeve gastrectomy (25.0%). Gastric reflux worsened (more symptoms or increase in therapy) more often after sleeve gastrectomy (31.8%) than after Roux-en-Y gastric bypass (6.3%). The number of patients with reoperations or interventions was 16/101 (15.8%) after sleeve gastrectomy and 23/104 (22.1%) after Roux-en-Y gastric bypass. Conclusions and Relevance Among patients with morbid obesity, there was no significant difference in excess BMI loss between laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass at 5 years of follow-up after surgery. Trial Registration clinicaltrials.gov Identifier: NCT00356213
Princess Alexandra Hospital1, Royal Brisbane and Women's Hospital2, University of Queensland3, National University of Singapore4, Nanyang Technological University5, Tan Tock Seng Hospital6, Istanbul Medipol University7, King Saud bin Abdulaziz University for Health Sciences8, Sapienza University of Rome9, University of Udine10, Monash University11, American University of Beirut12, North Shore Hospital13, Westmead Hospital14, University of Sydney15, University of Cape Town16, Illawarra Health & Medical Research Institute17, University of Wollongong18, Wollongong Hospital19, Middlemore Hospital20, King Fahad Specialist Hospital21, St. Vincent's Health System22, Fiona Stanley Hospital23, University of Western Australia24, Sunnybrook Health Sciences Centre25, QIMR Berghofer Medical Research Institute26, Mater Health Services27, Deakin University28, Monash University, Clayton campus29
TL;DR: Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality, and findings do not support use of piperACillin- tazobactsam in this setting.
Abstract: Importance Extended-spectrum β-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by these strains are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective “carbapenem-sparing” option to treat extended-spectrum β-lactamase producers. Objectives To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae . Design, Setting, and Participants Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study. Interventions Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician. Main Outcomes and Measures The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used. Results Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6% [1-sided 97.5% CI, −∞ to 14.5%]; P = .90 for noninferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group. Conclusions and relevance Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in this setting. Trial Registration anzctr.org.au Identifiers:ACTRN12613000532707andACTRN12615000403538and ClinicalTrials.gov Identifier:NCT02176122
University of North Carolina at Chapel Hill1, Harvard University2, Cleveland Clinic3, United States Department of Veterans Affairs4, Case Western Reserve University5, MetroHealth6, Northeast Ohio Medical University7, University of Pittsburgh8, University of Michigan9, Duke University10, University of Queensland11
TL;DR: Ceftazidime-avibactam may be a reasonable alternative to colistin in the treatment of K. pneumoniae carbapenemase-producing CRE infections and require confirmation in a randomized controlled trial.
Abstract: Background The efficacy of ceftazidime-avibactam-a cephalosporin-β-lactamase inhibitor combination with in vitro activity against Klebsiella pneumoniae carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CRE)-compared with colistin remains unknown. Methods Patients initially treated with either ceftazidime-avibactam or colistin for CRE infections were selected from the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE), a prospective, multicenter, observational study. Efficacy, safety, and benefit-risk analyses were performed using intent-to-treat analyses with partial credit and the desirability of outcome ranking approaches. The ordinal efficacy outcome was based on disposition at day 30 after starting treatment (home vs not home but not observed to die in the hospital vs hospital death). All analyses were adjusted for confounding using inverse probability of treatment weighting (IPTW). Results Thirty-eight patients were treated first with ceftazidime-avibactam and 99 with colistin. Most patients received additional anti-CRE agents as part of their treatment. Bloodstream (n = 63; 46%) and respiratory (n = 30; 22%) infections were most common. In patients treated with ceftazidime-avibactam versus colistin, IPTW-adjusted all-cause hospital mortality 30 days after starting treatment was 9% versus 32%, respectively (difference, 23%; 95% bootstrap confidence interval, 9%-35%; P = .001). In an analysis of disposition at 30 days, patients treated with ceftazidime-avibactam, compared with those treated within colistin, had an IPTW-adjusted probability of a better outcome of 64% (95% confidence interval, 57%-71%). Partial credit analyses indicated uniform superiority of ceftazidime-avibactam to colistin. Conclusions Ceftazidime-avibactam may be a reasonable alternative to colistin in the treatment of K. pneumoniae carbapenemase-producing CRE infections. These findings require confirmation in a randomized controlled trial.
TL;DR: Treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose‐limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo, in this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut.
Abstract: BACKGROUND Peanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life-threatening allergic reactions. METHODS In a phase 3 trial, we screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive AR101 (a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms. RESULTS Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; P<0.001). During the exit food challenge, the maximum severity of symptoms was moderate in 25% of the participants in the active-drug group and 59% of those in the placebo group and severe in 5% and 11%, respectively. Adverse events during the intervention period affected more than 95% of the participants 4 to 17 years of age. A total of 34.7% of the participants in the active-drug group had mild events, as compared with 50.0% of those in the placebo group; 59.7% and 44.4% of the participants, respectively, had events that were graded as moderate, and 4.3% and 0.8%, respectively, had events that were graded as severe. Efficacy was not shown in the participants 18 years of age or older. CONCLUSIONS In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo. (Funded by Aimmune Therapeutics; PALISADE ClinicalTrials.gov number, NCT02635776 .).
Hofstra University1, Charité2, University of Verona3, King's College London4, Copenhagen University Hospital5, Lundbeck6, Yale University7, Maastricht University8, University of Hong Kong9, The Feinstein Institute for Medical Research10, SUNY Downstate Medical Center11, Dartmouth College12, Boston University13, University of Calgary14, University of North Carolina at Chapel Hill15, Nathan Kline Institute for Psychiatric Research16, National Institutes of Health17
TL;DR: In this paper, the authors compared early intervention services (EIS) with treatment as usual (TAU) for early-phase psychosis and found that EIS was associated with better outcomes than TAU at the end of treatment for all 13 meta-analyzable outcomes.
Abstract: Importance The value of early intervention in psychosis and allocation of public resources has long been debated because outcomes in people with schizophrenia spectrum disorders have remained suboptimal. Objective To compare early intervention services (EIS) with treatment as usual (TAU) for early-phase psychosis. Data Sources Systematic literature search of PubMed, PsycINFO, EMBASE, and ClinicalTrials.gov without language restrictions through June 6, 2017. Study Selection Randomized trials comparing EIS vs TAU in first-episode psychosis or early-phase schizophrenia spectrum disorders. Data Extraction and Synthesis This systematic review was conducted according to PRISMA guidelines. Three independent investigators extracted data for a random-effects meta-analysis and prespecified subgroup and meta-regression analyses. Main Outcomes and Measures The coprimary outcomes were all-cause treatment discontinuation and at least 1 psychiatric hospitalization during the treatment period. Results Across 10 randomized clinical trials (mean [SD] trial duration, 16.2 [7.4] months; range, 9-24 months) among 2176 patients (mean [SD] age, 27.5 [4.6] years; 1355 [62.3%] male), EIS was associated with better outcomes than TAU at the end of treatment for all 13 meta-analyzable outcomes. These outcomes included the following: all-cause treatment discontinuation (risk ratio [RR], 0.70; 95% CI, 0.61-0.80; P P = .003), involvement in school or work (RR, 1.13; 95% CI, 1.03-1.24; P = .01), total symptom severity (standardized mean difference [SMD], −0.32; 95% CI, −0.47 to −0.17; P P P Conclusions and Relevance In early-phase psychosis, EIS are superior to TAU across all meta-analyzable outcomes. These results support the need for funding and use of EIS in patients with early-phase psychosis.
TL;DR: In patients with infected necrotising pancreatitis, the endoscopic step-up approach was not superior to the surgical step- up approach in reducing major complications or death, and the rate of pancreatic fistulas and length of hospital stay were lower in the endoscopy group.
University of Southampton1, St Mary's Hospital2, University Hospital Southampton NHS Foundation Trust3, Heidelberg University4, Swiss Institute of Allergy and Asthma Research5, National Institutes of Health6, Erasmus University Rotterdam7, Odense University Hospital8, Nippon Medical School9, University of Cyprus10, University of Edinburgh11, Charité12, University of Messina13, Eskişehir Osmangazi University14, Boston Children's Hospital15, Katholieke Universiteit Leuven16, Utrecht University17, Johns Hopkins University18, Athens State University19, University Medical Center Groningen20, University of Milan21, University College Hospital22, King's College London23, Medical University of Graz24, European Union25, Capital Medical University26, Transylvania University27, Northern General Hospital28, Hospital Clínico San Carlos29, Wrocław Medical University30, University of Amsterdam31, University of Padua32
TL;DR: In general, broad evidence for the clinical efficacy of AIT for AR exists but a product‐specific evaluation of evidence is recommended, and SCIT and SLIT are recommended for both seasonal and perennial AR for its short‐term benefit.
Abstract: Allergic rhinoconjunctivitis (AR) is an allergic disorder of the nose and eyes affecting about a fifth of the general population. Symptoms of AR can be controlled with allergen avoidance measures and pharmacotherapy. However, many patients continue to have ongoing symptoms and an impaired quality of life; pharmacotherapy may also induce some side-effects. Allergen immunotherapy (AIT) represents the only currently available treatment that targets the underlying pathophysiology, and it may have a disease-modifying effect. Either the subcutaneous (SCIT) or sublingual (SLIT) routes may be used. This Guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on AIT for AR and is part of the EAACI presidential project "EAACI Guidelines on Allergen Immunotherapy." It aims to provide evidence-based clinical recommendations and has been informed by a formal systematic review and meta-analysis. Its generation has followed the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included involvement of the full range of stakeholders. In general, broad evidence for the clinical efficacy of AIT for AR exists but a product-specific evaluation of evidence is recommended. In general, SCIT and SLIT are recommended for both seasonal and perennial AR for its short-term benefit. The strongest evidence for long-term benefit is documented for grass AIT (especially for the grass tablets) where long-term benefit is seen. To achieve long-term efficacy, it is recommended that a minimum of 3 years of therapy is used. Many gaps in the evidence base exist, particularly around long-term benefit and use in children.
University of Milan1, Instituto Português de Oncologia Francisco Gentil2, Paris Descartes University3, Leiden University Medical Center4, Vienna General Hospital5, University College London6, Lund University7, Leiden University8, Institut Jules Bordet9, Netherlands Cancer Institute10, Turku University Hospital11, University of Oxford12, Heidelberg University13, Ludwig Maximilian University of Munich14, Helsinki University Central Hospital15, The Royal Marsden NHS Foundation Trust16, Institute of Cancer Research17, University Medical Center Groningen18, Radboud University Nijmegen19, Institut Gustave Roussy20, Tel Aviv Sourasky Medical Center21, University Hospital of Lausanne22, University of Bologna23, University of Turin24, Weston Park Hospital25, Curie Institute26, Aarhus University27, Katholieke Universiteit Leuven28, Erasmus University Rotterdam29, Oslo University Hospital30, University College Hospital31, Claude Bernard University Lyon 132
TL;DR: Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy; Instituto Portugues de Oncologia de Lisboa Francisco Gentil, EPE, Lisbon, Portugal; University Hospital Essen, Essen Germany; Department of Oncological Orthopedics, Musculoskeletal Tissue Bank, IFO, Regina Elena National Cancer Institute, Rome, Italy.
TL;DR: Compared to upfront surgery, neoadjuvant chemoradiation provides oncological benefits in patients with BRPC, and this is the first prospective randomized controlled trial on the oncology benefits of neoadedjuvant treatment in BRPC.
Abstract: Objective:This study was performed to determine whether neoadjuvant treatment increases survival in patients with BRPC.Summary Background Data:Despite many promising retrospective data on the effect of neoadjuvant treatment for borderline resectable pancreatic cancer (BRPC), no high-level evidence e
TL;DR: In adults with out‐of‐hospital cardiac arrest, the use of epinephrine resulted in a significantly higher rate of 30‐day survival than theUse of placebo, but there was no significant between‐group difference in the rate of a favorable neurologic outcome.
Abstract: Background Concern about the use of epinephrine as a treatment for out-of-hospital cardiac arrest led the International Liaison Committee on Resuscitation to call for a placebo-controlled trial to determine whether the use of epinephrine is safe and effective in such patients. Methods In a randomized, double-blind trial involving 8014 patients with out-of-hospital cardiac arrest in the United Kingdom, paramedics at five National Health Service ambulance services administered either parenteral epinephrine (4015 patients) or saline placebo (3999 patients), along with standard care. The primary outcome was the rate of survival at 30 days. Secondary outcomes included the rate of survival until hospital discharge with a favorable neurologic outcome, as indicated by a score of 3 or less on the modified Rankin scale (which ranges from 0 [no symptoms] to 6 [death]). Results At 30 days, 130 patients (3.2%) in the epinephrine group and 94 (2.4%) in the placebo group were alive (unadjusted odds ratio for su...
TL;DR: The TIM-HF2 trial suggests that a structured remote patient management intervention, when used in a well defined heart failure population, could reduce the percentage of days lost due to unplanned cardiovascular hospital admissions and all-cause mortality.
TL;DR: The use of ROBINS-I in GRADE assessments may allow for a better comparison of evidence from randomized controlled trials (RCTs) and nonrandomized studies (NRSs) because they are placed on a common metric for risk of bias.
Carolyn S. Calfee1, Kevin L. Delucchi1, Pratik Sinha1, Michael A. Matthay1 +163 more•Institutions (7)
TL;DR: Although HARP-2 found no difference in 28-day survival between placebo and simvastatin, significantly different survival was identified across patients stratified by treatment and subphenotype (p<0·0001), and within the hyperinflammatory subphenotypes, patients treated with simVastatin had significantly higher 28- day survival than did those given placebo.
University of Cambridge1, Wayne State University2, University of Bristol3, University of Copenhagen4, Copenhagen University Hospital5, Innsbruck Medical University6, University of Glasgow7, Leiden University8, Leiden University Medical Center9, Utrecht University10, National Institute for Health Research11, University of Pennsylvania12, Wellcome Trust Sanger Institute13
TL;DR: The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe withCHD risk.
Abstract: Importance Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk. Objective To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD. Design, Setting, and Participants A mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018. Exposures GeneticLPA score and plasma Lp(a) mass concentration. Main Outcomes and Measures Coronary heart disease. Results Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951;P = 3 × 10−37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893;P = 2 × 10−12). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk. Conclusions and Relevance The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L).