NEJM original articles

Background. Apixaban and rivaroxaban are the oral anticoagulants most frequently used to treat acute venous thromboembolism. However, uncertainty remains about the difference in bleeding risk between the two medications.

Methods. In an international trial with a prospective, randomized, open-label, blinded end-point design, we assigned, in a 1:1 ratio, eligible patients with acute symptomatic pulmonary embolism or proximal deep-vein thrombosis to receive apixaban or rivaroxaban for 3 months. Apixaban was given at a dose of 10 mg twice daily for 7 days followed by 5 mg twice daily, and rivaroxaban was given at a dose of 15 mg twice daily for 21 days followed by 20 mg daily. The primary outcome was clinically relevant bleeding, a composite of major bleeding or clinically relevant nonmajor bleeding, as defined according to the International Society on Thrombosis and Haemostasis, during the 3-month trial period. Secondary outcomes included death from any cause.

Results. A total of 2760 patients underwent randomization: 1370 to the apixaban group and 1390 to the rivaroxaban group. A primary-outcome event occurred in 44 of 1345 patients (3.3%) in the apixaban group and 96 of 1355 patients (7.1%) in the rivaroxaban group (relative risk, 0.46; 95% confidence interval [CI], 0.33 to 0.65; P<0.001). Death from any cause occurred in 1 patient (0.1%) in the apixaban group and in 4 patients (0.3%) in the rivaroxaban group (relative risk, 0.25; 95% CI, 0.03 to 2.26). Serious adverse events unrelated to bleeding or venous thrombosis occurred in 36 patients (2.7%) in the apixaban group and in 30 patients (2.2%) in the rivaroxaban group.

Conclusions. Among patients with acute venous thromboembolism, the risk of clinically relevant bleeding was significantly lower with apixaban than with rivaroxaban during the 3-month treatment period. (Funded by the Canadian Institutes of Health Research and others; COBRRA ClinicalTrials.gov number, NCT03266783.).

Background. Chemotherapy-induced thrombocytopenia (CIT) is a common complication of chemotherapy that is associated with bleeding, reduced relative dose intensity, and potentially worse outcomes. No widely available therapies are approved for CIT.

Methods. We conducted a phase 3, international, double-blind, randomized, placebo-controlled trial involving patients with persistent CIT (platelet count, ≤85×10⁹ per liter on trial day 1) who were receiving oxaliplatin-based multiagent cytotoxic chemotherapy for gastrointestinal cancers. Patients were randomly assigned in a 2:1 ratio to receive romiplostim or placebo for three chemotherapy cycles. The primary end point was the absence of CIT-induced modifications of the chemotherapy dose (reduction, delay, omission, or discontinuation) in both the second and third chemotherapy cycles.

Results. Of the 165 patients who underwent randomization (109 in the romiplostim group and 56 in the placebo group), 75% had colorectal cancer, 13% had gastroesophageal cancer, and 12% had pancreatic cancer; 72% of the patients in the romiplostim group and 61% of those in the placebo group had stage 4 disease. The percentage of patients with no CIT-induced modifications of the chemotherapy dose was 84% (92 of 109 patients) with romiplostim and 36% (20 of 56 patients) with placebo, which corresponded to an odds ratio of 10.16 (95% confidence interval [CI], 4.44 to 23.72; P<0.001) and a risk ratio of 2.77 (95% CI, 1.78 to 4.30; P<0.001). Adverse events of grade 3 or higher occurred in 37% of the patients who received romiplostim and in 22% of those who received placebo, which primarily reflected chemotherapy effects. Adverse events that were considered by the investigator to be related to romiplostim or placebo occurred in 12% of patients who received romiplostim and in 7% who received placebo, with the most frequent being nausea (2% in each group) and headache (2% in the romiplostim group); none were serious or led to death or discontinuation of romiplostim, placebo, or chemotherapy. Thromboembolic events occurred in 2% of patients who received romiplostim and in no patients who received placebo.

Conclusions. In this phase 3, placebo-controlled trial, romiplostim was efficacious in treating CIT. (Funded by Amgen and the Biomedical Advanced Research and Development Authority; RECITE ClinicalTrials.gov number, NCT03362177.).

Background. Genetic deficiency of otoferlin, a protein critical to synaptic transmission by the sensory hair cells of the ear, causes congenital deafness. Medicines to treat the condition are lacking; children typically receive cochlear implants. DB-OTO is a dual adeno-associated virus 1 gene therapy that delivers human OTOF complementary DNA (encoding otoferlin) regulated by a hair cell-specific promoter.

Methods. We conducted an open-label, single-group, first-in-human registrational study to evaluate DB-OTO. Children with OTOF variants and profound deafness (defined by an average audiometric threshold of >90 decibel hearing level [dB HL], indicating an inability to hear a gas-powered lawn mower) received an intracochlear infusion of DB-OTO (7.2×10¹² vector genomes per ear) in one or both ears. The primary efficacy end point was an average threshold on behavioral pure-tone audiometry (PTA) at week 24 of 70 dB HL or less, a clinical standard that generally avoids cochlear implantation and enables natural acoustic hearing. A key secondary end point was the presence of an auditory brain-stem response to a click stimulus at a threshold at or below 90 dB normalized hearing level (db nHL) at week 24. Safety assessments included adverse events, laboratory results, and vestibular testing.

Results. A total of 12 children have been enrolled in the study. After a single infusion of DB-OTO, a PTA average threshold of 70 dB HL or less at week 24 (primary end point) and an auditory brain-stem response at or below 90 dB nHL (key secondary end point) were found in 9 of the 12 participants (75%; 95% confidence interval, 43 to 95; P = 1.1×10^-13 for both end points). Six participants could hear soft speech without assistive devices, and 3 had average normal hearing sensitivity. A total of 67 adverse events occurred or worsened during or after treatment, none of which led to discontinued participation in the study.

Conclusions. DB-OTO gene therapy improved hearing in patients with OTOF-related deafness, enabling natural acoustic hearing and normalizing hearing sensitivity in 3 of 12 treated patients. (Funded by Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT05788536.).

Background. Treatment of chronic lymphocytic leukemia (CLL) currently consists of two main approaches - continuous therapy with Bruton's tyrosine kinase inhibitors and fixed-duration regimens combining venetoclax with either CD20 antibodies or Bruton's tyrosine kinase inhibitors. Comparisons of these two therapeutic approaches are lacking.

Methods. We conducted an investigator-initiated, phase 3, randomized trial involving patients with previously untreated CLL. Patients were randomly assigned to receive continuous ibrutinib or fixed-duration venetoclax-obinutuzumab or venetoclax-ibrutinib. The primary end point was investigator-assessed progression-free survival (noninferiority margin for the hazard ratio, 1.608, corresponding to a noninferiority margin of 8 percentage points at 3 years). Secondary end points included minimal residual disease (MRD), response, overall survival, and safety.

Results. A total of 909 patients were assigned to venetoclax-obinutuzumab (303 patients), venetoclax-ibrutinib (305 patients), or ibrutinib (301 patients). The median follow-up was 34.2 months. In this prespecified interim analysis, 3-year progression-free survival was 81.1% in the venetoclax-obinutuzumab group, 79.4% in the venetoclax-ibrutinib group, and 81.0% in the ibrutinib group (hazard ratio for venetoclax-obinutuzumab vs. ibrutinib, 0.87 [98.3% confidence interval {CI}, 0.54 to 1.41]; hazard ratio for venetoclax-ibrutinib vs. ibrutinib, 0.84 [98.0% CI, 0.53 to 1.32]); the results for each comparison met the criterion for noninferiority. After the end of treatment, MRD in peripheral blood was undetectable in 73.3% of the patients in the venetoclax-obinutuzumab group, 47.2% in the venetoclax-ibrutinib group, and 0% in the ibrutinib group. Three-year overall survival was 91.5%, 96.0%, and 95.7%, respectively. The most common adverse events were infections, gastrointestinal disorders, and cytopenias.

Conclusions. In patients with previously untreated CLL, fixed-duration treatment with venetoclax-obinutuzumab or venetoclax-ibrutinib was noninferior to continuous ibrutinib with regard to investigator-assessed progression-free survival. (Funded by the University of Cologne and others; CLL17 ClinicalTrials.gov number, NCT04608318; EudraCT number, 2019-003854-99.).