TIMI Study Group, Cardiovascular Division (E.A.B., D.D.B., M.S.L., J.F.K., S.A.M., M.L.O., J.-G.P., C.T.R., S.D.W., V.B.-Z., M.S.S., D.A.M.), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Hematology Division (J.M.C.), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Circulation. 2022 Nov;146(18):1344-1356. doi: 10.1161/CIRCULATIONAHA.122.061533. Epub 2022 Aug 29.
The efficacy and safety of prophylactic full-dose anticoagulation and antiplatelet therapy in critically ill COVID-19 patients remain uncertain.
COVID-PACT (Prevention of Arteriovenous Thrombotic Events in Critically-ill COVID-19 Patients Trial) was a multicenter, 2×2 factorial, open-label, randomized-controlled trial with blinded end point adjudication in intensive care unit-level patients with COVID-19. Patients were randomly assigned to a strategy of full-dose anticoagulation or standard-dose prophylactic anticoagulation. Absent an indication for antiplatelet therapy, patients were additionally randomly assigned to either clopidogrel or no antiplatelet therapy. The primary efficacy outcome was the hierarchical composite of death attributable to venous or arterial thrombosis, pulmonary embolism, clinically evident deep venous thrombosis, type 1 myocardial infarction, ischemic stroke, systemic embolic event or acute limb ischemia, or clinically silent deep venous thrombosis, through hospital discharge or 28 days. The primary efficacy analyses included an unmatched win ratio and time-to-first event analysis while patients were on treatment. The primary safety outcome was fatal or life-threatening bleeding. The secondary safety outcome was moderate to severe bleeding. Recruitment was stopped early in March 2022 (≈50% planned recruitment) because of waning intensive care unit-level COVID-19 rates.
At 34 centers in the United States, 390 patients were randomly assigned between anticoagulation strategies and 292 between antiplatelet strategies (382 and 290 in the on-treatment analyses). At randomization, 99% of patients required advanced respiratory therapy, including 15% requiring invasive mechanical ventilation; 40% required invasive ventilation during hospitalization. Comparing anticoagulation strategies, a greater proportion of wins occurred with full-dose anticoagulation (12.3%) versus standard-dose prophylactic anticoagulation (6.4%; win ratio, 1.95 [95% CI, 1.08-3.55]; =0.028). Results were consistent in time-to-event analysis for the primary efficacy end point (full-dose versus standard-dose incidence 19/191 [9.9%] versus 29/191 [15.2%]; hazard ratio, 0.56 [95% CI, 0.32-0.99]; =0.046). The primary safety end point occurred in 4 (2.1%) on full dose and in 1 (0.5%) on standard dose (=0.19); the secondary safety end point occurred in 15 (7.9%) versus 1 (0.5%; =0.002). There was no difference in all-cause mortality (hazard ratio, 0.91 [95% CI, 0.56-1.48]; =0.70). There were no differences in the primary efficacy or safety end points with clopidogrel versus no antiplatelet therapy.
In critically ill patients with COVID-19, full-dose anticoagulation, but not clopidogrel, reduced thrombotic complications with an increase in bleeding, driven primarily by transfusions in hemodynamically stable patients, and no apparent excess in mortality.
URL: https://www.
gov; Unique identifier: NCT04409834.
在重症 COVID-19 患者中，预防性全剂量抗凝和抗血小板治疗的疗效和安全性仍不确定。
COVID-PACT（预防危重症 COVID-19 患者动静脉血栓事件试验）是一项多中心、2×2 析因、开放标签、随机对照临床试验，在 ICU 级别的 COVID-19 患者中进行了盲终点评估。患者被随机分配到全剂量抗凝或标准剂量预防性抗凝策略。如果没有抗血小板治疗的指征，患者还被随机分配接受氯吡格雷或不接受抗血小板治疗。主要疗效终点是归因于静脉或动脉血栓形成、肺栓塞、临床明显深静脉血栓形成、1 型心肌梗死、缺血性卒中、系统性栓塞事件或急性肢体缺血、或临床无症状深静脉血栓形成的死亡或因静脉或动脉血栓形成导致的死亡的分层复合终点，通过出院或 28 天达到。主要疗效分析包括治疗期间的非匹配赢比值和首次事件时间分析。主要安全性终点是致命或危及生命的出血。次要安全性终点是中度至重度出血。由于 ICU 级别的 COVID-19 发病率下降，该研究于 2022 年 3 月（约计划招募的 50%）提前停止。
在美国 34 个中心，390 名患者在抗凝策略之间随机分配，292 名患者在抗血小板策略之间随机分配（治疗期间分析分别为 382 名和 290 名）。随机分配时，99%的患者需要高级呼吸治疗，包括 15%需要有创机械通气；40%的患者在住院期间需要有创通气。与标准剂量预防性抗凝相比，全剂量抗凝的获胜比例更高（12.3%比 6.4%；赢比值，1.95[95%CI，1.08-3.55]；=0.028）。主要疗效终点的时间事件分析结果一致（全剂量组 19/191[9.9%]，标准剂量组 29/191[15.2%]；风险比，0.56[95%CI，0.32-0.99]；=0.046）。主要安全性终点发生在 4 名（2.1%）全剂量患者和 1 名（0.5%）标准剂量患者中（=0.19）；次要安全性终点发生在 15 名（7.9%）氯吡格雷组和 1 名（0.5%）无抗血小板治疗组（=0.002）。全因死亡率无差异（风险比，0.91[95%CI，0.56-1.48]；=0.70）。氯吡格雷与无抗血小板治疗在主要疗效或安全性终点上无差异。
在 COVID-19 重症患者中，全剂量抗凝（而非氯吡格雷）可降低血栓并发症的发生，同时增加出血风险，主要是由于血流动力学稳定的患者需要输血，且死亡率无明显增加。
网址：https://www.
NCT04409834。
