NEJM evidence最新文献

AbstractIn comparative clinical investigations for nearly all disease types, patient responses - signifying clinically meaningful improvements in health or reductions in disease burden - are routinely employed as key end points for assessing treatment activity or efficacy. Trials typically use the response rate to summarize treatment effects, a metric with limitations for investigating the temporal profile of the effect. In this Clinical Trials Workshop, the authors present a novel approach for analyzing time to response and duration of response in clinical trials using, as an example, data from the JAVELIN Renal-101 trial of avelumab and axitinib versus sunitinib for treating renal cell carcinoma.

Background: Intrauterine devices (IUDs) are effective contraceptives but are also associated with a higher ectopic pregnancy risk than other contraceptive methods. This study assessed ectopic pregnancy risk with varying hormonal IUD dosages compared with copper IUDs.

Methods: We conducted a nationwide cohort study using data from the French National Healthcare Data System (SNDS) and identified first-time IUD dispensations from 2018 to 2022. The primary outcome was ectopic pregnancy occurrence within 1 year of the index date, set 1 month post IUD dispensing. We used propensity score-based weighting and Cox regression analysis to compare ectopic pregnancy risk among users of levonorgestrel 13.5-mg, 19.5-mg, and 52-mg IUDs versus copper IUDs.

Results: Between 2018 and 2022, 45,450 women received a levonorgestrel 13.5-mg IUD, 212,301 received a levonorgestrel 19.5-mg IUD, 244,871 received a levonorgestrel 52-mg IUD, and 1,033,505 received a copper IUD. The mean age (standard deviation) was 26.8 (7.8), 29.7 (8.1), and 35.2 (8.2) years among levonorgestrel 13.5-mg, 19.5-mg, and 52-mg IUD users, respectively, and 29.1 (6.9) years in copper IUD users. At 1 year, ectopic pregnancy occurred in 71 levonorgestrel 13.5-mg IUD users (incidence rate, 0.18 per 100 person-years; 95% confidence interval [CI], 0.14 to 0.23), 182 levonorgestrel 19.5-mg IUD users (incidence rate, 0.10 per 100 person-years; 95% CI, 0.08 to 0.11), 88 levonorgestrel 52-mg users (incidence rate, 0.04 per 100 person-years; 95% CI, 0.03 to 0.05), and 682 copper IUD users (incidence rate, 0.07 per 100 person-years; 95% CI, 0.07 to 0.08). Compared with copper IUD users, the hazard ratios for ectopic pregnancy with hormonal IUDs were 2.57 (95% CI, 1.92 to 3.43) for 13.5-mg users, 1.37 (95% CI, 1.15 to 1.62) for 19.5-mg users, and 0.62 (95% CI, 0.49 to 0.80) for 52-mg users.

Conclusions: In this nationwide cohort study comparing three doses of hormonal IUDs and copper IUDs, the highest dose (levonorgestrel 52 mg) was associated with the lowest risk of ectopic pregnancy within 1 year compared with copper IUDs, whereas the 13.5-mg hormonal IUD was associated with the highest risk. (Funded by the French National Fund for Health Insurance and the French National Agency for Medicines and Health Products Safety.).

AbstractSodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) improve quality of life, functional capacity, and survival, and reduce hospitalization in adults with heart failure (HF). However, most controlled trials to date have enrolled few adults with advanced HF and multiple chronic illnesses. Despite favorable evidence in adults with HF, the safety and effectiveness of SGLT2 inhibitors on patient-centered outcomes in adults with advanced HF and multiple chronic illnesses remain unknown. This Tomorrow's Trial reviews the existing evidence and proposes a trial to address the question, "Do SGLT2 inhibitors improve end-of-life care in adults with advanced heart failure?"

Morning 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 62-year-old woman who presented with diarrhea and fatigue 8 weeks after haploidentical hematopoietic stem-cell transplantation. Using targeted questions, physical examination, and diagnostic testing, an illness script for the presentation emerges. As the clinical course progresses, the differential is refined until a final diagnosis is made.

Background: Diagnosis of endometriosis is a challenge. The recent development of a saliva-based micro-ribonucleic acid (miRNA) signature for the diagnosis of endometriosis may enable a timelier and less invasive approach, but this requires external validation.

Methods: The prospective, multicenter validation of the salivary miRNA signature of endometriosis (ENDOmiRNA) study aimed to assess the diagnostic accuracy, validate the biological reproducibility, and evaluate the clinical utility of a saliva miRNA signature of endometriosis. The study population comprised patients 18 to 43 years of age with signs and symptoms suggestive of endometriosis, who were recruited from diverse medical settings. Patients received a diagnosis of endometriosis by imaging, laparoscopic procedure, or both. All patients who were determined to not have endometriosis were classified as controls (and all underwent laparoscopy). Assessment of endometriosis status based on the saliva miRNA signature was established blinded to patients' endometriosis status, as determined by imaging and/or laparoscopy and/or histology.

Results: The external validation population was composed of 971 patients, including patients from a prior interim analysis, with an overall endometriosis prevalence of 77%. The saliva miRNA signature had an accuracy (defined as the probability of correct classification for both positive and negative results) of 96.6% (95% confidence interval [CI], 95.2 to 97.6%), a sensitivity of 97.3% (95% CI, 96.4 to 98.0%), a specificity of 94.1% (95% CI, 91.0 to 96.4%), a positive predictive value of 98.2% (95% CI, 97.3 to 98.9%), a negative predictive value of 91.3% (95% CI, 88.3 to 93.4%), a positive likelihood ratio of 16.6 (95% CI, 10.8 to 26.9), and a negative likelihood ratio of 0.03 (95% CI, 0.02 to 0.04). Among patients with surgical confirmation of the diagnosis, misclassification, underestimation, and overestimation rates were 4.6%, 2.4%, and 2.2%, respectively, for the saliva miRNA signature and 27.2%, 15.1%, and 12.2%, respectively, for imaging (either transvaginal ultrasound, magnetic resonance imaging, or both).

Conclusions: This prospective, multicenter external validation study demonstrated the accurate performance of a saliva-based miRNA signature for the diagnosis of endometriosis in this cohort. (Funded by Ziwig; ClinicalTrials.gov number, NCT05244668.).

Background: Older men with metastatic hormone-sensitive prostate cancer (mHSPC) are more likely to have comorbid medical conditions and die from causes other than prostate cancer. We aimed to determine if age impacts the overall survival (OS) benefit from systemic treatment intensification (TI) with androgen receptor pathway inhibitors (ARPIs) and/or chemotherapy in mHSPC.

Methods: A systematic literature search in MEDLINE, Embase, and conference proceedings was conducted to identify randomized phase 3 trials in mHSPC evaluating the role of TI between January 1, 2010, and January 1, 2024. Age was dichotomized as 70 years or older in all trials, except as 75 years or older in one trial. Meta-analyses were performed with random-effects modeling. Meta-regression was performed using Hartung-Knapp methods. Individual patient data (IPD) from three trials (TITAN, ARASENS, and LATITUDE) were used to validate the aggregate meta-analysis.

Results: Eleven randomized comparisons (n=13,648 patients; 8324 younger men and 5162 older men) were included in the aggregate meta-analysis. Overall, TI was associated with improved OS (hazard ratio, 0.73; 95% confidence interval [CI], 0.68 to 0.78). There was an interaction between age and TI on OS (P-interaction <0.001; younger men: hazard ratio, 0.63; 95% CI, 0.56 to 0.70; older men: hazard ratio, 0.82; 95% CI, 0.74 to 0.90). TI was not associated with improvement in OS in older men treated in trials utilizing predominantly triplet therapy (hazard ratio, 0.94; 95% CI, 0.77 to 1.14). These results were similar in the IPD analysis. In the IPD analysis, ARPI addition was associated with improved OS in men 70 years or older with high-volume synchronous disease (hazard ratio, 0.83; 95% CI, 0.70 to 0.99), but not in low-volume synchronous disease (hazard ratio, 0.89; 95% CI, 0.61 to 1.30).

Conclusions: We observed an interaction between age and systemic TI on OS for men with mHSPC. Our data provide information on potential treatment strategies for men 70 years or older, especially in low-volume synchronous disease, where radiotherapy to the primary site is the standard of care. (Funded by the National Institutes of Health and others.).

Background: Clinical trials of low-density lipoprotein cholesterol (LDL-C)-lowering medicines have shown improvement in cardiovascular disease risk. However, representation across diverse communities in such trials is limited. We set out to study whether or not more diverse human genetic studies could provide an opportunity to test whether these trial results can be generalized to poorly populations poorly represented in drug clinical trials.

Methods: We included six cohorts across 967,325 individuals (54.5% female), including 65,258 African, 45,393 admixed American, 179,521 East Asian, 616,045 European, 4686 Middle Eastern, and 56,422 South Asian individuals. Genetic ancestry was determined using genetic principal components and k-nearest neighbors. We constructed ancestry-specific LDL-C polygenic risk scores (PGS) using genome-wide association study (GWAS) summary statistics trained and externally validated on each ancestry. We associated each PGS with population LDL-C, scaled for a 40 mg/dl increase, and tested these scores against coronary artery disease (CAD) risk using hierarchical Bayesian meta-analyses.

Results: The associations between genetically predicted LDL-C levels and observed LDL-C were consistent across ancestries, supporting the validity of our genetic proxy. When scaled to mimic a 40 mg/dl increase in LDL-C, the PGS showed positive but heterogeneous associations with CAD. Posterior odds ratios for CAD ranged from 1.35 (95% credible interval, 1.05 to 1.68) in African populations to 1.82 (95% credible interval, 1.33 to 2.97) in Middle Eastern populations. Bayesian analysis revealed that 97.9% of posterior samples showed all population means greater than 0 on a log scale with a between-ancestry posterior variance (τ²) of 0.062 (95% credible interval, 0.001 to 0.352).

Conclusions: Our findings demonstrated a consistent association between LDL-C and CAD risk across diverse ancestry groups that are often poorly represented in clinical trials, although effect magnitudes varied. (Funded by the National Institutes of Health and others.).