Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19

Original Article: Geleris J, Sun Y, Platt J, et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med. 2020;382(25):2411-2418.

Author of summary: Carlotta Olivero; Reviewer: Sonia Fanelli

Original Article Published on May 7th, 2020

The aminoquinolines chloroquine and hydroxychloroquine are used for treatment of malaria and rheumatic diseases and were recently suggested as effective therapy against coronavirus disease 2019 (COVID 19) due to their anti-inflammatory and antiviral effects. In the United States, the Food and Drug Administration issued an Emergency Use Authorization on March 30, 2020 allowing the use of these drugs in patients with COVID-19 who were not enrolled in clinical trials. However, to date, there have been no robust clinical trials proving efficacy of these agents in such a disease. Not only the available data comes from small studies which lack proper control but also are underpowered to detect meaningful clinical effects.

The aim of the study was to examine the association between hydroxychloroquine use and intubation or death (primary end point) in patients affected by COVID-19 who presented with moderate to severe respiratory disease. The latter was defined as a resting oxygen saturation under 94% while breathing ambient air.

Data was obtained regarding consecutive patients hospitalized with COVID -19 from March 7 to April 8, 2020 excluding those who were intubated, died, or discharged within 24 hours after presentation to the emergency department. Hydroxychloroquine-treated patients were more severely ill at baseline than those who did not receive hydroxychloroquine.

The authors hypothesized that hydroxychloroquine is associated with a lower risk of a composite end point of intubation or death in analysis that was adjusted for major predictors of respiratory failure and weighted according to propensity scores assessing the probability of hydroxychloroquine use. Follow-up continued until April 25, 2020.

The loading dose suggested for hydroxychloroquine regimen was as follows:

  • 600 mg twice on day 1, followed by 400 mg daily for 4 additional days.
  • additional suggested therapeutic option: Azithromycin at a dose of 500 mg on day 1 and then 250 mg daily for 4 more days in combination with hydroxychloroquine.

The azithromycin suggestion was removed on April 12, 2020 and the hydroxychloroquine suggestion was removed on April 29, 2020. The decision to prescribe either or both medications was left to the discretion of the treating team for each individual patient.

Patients receiving sarilumab were allowed to continue hydroxychloroquine. Patients receiving remdesivir as part of a randomized trial did not receive or completed a course of treatmentwith hydroxychloroquine.

They used the following preadmission variables for each patient: age; sex; patient-reported race and ethnic group; current insurance carrier; first recorded vital signs on presentation; ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (Pao2:Fio2) at admission, bodymass index, first recorded inpatient laboratory tests; past and current diagnoses; patient-reported smoking status; and medication administration at baseline.

Methods: they calculated bivariate frequencies to examine the associations among the preadmission variables described above.  Cox proportional-hazards regression models were used to estimate the association between hydroxychloroquine use and the composite end point of intubation or death with the use of three propensity-score methods: inverse probability weighiting, propensity score matching, propensity score as covariable.

Results: Among 1446 consecutive patients with COVID-19 who were admitted to the hospital, a total of 70 patients were excluded from the study because they underwent intubation, died or were discharged within 24 hours after presentation to the emergency department. Over a median follow-up of 22.5 days, 811 (58.9%) received hydroxychloroquine (median duration of treatment, 5 days). Among the patients who received hydroxychloroquine, 45.8% received it in the 24 hours between their presentation to the emergency department and the start of study follow-up, and 85.9% received it within 48 hours.

The distribution of the patients’ baseline characteristics according to hydroxychloroquine exposure in the unmatched sample, differed according to age group, sex, race and ethnic group, body-mass index, insurance, smoking status, and current use of other medications.

In the matched analytic sample, 811 patients were exposed to hydroxychloroquine and 274 were not exposed. The differences between hydroxychloroquine and pre-treatment variables were attenuated in the propensity score–matched samples as compared with the unmatched samples.

Among the 1376 patients included in the analysis, the primary end point of respiratory failure developed in 346 patients (25.1%); a total of 180 patients were intubated, and 166 died without intubation. At the time of data cutoff on April 25, a total of 232 patients died (66 after intubation), 1025 survived to hospital discharge, and 119 were still hospitalized (only 24 of whom were not intubated).

In the crude, unadjusted analysis, patients who received hydroxychloroquine were more likely to have a primary end-point event than were patients who did not.

In the primary multivariable analysis with inverse probability weighting according to the propensity score, there was no significant association between hydroxychloroquine use and the composite primary end point.

There was also no significant association between treatment with azithromycin and the composite end point.

In conclusion, hydroxychloroquine administration was not associated with either a greatly lowered or an increased risk of primary end point. Further studies included randomized, controlled trials of hydroxychloroquine in patients with COVID -19 are still needed.

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