Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19

Abstract

Background: Hydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (Covid-19) on the basis of in vitro activity and data from uncontrolled studies and small, randomized trials.

Methods: In this randomized, controlled, open-label platform trial comparing a range of possible treatments with usual care in patients hospitalized with Covid-19, we randomly assigned 1561 patients to receive hydroxychloroquine and 3155 to receive usual care. The primary outcome was 28-day mortality.

Results: The enrollment of patients in the hydroxychloroquine group was closed on June 5, 2020, after an interim analysis determined that there was a lack of efficacy. Death within 28 days occurred in 421 patients (27.0%) in the hydroxychloroquine group and in 790 (25.0%) in the usual-care group (rate ratio, 1.09; 95% confidence interval [CI], 0.97 to 1.23; P = 0.15). Consistent results were seen in all prespecified subgroups of patients. The results suggest that patients in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98). Among the patients who were not undergoing mechanical ventilation at baseline, those in the hydroxychloroquine group had a higher frequency of invasive mechanical ventilation or death (30.7% vs. 26.9%; risk ratio, 1.14; 95% CI, 1.03 to 1.27). There was a small numerical excess of cardiac deaths (0.4 percentage points) but no difference in the incidence of new major cardiac arrhythmia among the patients who received hydroxychloroquine.

Conclusions: Among patients hospitalized with Covid-19, those who received hydroxychloroquine did not have a lower incidence of death at 28 days than those who received usual care. (Funded by UK Research and Innovation and National Institute for Health Research and others; RECOVERY ISRCTN number, ISRCTN50189673; ClinicalTrials.gov number, NCT04381936.).

Figure 1. Enrollment and Outcomes in the RECOVERY Trial.

The enrollment number that is shown is the total number of patients in the RECOVERY platform trial during the period in which adult patients could be recruited for the comparison between hydroxychloroquine and usual care. Patients could have more than one reason for not participating in the hydroxychloroquine trial. At the time of this analysis, data from the trial follow-up form were available for 1553 of 1561 patients (99.5%) in the hydroxychloroquine group and for 3140 of 3155 patients (99.5%) in the usual-care group. The subgroup of patients who later underwent a second randomization to tocilizumab versus usual care in the RECOVERY trial included 37 of 1561 patients (2.4%) in the hydroxychloroquine group and 89 of 3155 patients (2.8%) in the usual care group. In addition, 6 patients were randomly assigned to receive either convalescent plasma or usual care alone (1 patient [0.1%] in the hydroxychloroquine group and 5 patients [0.2%] in the usual-care group) in accordance with protocol version 6.0. Among the 167 sites at which at least 1 patient was assigned to receive hydroxychloroquine, the median number of patients who underwent randomization was 20 (interquartile range, 11 to 41).

Figure 2. Mortality at 28 Days.

Death at 28 days (the primary outcome) occurred in 421 patients (27.0%) in the hydroxychloroquine group and in 790 (25.0%) in the usual-care group. The inset shows the same data on an expanded y axis.

Figure 3. Mortality at 28 Days, According to Subgroup.

The size of the squares representing rate ratios is proportional to the amount of statistical information that was available for each comparison. The method that was used for calculating the baseline-predicted risk in each subgroup is described in the Supplementary Appendix. Race or ethnic group was recorded in the patient’s electronic health record.