Intubation and death neither higher nor lower with the drug

An observational study of the use of hydroxychloroquine for the treatment of patients with Covid-19 reported inconclusive results in the New England Journal of Medicine.

“In 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, 0.82-1.32),” wrote Joshua Geleris, MD, from the Vagelos College of Physicians and Surgeons, Columbia University, and New York–Presbyterian Hospital — Columbia University Irving Medical Center, and colleagues. The study authors noted that, given the study’s observational design, its conclusions should not be used to rule out or in the use of hydroxychloroquine.

“However, our findings do not support the use of hydroxychloroquine at present, outside randomized clinical trials testing its efficacy,” they wrote. They noted that at New York-Presbyterian Hospital — Columbia University Irving Medical Center, the suggestion to use hydroxychloroquine in the treatment of Covid-19 patients has been removed.

In an editorial accompanying the study, Eric J. Rubin, MD from the Department of Biostatistics, Harvard T.H. Chan School of Public Health, and the Department of Data Sciences, Dana–Farber Cancer Institute, Boston, and colleagues, noted that during this pandemic, there are many treatment choices confronting physicians.

“Should they use widely available agents such as hydroxychloroquine or azithromycin?” the editorialists asked. “The choice to use these drugs has already been made, probably in hundreds of thousands of patients, but with scant evidence about the risks and benefits.”

Rubin and his colleagues who work for NEJM noted that the journal decided to publish Geleris and colleagues’ study “so that clinicians will have some information that is based on rigorous analysis of available observational data… The findings … set broad parameters around the potential good (or harm) that these drugs could do. The results leave open the possibility that these agents could have a modest benefit but do not rule out a detrimental effect…” They again underscored that these open questions can only be answered in a well-designed and conducted randomized, controlled trial.

The primary endpoint for Geleris and colleagues’ study was a composite 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,” they explained.

They looked at 1,446 consecutive patients, excluding 70 patients who had been intubated, died, or discharged within 24 hours of presentation.

“Of the remaining 1,376 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),” they wrote.

They noted that nearly half (45.8%) of the patients received hydroxychloroquine within 24 hours of coming to the emergency departments, and 85.9% received it within 48 hours.

Those who were treated with hydroxychloroquine were sicker at baseline than those who did not receive the drug (median ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen, 223 versus 360).

The study authors noted the following:

  • 346(25.1%) of the patients included in the analysis developed respiratory failure.
  • 180 patients were intubated of whom 66 later died.
  • 166 died without intubation.

“In the crude, unadjusted analysis, patients who had received hydroxychloroquine were more likely to have had a primary end-point event than were patients who did not (hazard ratio, 2.37; 95% CI, 1.84 to 3.02),” the study authors wrote — however, as noted by the editorialists, “the clinical characteristics of the hydroxychloroquine treated patients and of those who had not received hydroxychloroquine differed substantially. Indeed, 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 (hazard ratio, 1.04; 95% CI, 0.82-1.32),” the study authors found.

Geleris and colleagues noted that the consistency of the results 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.”

Other limitations of the study include potentially missing some data for variables and inaccuracies in the electronic health records, e.g. not documenting smoking status.

Most of the patients in the study were Hispanic, less than half were age 60-79, about a quarter were 40-59, about 10% were age 40 or less, and just over 18% were 80 or older. Less than half were women.

  1. The risk of intubation or death was not significantly higher or lower among patients who received hydroxychloroquine in the treatment of Covid-19 than among those who did not (hazard ratio, 1.04; 95% CI, 0.82-1.32).

  2. Be aware that there is not yet a robust randomized, clinical controlled trial to show benefit or detriment in the use of hydroxychloroquine, however the study authors noted that at their facility, they have removed the recommendation for its use.

Candace Hoffmann, Managing Editor, BreakingMED

The study was funded by the National Institutes of Health

Geleris reported non-financial support from Allergan, Inc, non-financial support from Alexion Pharmaceuticals, Inc, non-financial support from Boehringer Ingelheim Pharmaceuticals, Inc., non-financial support from Janssen Pharmaceuticals, Inc., non-financial support from Pfizer, Inc., outside the submitted work.

Rubin, Hamel, Harrington, Hogan, Gatsonis, and Baden are all employed by The New England Journal of Medicine.

Baden also reported grants from Ragon Institute, grants from NIH/NIAID, grants from Gates Foundation, outside the submitted work; and he is involved in HIV vaccine clinical trials conducted in collaboration with the NIH, HIV Vaccine Trials Network (HVTN), International AIDS Vaccine Initiative (IAVI), Crucell/Janssen, Military HIV Research Program (MHRP), Gates Foundation, and the Ragon Institute. Baden is Chair of the AntiMicrobial Drug Advisory Committee (AMDAC), FDA.

Cat ID: 125

Topic ID: 79,125,254,930,501,728,791,932,125,190,926,192,927,151,725,928,925,934