NEJM original articles

Background. Whether surgical axillary staging as part of breast-conserving therapy can be omitted without compromising survival has remained unclear.

Methods. In this prospective, randomized, noninferiority trial, we investigated the omission of axillary surgery as compared with sentinel-lymph-node biopsy in patients with clinically node-negative invasive breast cancer staged as T1 or T2 (tumor size, ≤5 cm) who were scheduled to undergo breast-conserving surgery. We report here the per-protocol analysis of invasive disease-free survival (the primary efficacy outcome). To show the noninferiority of the omission of axillary surgery, the 5-year invasive disease-free survival rate had to be at least 85%, and the upper limit of the confidence interval for the hazard ratio for invasive disease or death had to be below 1.271.

Results. A total of 5502 eligible patients (90% with clinical T1 cancer and 79% with pathological T1 cancer) underwent randomization in a 1:4 ratio. The per-protocol population included 4858 patients; 962 were assigned to undergo treatment without axillary surgery (the surgery-omission group), and 3896 to undergo sentinel-lymph-node biopsy (the surgery group). The median follow-up was 73.6 months. The estimated 5-year invasive disease-free survival rate was 91.9% (95% confidence interval [CI], 89.9 to 93.5) among patients in the surgery-omission group and 91.7% (95% CI, 90.8 to 92.6) among patients in the surgery group, with a hazard ratio of 0.91 (95% CI, 0.73 to 1.14), which was below the prespecified noninferiority margin. The analysis of the first primary-outcome events (occurrence or recurrence of invasive disease or death from any cause), which occurred in a total of 525 patients (10.8%), showed apparent differences between the surgery-omission group and the surgery group in the incidence of axillary recurrence (1.0% vs. 0.3%) and death (1.4% vs. 2.4%). The safety analysis indicates that patients in the surgery-omission group had a lower incidence of lymphedema, greater arm mobility, and less pain with movement of the arm or shoulder than patients who underwent sentinel-lymph-node biopsy.

Conclusions. In this trial involving patients with clinically node-negative, T1 or T2 invasive breast cancer (90% with clinical T1 cancer and 79% with pathological T1 cancer), omission of surgical axillary staging was noninferior to sentinel-lymph-node biopsy after a median follow-up of 6 years. (Funded by the German Cancer Aid; INSEMA ClinicalTrials.gov number, NCT02466737.).

Background. Bloodstream infections are associated with substantial morbidity and mortality. Early, appropriate antibiotic therapy is important, but the duration of treatment is uncertain.

Methods. In a multicenter, noninferiority trial, we randomly assigned hospitalized patients (including patients in the intensive care unit [ICU]) who had bloodstream infection to receive antibiotic treatment for 7 days or 14 days. Antibiotic selection, dosing, and route were at the discretion of the treating team. We excluded patients with severe immunosuppression, foci requiring prolonged treatment, single cultures with possible contaminants, or cultures yielding Staphylococcus aureus. The primary outcome was death from any cause by 90 days after diagnosis of the bloodstream infection, with a noninferiority margin of 4 percentage points.

Results. Across 74 hospitals in seven countries, 3608 patients underwent randomization and were included in the intention-to-treat analysis; 1814 patients were assigned to 7 days of antibiotic treatment, and 1794 to 14 days. At enrollment, 55.0% of patients were in the ICU and 45.0% were on hospital wards. Infections were acquired in the community (75.4%), hospital wards (13.4%) and ICUs (11.2%). Bacteremia most commonly originated from the urinary tract (42.2%), abdomen (18.8%), lung (13.0%), vascular catheters (6.3%), and skin or soft tissue (5.2%). By 90 days, 261 patients (14.5%) receiving antibiotics for 7 days had died and 286 patients (16.1%) receiving antibiotics for 14 days had died (difference, -1.6 percentage points [95.7% confidence interval {CI}, -4.0 to 0.8]), which showed the noninferiority of the shorter treatment duration. Patients were treated for longer than the assigned duration in 23.1% of the patients in the 7-day group and in 10.7% of the patients in the 14-day group. A per-protocol analysis also showed noninferiority (difference, -2.0 percentage points [95% CI, -4.5 to 0.6]). These findings were generally consistent across secondary clinical outcomes and across prespecified subgroups defined according to patient, pathogen, and syndrome characteristics.

Conclusions. Among hospitalized patients with bloodstream infection, antibiotic treatment for 7 days was noninferior to treatment for 14 days. (Funded by the Canadian Institutes of Health Research and others; BALANCE ClinicalTrials.gov number, NCT03005145.).

Background. The effect of a liberal red-cell transfusion strategy as compared with a restrictive strategy in patients during the critical care period after an aneurysmal subarachnoid hemorrhage is unclear.

Methods. We randomly assigned critically ill adults with acute aneurysmal subarachnoid hemorrhage and anemia to a liberal strategy (mandatory transfusion at a hemoglobin level of ≤10 g per deciliter) or a restrictive strategy (optional transfusion at a hemoglobin level of ≤8 g per deciliter). The primary outcome was an unfavorable neurologic outcome, defined as a score of 4 or higher on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability), at 12 months. Secondary outcomes included 12-month functional independence as assessed with the Functional Independence Measure (FIM; scores range from 18 to 126) and quality of life as assessed with the EuroQol five-dimension, five-level (EQ-5D-5L) utility index (scores range from -0.1 to 0.95) and a visual analogue scale (VAS; scores range from 0 to 100); on each assessment, higher scores indicate better health status or quality of life.

Results. A total of 742 patients underwent randomization at 23 centers. The analysis of the primary outcome at 12 months included 725 patients (97.7%). An unfavorable neurologic outcome occurred in 122 of 364 patients (33.5%) in the liberal-strategy group and in 136 of 361 patients (37.7%) in the restrictive-strategy group (risk ratio, 0.88; 95% confidence interval [CI], 0.72 to 1.09; P = 0.22). The mean (±SD) FIM score was 82.8±54.6 in the liberal-strategy group and 79.8±54.5 in the restrictive-strategy group (mean difference, 3.01; 95% CI, -5.49 to 11.51). The mean EQ-5D-5L utility index score was 0.5±0.4 in both groups (mean difference, 0.02; 95% CI, -0.04 to 0.09). The mean VAS score was 52.1±37.5 in the liberal-strategy group and 50±37.1 in the restrictive-strategy group (mean difference, 2.08; 95% CI, -3.76 to 7.93). The incidence of adverse events was similar in the two groups.

Conclusions. In patients with aneurysmal subarachnoid hemorrhage and anemia, a liberal transfusion strategy did not result in a lower risk of an unfavorable neurologic outcome at 12 months than a restrictive strategy. (Funded by the Canadian Institutes of Health Research and others; SAHARA ClinicalTrials.gov number, NCT03309579.).

Background. Hospital studies suggest that scrub typhus is a leading cause of severe undifferentiated fever in regions across Asia where the disease is endemic, but the population-based incidence of infection and illness has been little studied.

Methods. We conducted a population-based cohort study to assess epidemiologic and clinical characteristics of scrub typhus in 37 villages in Tamil Nadu, India, where the disease is highly endemic. Study participants were visited every 6 to 8 weeks over a period of 2 years; a venous blood sample was obtained from those who had had fever since the last visit. A subcohort of participants underwent blood sampling to estimate the incidence of serologically confirmed Orientia tsutsugamushi infection.

Results. We systematically assessed 32,279 participants from 7619 households for acute febrile illness. During 54,588 person-years of follow-up, we observed 6175 episodes of fever. A blood sample was obtained in 4474 episodes (72.5%), of which 328 (7.3%) met the clinical case definition of scrub typhus (detection of IgM against O. tsutsugamushi on enzyme-linked immunosorbent assay [ELISA] or detection of O. tsutsugamushi on polymerase-chain-reaction assay). The incidence of clinical infection was 6.0 cases per 1000 person-years (95% confidence interval [CI], 4.8 to 7.5). A total of 71 clinical cases (21.6%) resulted in hospitalization (incidence, 1.3 events per 1000 person-years; 95% CI, 1.0 to 1.7). A total of 29 clinical cases (8.8%) were severe, as indicated by the presence of organ dysfunction or adverse pregnancy outcomes (incidence, 0.5 cases per 1000 person-years; 95% CI, 0.4 to 0.8). Among 2128 participants in the subcohort who provided samples at the beginning and end of a study year, the incidence of seroconversion independent of any symptoms was 81.2 events per 1000 person-years (95% CI, 70.8 to 91.6). The incidence of clinical infection was higher in older age groups than in younger age groups and higher among female participants than among male participants. By contrast, the age-adjusted rate of severe infection was similar among male and female participants. Among 5602 participants assessed at the start of the first year of the study, the seroprevalence of IgG as assessed with ELISA was 42.8% (95% CI, 35.8 to 50.2). IgG seropositivity at the beginning of years 1 or 2 did not protect against clinical illness during the subsequent year but was associated with less severe disease than IgG seronegativity.

Conclusions. We describe the burden of scrub typhus, including the incidence of asymptomatic infection, in a region of Asia where the disease is endemic. (Funded by the U.K. Medical Research Council; ClinicalTrials.gov number, NCT04506944.).

Background. Birth-related mortality is a major contributor to the burden of deaths worldwide, especially in low-income countries. The Safer Births Bundle of Care program is a combination of interventions developed to improve the quality of care for mother and baby with the goal of reducing birth-related mortality.

Methods. We performed a 3-year stepped-wedge cluster-randomized study of the Safer Births program at 30 high-burden facilities in five regions in Tanzania. The bundle of interventions in the program was aimed at continuous quality improvement through regular onsite simulation-based training, the collection and use of local clinical data, the assistance of trained local facilitators, and the use of innovative tools for perinatal care. The primary outcome was perinatal death, which included intrapartum stillbirth (suspected death during labor) and neonatal death within the first 24 hours after birth.

Results. A total of 281,165 mothers and 277,734 babies were included in the final analysis. The estimated incidence of perinatal death decreased from 15.3 deaths per 1000 births in the baseline period of the program to 12.5 deaths per 1000 births after implementation (adjusted relative risk, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P = 0.001), with substantial heterogeneity among regions. The incidence of intrapartum stillbirths was 8.6 deaths per 1000 births in the baseline period and 8.7 deaths per 1000 births after implementation (adjusted relative risk, 1.01; 95% CI, 0.87 to 1.17), and the incidence of neonatal deaths within the first 24 hours after birth was 6.4 and 3.9 deaths per 1000 births, respectively (adjusted relative risk, 0.61; 95% CI, 0.49 to 0.77). No serious adverse events were reported.

Conclusions. Implementation of the Safer Births Bundle of Care program showed the feasibility of integrating quality-improvement efforts targeting birth-related emergencies in resource-limited settings and was associated with a significant reduction in perinatal mortality. (Funded by the Global Financing Facility; ISRCTN Registry number, ISRCTN30541755.).