NEJM original articles

Background. Blood-pressure reduction is the only proven treatment to prevent stroke. Whether a single pill that combines three antihypertensive drugs at low doses, in addition to standard antihypertensive treatment, can lower blood pressure more than standard care alone and reduce the risk of recurrent stroke after intracerebral hemorrhage is uncertain.

Methods. We conducted a multinational, double-blind, randomized, placebo-controlled trial involving patients with a history of intracerebral hemorrhage. Patients were eligible for the trial if they had a systolic blood pressure of 130 to 160 mm Hg at baseline and were in clinically stable condition. After a 2-week active run-in phase during which all the patients received a once-daily pill containing three antihypertensive agents at low doses (telmisartan at 20 mg, amlodipine at 2.5 mg, and indapamide at 1.25 mg; the triple pill), the patients were randomly assigned to continue receiving the triple pill or to receive matching placebo. The primary outcome was the first recurrent stroke. Secondary outcomes included blood-pressure control, major cardiovascular events, death from cardiovascular causes, and safety.

Results. Of 1670 patients who underwent randomization, 833 were assigned to receive the triple pill and 837 to receive placebo. The mean age of the patients was 58 years. At a median follow-up of 2.5 years, recurrent stroke had occurred in 38 patients (4.6%) in the triple-pill group and 62 (7.4%) in the placebo group (hazard ratio, 0.61; 95% confidence interval [CI], 0.41 to 0.92; P = 0.02). The mean systolic blood pressure during follow-up was 127 mm Hg and 138 mm Hg, respectively. The incidence of major cardiovascular events was lower with the triple pill than with placebo (6.6% vs. 9.8%; P = 0.04). Serious adverse events occurred in 23.2% of the patients in the triple-pill group and 26.0% of those in the placebo group. Early discontinuation of the trial regimen due to an adverse event occurred in 13.6% and 6.0%, respectively. The most common adverse event leading to discontinuation was an increase of 20% or more in the serum creatinine level.

Conclusions. Among patients with intracerebral hemorrhage, treatment with a combination of three low-dose antihypertensive agents in a single pill, in addition to standard care, was associated with a lower incidence of recurrent stroke and major cardiovascular events than placebo. (Funded by the National Health and Medical Research Council of Australia and the Brazilian Ministry of Health; TRIDENT ClinicalTrials.gov number, NCT02699645; Australian New Zealand Clinical Trials Registry number, ACTRN12616000327482.).

Background. Nirmatrelvir-ritonavir has been shown to reduce progression to severe illness from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unvaccinated high-risk outpatients. The effectiveness of nirmatrelvir-ritonavir in persons who have been vaccinated, infected naturally, or both is unclear.

Methods. In two open-label platform trials (PANORAMIC in the United Kingdom and CanTreatCOVID in Canada), we enrolled higher-risk adults (≥50 years of age or ≥18 years of age with coexisting conditions) in the community who tested positive for SARS-CoV-2 and had been unwell for 5 days or less. The participants were randomly assigned to receive usual care plus nirmatrelvir (300 mg)-ritonavir (100 mg) twice a day for 5 days or to receive usual care alone. The primary outcome was hospitalization or death from any cause within 28 days after randomization.

Results. From December 8, 2021, to September 30, 2024, a total of 3516 participants in the PANORAMIC trial and 716 participants in the CanTreatCOVID trial underwent randomization. In the PANORAMIC trial, 14 of 1698 participants (0.8%) in the nirmatrelvir-ritonavir group and 11 of 1673 participants (0.7%) in the usual-care group were hospitalized or died (adjusted odds ratio, 1.18; 95% Bayesian credible interval, 0.55 to 2.62; probability of superiority, 0.334). In the CanTreatCOVID trial, 2 of 343 participants (0.6%) in the nirmatrelvir-ritonavir group and 4 of 324 participants (1.2%) in the usual-care group were hospitalized or died (adjusted odds ratio, 0.48; 95% Bayesian credible interval, 0.08 to 2.23; probability of superiority, 0.830). In a substudy involving 634 participants, viral load was reduced by the end of treatment with nirmatrelvir-ritonavir. Serious adverse events with nirmatrelvir-ritonavir were reported in 9 participants in the PANORAMIC trial and in 4 participants in the CanTreatCOVID trial.

Conclusions. In two open-label trials, nirmatrelvir-ritonavir did not reduce the incidence of hospitalization or death among vaccinated higher-risk participants with SARS-CoV-2 infection. (Funded by the National Institute for Health and Care Research, and others; PANORAMIC ISRCTN number, 2021-005748-31; CanTreatCOVID ClinicalTrials.gov number, NCT05614349.).

Background. Transdermal estradiol (tE2) is an alternative to luteinizing hormone-releasing hormone (LHRH) agonists as androgen-deprivation therapy in patients with prostate cancer. With tE2, testosterone is suppressed, and the side effects of estrogen depletion due to LHRH agonists and the thromboembolic side effects of oral estrogen are mitigated.

Methods. In this phase 3, noninferiority, randomized trial, we assigned men with locally advanced (M0 and N0 or N+) prostate cancer to receive tE2 patches (100 μg of estradiol every 24 hours) or LHRH agonists. The primary outcome was 3-year metastasis-free survival. The noninferiority margin was 4 percentage points; this corresponded to a target hazard ratio of 1.31, as derived from the observed 3-year metastasis-free survival in the LHRH agonist group. Secondary outcomes included castrate levels of testosterone (<1.7 nmol per liter), overall survival, and safety.

Results. Between 2007 and 2022, we recruited 1360 patients at 75 U.K. centers. The median age of the patients was 72 years (interquartile range, 68 to 77); 85% had a T3 tumor stage and 65% an N0 nodal stage. Observed 3-year metastasis-free survival was 87.1% with tE2 and 85.9% with LHRH agonists (hazard ratio for confirmed metastasis or death, 0.96; upper limit of the one-sided 95% confidence interval [CI], 1.11, which met the criterion for noninferiority). Among patients continuing the assigned treatment, castrate levels of testosterone were sustained during the first year after randomization in 85% in each group. Observed 5-year overall survival was 81.1% with tE2 and 79.2% with LHRH agonists (hazard ratio for death, 0.90; 95% CI, 0.75 to 1.07). During treatment, hot flashes occurred in 44% of the patients who received tE2 and 89% of those who received LHRH agonists (grade ≥2 events, 8% and 37%, respectively) and gynecomastia in 85% and 42% (grade ≥2 events, 37% and 9%).

Conclusions. In patients with locally advanced prostate cancer, tE2 was noninferior to LHRH agonists for 3-year metastasis-free survival, with a lower incidence of hot flashes but a higher incidence of gynecomastia. (Funded by Cancer Research U.K. and the U.K. Research Institute Medical Research Council; PATCH ClinicalTrials.gov number, NCT00303784; STAMPEDE-1 ClinicalTrials.gov number, NCT00268476.).

Background. For critically ill adults undergoing tracheal intubation, observational studies suggest that the use of etomidate to induce anesthesia may increase the risk of death. Whether the use of ketamine rather than etomidate decreases the risk of death is uncertain.

Methods. In a randomized trial conducted in 14 emergency departments and intensive care units in the United States, we randomly assigned critically ill adults who were undergoing tracheal intubation to receive ketamine or etomidate for the induction of anesthesia. The primary outcome was in-hospital death from any cause by day 28. The secondary outcome was cardiovascular collapse during intubation, defined by the occurrence of a systolic blood pressure below 65 mm Hg, receipt of a new or increased dose of vasopressors, or cardiac arrest.

Results. A total of 2365 patients underwent randomization and were included in the trial population; 1176 were assigned to the ketamine group and 1189 to the etomidate group. In-hospital death by day 28 occurred in 330 of 1173 patients (28.1%) in the ketamine group and in 345 of 1186 patients (29.1%) in the etomidate group (risk difference adjusted for trial site, -0.8 percentage points; 95% confidence interval [CI], -4.5 to 2.9; P = 0.65). Cardiovascular collapse during intubation occurred in 260 of 1176 patients (22.1%) in the ketamine group and in 202 of 1189 patients (17.0%) in the etomidate group (risk difference, 5.1 percentage points; 95% CI, 1.9 to 8.3). Prespecified safety outcomes were similar in the two groups.

Conclusions. Among critically ill adults undergoing tracheal intubation, the use of ketamine to induce anesthesia did not result in a significantly lower incidence of in-hospital death by day 28 than etomidate. (Funded by the Patient-Centered Outcomes Research Institute and others; RSI ClinicalTrials.gov number, NCT05277896.).