Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data

Abstract

Objective

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.

SciScore for 10.1101/2020.04.10.20060699: (What is this?)

Please note, not all rigor criteria are appropriate for all manuscripts.

Table 1: Rigor

Institutional Review Board Statement	not detected.
Randomization	Statistical analysis: An inverse probability of treatment weighting (IPTW) approach was used to “emulate” randomisation and balance the differences in baseline variables between treatment groups.
Blinding	not detected.
Power Analysis	not detected.
Sex as a biological variable	not detected.

Table 2: Resources

No key resources detected.

Results from OddPub: Thank you for sharing your data.

Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:

Although this may appear to be a limitation, we used robust clinical outcomes here, i.e., death and ICU admission, which are substantially more clinically relevant. COVID-19 pneumonia progression in the second week of illness is associated with a so-called “cytokine storm”,17,22 which is thought to be responsible for the clinical worsening of many patients. Most of the patients included in this study had an inflammatory syndrome defined by C-reactive-protein higher than 40 mg/l, which suggests that a cytokine storm syndrome had already begun.23 Drugs decreasing virus shedding may therefore be inadequate at this stage; this is why many anti-inflammatory drugs are currently being tested, such as tocilizumab, corticosteroids, and others. Despite the immunomodulatory properties of HCQ, which include regulation of the production of pro-inflammatory cytokines such as IL-2, IL-1, IL-6 and TNFα,24 and endosomal inhibition of toll-like receptors, which play a major role in innate immune response,25 this treatment showed no effectiveness in this specific population. Finally, HCQ blocks the KCNH2-encoded hERG/Kv11.1 potassium channel and can potentially prolong the QTc, with potential severe consequences such as sudden cardiac death and cardiac arrhythmia.26 Besides QTc prolongations, we observed 2 other significant cardiologic events in this study, and the French national drug agency has reported 3 deaths potentially related to HCQ since its promotion to the public as a potential treat...

Results from TrialIdentifier: No clinical trial numbers were referenced.

Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

Results from JetFighter: We did not find any issues relating to colormaps.

Results from rtransparent:

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No protocol registration statement was detected.

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