Early hydroxychloroquine but not chloroquine use reduces ICU admission in COVID-19 patients
A J J Lammers, R M Brohet, R E P Theunissen, C Koster, R Rood, D W M Verhagen, K Brinkman, R J Hassing, A Dofferhoff, R El Moussaoui, G Hermanides, J Ellerbroek, N Bokhizzou, H Visser, M Van Den Berge, H Bax, D F Postma, P H P Groeneveld
International Journal of Infectious Diseases, doi:10.1016/j.ijid.2020.09.1460
Background: The global push for the use of hydroxychloroquine (HCQ) and chloroquine (CQ) against COVID-19 has resulted in an ongoing discussion about the effectivity and toxicity of these drugs. Recent studies report no effect of (H)CQ on 28-day mortality. We investigated the effect of HCQ and CQ in hospitalized patients on the non-ICU COVID-ward. Methods: A nationwide, observational cohort study was performed in The Netherlands. Hospitals were given the opportunity to decide independently on the use of three different COVID-19 treatment strategies: HCQ, CQ, or no treatment. We compared the outcomes between these groups. The primary outcomes were 1) death on the COVID-19 ward, and 2) transfer to the intensive care unit (ICU). Results: The analysis included 1064 patients from 14 hospitals: 566 patients received treatment with either HCQ (n = 189) or CQ (n = 377), and 498 patients received no treatment. In a multivariate propensitymatched weighted competing regression analysis, there was no significant effect of (H)CQ on mortality on the COVID ward. However, HCQ was associated with a significantly decreased risk of transfer to the ICU (hazard ratio (HR) = 0.47, 95% CI = 0.27-0.82, p = 0.008) when compared with controls. This effect was not found in the CQ group (HR = 0.80, 95% CI = 0.55-1.15, p = 0.207).
Conclusion: The results of this observational study demonstrate a lack of effect of (H)CQ on non-ICU mortality. However, we show that the use of HCQbut not CQis associated with a 53% reduction in risk of transfer of COVID-19 patients from the regular ward to the ICU. Recent prospective studies have reported on 28-day, all-cause mortality only; therefore, additional prospective data on the early effects of HCQ in preventing transfer to the ICU are still needed.
Conflict of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Ethical approval The Medical Ethics Review Committee waived ethical approval for this study.
References
Arayssi, Harfouche, Darzi, Emadi, Alnaqbi et al., Recommendations for the management of rheumatoid arthritis in the Eastern Mediterranean region: an adolopment of the 2015 American College of Rheumatology guidelines, Clin Rheumatol
Arshad, Kilgore, Chaudhry, Jacobsen, Wang et al., Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19, Int J Infect Dis
Austin, The performance of different propensity score methods for estimating marginal hazard ratios, Stat Med
Borba, Val, Sampaio, Alexandre, Melo 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
Boulware, Pullen, Bangdiwala, Pastick, Lofgren et al., A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19, N Engl J Med
Chen, Hu, Zhang, Jiang, Han et al., Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial, medRxiv
Corman, Landt, Kaiser, Molenkamp, Meijer et al., Detection of 2019 -nCoV by RT-PCR, Euro Surveill
Cortegiani, Ippolito, Ingoglia, Iozzo, Giarratano et al., Update I. A systematic review on the efficacy and safety of chloroquine/hydroxychloroquine for COVID-19, J Crit Care,
doi:10.1016/j.jcrc.2020.06.019Drugbank, Chloroquine, None
Drugbank, Hydroxychloroquine
Fine, Gray, A proportional hazards model for the subdistribution of a competing risk, J Am Stat Assoc
Fiolet, Guihur, Rebeaud, Mulot, Peiffer-Smadja et al., Effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients: a systematic review and meta-analysis, Clin Microbiol Infect
Fosbøl, Butt, Østergaard, Andersson, Selmer et al., Association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with COVID-19 diagnosis and mortality, JAMA
Furst, Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases, Lupus
Gao, Tian, Yang, Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies, Bioscience Trends
Gautret, Lagier, Parola, Hoang, Meddeb et al., Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an openlabel non-randomized clinical trial, Int J Antimicrob Agents,
doi:10.1016/j.ijantimicag.2020.105949Geleris, Sun, Platt, Zucker, Baldwin et al., Observational study of hydroxychloroquine in hospitalized patients with Covid-19, N Engl J Med
Godaert, Emeline, Demoustier-Tampere, Coulibaly, Hequet et al., Letters to editors: clinical characteristics of older patients: the experience of a geriatric short-stay unit dedicated to patients with COVID-19 in France
Guan, Ni, Hu, Liang, Ou et al., Clinical characteristics of coronavirus disease 2019 in China, N Engl J Med
Horby, No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19 5 June
Kim, Mccarten, Hydroxychloroquine and chloroquine: all adverse events in the setting of COVID-19 Available from
Lammers, Brohet, Theunissen, None, International Journal of Infectious Diseases
Magagnoli, Narendran, Pereira, Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19, Med
Mahevas, Tran, Roumier, No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial, medRxiv
Maisonnasse, Guedj, Contreras, Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates, Nature
Majmundar, Kansara, Lenik, Efficacy of corticosteroids in non-intensive care unit patients with COVID-19 pneumonia from the New York Metropolitan region, PLoS One,
doi:10.1371/journal.pone.0238827Perinel, Launay, Élisabeth, Diconne, Louf-Durier et al., Towards optimization of hydroxychloroquine dosing In Intensive Care Unit COVID-19 patients, Clinical Infectious Diseases
Prokop, Van Everdingen, Van, Vellinga, Quarles Van Ufford et al., CO-RADS -A categorical CT assessment scheme for patients with suspected COVID-19: definition and evaluation, Radiology
Rivm, Coronavirus disease (COVID-19) 3
Sanders, Monogue, Jodlowski, Cutrell, Pharmacologic treatments for coronavirus disease 2019 (COVID-19). A review, JAMA
Schrezenmeier, Dörner, Siddiqi, Hk, Mehra, COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal, J Hear Lung Transplant,
doi:10.1038/s41584-020-0372Tang, Cao, Han, Wang, Chen et al., Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: Open label, randomised controlled trial, BMJ
Van De Veerdonk, Netea, Van Deuren, Van Der Meer, De Mast et al., Kinins and cytokines in COVID-19: a comprehensive pathophysiological approach, Preprints
Wang, Cao, Zhang, Yang, Liu et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res 2020b
Wang, Hu, Hu, Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China, JAMA 2020a
Zhang, Zhu, Cai, Lei, Qin et al., Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19, Circ Res
Zhou, Dai, Tong, COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression, J Antimicrob Chemother
