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Clinical Efficacy of Hydroxychloroquine in Patients With COVID-19 Pneumonia Who Require Oxygen
abstract
This abstract is available on the publisher's site.
Access this abstract nowOBJECTIVE
To assess the effectiveness of hydroxychloroquine in patients admitted to hospital with coronavirus disease 2019 (covid-19) pneumonia who require oxygen.
DESIGN
Comparative observational study using data collected from routine care.
SETTING
Four French tertiary care centres providing care to patients with covid-19 pneumonia between 12 March and 31 March 2020.
PARTICIPANTS
181 patients aged 18-80 years with documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia who required oxygen but not intensive care.
INTERVENTIONS
Hydroxychloroquine at a dose of 600 mg/day within 48 hours of admission to hospital (treatment group) versus standard care without hydroxychloroquine (control group).
MAIN OUTCOME MEASURES
The primary outcome was survival without transfer to the intensive care unit at day 21. Secondary outcomes were overall survival, survival without acute respiratory distress syndrome, weaning from oxygen, and discharge from hospital to home or rehabilitation (all at day 21). Analyses were adjusted for confounding factors by inverse probability of treatment weighting.
RESULTS
In the main analysis, 84 patients who received hydroxychloroquine within 48 hours of admission to hospital (treatment group) were compared with 89 patients who did not receive hydroxychloroquine (control group). Eight additional patients received hydroxychloroquine more than 48 hours after admission. In the weighted analyses, the survival rate without transfer to the intensive care unit at day 21 was 76% in the treatment group and 75% in the control group (weighted hazard ratio 0.9, 95% confidence interval 0.4 to 2.1). Overall survival at day 21 was 89% in the treatment group and 91% in the control group (1.2, 0.4 to 3.3). Survival without acute respiratory distress syndrome at day 21 was 69% in the treatment group compared with 74% in the control group (1.3, 0.7 to 2.6). At day 21, 82% of patients in the treatment group had been weaned from oxygen compared with 76% in the control group (weighted risk ratio 1.1, 95% confidence interval 0.9 to 1.3). Eight patients in the treatment group (10%) experienced electrocardiographic modifications that required discontinuation of treatment.
CONCLUSIONS
Hydroxychloroquine has received worldwide attention as a potential treatment for covid-19 because of positive results from small studies. However, the results of this study do not support its use in patients admitted to hospital with covid-19 who require oxygen.
Additional Info
Clinical Efficacy of Hydroxychloroquine in Patients With Covid-19 Pneumonia Who Require Oxygen: Observational Comparative Study Using Routine Care Data
BMJ 2020 May 14;369(xx)m1844, M Mahévas, VT Tran, M Roumier, A Chabrol, R Paule, C Guillaud, E Fois, R Lepeule, TA Szwebel, FX Lescure, F Schlemmer, M Matignon, M Khellaf, E Crickx, B Terrier, C Morbieu, P Legendre, J Dang, Y Schoindre, JM Pawlotsky, M Michel, E Perrodeau, N Carlier, N Roche, V de Lastours, C Ourghanlian, S Kerneis, P Ménager, L Mouthon, E Audureau, P Ravaud, B Godeau, S Gallien, N Costedoat-ChalumeauFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
We are learning that pandemics can alter not only our lives but also our scientific approach to clinical research. In our pre-COVID world, the standards for scientific publications included controlled comparisons, randomization, risk control, and rigorous statistical analysis of relevant outcomes, to name but a few. The article by Mahévas et al applies rigorous statistical analysis to real-world data, but it lacks many of the traditional design standards. Their data are gathered from the new pandemic reality where clinical decisions and research designs are often based on fear and hope, rather than evidence and rigorous methodology. In this analysis of observational data, two groups of patients were chosen for comparison: a group of 84 patients treated with hydroxychloroquine (HCQ) because of “local medical consensus” and 89 who, for unknown reasons, were not chosen to receive HCQ. To counter the lack of randomization, robust and impressive statistical analyses were applied to examine for any potential imbalances of baseline variables and propensity scores were used to estimate each patient’s probability of receiving HCQ.
Despite the extensive statistical analyses that suggested the two groups might be balanced, the control group of 89 patients had numerically more patients with COPD (16 vs 6), CHF (6 vs 1), diabetes (12 vs 5), chronic renal failure (9 vs 1), cardiovascular disease (57 vs 45), and immunosuppression (14 vs 10). Much of the available data for COVID-19 suggests that comorbidities are major factors contributing to poor outcomes. It is also worth noting the potential impact on outcomes caused by differences in clinical management for the two groups. For example, azithromycin was given to 15 patients in the HCQ group versus 26 in the untreated group, which was associated with 5 deaths (no mention of their QTc). Furthermore, withdrawal of HCQ therapy in 8 patients (10%) due to excessive QTc prolongation could have influenced outcomes. Despite the greater number of comorbidities in the control group and differences in their clinical management that could bias outcomes in favor of HCQ, at day 21 there were 9 deaths (11%) in the treated group and only 8 in the control group (9%).
In the “Limitations” section, the authors acknowledge their use of observational data, lack of randomization, imbalanced comparison groups and unmeasured confounders. These weaknesses tempered the authors’ conclusions that “hydroxychloroquine seemed (emphasis added) to have no effect.” I would suggest adding, “when given by local medical consensus.”
The lack of observable efficacy for HCQ against COVID-19 in this study is consistent with many other reports now reaching the literature. However, there remains the real possibility that HCQ is not just ineffective but instead could lead to worsened outcomes, such as was found when randomization was used to compare high- and low-dose chloroquine.1 Uncontrolled studies of this type, perhaps understandable in the tumult of the times, can lead to erroneous conclusions, and results must be carefully weighed in the context of the limitations.
Reference