NEJM original articles

Background. In randomized trials, finerenone, a nonsteroidal mineralocorticoid receptor antagonist, improved kidney and cardiovascular outcomes in patients with type 2 diabetes and chronic kidney disease (CKD). Whether finerenone has similar effects in patients without diabetes who have CKD is unknown.

Methods. We randomly assigned adults without diabetes who had CKD (estimated glomerular filtration rate [eGFR], 25 to <90 ml per minute per 1.73 m² of body-surface area) and albuminuria (urinary albumin-to-creatinine ratio, 200 to ≤3500, with albumin in milligrams and creatinine in grams) and were using a renin-angiotensin system inhibitor to receive finerenone (10 or 20 mg daily) or placebo. The primary outcome was the total eGFR slope (mean annual rate of change in the eGFR from baseline to month 32), assessed with a two-slope linear spline mixed-effects model. Secondary outcomes included a composite of kidney or cardiovascular events (reduction from baseline of at least 57% in the eGFR, kidney failure, hospitalization for heart failure, or death from cardiovascular causes), a composite of the two kidney events, and a composite of the two cardiovascular events.

Results. A total of 1584 participants underwent randomization - 793 were assigned to the finerenone group, and 791 to the placebo group. The mean (±SD) baseline eGFR was 46.8±16.2 ml per minute per 1.73 m² with finerenone and 46.6±16.0 ml per minute per 1.73 m² with placebo. The mean annual rate of change in the eGFR from baseline to month 32 was -3.3 ml per minute per 1.73 m² (95% confidence interval [CI], -3.6 to -3.1) with finerenone and -4.0 ml per minute per 1.73 m² (95% CI, -4.3 to -3.8) with placebo (difference, 0.7; 95% CI, 0.3 to 1.1; P<0.001). Prespecified hierarchical testing showed that the risk of a composite kidney or cardiovascular outcome event was lower with finerenone than with placebo (hazard ratio, 0.77; 95% CI, 0.60 to 0.99; P = 0.04); the hazard ratio was 0.78 (95% CI, 0.60 to 1.01) for the composite of the two kidney events and 0.60 (95% CI, 0.27 to 1.33) for the composite of the two cardiovascular events. The most common adverse event was hyperkalemia (135 participants [17.0%] with finerenone and 105 [13.3%] with placebo); hyperkalemia events led to discontinuation of the trial regimen in 12 participants (1.5%) and 1 participant (0.1%), respectively, and to hospitalization in 7 (0.9%) and 5 (0.6%).

Conclusions. Among adults with CKD who did not have diabetes, finerenone led to a slower decrease in the eGFR than placebo over 32 months. (Funded by Bayer; FIND-CKD ClinicalTrials.gov number, NCT05047263.).

Background. Radical prostatectomy is potentially curative in patients with high-risk localized or locally advanced prostate cancer; however, relapse occurs within 5 years in up to 50% of patients.

Methods. We conducted a phase 3, double-blind, placebo-controlled trial in which patients with newly diagnosed high-risk localized or locally advanced prostate cancer were randomly assigned in a 1:1 ratio to receive androgen-deprivation therapy (ADT) plus apalutamide (240 mg per day) or ADT plus placebo for 6 cycles (28 days each) before and after radical prostatectomy with pelvic lymph-node dissection. The dual primary end points were a composite of pathological complete response or minimal residual disease (defined as a pathological stage of ypT2 or lower, with a tumor size of ≤5 mm in the greatest dimension) and metastasis-free survival, as assessed with conventional imaging or prostate-specific membrane antigen positron-emission tomography. Secondary end points included event-free survival, first subsequent treatment, and distant metastasis (assessed in time-to-event analyses), as well as safety.

Results. A total of 2109 patients underwent randomization: 1057 were assigned to receive ADT plus apalutamide, and 1052 to receive ADT plus placebo. The median follow-up was 61.7 months. The percentage of patients with a pathological complete response or minimal residual disease was significantly higher in the apalutamide group than in the placebo group (8.9% vs. 1.0%; odds ratio, 10.17; 95% confidence interval [CI], 5.27 to 19.64; P<0.001), as was the percentage of patients with metastasis-free survival (probability of metastasis-free survival at 5 years, 78.2% vs. 73.5%; hazard ratio for distant metastasis or death, 0.80; 95% CI, 0.67 to 0.96; P = 0.02). Event-free survival, time to the first subsequent treatment, and time to distant metastasis significantly favored ADT plus apalutamide over ADT plus placebo (P<0.001 for all between-group comparisons). Grade 3 or 4 adverse events occurred in 39.6% of the patients in the apalutamide group and in 31.0% of those in the placebo group, with the difference between the groups driven primarily by a higher incidence of rash in the apalutamide group.

Conclusions. Perioperative treatment with ADT plus apalutamide was associated with better oncologic outcomes of radical prostatectomy in patients with high-risk localized or locally advanced prostate cancer than treatment with ADT plus placebo. Adverse events were more common in the apalutamide group than in the placebo group. (Funded by Johnson & Johnson; PROTEUS ClinicalTrials.gov number, NCT03767244.).

Background. Whether sirolimus-coated balloon angioplasty for infrainguinal artery disease reduces the incidence of major adverse limb events remains unknown.

Methods. In this prospective, open-label, noninferiority trial with a prespecified sequential testing strategy for superiority and blinded outcome adjudication, we randomly assigned patients with infrainguinal artery disease in a 1:1 ratio to undergo angioplasty with a sirolimus-coated balloon or with an uncoated balloon. The primary outcome was a composite of unplanned major amputation affecting the target limb or endovascular or surgical revascularization of the target lesion for critical limb ischemia within 1 year after randomization. The key secondary outcome was a composite of any unplanned amputation affecting the target limb or revascularization of the target lesion for critical or noncritical limb ischemia within 1 year after randomization. The noninferiority margin was 5 percentage points. The primary safety outcome was death from any cause within 1 year after randomization.

Results. A total of 1252 patients were enrolled in the trial: 626 patients were assigned to the sirolimus-coated-balloon group and 626 to the uncoated-balloon group. The median age of the patients was 75 years, and 35.1% were women. A primary-outcome event occurred in 55 patients (8.8%) in the sirolimus-coated-balloon group and in 94 patients (15.0%) in the uncoated-balloon group (median unbiased estimate of risk difference, -4.9 percentage points; 95% confidence interval [CI], -8.5 to -1.3; P<0.001 for noninferiority; P = 0.009 for superiority); a key secondary-outcome event occurred in 144 patients (23.0%) and 193 patients (30.8%), respectively (risk difference, -7.8 percentage points; 95% CI, -12.7 to -2.9; P = 0.002). Death occurred in 74 patients (11.8%) in the sirolimus-coated-balloon group and in 80 patients (12.8%) in the uncoated-balloon group (risk difference, -1.0 percentage points; 95% CI, -4.6 to 2.7; P = 0.67). The incidence of adverse events appeared to be similar in the two groups.

Conclusions. Among patients with infrainguinal artery disease undergoing endovascular treatment, angioplasty with sirolimus-coated balloons led to a lower incidence of major adverse limb events at 1 year than angioplasty with uncoated balloons. (Funded by Concept Medical and others; SirPAD ClinicalTrials.gov number, NCT04238546.).

Background. In patients who are unresponsive after resuscitation from cardiac arrest, limiting oxygen exposure to that necessary to achieve acceptable oxygenation may increase the likelihood of survival with a favorable functional outcome.

Methods. We randomly assigned unresponsive adults receiving mechanical ventilation in the intensive care unit (ICU) after cardiac arrest to conservative or liberal oxygen therapy. In the two groups, the default lower limit of arterial oxygen saturation as measured by pulse oximetry (Spo₂) was 90%. In the conservative-oxygen group, the alarm for the upper limit of the Spo₂ was set at 95%, and the fraction of inspired oxygen (Fio₂) was decreased to 0.21 provided that the Spo₂ was above the lower limit. In the liberal-oxygen group, there were no measures limiting the upper Spo₂, but the minimum Fio₂ permitted during mechanical ventilation was 0.3. The primary outcome was survival with a favorable functional outcome at 180 days, assessed with the Extended Glasgow Outcome Scale (GOS-E). Levels on the GOS-E range from 1 (death) to 8 ("upper good recovery"). We defined survival with a favorable functional outcome as a GOS-E level of 5 ("lower moderate disability") or higher.

Results. A total of 1840 patients were recruited from 53 ICUs in Australia, New Zealand, and Ireland, with 882 assigned to conservative oxygen therapy and 958 assigned to liberal oxygen therapy. A favorable functional outcome at 180 days was observed for 313 of 819 patients (38.2%) in the conservative-oxygen group and 353 of 890 patients (39.7%) in the liberal-oxygen group (relative risk, 0.97; 95% confidence interval, 0.87 to 1.09; P = 0.65). No adverse events were reported.

Conclusions. Among unresponsive adults undergoing mechanical ventilation in the ICU after a cardiac arrest, the percentage who survived with a favorable functional outcome was not higher with conservative oxygen therapy than with liberal oxygen therapy. (Funded by the Health Research Council of New Zealand and others; LOGICAL Australian New Zealand Clinical Trials Registry number, ACTRN12621000518864.).