NEJM original articles

Background. The preferred method of renal-replacement therapy for acute kidney injury in critically ill patients remains uncertain.

Methods. In this multicenter, open-label, noninferiority trial, we randomly assigned critically ill adults with acute kidney injury who had indications for renal-replacement therapy to undergo intermittent hemodialysis or continuous renal-replacement therapy as the initial treatment. The primary outcome was a major adverse kidney event - defined as death, dependence on renal-replacement therapy, or a serum creatinine concentration more than 25% above the baseline value - by day 90.

Results. The trial was stopped early after sequential interim analyses showed a sustained signal of higher mortality with intermittent hemodialysis than with continuous renal-replacement therapy. A total of 554 patients underwent randomization, with 272 patients assigned to undergo intermittent hemodialysis and 282 to undergo continuous renal-replacement therapy; 535 patients (260 in the intermittent group and 275 in the continuous group) were included in the intention-to-treat population. A major adverse kidney event occurred by day 90 in 203 patients (78.1%) in the intermittent group and in 197 patients (71.6%) in the continuous group (adjusted absolute risk difference, 6.28 percentage points; 95% confidence interval [CI], -1.22 to 13.79). Death by day 90 occurred in 164 patients (63.1%) and in 147 patients (53.5%), respectively. Kaplan-Meier mortality estimates at day 90 were 63.3% and 53.6% (hazard ratio, 1.30; 95% CI, 1.04 to 1.63). The most common complication potentially related to acute kidney injury or renal-replacement therapy was hypotension, which occurred in 179 patients (68.8%) in the intermittent group and in 183 patients (66.5%) in the continuous group.

Conclusions. Among critically ill patients with acute kidney injury who had indications for renal-replacement therapy, intermittent hemodialysis as the initial treatment approach was not shown to be noninferior to continuous renal-replacement therapy with respect to major adverse kidney events by day 90 and was associated with higher mortality. (Funded by the French Ministry of Health; ICRAKI ClinicalTrials.gov number, NCT06032884.).

Background. In patients with syncope who present to the emergency department for evaluation, diagnosing an underlying cardiac arrhythmia remains difficult.

Methods. We conducted an open-label, randomized, controlled trial at 45 hospitals in the United Kingdom to assess the effects of 14-day cardiac monitoring on diagnosis, treatment, and outcomes among patients with syncope. Adults with syncope that remained unexplained after an evaluation in the emergency department were assigned in a 1:1 ratio to undergo 14-day ambulatory electrocardiographic (ECG) monitoring (the intervention group) or to receive the standard care provided for patients with unexplained syncope at each participating site (the standard-care group). The primary outcome was the mean number of patient-reported episodes of syncope at 1 year.

Results. A total of 2234 patients underwent randomization: 1123 were assigned to the intervention group and 1111 to the standard-care group. The mean age of the patients was 58.3 years, and 52.1% were male. After the exclusion of patients who did not complete any follow-up, a total of 1970 patients (1004 in the intervention group and 966 in the standard-care group) were included in the primary analysis. The mean (±SD) number of patient-reported syncope episodes at 1 year was 1.37±5.10 in the intervention group and 1.58±8.56 in the standard-care group (incidence rate ratio, 0.89; 95% confidence interval, 0.68 to 1.18; P = 0.42). A total of 49 adverse events were reported in the intervention group, and 8 adverse events were reported in the standard-care group, with 1 serious adverse event in each group.

Conclusions. Among patients with syncope that remained unexplained after evaluation in the emergency department, the use of 14-day ambulatory ECG monitoring did not result in significantly fewer patient-reported syncope episodes at 1 year than standard care. (Funded by the British Heart Foundation and National Health Service Research Scotland; ASPIRED ISRCTN Registry number, ISRCTN10278811.).

Background. Many patients with chronic obstructive pulmonary disease (COPD) have exacerbations despite receiving standard-of-care inhaled maintenance therapy. Dysregulated interleukin-33 signaling is implicated in the pathogenesis of COPD. Tozorakimab is a monoclonal antibody that inhibits the activity of interleukin-33.

Methods. In two replicate phase 3 trials (OBERON and TITANIA), we enrolled adults with COPD who were current or former smokers and had a history of exacerbations in the previous year despite receiving stable standard-of-care inhaled maintenance therapy. There were no eligibility criteria related to blood eosinophil count. Patients were randomly assigned to receive add-on subcutaneous tozorakimab (300 mg) or placebo every 4 weeks for 52 weeks. The primary end point was the annualized rate of moderate or severe exacerbations that occurred over a 52-week period among former smokers, and the first key secondary end point was the annualized rate of moderate or severe exacerbations in the overall population. Safety was also assessed.

Results. The overall population in OBERON included 446 patients in the tozorakimab group and 431 in the placebo group, and in TITANIA included 438 in the tozorakimab group and 435 in the placebo group. The annualized rate of moderate or severe exacerbations among former smokers was 1.34 events in the tozorakimab group and 1.90 events in the placebo group (rate ratio, 0.71; 95% confidence interval [CI], 0.57 to 0.88; P = 0.002) in OBERON, and 1.37 events and 2.07 events, respectively (rate ratio, 0.66; 95% CI, 0.55 to 0.80; P<0.001), in TITANIA. In the overall population, the annualized rate of moderate or severe exacerbations was 1.41 events in the tozorakimab group and 2.00 events in the placebo group (rate ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001) in OBERON, and 1.44 events and 2.03 events, respectively (rate ratio, 0.71; 95% CI, 0.59 to 0.84; P<0.001), in TITANIA. Adverse events occurred in 70.4% of the patients in the tozorakimab group and in 77.2% of those in the placebo group in OBERON, and in 80.1% and 79.8%, respectively, in TITANIA.

Conclusions. Among patients with COPD, treatment with tozorakimab resulted in a significantly lower rate of moderate or severe exacerbations than placebo in the cohort of former smokers and in the overall population of current and former smokers. (Funded by AstraZeneca; OBERON ClinicalTrials.gov number, NCT05166889; TITANIA ClinicalTrials.gov number, NCT05158387.).

Background. Continuous glucose monitoring (CGM) has been shown to be beneficial in persons with type 1 diabetes and others with insulin-treated type 2 diabetes, but its role in the treatment of persons with type 2 diabetes not being treated with insulin has needed further study.

Methods. In a 26-week trial conducted at 22 primary care practices in the United States, we randomly assigned adults with type 2 diabetes who were not using insulin to either CGM or routine care (control). The primary outcome was the glycated hemoglobin level at 26 weeks. Key CGM-measured secondary outcomes were tested hierarchically to control the type I error rate.

Results. A total of 145 participants were assigned to the CGM group, and 138 to the routine-care group. Participants ranged in age from 21 to 84 years. The mean (±SD) glycated hemoglobin level decreased from 8.8±1.3% at baseline to 7.2±1.1% at 26 weeks in the CGM group and from 8.7±1.2% to 8.0±1.4% in the routine-care group (adjusted mean difference, -0.9 percentage points; 95% confidence interval [CI], -1.1 to -0.6; P<0.001). The mean percentage of time that the CGM-measured glucose level was in the glucose-level range of 70 to 180 mg per deciliter was 21 percentage points higher (95% CI, 16 to 26) with CGM than with routine care (P<0.001). The between-group difference in the percentage of time that the glucose level was below 54 mg per deciliter was -0.17 percentage points (95% CI, -0.27 to -0.11; P<0.001 for noninferiority); the difference in the percentage of time that the glucose level was below 70 mg per deciliter was -0.20 percentage points (95% CI, -0.43 to -0.09; P<0.001 for noninferiority; P = 0.004 for superiority). No severe hypoglycemia events were reported.

Conclusions. Among adults with type 2 diabetes that was not being treated with insulin and was being managed in a primary care setting, the use of CGM led to a greater reduction in the glycated hemoglobin level and to a lower risk of hyperglycemia than routine care. (Funded by Dexcom; CONNECT ClinicalTrials.gov number, NCT06601166.).