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  

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 

🚨 New insights on proximal hamstring tear treatment! 🚨      Surgical repair of proximal hamstring tears is a technically challenging surgery and carries substantial risks (e.g., sciatic nerve injury, infection, deep vein thrombosis). Until the trial by Pihl et al., the results from which are now published in NEJM Evidence, the data supporting the benefits of surgical repair were restricted to observational studies. This trial was an international, multicenter, randomized trial that also included an observational arm for patients who declined to be randomly assigned to treatment. The investigators randomly assigned 119 patients 30 to 70 years of age with proximal hamstring tears to receive either operative or nonoperative management and found minimal differences in the mean Perth Hamstring Assessment Tool (PHAT) score between the two groups at the 2-year follow-up.      Proximal hamstring repair has been a relatively recent addition to an orthopedic surgeon’s practice. Before 2000, most patients with this injury managed relatively well without surgery. In the last few decades, there has been a trend to repair some proximal hamstring tears in young, active patients, because most of the previous literature (which consisted of relatively small retrospective or prospective cohort studies) showed some evidence of increased strength and return to sports in patients undergoing surgical intervention.      The trial by Pihl et al. shows minimal differences in outcomes between surgical and non-surgical management. However, surgery may be the better option for young, active patients wanting to return to sports.    Read the editorial “Acute Proximal Hamstring Tear — Who Will Benefit from Surgical Intervention?” by Maegan Shields, MD, MSc, and Tim Dwyer, MBBS, PhD: https://eviden.cc/3zKBc9J    𝗙𝗨𝗥𝗧𝗛𝗘𝗥 𝗥𝗘𝗔𝗗𝗜𝗡𝗚  Original Article by E. Pihl et al.: Operative versus Nonoperative Treatment of Proximal Hamstring Avulsions https://eviden.cc/4d87cTx    #ClinicalTrials #MedicalResearch 

📣️ New clinical trial on rivaroxaban in patients with peripheral artery disease and intermittent claudication    The combination of rivaroxaban plus aspirin compared with aspirin alone reduces the risk of major adverse cardiovascular and limb events for high-risk patients with peripheral artery disease. It is unknown whether rivaroxaban plus aspirin improves intermittent claudication for adults with lower-risk peripheral arterial disease.    In an open-label, multicenter, 24-week clinical trial, Ramacciotti et al. randomly assigned patients with peripheral artery disease and intermittent claudication to receive either 2.5 mg of rivaroxaban twice daily plus 100 mg of aspirin once daily or 100 mg of aspirin once daily. The primary outcome was a 24-week change in total walking distance, measured by the 6-minute walking test. The primary safety outcome was the incidence of major bleeding or clinically relevant nonmajor bleeding.    In patients with peripheral artery disease and intermittent claudication, 2.5 mg of rivaroxaban twice daily plus 100 mg of aspirin daily improved the total walking distance assessed by a 6-minute walking test compared with 100 mg of aspirin daily alone.    Read the Original Article “Rivaroxaban for Patients with Intermittent Claudication” by E. Ramacciotti et al.: https://eviden.cc/3Mku8Ug    𝗙𝗨𝗥𝗧𝗛𝗘𝗥 𝗥𝗘𝗔𝗗𝗜𝗡𝗚  Editorial by Charles de Mestral, MD, PhD: Can Rivaroxaban Improve Claudication Symptoms? A Promise Never Made https://eviden.cc/4dVpQyt    #ClinicalTrials #MedicalResearch 

In a meta-analysis of critically ill adults, published in NEJM Evidence, Adigli et al. showed that intensive glucose control, defined as a target blood glucose level of 120mg/dl or less (≤6.6mmol/l), did not decrease the risk of in-hospital mortality (risk ratio, 1.02; 95% confidence interval [CI], 0.96 to 1.07) but increased the risk  of severe hypoglycemia (blood glucose <40mg/dl [<2.2mmol/l]) compared with higher glucose targets (risk ratio, 3.38; 95% CI, 2.99 to 3.83).     In an editorial, Shohinee Sarma, MD, MPH, FRCPC, comments that the study of 20 randomized controlled trials with 14,171 patients supports conventional glucose targets (140-180 mg/dL).    Read the full editorial: https://eviden.cc/4cdAtvB    𝗙𝗨𝗥𝗧𝗛𝗘𝗥 𝗥𝗘𝗔𝗗𝗜𝗡𝗚  Original Article by D. Adigbli et al.: A Patient-Level Meta-Analysis of Intensive Glucose Control in Critically Ill Adults https://eviden.cc/4cdAtvB    #ClinicalTrials #MedicalResearch