NEJM original articles

Background. The effect of transcatheter tricuspid-valve repair on clinical outcomes, including death and hospitalization for heart failure, in patients with severe tricuspid regurgitation remains uncertain.

Methods. We randomly assigned patients with symptomatic severe tricuspid regurgitation and an increased risk of future heart-failure events in a 2:1 ratio to tricuspid-valve repair plus medical therapy (tricuspid-repair group) or medical therapy alone (medical-therapy group). The first primary end point was a hierarchical composite of death from any cause, hospitalization for heart failure, and quality-of-life improvement at 1 year, assessed by win ratio. If the between-group difference was significant, a second primary end point would be tested: a composite of death from any cause or hospitalization for heart failure through 3 years.

Results. A total of 360 patients underwent randomization (237 patients were assigned to the tricuspid-repair group and 123 to the medical-therapy group). The mean (±SD) age of the patients was 80.3±6.4 years, and 56.4% were women. The win ratio for the first primary end point was 2.42 (95% confidence interval [CI], 1.76 to 3.33; P<0.001), favoring tricuspid-valve repair. The Kaplan-Meier estimate for freedom from death from any cause or hospitalization for heart failure (second primary end point) through 3 years was 52.4% (95% CI, 43.2 to 63.6) in the tricuspid-repair group and 21.0% (95% CI, 12.7 to 34.6) in the medical-therapy group (hazard ratio for death from any cause or hospitalization for heart failure, 0.40; 95% CI, 0.29 to 0.55; P<0.001). Major adverse events within 30 days occurred in 14 patients (5.9%) in the tricuspid-repair group.

Conclusions. Among patients with symptomatic severe tricuspid regurgitation, transcatheter tricuspid-valve repair plus medical therapy was superior to medical therapy alone with respect to a hierarchical composite of death from any cause, hospitalization for heart failure, and quality-of-life improvement at 1 year and was also associated with a lower risk of a composite of death from any cause or hospitalization for heart failure through 3 years. (Funded by the German Center for Cardiovascular Research and others; TRIC-I-HF ClinicalTrials.gov number, NCT04634266.).

Background. Whether screening with blood-based early-detection tests for multiple cancers in addition to usual care has clinical utility is unknown.

Methods. In a randomized, controlled trial conducted in England, we obtained peripheral blood from persons 50 to 77 years of age at up to three annual visits. After baseline blood collection, participants were randomly assigned in a 1:1 ratio to the intervention group (participants whose blood was tested) or the control group (participants whose blood was stored). Participants and trial personnel were initially unaware of the group assignments. The primary end point was stage III or IV cancer among 12 prespecified types of cancer, and a key secondary end point was stage IV cancer among the 12 prespecified types. The differences between the groups in the incidence rate (the number of first eligible events divided by person-years at risk) were measured after three screening rounds and at least 12 months of follow-up after the last participant's third visit.

Results. Overall, 71,122 participants were randomly assigned to the intervention group and 71,128 to the control group. The incidence rate of stage III or IV cancer (primary end point) did not differ significantly between the groups (incidence rate ratio [intervention vs. control], 1.03; 95% confidence interval [CI], 0.92 to 1.14, P = 0.63). The incidence rate ratio for stage IV cancer (a key secondary end point) after 3 screening rounds was 0.86 (95% CI, 0.74 to 1.00). Less than 1% of participants had trial-related adverse events; none were serious.

Conclusions. In this trial, we did not observe a lower incidence rate of stage III or IV cancers across 12 prespecified cancers after three screening rounds with multicancer early-detection testing plus usual care than with usual care alone. Further follow-up is warranted to assess the way in which findings for stage III or IV cancers and the between-group difference in stage IV cancers evolve over time. (Funded by Grail; NHS-Galleri ClinicalTrials.gov number, NCT05611632; ISRCTN number, ISRCTN91431511.).

Background. The optimal approach to early resuscitation in septic shock is unknown. Equipoise exists between the use of larger volumes of intravenous fluids to restore perfusion and the use of early vasopressor therapy along with smaller volumes of fluids to minimize potential harm from excess fluid.

Methods. We randomly assigned adult patients who presented to the emergency department with septic shock to receive either fluids at restricted volumes and early vasopressor therapy (vasopressor group) or higher volumes of fluids and later vasopressor therapy (fluids group) for at least 6 hours and up to 24 hours. The primary outcome was days alive and out of the hospital from randomization to day 90.

Results. A total of 1000 patients underwent randomization, with 499 assigned to the vasopressor group and 501 to the fluids group. Informed consent was not obtained for 37 patients, which left 963 patients in the intention-to-treat population (481 in the vasopressor group and 482 in the fluids group). Three patients in the fluids group were lost to follow-up for the primary outcome. In the first 24 hours after randomization, patients in the vasopressor group received less intravenous fluid than those in the fluids group (median difference, -1108 ml; 95% confidence interval [CI], -1395 to -850). The percentage of patients who received vasopressors was higher by 18.9 percentage points (95% CI, 13.3 to 24.5) in the vasopressor group. The median number of days alive and out of the hospital at day 90 was 76 (interquartile range, 55 to 83) in the vasopressor group and 76 (interquartile range, 55 to 82) in the fluids group (difference, 0.0 days; 95% CI, -2.7 to 2.7; P = 1.00). Adverse events occurred in similar percentages of patients in the two groups, except for pulmonary edema (0.6% in the vasopressor group vs. 5.0% in the fluids group; P<0.001).

Conclusions. Among adult patients who presented to the emergency department with septic shock, an approach that involved restricted fluid volume and early vasopressors did not result in a greater number of days alive and out of the hospital at day 90 than an approach involving greater fluid volume and later administration of vasopressors. (Funded by the Australian National Health and Medical Council Medical Research Future Fund and the New Zealand Health Research Council; ARISE FLUIDS ClinicalTrials.gov number, NCT04569942.).

Background. Retinitis pigmentosa is an inherited degenerative retinal disease that can lead to irreversible blindness. Optogenetic therapy has shown potential for restoring visual function at late stages of the disease.

Methods. In this open-label study, we evaluated the safety of ganglion cell-directed optogenetic therapy in 10 participants with blindness due to advanced retinitis pigmentosa. Each participant received a single intravitreal injection of an adeno-associated viral (AAV) vector encoding the red-shifted channelrhodopsin ChrimsonR in the worse-seeing eye. The primary outcome was safety. Secondary outcomes included changes in light sensitivity as measured by full-field stimulus threshold (FST) testing conducted with the untreated eye patched and with the use of light-stimulating goggles designed to activate ChrimsonR. The definition of a clinically meaningful improvement in the FST (based on evidence from the literature and not prespecified in the protocol) was a decrease of at least 0.6 log units (i.e., an increase in light sensitivity by a factor of approximately 4).

Results. A total of 34 ocular adverse events occurred among 9 of the 10 participants, including 23 mild events and 10 moderate events. One severe event occurred: transient occlusion of the central retinal artery that occurred immediately after intravitreal injection and resolved within minutes after instillation of iopidine. Light sensitivity increased in 7 of the 10 participants, with increases ranging from a factor of 2.0 to a factor of 62.3; 6 participants had a clinically meaningful increase in light sensitivity.

Conclusions. Within the limits of this small study, intravitreal administration of a ChrimsonR-expressing AAV vector targeting retinal ganglion cells combined with use of light-stimulating goggles was safe. Additional research is needed to further assess safety and efficacy. (Funded by GenSight Biologics; PIONEER ClinicalTrials.gov number, NCT03326336.).