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.
We report a comparative study that uses real world data collected from routine care to assess the efficacy and safety of hydroxychloroquine in a population of 181 patients admitted to hospital with covid-19 hypoxaemic pneumonia. We found that hydroxychloroquine treatment at 600 mg/day added to standard care was not associated with a reduction of admissions to the intensive care unit or death 21 days after hospital admission compared with standard care alone. Additionally the rate of survival without acute respiratory distress syndrome did not increase. These results were unchanged when the eight patients who received hydroxychloroquine after 48 hours were included in the analysis, regardless of whether they were analysed in the treatment group (mimicking an as-treated analysis) or in the standard of care (control) group (mimicking an intention-to-treat analysis).
Our population of patients admitted to hospital because they required oxygen is similar to that reported by other studies, and the proportion of patients transferred to the intensive care unit was similar to that reported in a Chinese cohort of 138 patients admitted to hospital with covid-19 pneumonia.The clinical features of included patients were also consistent with other reports, with a predominance of men and patients with cardiovascular comorbidities or obesity.Apart from azithromycin, the patients in this study did not receive any other drugs; in particular, potential confounders such as antiviral and anti-inflammatory treatments, including steroids, before admission to intensive care.
It could be argued that the timing of antiviral treatment initiation might be critical in reducing SARS-Cov-2 viral load.In the recent lopinavir-ritonavir trial, a post hoc subgroup analysis suggested that lopinavir-ritonavir might have a clinical benefit when started earlier than 12 days after symptom onset. In our study, however, patients had a short median time from symptom onset to inclusion (seven days) and were treated with hydroxychloroquine within 48 hours of admission. We also found that viral ribonucleic acid for SARS-CoV-2 was detectable among all patients at inclusion, showing active viral shedding. Nevertheless, we cannot rule out the possibility that hydroxychloroquine could be beneficial at symptom onset; this question must be assessed in future trials.
A previous report indicates that hydroxychloroquine should have been expected to show some antiviral efficacy. We did not check the results of subsequent SARS-Cov-2 PCR in this study and therefore cannot reach a conclusion about its potential efficacy for decreasing viral shedding. Although this might seem to be a limitation, we used robust clinical outcomes; that is, death, admission to the intensive care unit, acute respiratory distress syndrome, and oxygen requirement, which are substantially more clinically relevant.
Progression of covid-19 pneumonia in the second week of illness is associated with a so called cytokine storm,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 a C reactive protein level higher than 40 mg/L, which suggests that a cytokine storm syndrome had already begun.Therefore, drugs that decrease virus shedding could be inadequate at this stage, which is why many anti-inflammatory drugs are currently being tested, such as tocilizumab and corticosteroids. However, hydroxychloroquine could still be effective in this setting because of its immunomodulatory properties, which include regulation of the production of proinflammatory cytokines such as interleukin 2, interleukin 1, interleukin 6, and tumour necrosis factor α,and endosomal inhibition of toll-like receptors, which have a major role in innate immune response. Nonetheless, hydroxychloroquine treatment showed no effectiveness in this specific population.
Finally, hydroxychloroquine blocks the KCNH2 encoded hERG/Kv11.1 potassium channel and can potentially prolong the corrected QT interval, with potentially severe consequences, such as sudden cardiac death and cardiac arrhythmia in patients with covid-19.26 In addition to prolongations of corrected QT intervals, we observed two other major cardiac events in this study, and the French national drug agency has reported three deaths potentially related to hydroxychloroquine since its promotion as a potential treatment for covid-19. Although hydroxychloroquine is considered safe in the context of systemic lupus erythematosus, these adverse events might be explained by the use of high dose hydroxychloroquine in patients older than 75 years with renal impairment and frequent drug interactions. We cannot rule out the possibility that these cardiac effects attributed to hydroxychloroquine were caused by covid-19, especially given electrocardiograms were unavailable during follow-up in the control group. However, these possible side effects of hydroxychloroquine plus the negative clinical results of this study argue against the widespread use of hydroxychloroquine in patients with covid-19 pneumonia.
Limitations of this study Our study has several limitations. Firstly, although we used robust methods and statistical techniques to draw causal inferences from observational data, treatment was not randomly assigned and potential unmeasured confounders could bias our results. Secondly, four potentially important prognostic variables could not be balanced in the propensity score model because none or only one patient in the treatment group presented with these variables. Accordingly, caution is required in interpreting these results, especially for overall mortality for which only a few events were observed. Nevertheless, this limitation did favour the hydroxychloroquine group and the absence of any difference between treated and untreated patients further strengthens our conclusions. Thirdly, we did not take a centre effect into account in the propensity score model because the number of patients treated with hydroxychloroquine in centres was unbalanced (some centres treated all their patients, whereas others did not). Nevertheless, that the decision to treat or not treat patients with hydroxychloroquine was based on local medical consensus rather than on their characteristics should reduce this bias. Fourthly, our sample was limited to the number of eligible patients available at the time of analysis; we cannot rule out the possibility that our findings are owing to a lack of power. Fifthly, because we included only patients admitted to hospital, we cannot reach a conclusion about the possible efficacy of hydroxychloroquine in preventing covid-19 or in preventing severe forms of the disease. Finally, our study was not designed to assess the efficacy of the association of hydroxychloroquine and azithromycin, and no conclusion about its efficacy can be reached. Further research is ongoing.
Conclusions In patients admitted to hospital with covid-19 pneumonia who require oxygen, hydroxychloroquine treatment seemed to have no effect on reducing admissions to intensive care or deaths at day 21 after hospital admission. Additionally, hydroxychloroquine treatment did not have any effect on survival without acute respiratory distress syndrome at day 21 after hospital admission. These results do not support the use of hydroxychloroquine in these patients.
Reference & Source information: https://www.bmj.com/
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