Efficacy and Safety of Anakinra Plus Standard of Care for Patients With Severe COVID-19: A Randomized Phase 2/3 Clinical Trial.

Importance: COVID-19 pneumonia is often associated with hyperinflammation. The efficacy and safety of anakinra in treating patients with severe COVID-19 pneumonia and hyperinflammation are still unclear. Objective: To assess the efficacy and safety of anakinra vs standard of care alone for patients with severe COVID-19 pneumonia and hyperinflammation. Design, Setting, and Participants: The Clinical Trial of the Use of Anakinra in Cytokine Storm Syndrome Secondary to COVID-19 (ANA-COVID-GEAS) was a multicenter, randomized, open-label, 2-group, phase 2/3 clinical trial conducted at 12 hospitals in Spain between May 8, 2020, and March 1, 2021, with a follow-up of 1 month. Participants were adult patients with severe COVID-19 pneumonia and hyperinflammation. Hyperinflammation was defined as interleukin-6 greater than 40 pg/mL, ferritin greater than 500 ng/mL, C-reactive protein greater than 3 mg/dL (rationale, ≥5 upper normal limit), and/or lactate dehydrogenase greater than 300 U/L. Severe pneumonia was considered if at least 1 of the following conditions was met: ambient air oxygen saturation 94% or less measured with a pulse oximeter, ratio of partial pressure O2 to fraction of inspired O2 of 300 or less, and/or a ratio of O2 saturation measured with pulse oximeter to fraction of inspired O2 of 350 or less. Data analysis was performed from April to October 2021. Interventions: Usual standard of care plus anakinra (anakinra group) or usual standard of care alone (SoC group). Anakinra was given at a dose of 100 mg 4 times a day intravenously. Main Outcomes and Measures: The primary outcome was the proportion of patients not requiring mechanical ventilation up to 15 days after treatment initiation, assessed on an intention-to-treat basis. Results: A total of 179 patients (123 men [69.9%]; mean [SD] age, 60.5 [11.5] years) were randomly assigned to the anakinra group (92 patients) or to the SoC group (87 patients). The proportion of patients not requiring mechanical ventilation up to day 15 was not significantly different between groups (64 of 83 patients [77.1%] in the anakinra group vs 67 of 78 patients [85.9%] in the SoC group; risk ratio [RR], 0.90; 95% CI, 0.77-1.04; P = .16). Anakinra did not result in any difference in time to mechanical ventilation (hazard ratio, 1.72; 95% CI, 0.82-3.62; P = .14). There was no significant difference between groups in the proportion of patients not requiring invasive mechanical ventilation up to day 15 (RR, 0.99; 95% CI, 0.88-1.11; P > .99). Conclusions and Relevance: In this randomized clinical trial, anakinra did not prevent the need for mechanical ventilation or reduce mortality risk compared with standard of care alone among hospitalized patients with severe COVID-19 pneumonia. Trial Registration: ClinicalTrials.gov Identifier: NCT04443881.

Predicting recurrences or major bleeding in women with cancer and venous thromboembolism. Findings from the RIETE Registry.

BACKGROUND: Cancer patients with venous thromboembolism (VTE) have an increased incidence of recurrences and bleeding complications Reliable information on the factors determining the risk for such complications may facilitate better use of therapy. METHODS: RIETE Registry is an ongoing, international registry of consecutive patients presenting with symptomatic acute VTE confirmed by objective tests. We assessed the 3-month outcome in all women with active cancer, trying to identify if differences exist according to the tumor site. RESULTS: Up to May 2007, 18,883 patients had been enrolled. Of them, 3805 (20%) had active cancer, 1719 (45%) were women. During the 3-month study period, 40 (2.3%) had recurrent deep vein thrombosis, 39 (2.3%) recurrent pulmonary embolism (PE), 67 (3.9%) major bleeding, 394 (23%) died. Of these, 13 (33%) women with recurrent PE died of the PE, 17 (42%) with major bleeding had fatal bleeding. In women with gastrointestinal (5.7% vs. 4.3%) or genitourinary (6.4% vs. 4.7%) cancers the incidence of bleeding complications exceeded that of VTE recurrences, while in those with brain (3.4% vs. 13%) or lung cancer (2.6% vs. 11%) the rate of recurrences outweighed that of major bleeding. CONCLUSIONS: We identified significant differences in outcome according to the site of cancer that may help to identify those women with cancer and VTE at a higher risk for recurrences or major bleeding.

Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Findings from the RIETE Registry.

A score that can accurately determine the risk of major bleeding during anticoagulant therapy may help to make decisions on anticoagulant use. RIETE is an ongoing registry of consecutive patients with acute venous thromboembolism (VTE). We composed a score to predict the risk for major bleeding within three months of anticoagulant therapy. Of 19,274 patients enrolled, 13,057 (67%) were randomly assigned to the derivation sample, 6,572 to the validation sample. In the derivation sample 314 (2.4%) patients bled (fatal bleeding, 105). On multivariate analysis, age >75 years, recent bleeding, cancer, creatinine levels >1.2 mg/dl, anemia, or pulmonary embolism at baseline were independently associated with an increased risk for major bleeding. A score was composed assigning 2 points to recent bleeding, 1.5 to abnormal creatinine levels or anemia, 1 point to the remaining variables. In the derivation sample 2,654 (20%) patients scored 0 points (low risk); 9,645 (74%) 1-4 points (intermediate); 758 (5.8%) >4 points (high risk). The incidences of major bleeding were: 0.3% (95% confidence interval [CI]: 0.1-0.6), 2.6% (95% CI: 2.3-2.9), and 7.3% (95% CI: 5.6-9.3), respectively. The likelihood ratio test was: 0.14 (95% CI: 0.07-0.27) for patients at low risk;2.96 (95% CI: 2.18-4.02) for those at high risk. In the validation sample the incidence of major bleeding was: 0.1%, 2.8%, and 6.2%, respectively. In conclusion, a risk score based on six variables documented at entry can identify VTE patients at low, intermediate, or high risk for major bleeding during the first three months of therapy.