BACKGROUND
Hydroxychloroquine has been widely administered to patients with Covid-19 without robust evidence supporting its use.
METHODS
We examined the association between hydroxychloroquine use and intubation or death at a large medical center in New York City. Data were obtained regarding consecutive patients hospitalized with Covid-19, excluding those who were intubated, died, or discharged within 24 hours after presentation to the emergency department (study baseline). The primary end point was a composite of intubation or death in a time-to-event analysis. We compared outcomes in patients who received hydroxychloroquine with those in patients who did not, using a multivariable Cox model with inverse probability weighting according to the propensity score.
RESULTS
Of 1446 consecutive patients, 70 patients were intubated, died, or discharged within 24 hours after presentation and were excluded from the analysis. Of the remaining 1376 patients, during a median follow-up of 22.5 days, 811 (58.9%) received hydroxychloroquine (600 mg twice on day 1, then 400 mg daily for a median of 5 days); 45.8% of the patients were treated within 24 hours after presentation to the emergency department, and 85.9% within 48 hours. Hydroxychloroquine-treated patients were more severely ill at baseline than those who did not receive hydroxychloroquine (median ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen, 223 vs. 360). Overall, 346 patients (25.1%) had a primary end-point event (180 patients were intubated, of whom 66 subsequently died, and 166 died without intubation). In the main analysis, there was no significant association between hydroxychloroquine use and intubation or death (hazard ratio, 1.04, 95% confidence interval, 0.82 to 1.32). Results were similar in multiple sensitivity analyses.
CONCLUSIONS
In this observational study involving patients with Covid-19 who had been admitted to the hospital, hydroxychloroquine administration was not associated with either a greatly lowered or an increased risk of the composite end point of intubation or death. Randomized, controlled trials of hydroxychloroquine in patients with Covid-19 are needed.
n this analysis involving a large sample of consecutive patients who had been hospitalized with Covid-19, the risk of intubation or death was not significantly higher or lower among patients who received hydroxychloroquine than among those who did not (hazard ratio, 1.04; 95% CI, 0.82 to 1.32). Given the observational design and the relatively wide confidence interval, the study should not be taken to rule out either benefit or harm of hydroxychloroquine treatment. However, our findings do not support the use of hydroxychloroquine at present, outside randomized clinical trials testing its efficacy.
As we noted in the introduction, the findings from an early study showing a benefit of hydroxychloroquine in 26 patients who had been treated in French hospitals are difficult to interpret, given the small size of that study, the lack of a randomized control group, and the omission of 6 patients from the analysis.6 A clinical trial testing two doses of chloroquine in patients with Covid-19 planned to include 440 patients but was halted after 81 patients had been enrolled because of excessive QTc prolongation and an indication of higher mortality in the high-dose group (in which patients received 600 mg twice daily for 10 days) than in the low-dose group (in which patients received 450 mg daily for 4 days after an initial dose of 450 mg administered twice on the first day).Two small, randomized trials from China have been reported. Physicians in Wuhan randomly assigned 62 patients with mild illness to either the control group (in which patients could receive supplemental oxygen, unspecified antiviral agents, antibiotic agents, and immune globulin, with or without glucocorticoids) or the experimental group (in which patients also received 400 mg of hydroxychloroquine daily). This report has not yet been fully peer-reviewed, but results were posted to the MedRxiv website for public comment.Investigators reported a faster mean time to clinical recovery (resolution of fever and cough and improvement on chest radiography) in the experimental group than in the control group. Four patients (all in the control group) had progression to severe infection. A small, randomized trial involving 30 patients in Shanghai reported on outcomes in patients treated with 400 mg of hydroxychloroquine daily for 5 days, as compared with a control group in which patients received “conventional treatment only.”This trial showed that by day 7, a total of 86% of the patients in the hydroxychloroquine-treated group and 93% of those in the control group had negative results on viral throat swabs. All the patients in this trial also received aerosolized interferon alfa by nebulizer.
A randomized clinical trial is the best approach to determine whether benefit can be ascribed to any given therapeutic intervention because this trial design minimizes the two major problems inherent in observational studies: unmeasured confounding and bias. With the analytic approaches we used in this examination of our observational cohort, we have tried to minimize possible confounding in a variety of ways.
In the main analysis, a multivariable regression model with inverse probability weighting according to the propensity score, there was no significant association between hydroxychloroquine use and the risk of intubation or death. We also performed a series of analyses using several propensity-score approaches. Findings were similar in multiple sensitivity analyses. The consistency of the results across these analyses is reassuring. In our analysis, we adjusted for likely confounders, including age, race and ethnic group, body-mass index, diabetes, underlying kidney disease, chronic lung disease, hypertension, baseline vital signs, Pao2:Fio2, and inflammatory markers of the severity of illness. Despite this extensive adjustment, it is still possible that some amount of unmeasured confounding remains. Additional limitations of our study include missing data for some variables and potential for inaccuracies in the electronic health records, such as lack of documentation of smoking and coexisting illness for some patients. Nonetheless, we used contemporary methods to deal with missing data to minimize bias. Finally, the single-center design may limit the generalizability of these results.
Clinical guidance at our medical center has been updated to remove the suggestion that patients with Covid-19 be treated with hydroxychloroquine. In our analysis involving a large sample of consecutive patients who had been hospitalized with Covid-19, hydroxychloroquine use was not associated with a significantly higher or lower risk of intubation or death (hazard ratio, 1.04; 95% CI, 0.82 to 1.32). The study results should not be taken to rule out either benefit or harm of hydroxychloroquine treatment, given the observational design and the 95% confidence interval, but the results do not support the use of hydroxychloroquine at present, outside randomized clinical trials testing its efficacy.
Reference & Source information: https://www.nejm.org/
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