NEJM Evidence

Volume 3 Issue 10 of 𝘕𝘌𝘑𝘔 𝘌𝘷𝘪𝘥𝘦𝘯𝘤𝘦 is now available! Here is a preview of the latest content:      𝗢𝗿𝗶𝗴𝗶𝗻𝗮𝗹 𝗔𝗿𝘁𝗶𝗰𝗹𝗲𝘀  Automated Insulin Delivery for Young People with Type 1 Diabetes and Elevated A1c https://eviden.cc/3ZCstS6     Ertugliflozin to Reduce Arrhythmic Burden in Patients with ICDs/CRT-Ds https://eviden.cc/476qaIL    Tecovirimat Use under Expanded Access to Treat Mpox in the United States, 2022–2023 https://eviden.cc/4dTN9ZS    Sequencing of Checkpoint or BRAF/MEK Inhibitors on Brain Metastases in Melanoma https://eviden.cc/3XTlAKB    𝗥𝗲𝘃𝗶𝗲𝘄 𝗔𝗿𝘁𝗶𝗰𝗹𝗲  Sleep Disorders https://eviden.cc/4eqy1Dk      𝗠𝗼𝗿𝗻𝗶𝗻𝗴 𝗥𝗲𝗽𝗼𝗿𝘁   A 59-Year-Old Man with a Rash and Hearing Loss https://eviden.cc/4exCNPt    𝗣𝗮𝘁𝗶𝗲𝗻𝘁 𝗣𝗹𝗮𝘁𝗳𝗼𝗿𝗺  Understanding Over-Treatment — Lessons from a Clinical Trial https://eviden.cc/3B90MG7    Explore all the latest original research and specialty articles in the October issue: https://eviden.cc/current  

“The term clinical trial was something that never entered my mind until a year ago when I was diagnosed with pancreatic cancer. Pancreatic cancer — What do you mean, stage 4? I thought I was a healthy person. I had just retired from my 30-year career and celebrated my milestone birthday of turning 60. The ironic thing is that my husband and I were going to volunteer with Red Cross to drive cancer patients to and from appointments. Little did I know that I would be one of them.”    In this Patient Platform, Bernice Blanchard shares her experience as a participant in a clinical trial for the treatment of pancreatic cancer. She offers her perspective on some of the challenges she has faced.    Read “Looking in the Mirror — My Experience in a Clinical Trial for the Treatment of Pancreatic Cancer” by Bernice Blanchard: https://eviden.cc/3T2cUz3     #Oncology #ClinicalTrials 

During the ongoing outbreak of clade II monkeypox virus (MPXV), many U.S. patients were prescribed tecovirimat, an antiviral drug that was made available under an expanded access Investigational New Drug (EA-IND) program. Yu et al. evaluated EA-IND data to summarize characteristics of treated patients, outcomes, and serious adverse events (SAEs).    Yu et al. evaluated data from patients prescribed tecovirimat from May 29, 2022, through July 10, 2023. Baseline patient characteristics, clinical courses, and outcomes were evaluated via intake forms, outcome forms, and patient diaries. Data were summarized in aggregate by human immunodeficiency virus (HIV) status and by comorbidities of special interest. Reported SAEs were also compiled.    Tecovirimat was prescribed for over 7100 patients in the United States, most often for lesions in sensitive anatomical areas, such as certain anogenital lesions (83.5%; 5135 out of 6148 patients), and pain (52.5%; 3227 out of 6148 patients). The demographic and clinical characteristics mirrored those of patients worldwide. Among the 7181 patients with returned intake forms, 1626 also had returned outcome forms (22.6%). Many patients with severe immunocompromise (e.g., HIV with CD4 counts <200 cells/μl) received multiple courses of tecovirimat (43.1%; 22 out of 51 patients), including intravenously, and often experienced poor outcomes (35.3%; 18 out of 51 patients). Overall, 223 SAEs and 40 deaths were reported. Most SAEs were among patients who were severely immunocompromised, one of whom experienced hallucinations after tecovirimat was administered at twice the standard dose.    Tecovirimat was used extensively. The returned EA-IND data suggest that life-threatening or protracted infections occurred in persons who were severely immunocompromised. SAEs were not commonly reported. The EA-IND data are not definitive; controlled clinical trial data are essential to elucidating if and how tecovirimat should be used.    Read the Original Article “Tecovirimat Use under Expanded Access to Treat Mpox in the United States, 2022–2023” by P. Yu et al. https://eviden.cc/4dTN9ZS    𝗙𝗨𝗥𝗧𝗛𝗘𝗥 𝗥𝗘𝗔𝗗𝗜𝗡𝗚  Editorial by H. Clifford Lane, MD, and Anthony S. Fauci, MD: Expanded Access of Unproven Drugs: Not the Final Word https://eviden.cc/3NhGmhf    #ClinicalTrials #InfectiousDisease 

A 36-year-old man sought evaluation for the sudden onset of sharp, shooting pain across the right half of his head. The pain lasted for a few seconds and occurred about 5 to 10 times each day. He noticed that his right lower cheek would be numb after each episode of the pain. He had no chest pain, dyspnea, vertigo, nausea, or vomiting. He sought evaluation with a primary care physician who prescribed a tricyclic antidepressant for possible tension-type headache. However, the symptoms persisted for the next 6 months, and he sought evaluation in a neurology clinic.    Read the Morning Report "A 36-Year-Old Man with Persistent Headache” by Vincent Matthijs, MD, Nicolas Vandenbussche, MD, and Ludo Vanopdenbosch, MD https://eviden.cc/3yEg7hi    #MedicalEducation #Neurology 

Tuberculosis remains a global health concern, and half of cured patients have permanent lung injury. N-acetylcysteine (NAC) has shown beneficial antimicrobial, antioxidant, and immunomodulatory effects in preclinical tuberculosis models. Wallis et al. examined its effects on tuberculosis treatment outcomes.    Specifically, the trial tested whether NAC had an impact on TB cure and post-treatment lung function in adults with advanced TB given standard therapy +/- oral NAC. NAC had no impact on cure, but potentially improved recovery of lung function.    Read the Original Article “Adjunctive N-Acetylcysteine and Lung Function in Pulmonary Tuberculosis” by R.S. Wallis et al.: https://eviden.cc/3XhfHa7    𝗙𝗨𝗥𝗧𝗛𝗘𝗥 𝗥𝗘𝗔𝗗𝗜𝗡𝗚  Editorial by Akshay Gupte, PhD, MBBS, MSPH, and Edward A. Nardell, MD: Host-Directed Therapies for Posttuberculosis Lung Disease https://eviden.cc/4dXsqUz    #ClinicalTrials #MedicalResearch 

Our editorial for the ERASe trial is now out in NEJM Evidence!🚨 NEJM Group Can SGLT2i's erase 🫀arrhythmias? 💊 The ERASe trial was an RCT aimed at assessing the effect of ertugliflozin on arrhythmic burden in patients with ICD/CRT-Ds ❤️🩹 Read our take on the ERASe trial results! 📖 Link: https://lnkd.in/eSYntKzP ERASe trial full paper: https://lnkd.in/eGbQkUQy Thanks to Michael Colacci for collaboration on this and to Michael Fralick for the opportunity!

#ClinicalTrials investigating novel or high-risk interventions often use data monitoring committees (DMCs) to ensure that the participants’ best interests are safeguarded. The typical DMC charter describes procedures by which the DMC operates, including important details concerning organizational structure, membership, meeting frequency, statistical monitoring guidelines, and contents of DMC reports for interim review. These charters, however, are not routinely publicly available; in some cases, their access could be important to the interpretation of trial results. Zarin et al. recommend including DMC charters for such trials in ClinicalTrials.gov at the time of trial completion; trial protocols, informed consent documents, and statistical analysis plans are already available in this repository.    Read the Clinical Trials Workshop article “The Case for Access to Data Monitoring Committee Charters” by D. Zarin et al.: https://eviden.cc/3yRs8jg    #HealthPolicy 

Sodium–glucose cotransporter 2 inhibitors (SGLT2is) have beneficial pleiotropic effects, contributing to improved cardiovascular and renal outcomes for patients with and without diabetes. The impact of SGLT2is on arrhythmic burden remains largely unexplored through randomized trials.    In this multicenter, double-blind, randomized, placebo-controlled trial, Benedikt et al. investigated the effects of ertugliflozin on arrhythmic burden among patients with heart failure with an ejection fraction less than 50%. All patients had an implantable cardioverter–defibrillator (ICD) with or without a cardiac resynchronization therapy device (CRT-D) and were randomized (1:1) to receive either ertugliflozin 5 mg once daily or placebo. The primary end point was the number of incident sustained (>30 seconds) ventricular tachycardia or ventricular fibrillation events from baseline to week 52. Secondary end points included the total number of non-sustained ventricular tachycardias, appropriate ICD therapies, changes in N-terminal pro-brain–type natriuretic peptide (NTproBNP) levels, and the number of heart failure hospitalizations.    Randomization was prematurely terminated, after class IA guideline recommendations were published for SGLT2is in patients with heart failure regardless of the ejection fraction. The final analysis included 46 patients (11% of the originally planned sample size). The yearly rate of the primary end point was 3.5 (95% confidence interval [CI] 2.8 to 4.4) with ertugliflozin compared with 13.3 with placebo (95% CI 11.8 to 14.8; rate ratio 0.16, 95% CI 0.04 to 0.61; P<0.001). There were no apparent differences in appropriate ICD therapies, hospitalizations, NTproBNP levels, or predefined adverse and serious adverse events.    Ertugliflozin reduced sustained ventricular tachycardia or ventricular fibrillation events in adults with heart failure and an ICD compared with placebo; however, the trial ended early and thus results should be interpreted with caution.    Read the Original Article “Ertugliflozin to Reduce Arrhythmic Burden in Patients with ICDs/CRT-Ds” by M. Benedikt et al.: https://eviden.cc/476qaIL     𝗙𝗨𝗥𝗧𝗛𝗘𝗥 𝗥𝗘𝗔𝗗𝗜𝗡𝗚  📄 Editorial by Michael Colacci, MD, FRCPC, and Mats Christian Højbjerg Lassen, MD: Can SGLT2 Inhibitors ERASe Arrhythmias? https://eviden.cc/3XUJZQ8  📄 Editorial by Armando Teixeira-Pinto, PhD, and Liliana Laranjo, MD, MPH, PhD: Methodological Insights from the ERASe Trial https://eviden.cc/3TERo3q    #ClinicalTrials #MedicalResearch 

Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors are an oral treatment for anemia of chronic kidney disease (CKD). In this systematic review and meta-analysis, Ha et al. assessed long-term safety of HIF prolyl hydroxylase inhibitors.    The authors searched MEDLINE, Embase, and Cochrane databases for randomized trials comparing HIF prolyl hydroxylase inhibitors with an erythropoiesis-stimulating agent (ESA) or placebo with greater than or equal to 48 weeks of follow-up. The primary outcome was major adverse cardiovascular event (MACE), defined as a composite of all-cause death, myocardial infarction, or stroke. Treatment effects were pooled using random-effects models.    Twenty-five trials involving 26,478 participants were included. Of these, 13 trials enrolled 13,230 participants with dialysis-dependent CKD, and 12 trials enrolled 13,248 participants with nondialysis-dependent CKD. There was no evidence that HIF prolyl hydroxylase inhibitors and ESA had different effects on MACE in people with dialysis-dependent CKD (risk ratio, 0.99; 95% confidence interval [CI], 0.92 to 1.08) or people with nondialysis-dependent CKD (risk ratio, 1.08; 95% CI, 0.95 to 1.22). Similarly, there was no evidence that HIF prolyl hydroxylase inhibitors and placebo had different effects on MACE (risk ratio, 1.10; 95% CI, 0.96 to 1.27) in people with nondialysis-dependent CKD. The lack of difference between HIF prolyl hydroxylase inhibitors and ESA or placebo was observed for individual components of MACE and cardiovascular death. Safety of HIF prolyl hydroxylase inhibitors for other outcomes was comparable with ESA in dialysis-dependent CKD. In nondialysis-dependent CKD, dialysis access thrombosis, venous thromboembolism, infections, and hyperkalemia occurred more frequently with HIF prolyl hydroxylase inhibitors in placebo-controlled trials but not in ESA-controlled trials.    There was no evidence of a difference in the long-term cardiovascular safety profile of HIF prolyl hydroxylase inhibitors and ESA in adults with dialysis-dependent CKD and adults with nondialysis-dependent CKD.    Read the Original Article “Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors in Kidney Disease” by J. Ha et al.: https://eviden.cc/3z2CLzM    #ClinicalTrials #MedicalResearch 

Tubal sterilization is the most commonly used method of contraception in the United States. Because contraceptive effectiveness influences contraceptive selection, Schwarz et al. examined typical use failure rates after tubal sterilization in the United States.      The investigators estimated rates of pregnancy after tubal sterilization using data from four waves of the National Survey of Family Growth (NSFG), representative samples of U.S. women aged 15 to 44 years, collected in 2002, 2006 to 2010, 2011 to 2013, and 2013 to 2015. Survey weighting was used in survival analysis to examine time to first pregnancy after tubal sterilization. Data from these participants were censored after a tubal reversal procedure, infertility treatment, hysterectomy, or bilateral oophorectomy. Reported pregnancy rates after tubal sterilization procedures were examined by using Kaplan–Meier curves and then multivariable Cox proportional-hazards models to examine the effects of age at tubal sterilization, race/ethnicity, education, Medicaid funding, and postpartum versus interval procedures.      Pregnancy after tubal sterilization was reported by 2.9 to 5.2% of participants across NSFG waves. In the most recent survey wave (2013 to 2015), the estimated percentage of participants with pregnancies within the first 12 months after a tubal sterilization procedure was 2.9%; at 120 months after tubal sterilization, the estimated percentage with a pregnancy was 8.4%. At all the time points examined, pregnancy after tubal sterilization was less common after postpartum procedures than after interval procedures; however, this difference was not evident in multivariable models. In multivariable models, chance of pregnancy decreased with age at time of tubal sterilization. Race/ethnicity, education, and Medicaid funding were not consistently associated with pregnancy after tubal sterilization.      These data suggest that there may be nontrivial rates of pregnancy after tubal sterilization.    Read the Original Article “Pregnancy after Tubal Sterilization in the United States, 2002 to 2015” by E.B. Schwarz et al.: https://eviden.cc/3YWvBI1    𝗙𝗨𝗥𝗧𝗛𝗘𝗥 𝗥𝗘𝗔𝗗𝗜𝗡𝗚  📄 Editorial by Julia Tasset, MD, MPH, and Maria Rodriguez, MD, MPH: “Permanent” Contraception — Reexamining Modern Tubal Sterilization Effectiveness https://eviden.cc/3T37m7f  📄 Editorial by Hyungjin Myra Kim, ScD: Challenges and Opportunities in Utilizing National Survey Data for Research https://eviden.cc/3Xe7tPY    #ClinicalTrials #MedicalResearch