Importance Acutely ill inpatients with COVID-19 typically receive antithrombotic therapy, although the risks and benefits of this intervention among outpatients with COVID-19 have not been established. Objective To assess whether anticoagulant or antiplatelet therapy can safely reduce major adverse cardiopulmonary outcomes among symptomatic but clinically stable outpatients with COVID-19. Design, Setting, and Participants The ACTIV-4B Outpatient Thrombosis Prevention Trial was designed as a minimal-contact, adaptive, randomized, double-blind, placebo-controlled trial to compare anticoagulant and antiplatelet therapy among 7000 symptomatic but clinically stable outpatients with COVID-19. The trial was conducted at 52 US sites between September 2020 and June 2021; final follow-up was August 5, 2021. Prior to initiating treatment, participants were required to have platelet count greater than 100 000/mm3 and estimated glomerular filtration rate greater than 30 mL/min/1.73 m2. Interventions Random allocation in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days. Main Outcomes and Measures The primary end point was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause. The primary analyses for efficacy and bleeding events were limited to participants who took at least 1 dose of trial medication. Results On June 18, 2021, the trial data and safety monitoring board recommended early termination because of lower than anticipated event rates; at that time, 657 symptomatic outpatients with COVID-19 had been randomized (median age, 54 years [IQR, 46-59]; 59% women). The median times from diagnosis to randomization and from randomization to initiation of study treatment were 7 days and 3 days, respectively. Twenty-two randomized participants (3.3%) were hospitalized for COVID-19 prior to initiating treatment. Among the 558 patients who initiated treatment, the adjudicated primary composite end point occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5-mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group. The risk differences compared with placebo for the primary end point were 0.0% (95% CI not calculable) in the aspirin group, 0.7% (95% CI, -2.1% to 4.1%) in the 2.5-mg apixaban group, and 1.4% (95% CI, -1.5% to 5.0%) in the 5-mg apixaban group. Risk differences compared with placebo for bleeding events were 2.0% (95% CI, -2.7% to 6.8%), 4.5% (95% CI, -0.7% to 10.2%), and 6.9% (95% CI, 1.4% to 12.9%) among participants who initiated therapy in the aspirin, prophylactic apixaban, and therapeutic apixaban groups, respectively, although none were major. Findings inclusive of all randomized patients were similar. Conclusions and Relevance Among symptomatic clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome. However, the study was terminated after enrollment of 9% of participants because of an event rate lower than anticipated. Trial Registration ClinicalTrials.gov Identifier: NCT04498273.

中文翻译：

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抗血栓治疗对临床症状稳定的 COVID-19 门诊患者临床结果的影响：ACTIV-4B 随机临床试验。


重要性 尽管这种干预措施对门诊 COVID-19 患者的风险和益处尚未确定，但患有 COVID-19 的急性住院患者通常会接受抗血栓治疗。目的 评估抗凝或抗血小板治疗是否可以安全地减少有症状但临床稳定的 COVID-19 门诊患者的主要不良心肺结局。设计、设置和参与者 ACTIV-4B 门诊血栓预防试验被设计为一项最小接触、适应性、随机、双盲、安慰剂对照试验，旨在比较 7000 名有症状但临床稳定的新冠肺炎门诊患者的抗凝和抗血小板治疗。 19.该试验于 2020 年 9 月至 2021 年 6 月期间在美国 52 个地点进行；最后一次随访时间为 2021 年 8 月 5 日。在开始治疗之前，参与者的血小板计数必须大于 100 000/mm3，估计肾小球滤过率大于 30 mL/min/1.73 m2。干预措施 按 1:1:1:1 比例随机分配阿司匹林（81 mg，每日一次口服；n = 164）、预防剂量阿哌沙班（2.5 mg，每日口服两次；n = 165）、治疗剂量阿哌沙班（5 mg）每天口服两次；n = 164），或安慰剂（n = 164），持续 45 天。主要结局和措施 主要终点是全因死亡率、有症状的静脉或动脉血栓栓塞、心肌梗塞、中风或因心血管或肺部原因住院的复合终点。疗效和出血事件的主要分析仅限于至少服用一剂试验药物的参与者。 结果 2021 年 6 月 18 日，试验数据和安全监察委员会因事件发生率低于预期而建议提前终止；当时，657 名有症状的 COVID-19 门诊患者被随机分组​​（中位年龄 54 岁 [IQR，46-59]；59% 为女性）。从诊断到随机分组以及从随机分组到开始研究治疗的中位时间分别为 7 天和 3 天。 22 名随机参与者 (3.3%) 在开始治疗前因 COVID-19 住院。在开始治疗的 558 名患者中，判定的主要复合终点发生在阿司匹林组 1 名患者（0.7%）、2.5 mg 阿哌沙班组 1 名患者（0.7%）、5 毫克阿哌沙班组 2 名患者（1.4%）。 -mg 阿哌沙班组和安慰剂组有 1 名患者 (0.7%)。与安慰剂相比，阿司匹林组的主要终点风险差异为 0.0%（95% CI 无法计算），2.5 mg 阿哌沙班组为 0.7%（95% CI，-2.1% 至 4.1%），1.4%。 5 mg 阿哌沙班组的 %（95% CI，-1.5% 至 5.0%）。与安慰剂相比，出血事件的风险差异分别为 2.0%（95% CI，-2.7% 至 6.8%）、4.5%（95% CI，-0.7% 至 10.2%）和 6.9%（95% CI，1.4% 至 10.2%）。分别在阿司匹林组、预防性阿哌沙班组和治疗性阿哌沙班组中开始治疗的参与者中，这一比例为 12.9%，尽管没有一个是主要的。包括所有随机患者在内的结果相似。结论和相关性 在临床症状稳定的 COVID-19 门诊患者中，与安慰剂相比，阿司匹林或阿哌沙班治疗并未降低复合临床结果的发生率。然而，由于事件发生率低于预期，该研究在 9% 的参与者入组后终止。试验注册 ClinicalTrials.gov 标识符：NCT04498273。