NEJM original articles

Background. Hypokalemia and even low-normal plasma potassium levels increase the risk of ventricular arrhythmias among patients with cardiovascular disease. An assessment of a strategy of actively increasing plasma potassium levels to the high-normal range is needed.

Methods. In this multicenter, open-label, event-driven, randomized superiority trial conducted in Denmark, we enrolled participants at high risk for ventricular arrhythmias (defined as those with an implantable cardioverter-defibrillator [ICD]) and with a baseline plasma potassium level of 4.3 mmol per liter or lower. Participants were randomly assigned, in a 1:1 ratio, to a treatment regimen aimed at increasing the plasma potassium level to a high-normal level (4.5 to 5.0 mmol per liter) by means of potassium supplementation, a mineralocorticoid receptor antagonist, or both plus dietary guidance and standard care (high-normal potassium group) or to standard care only (standard-care group). The primary end point was a composite of documented sustained ventricular tachycardia or appropriate ICD therapy, unplanned hospitalization (>24 hours) for arrhythmia or heart failure, or death from any cause, assessed in a time-to-first-event analysis.

Results. Among the 1200 participants who underwent randomization (600 assigned to each group), the median duration of follow-up was 39.6 months (interquartile range, 26.4 to 49.3). A primary end-point event occurred in 136 participants (22.7%; 7.3 events per 100 person-years) in the high-normal potassium group, as compared with 175 participants (29.2%; 9.6 events per 100 person-years) in the standard-care group (hazard ratio, 0.76; 95% confidence interval, 0.61 to 0.95; P = 0.01). The incidence of hospitalization for hyperkalemia or hypokalemia was similar in the two groups.

Conclusions. Among participants with any cardiovascular disease who had an ICD and were at high risk for ventricular arrhythmias, a treatment-induced increase in plasma potassium levels led to a significantly lower risk of appropriate ICD therapy, unplanned hospitalization for arrhythmia or heart failure, or death from any cause than standard care. (Funded by the Independent Research Fund Denmark and others; POTCAST ClinicalTrials.gov number, NCT03833089.).

Background. Among older adults with frailty, evidence on the benefits and risks of discontinuing antihypertensive drugs is limited.

Methods. In a multicenter, randomized, controlled trial conducted in France, we assigned, in a 1:1 ratio, nursing home residents 80 years of age or older who were receiving more than one antihypertensive drug and had a systolic blood pressure below 130 mm Hg to a protocol-driven strategy of progressive reduction of antihypertensive treatment (step-down group) or to receive usual care (usual-care group). Patients were to be followed for up to 4 years. The primary end point was death from any cause. Secondary end points included the changes in the number of antihypertensive drugs being used from baseline to the last trial visit and the change in systolic blood pressure during the follow-up period.

Results. A total of 1048 patients underwent randomization: 528 to the step-down group and 520 to the usual-care group. The estimated median potential follow-up was 38.4 months. Between baseline and the last trial visit, the mean (±SD) number of antihypertensive drugs being used decreased from 2.6±0.7 to 1.5±1.1 in the step-down group and from 2.5±0.7 to 2.0±1.1 in the usual-care group. The adjusted mean between-group difference (step-down group minus usual-care group) in the change in systolic blood pressure during the follow-up period was 4.1 mm Hg (95% confidence interval [CI], 1.9 to 5.7). Death from any cause occurred in 326 patients (61.7%) in the step-down group and in 313 (60.2%) in the usual-care group (adjusted hazard ratio, 1.02; 95% CI, 0.86 to 1.21; P = 0.78). There were no apparent differences in adverse events between the trial groups.

Conclusions. Among older nursing home residents with frailty who were receiving treatment with antihypertensive agents and had a systolic blood pressure below 130 mm Hg, an antihypertensive treatment step-down strategy did not lead to lower all-cause mortality than usual care. (Funded by the French Ministry of Health and others; RETREAT-FRAIL ClinicalTrials.gov number, NCT03453268.).

Background. Influenza remains a major health burden despite the use of licensed vaccines. Nucleoside-modified messenger RNA (modRNA) influenza vaccines have shown promising immunogenicity against influenza and an acceptable safety profile in a phase 1-2 trial.

Methods. In this phase 3 trial, we randomly assigned healthy adults between the ages of 18 and 64 years to receive either a quadrivalent modRNA influenza vaccine (modRNA group) or a licensed inactivated quadrivalent influenza vaccine (control group) during the 2022-2023 influenza season in the United States, South Africa, and the Philippines. The primary end point was relative efficacy, defined by the reduction in the percentage of participants with laboratory-confirmed influenza associated with influenza-like illness at least 14 days after vaccination with the modRNA vaccine, as compared with the control vaccine, and analyzed for noninferiority and superiority. Immunogenicity was evaluated by means of a hemagglutination inhibition (HAI) assay. We assessed reactogenicity within 7 days after vaccination, adverse events through 1 month, and serious adverse events through 6 months. We assessed vaccine efficacy, immunogenicity, and safety in the modRNA group.

Results. A total of 18,476 participants underwent randomization: 9225 were assigned to receive the modRNA vaccine and 9251 to receive the control vaccine. The relative efficacy of the modRNA vaccine as compared with the control vaccine against influenza-like illness was 34.5% (95% confidence interval [CI], 7.4 to 53.9) on the basis of 57 cases in the modRNA group and 87 cases in the control group, a finding that met the criteria for both noninferiority and superiority. Cases of influenza-like illness were caused by A/H3N2 and A/H1N1 strains but almost no B strains. The noninferiority of the antibody response on HAI assay was shown for influenza A strains but not for B strains. Primarily mild or moderate reactogenicity was observed in both vaccine groups but was reported more frequently in the modRNA group (overall local reactions, 70.1% vs. 43.1%; overall systemic events, 65.8% vs. 48.7%). Fever occurred in 5.6% of the participants in the modRNA group and in 1.7% of those in the control group. Adverse event profiles were similar in the two groups.

Conclusions. The modRNA vaccine had statistically superior efficacy over the control vaccine, with greater immune responses to A/H3N2 and A/H1N1 strains, but was associated with more reactogenicity events. (Funded by Pfizer; C4781004 ClinicalTrials.gov number, NCT05540522.)See also in NEJM Evidence: Human clinical trial of a nucleoside-modified mRNA influenza vaccine.

Background. Pheochromocytoma and paraganglioma are neoplasms originating in the adrenal medulla and extraadrenal paraganglia, respectively. Most cases of metastatic pheochromocytoma and paraganglioma are driven by dysregulation of the hypoxia-inducible factor 2α (HIF-2α) pathway. Belzutifan is a HIF-2α inhibitor that may provide antitumor activity in patients with advanced pheochromocytoma or paraganglioma.

Methods. We conducted a phase 2, international, single-group trial involving 72 participants with locally advanced or metastatic pheochromocytoma or paraganglioma that was not amenable to surgery or curative-intent treatment. Participants received belzutifan at a dose of 120 mg once daily until the occurrence of progression, unacceptable toxic effects, or withdrawal from the trial. The primary end point was confirmed objective response (complete or partial response) as assessed by blinded independent central review. Secondary and other key end points included the duration of response, disease control, progression-free survival as assessed by blinded independent central review, overall survival, safety, and a reduction from baseline in antihypertensive medication.

Results. At a median follow-up of 30.2 months (range, 23.3 to 37.6), the percentage of participants with a confirmed objective response was 26% (95% confidence interval [CI], 17 to 38) and the percentage of participants with disease control was 85% (95% CI, 74 to 92). The median duration of response was 20.4 months (95% CI, 8.3 to not reached), with a median duration of progression-free survival of 22.3 months (95% CI, 13.8 to not reached). Overall survival was 76% at 24 months. Among the 60 participants who were receiving antihypertensive medications, 19 (32%) had a reduction of at least 50% in the total daily dose of at least one antihypertensive medication for at least 6 months after starting treatment with belzutifan. Treatment-related adverse events occurred in 71 participants (99%); anemia of grade 3 was noted in 22% of the participants. Eight participants (11%) had treatment-related serious adverse events.

Conclusions. Belzutifan showed antitumor activity with durable responses in participants with advanced pheochromocytoma or paraganglioma. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; LITESPARK-015 ClinicalTrials.gov number, NCT04924075.).