Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Yale/YNHH Center for Outcomes Research & Evaluation, New Haven, CT, USA; Cardiovascular Research Foundation (CRF), New York, NY, USA.
Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran.
Thromb Res. 2020 Dec;196:382-394. doi: 10.1016/j.thromres.2020.09.027. Epub 2020 Sep 24.
Microvascular and macrovascular thrombotic events are among the hallmarks of coronavirus disease 2019 (COVID-19). Furthermore, the exuberant immune response is considered an important driver of pulmonary and extrapulmonary manifestations of COVID-19. The optimal management strategy to prevent thrombosis in critically-ill patients with COVID-19 remains unknown.
The Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) and INSPIRATION-statin (INSPIRATION-S) studies test two independent hypotheses within a randomized controlled trial with 2 × 2 factorial design. Hospitalized critically-ill patients with reverse transcription polymerase chain reaction confirmed COVID-19 will be randomized to intermediate-dose versus standard dose prophylactic anticoagulation. The 600 patients undergoing this randomization will be screened and if meeting the eligibility criteria, will undergo an additional double-blind stratified randomization to atorvastatin 20 mg daily versus matching placebo. The primary endpoint, for both hypotheses will be tested for superiority and includes a composite of adjudicated acute arterial thrombosis, venous thromboembolism (VTE), use of extracorporeal membrane oxygenation, or all-cause death within 30 days from enrollment. Key secondary endpoints include all-cause mortality, adjudicated VTE, and ventilator-free days. Key safety endpoints include major bleeding according to the Bleeding Academic Research Consortium definition and severe thrombocytopenia (platelet count <20,000/fL) for the anticoagulation hypothesis. In a prespecified secondary analysis for non-inferiority, the study will test for the non-inferiority of intermediate intensity versus standard dose anticoagulation for major bleeding, considering a non-inferiority margin of 1.8 based on odds ratio. Key safety endpoints for the statin hypothesis include rise in liver enzymes >3 times upper normal limit and clinically-diagnosed myopathy. The primary analyses will be performed in the modified intention-to-treat population. Results will be tested in exploratory analyses across key subgroups and in the intention-to-treat and per-protocol cohorts.
INSPIRATION and INSPIRATON-S studies will help address clinically-relevant questions for antithrombotic therapy and thromboinflammatory therapy in critically-ill patients with COVID-19.
微血管和大血管血栓事件是 2019 年冠状病毒病（COVID-19）的标志之一。此外，过度的免疫反应被认为是 COVID-19 肺外和肺表现的重要驱动因素。对于 COVID-19 重症患者，预防血栓形成的最佳管理策略仍不清楚。
中等剂量与标准剂量预防抗凝在 COVID-19 重症患者中的比较：一项开放标签随机对照试验（INSPIRATION）和 INSPIRATION-他汀（INSPIRATION-S）研究在一项随机对照试验中测试了两个独立的假设，采用 2×2 析因设计。经逆转录聚合酶链反应确诊 COVID-19 的住院重症患者将被随机分为中等剂量与标准剂量预防抗凝组。接受这种随机分组的 600 例患者将进行筛查，如果符合入选标准，将进行额外的双盲分层随机分组，每日接受阿托伐他汀 20mg 或匹配安慰剂。两个假设的主要终点均为优效性检验，包括 30 天内经裁决的急性动脉血栓形成、静脉血栓栓塞（VTE）、体外膜氧合的应用或全因死亡的复合终点。主要次要终点包括全因死亡率、经裁决的 VTE 和无呼吸机天数。主要安全性终点包括根据 Bleeding Academic Research Consortium 定义的大出血和抗凝假设的严重血小板减少症（血小板计数<20,000/fL）。在非劣效性的预设二次分析中，该研究将测试中等强度与标准剂量抗凝在大出血方面的非劣效性，考虑到基于比值比的 1.8 的非劣效性边界。他汀假设的主要安全性终点包括肝酶升高超过正常上限 3 倍和临床诊断的肌病。主要分析将在改良意向治疗人群中进行。结果将在关键亚组和意向治疗及方案人群中进行探索性分析。
INSPIRATION 和 INSPIRATON-S 研究将有助于解决 COVID-19 重症患者抗血栓治疗和血栓炎症治疗的临床相关问题。
