摘要
背景
羟氯喹已被广泛应用于COVID-19患者,但尚无支持用药的可靠证据。
方法
我们在纽约市一家大型医疗中心研究了羟氯喹用药和插管或死亡之间的关联,获得了连续的COVID-19住院患者的数据,排除了在急诊就诊(研究基线)后24小时内插管、死亡或出院的患者。主要终点是在至事件发生的时间分析中,由插管或死亡构成的复合终点。我们根据倾向评分的逆概率加权多变量Cox模型,比较了接受羟氯喹治疗的患者和未接受羟氯喹治疗的患者。
结果
在1,446例连续患者中,70例患者在就诊后24小时内插管、死亡或出院,并被排除出分析。在其余1,376例患者中,在22.5日的中位随访期间,811例(58.9%)接受了羟氯喹治疗(第1日用药2次,每次600 mg,之后每日用药400 mg,中位用药持续时间5日);45.8%的患者在急诊就诊后24小时内接受了治疗,85.9%在48小时内接受了治疗。与未接受羟氯喹的患者相比,接受羟氯喹治疗的患者在基线时病情较重(动脉氧分压与吸入氧分数的中位比值,223 vs. 360)。总体上,346例患者(25.1%)发生了主要终点事件(180例患者插管,其中66例随后死亡,166例死亡但未插管)。在主要分析中,羟氯喹用药与插管或死亡之间无显著关联(风险比,1.04;95%置信区间[CI],0.82~1.32)。多项敏感性分析的结果相似。
结论
对COVID-19住院患者开展的这项观察性研究表明,羟氯喹用药与复合终点(由插管或死亡构成)风险大幅降低和大幅升高均不相关。我们仍需开展羟氯喹治疗COVID-19患者的随机对照试验(由美国国立卫生研究院资助)。
作者信息
Joshua Geleris, M.D., Yifei Sun, Ph.D., Jonathan Platt, Ph.D., Jason Zucker, M.D., Matthew Baldwin, M.D., George Hripcsak, M.D., Angelena Labella, M.D., Daniel K. Manson, M.D., Christine Kubin, Pharm.D., R. Graham Barr, M.D., Dr.P.H., Magdalena E. Sobieszczyk, M.D., M.P.H., and Neil W. Schluger, M.D.
From the Divisions of General Medicine, Infectious Diseases, and Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine (J.G., J.Z., M.B., A.L., D.K.M., C.K., R.G.B., M.E.S., N.W.S.), the Departments of Biostatistics (Y.S.) and Epidemiology (J.P., R.G.B., N.W.S.), Mailman School of Public Health, and the Department of Biomedical Informatics (G.H.), Vagelos College of Physicians and Surgeons, Columbia University, and New York–Presbyterian Hospital–Columbia University Irving Medical Center (J.G., J.Z., M.B., A.L., D.K.M., C.K.,R.G.B., M.E.S., N.W.S.) — all in New York. Address reprint requests to Dr. Schluger at the Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University Irving Medical Center, PH-8 E., Rm. 101, 622 W. 168th St., New York, NY 10032, or at ns311@cumc.columbia.edu.
参考文献
1. Biot C, Daher W, Chavain N, et al. Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities. J Med Chem 2006;49:2845-2849.
2. Fox RI. Mechanism of action of hydroxychloroquine as an antirheumatic drug. Semin Arthritis Rheum 1993;23:Suppl 1:82-91.
3. Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents 2020 March 12 (Epub ahead of print).
4. Fantini J, Di Scala C, Chahinian H, Yahi N. Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection. Int J Antimicrob Agents 2020 April 3 (Epub ahead of print).
5. Wilson KC, Chotirmall SH, Bai C, Rello J. COVID-19: interim guidance on management pending empirical evidence. April 3, 2020 (https://www.thoracic.org/covid/covid-19-guidance.pdf. opens in new tab).
6. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020 March 20 (Epub ahead of print).
7. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020 March 9 (Epub ahead of print).
8. Brown SM, Duggal A, Hou PC, et al. Nonlinear imputation of PaO2/FIO2 from SpO2/FIO2 among mechanically ventilated patients in the ICU: a prospective, observational study. Crit Care Med 2017;45:1317-1324.
9. Brown SM, Grissom CK, Moss M, et al. Nonlinear imputation of Pao2/Fio2 from Spo2/Fio2 among patients with acute respiratory distress syndrome. Chest 2016;150:307-313.
10. Robins JM. Marginal structural models. 1998 (https://cdn1.sph.harvard.edu/wp-content/uploads/sites/343/2013/03/msm-web.pdf. opens in new tab).
11. Rubin DB. Multiple imputation for nonresponse in surveys. New York: John Wiley, 1987.
12. Borba MGS, Val FFA, Sampaio VS, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Netw Open 2020;3(4):e208857-e208857.
13. Chen Z, Hu J, Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. MedRxiv. 2020 (https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v3. opens in new tab) (preprint).
14. Chen J, Liu D, Liu L, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Univ (Med Sci) 2020 (http://www.zjujournals.com/med/EN/10.3785/j.issn.1008-9292.2020.03.03. opens in new tab).