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Background. For patients with atrial fibrillation, the use of oral anticoagulant therapy to prevent stroke is limited by the risk of bleeding. Left atrial appendage closure is considered for patients who are unsuitable candidates for long-term anticoagulation, but its role in patients who are eligible for anticoagulants has not been established.
Methods. In this ongoing, prospective, international, randomized trial involving patients with atrial fibrillation who were suitable candidates for anticoagulation, we randomly assigned patients in a 1:1 ratio to receive either device-based left atrial appendage closure (device group) or non-vitamin K antagonist oral anticoagulant (NOAC) therapy (anticoagulation group). The primary efficacy end point - a composite of death from cardiovascular causes, stroke, or systemic embolism - was tested for noninferiority (noninferiority margin, 4.8 percentage points) after 3 years of follow-up. The primary safety end point, non-procedure-related bleeding, was tested for superiority.
Results. Of the 3000 patients who underwent randomization, 1499 were assigned to the device group and 1501 to the anticoagulation group. The mean (±SD) age of the patients was 71.7±7.5 years, 31.9% of the patients were women, and the mean CHA2DS2-VASc score was 3.5±1.3. At 3 years, a primary efficacy end-point event had occurred in 81 patients (Kaplan-Meier estimate, 5.7%) in the device group and in 65 patients (Kaplan-Meier estimate, 4.8%) in the anticoagulation group (difference, 0.9 percentage points; 95% confidence interval [CI], -0.8 to 2.6; P<0.001 for noninferiority). Non-procedure-related bleeding occurred in 154 patients (Kaplan-Meier estimate, 10.9%) in the device group and in 260 patients (Kaplan-Meier estimate, 19.0%) in the anticoagulation group (hazard ratio, 0.55; 95% CI, 0.45 to 0.67; P<0.001 for superiority).
Conclusions. Among patients with atrial fibrillation who were candidates for anticoagulation, device-based left atrial appendage closure was noninferior to NOAC therapy with respect to a composite of death from cardiovascular causes, stroke, or systemic embolism and was superior to NOAC therapy for non-procedure-related bleeding at 3 years. (Funded by Boston Scientific; CHAMPION-AF ClinicalTrials.gov number, NCT04394546.).
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Background. Data are needed on the effect of oxygen delivered through a high-flow nasal cannula, as compared with standard oxygen therapy, on intubation and mortality in patients with acute hypoxemic respiratory failure.
Methods. In this multicenter, open-label trial, we randomly assigned patients who had acute hypoxemic respiratory failure to receive high-flow-oxygen or standard-oxygen therapy. All the patients had a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of 200 or less, a respiratory rate of more than 25 breaths per minute, and pulmonary infiltrate on chest imaging. The primary outcome was death by day 28.
Results. A total of 1116 patients underwent randomization. Of these patients, 1110 (556 in the high-flow-oxygen group and 554 in the standard-oxygen group) were included in the analysis. Mortality at day 28 was 14.6% (in 81 of 556 patients) in the high-flow-oxygen group and 14.6% (in 81 of 554 patients) in the standard-oxygen group (difference, -0.05 percentage points; 95% confidence interval [CI], -4.21 to 4.10; P = 0.98). The incidence of intubation by day 28 was 42.4% (in 236 of 556 patients) in the high-flow-oxygen group and 48.4% (in 268 of 554 patients) in the standard-oxygen group (difference, -5.93 percentage points; 95% CI, -11.78 to -0.08). Serious adverse events (cardiac arrest or pneumothorax) occurred during spontaneous breathing in 13 patients (2.3%) in the high-flow-oxygen group and in 6 patients (1.1%) in the standard-oxygen group.
Conclusions. Among patients with acute hypoxemic respiratory failure, the use of oxygen delivered through a high-flow nasal cannula did not significantly reduce mortality at day 28. (Funded by the French Ministry of Health and Fisher and Paykel Healthcare; SOHO ClinicalTrials.gov number, NCT04468126.).
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Background. For patients with acute myeloid leukemia (AML) who are 75 years of age or older or who are ineligible for intensive induction chemotherapy, azacitidine or decitabine plus venetoclax is the standard of care, but parenteral administration imposes a burden on patients and providers. Oral decitabine-cedazuridine, approved in Europe for AML, has pharmacokinetic properties equivalent to those of intravenous decitabine but provides limited survival benefit as monotherapy.
Methods. In this phase 1-2, open-label, multicenter, nonrandomized trial, we assigned patients with newly diagnosed AML who were 75 years of age or older or who were ineligible for intensive chemotherapy to receive oral decitabine-cedazuridine plus oral venetoclax. To mitigate myelosuppression observed in phase 1, schedule adjustments were encouraged in phase 2b after bone marrow blast clearance. The primary end points were the venetoclax area under the curve from 0 to 24 hours and maximum observed concentration with or without decitabine-cedazuridine (measures of drug interaction) on days 5 and 15 of cycle 2 (phase 1-2a) and complete response (phase 2a-b).
Results. A total of 189 patients were enrolled (30 patients in phase 1, 58 patients in phase 2a, and 101 patients in phase 2b). No drug-drug interactions were observed between decitabine-cedazuridine and venetoclax. In the pivotal phase 2b, the percentage of patients with a complete response was 47% (95% confidence interval [CI], 36 to 57), the percentage with a complete response or complete response with incomplete hematologic recovery was 63% (95% CI, 53 to 73), and median overall survival was 15.5 months (95% CI, 7.6 to could not be estimated). Common adverse events of grade 3 or higher in phase 2b were anemia (in 30% of the patients), neutropenia (in 26%), and febrile neutropenia (in 25%). Mortality was 3% at 30 days and 10% at 60 days.
Conclusions. Among patients with newly diagnosed AML who were ineligible for intensive chemotherapy, all-oral decitabine-cedazuridine plus venetoclax caused no drug interactions and resulted in a complete response in nearly half the patients, with myelosuppressive effects. (Funded by Taiho Oncology; ASCERTAIN-V ClinicalTrials.gov number, NCT04657081.).
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HLA sensitization poses a major challenge to kidney transplantation for patients with end-stage kidney disease, especially for highly sensitized candidates. Attempts at antibody elimination (desensitization) have had inconsistent efficacy and have often failed to produce sustained reductions in anti-HLA antibodies in patients with the highest level of sensitization (calculated panel-reactive antibody score, ≥99.9%). We now report the results for the safety run-in cohort of a multicenter phase 1 clinical study evaluating the safety and efficacy of combined CD19-targeted and B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cells in eliminating the cellular sources of preformed anti-HLA antibodies (ClinicalTrials.gov number, NCT06056102). Kidney transplantation was performed in two highly sensitized candidates after desensitization with the use of dual CAR T-cell therapy.
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Recombinant adeno-associated virus (AAV) vectors are predominantly nonintegrating, but rare genomic integration events have been associated with oncogenesis in neonatal murine models. Here we report a case of a neuroepithelial tumor that developed in a 5-year-old boy with severe mucopolysaccharidosis type I (MPSI, Hurler subtype) 4 years after intracisternal magna administration of AAV serotype 9 gene therapy. The patient underwent successful resection of the primary tumor. Postoperatively, he has continued to have advanced cognitive function for his age, a finding that indicates mitigation of MPSI. Molecular analysis of the tumor showed clonal integration of rearranged AAV vector elements into the gene PLAG1 and expression of a chimeric AAV-PLAG1 transcript.
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