新冠肺炎患者院外使用利伐沙班抗凝安全性和有效性的meta分析

doi:10.3969/j.issn.1004-583X.2024.06.001

摘要/Abstract

摘要：

目的评估新冠患者院外使用利伐沙班抗凝的安全性和有效性。方法检索了Embase、PubMed、Scopus、Cochrane library、Web of Science、MedRxiv和ClinicalTrials数据库。2名独立研究人员根据预先确定的纳入和排除标准分别进行文献筛选和数据提取。结果纳入6项研究,共4605例新冠患者,其中包括4项随机对照试验和2项队列研究。结果显示,接受利伐沙班治疗的患者与未接受利伐沙班治疗的患者死亡率差异无统计学意义(0.50% vs 1.50%;OR:0.40;95%CI:0.11-1.44;P=0.16),亚组分析显示,当仅选择RCTs进行meta分析时,两组死亡率差异仍无统计学意义,经试验序贯分析(TSA)校正分析后证实为阴性结果(TSA校正后CI: 0.09-6.23)。两组大出血事件发生率差异也无统计学意义,通过TSA进行调整后得出同样结果(0.12% vs 0%;OR:2.73;95%CI:0.43-17.4;P=0.29;TSA校正后CI:0.08-114.92)。利伐沙班组血栓事件发生率低于对照组(0.42% vs 1.53%;OR:0.28;95%CI:0.11-0.74;P=0.01;TSA校正后CI:0.08-1.08),亚组分析显示,接受利伐沙班治疗的出院患者死亡率和血栓事件发生率降低。结论利伐沙班可以使院外新冠患者受益,特别是对于出院之后的新冠患者,能够在不增加大出血和死亡的情况下减少血栓事件的发生。

关键词: 新型冠状病毒感染, 抗凝治疗, 利伐沙班, 出血, 血栓事件

Abstract:

Objective To evaluate the safety and efficacy of anticoagulation with rivaroxaban in discharged COVID-19 patients. Methods We searched related literatures on Embase, PubMed, Scopus, Cochrane library, Web of Science, Med Rxiv and Clinical Trials. Two independent researchers conducted literature selection and data extraction according to pre-determined inclusion and exclusion criteria. Results We included 6 studies with a total of 4605 patients with COVID-19, including 4 randomized controlled trials (RCTs) and 2 cohort studies. The results showed that no significant difference in mortality between patients with rivaroxaban and those without rivaroxaban (0.50% vs 1.50%; OR: 0.40; 95%CI: 0.11-1.44; P=0.16). When only RCTs were selected for meta-analysis, there was still no significant difference in mortality between subgroups, which negative result was confirmed after being adjusted by trial sequential analysis (TSA-adjusted CI: 0.09-6.23). There was also no difference in the incidence of major bleeding events between two groups, even adjusted by TSA (0.12% vs 0%; OR: 2.73; 95%CI: 0.43-17.4; P=0.29; TSA-adjusted CI: 0.08-114.92). The incidence of thrombotic events in the rivaroxaban group was significantly lower than that in the control group (0.42% vs 1.53%; OR: 0.28; 95%CI: 0.11-0.74; P=0.01; TSA-adjusted CI: 0.08-1.08). In addition, subgroup analysis results showed that mortality and thrombotic events were reduced in discharged patients treated with rivaroxaban. Conclusion Rivaroxaban can benefit COVID-19 patients, and reduce the occurrence of thrombotic events without increasing major bleeding, especially in discharged COVID-19 patients.

Key words: COVID-19, anticoagulation, rivaroxaban, major bleeding, thrombosis

中图分类号:

R563.12

于菁怡, 司元国, 兰翠霞, 邢家璇. 新冠肺炎患者院外使用利伐沙班抗凝安全性和有效性的meta分析[J]. 临床荟萃, 2024, 39(6): 485-493.

Yu Jingyi, Si Yuanguo, Lan Cuixia, Xing Jiaxuan. Safety and efficacy of rivaroxaban in the treatment of discharged COVID-19 patients: A meta-analysis[J]. Clinical Focus, 2024, 39(6): 485-493.

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链接本文: https://huicui.hebmu.edu.cn/CN/10.3969/j.issn.1004-583X.2024.06.001

https://huicui.hebmu.edu.cn/CN/Y2024/V39/I6/485

图/表 13

表1 Embase数据库检索策略

Tab.1 Search strategies of Embase database

数据库	检索策略		结果
Embase	#1 ‘covid-19’	382, 015
	#2 ‘novel coronavirus’	14, 176
	#3 ‘sars-cov-2’	160, 591
	#4 ‘2019-ncov’	2, 897	1020
	#5 ‘coronavirus disease 2019’	359, 786
	#6 #1 OR #2 OR #3 OR #4 OR #5	452, 099
	#7 ‘rivaroxaban’	28, 586
	#8 #6 AND #7	1, 020

图1 文献筛选流程

Fig.1 Flowchart of literature selection process

表2 纳入文献的基本特征

Tab.2 Basic characteristics of the included studies

	作者	年限	研究类型	研究范围	患者类型	样本量		药物与剂量
	作者	年限	研究类型	研究范围	患者类型	干预组	对照组	干预组	对照组
1	Ananworanich et al^[17]	2022	RCT	多中心	Outpatients	222	222	Rivaroxaban 10 mg qd	Placebo multivitamin 1 tablet qd
2	Piazza et al^[18]	2023	RCT	多中心	Outpatients	641	643	Rivaroxaban 10 mg qd	Placebo 1 tablet qd
3	Avezum et al^[19]	2023	RCT	多中心	Outpatients	327	330	Rivaroxaban 10 mg qd	Routine care
4	Ramacciotti et al^[20]	2022	RCT	多中心	Discharged	159	159	Rivaroxaban 10 mg qd	No anticoagulation
5	Fiedler et al^[21]	2023	队列研究	单中心	Discharged	996	808	Rivaroxaban 10 mg qd	No anticoagulation
6	Szuman et al^[22]	2021	队列研究	单中心	Discharged	57	41	Rivaroxaban 10 mg qd	No anticoagulation

图2 纳入研究偏倚风险总体分布图

Fig.2 Overall distribution chart of risk of bias in included studies

图3 研究风险偏倚分布图

Fig.3 Distribution map of risk of bias for studies

图4 利伐沙班对新冠患者死亡风险的影响

Fig.4 Effect of Rivaroxaban on risk of mortality in patients with COVID-19

图5 随机对照试验或队列研究进行亚组分析

Fig.5 Subgroup analysis according to RCTs or cohort studies

图6 死亡和大出血结局的试验序贯分析

Fig.6 Trial sequential analysis of mortality and major bleeding outcomes

图7 门诊患者或出院后患者进行亚组分析

Fig.7 Subgroup analysis according to outpatients or discharged patients

图8 利伐沙班对新冠患者大出血风险的影响

Fig.8 Effect of Rivaroxaban on risk of major bleeding in patients with COVID-19

图9 利伐沙班对新冠患者发生血栓事件风险的影响

Fig.9 Effect of Rivaroxaban on risk of thrombotic event in patients with COVID-19

图10 发表偏倚的漏斗图分析

Fig.10 Funnel plot analysis of publication bias

表3 纳入队列研究质量评价

Tab.3 The quality assessment of included cohort studies

Study	Selection				Comparability ⑤	Outcome			Total
Study	①	②	③	④	Comparability ⑤	⑥	⑦	⑧	Total
Fiedler et al	★		★	★	★★	★	★	★	8
Szuman et al	★		★	★		★	★	★	6

参考文献 45

[1]	Majumder J, Minko T. Recent developments on therapeutic and diagnostic approaches for COVID-19[J]. Aaps J, 2021, 23(1): 14.
[2]	Milross L, Majo J, Cooper N, et al. Post-mortem lung tissue: The fossil record of the pathophysiology and immunopathology of severe COVID-19[J]. Lancet Respir Med, 2022, 10(1): 95-106.
[3]	Safiabadi Tali SH, Leblanc JJ, Sadiq Z, et al. Tools and techniques for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/COVID-19 detection[J]. Clin Microbiol Rev, 2021, 34(3).
[4]	Yuan Y, Jiao B, Qu L, et al. The development of COVID-19 treatment[J]. Front Immunol, 2023, 14: 1125246.
[5]	Loo J, Spittle DA, Newnham M. COVID-19, immunothrombosis and venous thromboembolism: Biological mechanisms[J]. Thorax, 2021, 76(4): 412-420. doi: 10.1136/thoraxjnl-2020-216243 pmid: 33408195
[6]	Chan N, Eikelboom J. Hypercoagulability and thrombosis in COVID-19: A modifiable cause for mortality?[J]. Eur Heart J, 2021, 42(33): 3143-3145.
[7]	Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19[J]. N Engl J Med, 2020, 383(2): 120-128.
[8]	Parra-Medina R, Herrera S, Mejia J. Systematic review of microthrombi in COVID-19 autopsies[J]. Acta Haematol, 2021, 144(5): 476-483.
[9]	Farge D, Frere C, Connors JM, et al. 2022 International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer, including patients with COVID-19[J]. Lancet Oncol, 2022, 23(7): E334-E347.
[10]	Barnes GD, Burnett A, Allen A, et al. Thromboembolic prevention and anticoagulant therapy during the COVID-19 pandemic: Updated clinical guidance from the anticoagulation forum[J]. J Thromb Thrombolysis, 2022, 54(2): 197-210.
[11]	Giossi R, Menichelli D, Pani A, et al. A systematic review and a meta-analysis comparing prophylactic and therapeutic low molecular weight heparins for mortality reduction in 32, 688 COVID-19 patients[J]. Front Pharmacol, 2021, 12: 698008.
[12]	Lawler PR, Goligher EC, Berger JS, et al. Therapeutic anticoagulation with heparin in noncritically ill patients with covid-19[J]. N Engl J Med, 2021, 385(9): 790-802.
[13]	Spyropoulos AC, Goldin M, Giannis D, et al. Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: The HEP-COVID randomized clinical trial[J]. JAMA Intern Med, 2021, 181(12): 1612-1620. doi: 10.1001/jamainternmed.2021.6203 pmid: 34617959
[14]	Dai MF, Xin WX, Kong S, et al. Effectiveness and safety of extended thromboprophylaxis in post-discharge patients with COVID-19: A systematic review and meta-analysis[J]. Thromb Res., 2023, 221: 105-112.
[15]	Verma AK, Brighton TA. The direct factor Xa inhibitor rivaroxaban[J]. Med J Aust, 2009, 190(7): 379-383. doi: 10.5694/j.1326-5377.2009.tb02453.x pmid: 19351313
[16]	Lopes RD, Furtado RHM, et al. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): An open-label, multicentre, randomised, controlled trial[J]. Lancet, 2021, 397(10291): 2253-2263. doi: 10.1016/S0140-6736(21)01203-4 pmid: 34097856
[17]	Meroni PL, Croci S, Lonati PA, et al. Complement activation predicts negative outcomes in COVID-19: The experience from Northen Italian patients[J]. Autoimmun Rev, 2023, 22(1): 103232.
[18]	Turner S, Khan MA, Putrino D, et al. Long COVID: Pathophysiological factors and abnormalities of coagulation[J]. Trends Endocrinol Metab, 2023, 34(6): 321-344.
[19]	Sciaudone A, Corkrey H, Humphries F, et al. Platelets and SARS-CoV-2 During COVID-19: Immunity, thrombosis, and beyond[J]. Circ Res, 2023, 132(10): 1272-1289. doi: 10.1161/CIRCRESAHA.122.321930 pmid: 37167360
[20]	Conway EM, Mackman N, Warren RQ, et al. Understanding COVID-19-associated coagulopathy[J]. Nat Rev Immunol, 2022, 22(10): 639-649. doi: 10.1038/s41577-022-00762-9 pmid: 35931818
[21]	Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease: Implications for prevention, antithrombotic therapy, and follow[J]. J Am Coll Cardiol, 2020, 75(23): 2950-2973.
[22]	Scavone C, Mascolo A, Rafaniello C, et al. Therapeutic strategies to fight COVID-19: Which is the status artis?[J]. Br J Pharmacol, 2022, 179(10): 2128-2148.
[23]	Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19[J]. J Thromb Haemost, 2020, 18(5): 1023-1026. doi: 10.1111/jth.14810 pmid: 32338827
[24]	Goligher EC, Bradbury CA, Mcverry BJ, et al. Therapeutic anticoagulation with heparin in critically Ill patients with covid-19[J]. N Engl J Med, 2021, 385(9): 777-789.
[25]	Chalmers JD, Crichton ML, Goeminne PC, et al. Management of hospitalised adults with coronavirus disease 2019 (COVID-19): A European Respiratory Society living guideline[J]. Eur Respir J, 2021, 57(4): 2100048.
[26]	Garcia D, Libby E, Crowther MA. The new oral anticoagulants[J]. Blood, 2010, 115(1): 15-20. doi: 10.1182/blood-2009-09-241851 pmid: 19880491
[27]	Carter NJ, Plosker GL. Rivaroxaban: A review of its use in the prevention of stroke and systemic embolism in patients with atrial fibrillation[J]. Drugs, 2013, 73(7): 715-739. doi: 10.1007/s40265-013-0056-9 pmid: 23677801
[28]	Burness CB, Perry CM. Rivaroxaban: A review of its use in the treatment of deep vein thrombosis or pulmonary embolism and the prevention of recurrent venous thromboembolism[J]. Drugs, 2014, 74(2): 243-262. doi: 10.1007/s40265-013-0174-4 pmid: 24430916
[29]	Hess CN, Debus ES, Nehler MR, et al. Reduction in acute limb ischemia with rivaroxaban versus placebo in peripheral artery disease after lower extremity revascularization: Insights from VOYAGER PAD[J]. Circulation, 2021, 144(23): 1831-1841. doi: 10.1161/CIRCULATIONAHA.121.055146 pmid: 34637332
[30]	Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome[J]. N Engl J Med, 2012, 366(1): 9-19.
[31]	Zannad F, Anker SD, Byra WM, et al. Rivaroxaban in patients with heart failure, sinus rhythm, and coronary disease[J]. N Engl J Med, 2018, 379(14): 1332-1342.
[32]	Zhou S, Xiao Y, Zhou C, et al. Effect of rivaroxaban vs enoxaparin on major cardiac adverse events and bleeding risk in the acute phase of acute coronary syndrome: The H-REPLACE randomized equivalence and noninferiority trial[J]. JAMA Netw Open, 2023, 6(2): e2255709.
[33]	Nopp S, Moik F, Jilma B, et al. Risk of venous thromboembolism in patients with COVID-19: A systematic review and meta-analysis[J]. Res Pract Thromb Haemost, 2020, 4(7): 1178-1191. doi: 10.1002/rth2.12439 pmid: 33043231
[34]	Lund LC, Hedberg P, Andreasen AH, et al. Prophylactic anticoagulation with low molecular weight heparin in COVID-19: Cohort studies in Denmark and Sweden[J]. PClin Microbiol Infect, 2022, 28(9):1291.e1-1291.e5.
[35]	Ramacciotti E, Agati LB, Calderaro D, et al. Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): An open-label, multicentre, randomised, controlled trial[J]. Lancet, 2022, 399(10319): 50-59. doi: 10.1016/S0140-6736(21)02392-8 pmid: 34921756
[36]	Piazza GC, Spyropoulos A, Hsia J, et al. Rivaroxaban for prevention of thrombotic events, hospitalization, and death in outpatients with COVID-19: A randomized clinical trial[J]. Circulation, 2023, 147(25): 1891-1901. doi: 10.1161/CIRCULATIONAHA.123.063901 pmid: 37154020
[37]	Avezum A, Oliveira Junior HA, Neves PDMM, et al. Rivaroxaban to prevent major clinical outcomes in non-hospitalised patients with COVID-19: The CARE-COALITION VIII randomised clinical trial[J]. EClinicalMedicine, 2023, 60: 102004.
[38]	Nemetski SM, Ip A, Josephs J, et al. Clotting events among hospitalized patients infected with COVID-19 in a large multisite cohort in the United States[J]. PLoS One, 2022, 17(1): e0262352.
[39]	Fan Y, Li X, Zhang L, et al. SARS-CoV-2 Omicron variant: Recent progress and future perspectives[J]. Signal Transduct Target Ther, 2022, 7(1): 141.
[40]	Chan N, Sobieraj-Teague M, Eikelboom JW. Direct oral anticoagulants: Evidence and unresolved issues[J]. Lancet, 2020, 396(10264): 1767-1776. doi: 10.1016/S0140-6736(20)32439-9 pmid: 33248499
[41]	Castellucci LA, Cameron C, Le Gal G, et al. Clinical and safety outcomes associated with treatment of acute venous thromboembolism a systematic review and meta-analysis[J]. JAMA, 2014, 312(11): 1122-1135. doi: 10.1001/jama.2014.10538 pmid: 25226478
[42]	Fredenburgh JC, Weitz JI. News at XI: Moving beyond factor Xa inhibitors[J]. J Thromb Haemost, 2023, 21(7): 1692-1702.
[43]	Ananworanich J, Mogg R, Dunne MW, et al. Randomized study of rivaroxaban vs placebo on disease progression and symptoms resolution in high-risk adults with mild coronavirus disease 2019[J]. Clin Infect Dis, 2022, 75(1): e473-e481.
[44]	Fiedler L, Motloch LJ, Dieplinger AM, et al. Prophylactic rivaroxaban in the early post-discharge period reduces the rates of hospitalization for atrial fibrillation and incidence of sudden cardiac death during long-term follow-up in hospitalized COVID-19 survivors[J]. Front Pharmacol, 2023, 14: 1093396.
[45]	Szuman A, Kirkham Z, Price R, et al. Extended outpatient thromboprophylaxis for individuals with COVID-19[J]. Res Pract Thromb Haemost, 2021, 5(SUPPL 2).