NEJM evidence最新文献

AbstractEnhanced Recovery After Surgery (ERAS) is a global initiative comprised of a series of evidence-based interventions in the preoperative, intraoperative, and postoperative surgical phases. When implemented as a bundle, ERAS interventions both improve clinical outcomes and provide cost savings to the health care system. This review provides an update on the current evidence for individual ERAS elements to improve quality of care as well as practical recommendations for multidisciplinary teams to implement their own ERAS programs.

Background: Hemoglobin SC (HbSC) is a common sickle hemoglobinopathy that causes acute complications, chronic organ damage, and early death with no established disease-modifying treatment. In this trial, we examined the safety and efficacy of hydroxyurea treatment in patients with HbSC.

Methods: Prospective Identification of Variables as Outcomes for Treatment (PIVOT) was a double-blind, randomized, placebo-controlled, non-inferiority phase 2 trial in which we assigned children and adults with HbSC in Ghana to 12 months of hydroxyurea or placebo. The primary end point was hematologic dose-limiting toxicities (DLTs), including cytopenias or elevated hemoglobin levels during 12 months of blinded treatment. Clinical end points included vaso-occlusive pain events, acute chest syndrome, hospitalizations, transfusions, and malaria. Quality-of-life measures, organ function assessments, and rheological measurements were also collected.

Results: Of the 243 enrolled patients (118 female), 212 eligible participants initiated blinded treatment at 20.0±5.0 mg/kg/day. DLTs occurred in more participants on hydroxyurea (33%) than the placebo (11%), with a difference of 22 percentage points (95% confidence interval [CI],11 to 34 percentage points), which exceeded the predefined 15 percentage point noninferiority margin. Elevated levels of hemoglobin occurred in 12 participants on hydroxyurea and 10 on the placebo. Hydroxyurea treatment was associated with 57.0 versus 149.6 vaso-occlusive pain events per 100 person-years (incidence rate ratio [IRR] 0.38; 95% CI, 0.28 to 0.52), and 12.9 versus 30.6 hospitalizations per 100 person-years (IRR 0.42; 95% CI, 0.22 to 0.81). A composite of acute sickle-related events occurred in 37 participants on hydroxyurea versus 69 participants on placebo (IRR 0.39; (95% CI, 0.26 to 0.59), a difference observed in both children and adults.

Conclusions: The PIVOT trial did not meet its primary end point. Hydroxyurea at 20 mg/kg in patients with HbSC was associated with more hematologic DLTs than placebo, but most were mild and transient. Hydroxyurea was associated with less vaso-occlusive pain and fewer sickle-related events in both children and adults; a new trial will need to be done to establish the efficacy of this approach. (Funded by Theravia; Pan-African Clinical Trials Registry number, PACTR 202108893981080).

Background: Larsucosterol is a DNA methyltransferase inhibitor in development for alcohol-associated hepatitis (AH), a disease for which there is no approved therapy.

Methods: In this phase 2b trial, patients with severe AH were randomly assigned 1:1:1 to receive 30 mg or 90 mg of larsucosterol or placebo; a second dose was administered after 72 hours if the patient remained hospitalized. All patients received supportive care as determined by investigators. Patients in the placebo group, if prescribed, received 32 mg of methylprednisolone, while patients in the larsucosterol groups received matching placebo capsules. The primary end point was 90-day mortality or liver transplant (LT) rate. The key secondary end point was 90-day mortality. We prespecified the reporting of U.S. results separately.

Results: Among 307 enrolled patients, 301 received at least one treatment dose. The difference in 90-day mortality or LT between the 30-mg or 90-mg larsucosterol and placebo groups did not reach statistical significance. Ninety-day mortality in the placebo and the 30-mg and 90-mg groups was 25 out of 103, 15 out of 102, and 17 out of 102, respectively. Among U.S. patients (76% of all enrolled patients), there were 21 deaths and 4 LTs among 77 patients in the placebo group, 8 deaths and 5 LTs among 73 patients in the 30-mg larsucosterol group, and 10 deaths and 8 LTs among 77 patients in the 90-mg larsucosterol group. In patients who were treated within less than 10 days of hospitalization (75%), mortality in the placebo group was 20 out of 79 (U.S. patients 17/57), mortality in the 30-mg larsucosterol group was 7 out of 74 (U.S. patients 4/57), and mortality in the 90-mg larsucosterol group was 13 out of 77 (U.S. patients 9/66). Most adverse events arising during treatment were attributable to hepatic disease, and there was no imbalance in adverse events that could not be ascribed to liver disease.

Conclusions: The trial did not meet the primary end point of showing a beneficial effect of larsucosterol on 90-day mortality or LT in patients with severe AH. Equipoise has been established for a further trial of larsucosterol on AH survival. (The trial was funded by the DURECT Corporation; its ClinicalTrials.gov number is NCT04563026.).

AbstractMorning Report is a time-honored tradition where physicians-in-training present cases to their colleagues and clinical experts to collaboratively examine an interesting patient presentation. The Morning Report section seeks to carry on this tradition by presenting a patient's chief concern and story, inviting the reader to develop a differential diagnosis and discover the diagnosis alongside the authors of the case. This report examines the story of a 26-year-old woman who developed acute hepatocellular liver injury following a cesarean delivery for fetal distress. Using targeted questions, physical examination, and diagnostic testing, an illness script for the presentation emerges. As the clinical course progresses, the differential is iteratively refined until a final diagnosis is made.

Background: The current regimen for early medication abortion in many countries is mifepristone and misoprostol, but mifepristone is relatively expensive and limited in many regions. Ulipristal acetate, with a similar chemical profile, might be an alternative. This proof-of-concept study evaluated ulipristal acetate and misoprostol for medication abortion through 63 days of gestation.

Methods: We conducted a two-stage clinical study to choose an effective and acceptable ulipristal-misoprostol regimen. First, we undertook a dose-finding study. Sixty-six participants were randomly assigned to either 60 mg or 90 mg of oral ulipristal, followed by 800 μg of buccal misoprostol. Because the two groups had similar efficacy and safety profiles, we opted for the 60-mg ulipristal dose for an open-label study with 100 additional participants, resulting in a total of 133 participants using the same regimen. To evaluate acceptability, we applied a structured questionnaire at the end of the follow-up visit.

Results: Pregnancy termination occurred with the combination of oral ulipristal 60 mg and buccal misoprostol 800 μg in 129 out of 133, or 97.0%, (95% confidence interval [CI], 94.1 to 99.9%), of participants. Among those for whom this regimen did not result in pregnancy termination, one participant had a completion with sharp curettage, two received manual vacuum aspiration, and one underwent a repeat medication abortion with misoprostol alone. Side effects included chills (77.4%; 95% CI, 70.3 to 84.5%), diarrhea (66.9%; 95% CI, 59.0 to 74.8%), and nausea (48.1%; 95% CI, 39.7 to 56.5%). No serious adverse events were reported. The regimen was deemed "acceptable" or "highly acceptable" by 97.7% (95% CI, 95.2 to 100.0%) of participants.

Conclusions: This study suggests that ulipristal acetate followed by misoprostol is an effective and acceptable medication abortion regimen with no reported serious adverse events. (This project is supported by the OPTions Initiative. The study registered as ISRCTN35625202.).

AbstractBecause symptoms of cardiopulmonary disease often occur with exertion, cardiopulmonary exercise testing (CPET) has a unique role in the assessment of patient symptoms, disease severity, prognosis, and response to therapy. In addition to the evaluation of cardiovascular and pulmonary physiology, CPET provides an assessment of the interaction of the cardiovascular and pulmonary systems with the musculoskeletal, nervous, and hematological systems. In this article, we review key CPET variables, protocols, and clinical indications.