Importance Hydroxychloroquine, with or without azithromycin, has been considered as a possible therapeutic agent for patients with coronavirus disease 2019 (COVID-19). However, there are limited data on efficacy and associated adverse events.
Objective To describe the association between use of hydroxychloroquine, with or without azithromycin, and clinical outcomes among hospital inpatients diagnosed with COVID-19.
Design, Setting, and Participants Retrospective multicenter cohort study of patients from a random sample of all admitted patients with laboratory-confirmed COVID-19 in 25 hospitals, representing 88.2% of patients with COVID-19 in the New York metropolitan region. Eligible patients were admitted for at least 24 hours between March 15 and 28, 2020. Medications, preexisting conditions, clinical measures on admission, outcomes, and adverse events were abstracted from medical records. The date of final follow-up was April 24, 2020.
Exposures Receipt of both hydroxychloroquine and azithromycin, hydroxychloroquine alone, azithromycin alone, or neither.
Main Outcomes and Measures Primary outcome was in-hospital mortality. Secondary outcomes were cardiac arrest and abnormal electrocardiogram findings (arrhythmia or QT prolongation).
Results Among 1438 hospitalized patients with a diagnosis of COVID-19 (858 [59.7%] male, median age, 63 years), those receiving hydroxychloroquine, azithromycin, or both were more likely than those not receiving either drug to have diabetes, respiratory rate >22/min, abnormal chest imaging findings, O2 saturation lower than 90%, and aspartate aminotransferase greater than 40 U/L. Overall in-hospital mortality was 20.3% (95% CI, 18.2%-22.4%). The probability of death for patients receiving hydroxychloroquine + azithromycin was 189/735 (25.7% [95% CI, 22.3%-28.9%]), hydroxychloroquine alone, 54/271 (19.9% [95% CI, 15.2%-24.7%]), azithromycin alone, 21/211 (10.0% [95% CI, 5.9%-14.0%]), and neither drug, 28/221 (12.7% [95% CI, 8.3%-17.1%]). In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in mortality for patients receiving hydroxychloroquine + azithromycin (HR, 1.35 [95% CI, 0.76-2.40]), hydroxychloroquine alone (HR, 1.08 [95% CI, 0.63-1.85]), or azithromycin alone (HR, 0.56 [95% CI, 0.26-1.21]). In logistic models, compared with patients receiving neither drug cardiac arrest was significantly more likely in patients receiving hydroxychloroquine + azithromycin (adjusted OR, 2.13 [95% CI, 1.12-4.05]), but not hydroxychloroquine alone (adjusted OR, 1.91 [95% CI, 0.96-3.81]) or azithromycin alone (adjusted OR, 0.64 [95% CI, 0.27-1.56]), . In adjusted logistic regression models, there were no significant differences in the relative likelihood of abnormal electrocardiogram findings.
Conclusions and Relevance Among patients hospitalized in metropolitan New York with COVID-19, treatment with hydroxychloroquine, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. However, the interpretation of these findings may be limited by the observational design.
In this study, during rapidly expanding hospitalization for COVID-19, 70% of patients received hydroxychloroquine alone or with azithromycin. Patients who received hydroxychloroquine with or without azithromycin were more likely (relative to patients receiving neither drug) to be male, have preexisting medical conditions, and have impaired respiratory or liver function at presentation. There were no significant differences in in-hospital mortality between patients who received hydroxychloroquine with or without azithromycin and patients who received neither drug.
The lack of observed benefit of hydroxychloroquine associated with in-hospital mortality, following adjustment for preexisting disease and severity of illness on admission, is consistent with recently reported data from other observational studies.To our knowledge, this study is the largest report of adverse effects of hydroxychloroquine among patients with COVID-19. Cardiac arrest was more frequent in patients who received hydroxychloroquine with azithromycin, compared with patients who received neither drug, even after adjustment. This is in the context of similar levels of preexisting coronary artery disease and hypertension, although patients receiving hydroxychloroquine with or without azithromycin were overall sicker on presentation.25,26 Increased clinician vigilance for arrhythmias among patients receiving hydroxychloroquine may have led to a detection bias due to more frequent ECG performance. Given the lower association for arrhythmias than cardiac arrest, this may not have been a significant source of error. In the group of patients not receiving mechanical ventilation, risk for cardiac arrest remained statistically significantly elevated for hydroxychloroquine only compared with azithromycin only, suggesting that this risk was not mediated by mechanical ventilation.
The findings of this study also confirm what other studies have shown about the natural history of COVID-19 infection in the US: poor hospital outcomes were associated with male sex; preexisting conditions such as hypertension, obesity, and diabetes; and presenting findings such as elevated liver enzymes and abnormal kidney function.These findings are comparable to other metropolitan New York single hospital-system COVID-19 patient case series,but the design, which sampled from among 25 facilities representing 88.2% of the region’s hospitalized patients, provides additional generalizability, given potential heterogeneity in hospital populations, protocols, and outcomes. There was no evidence in this study that black or Hispanic persons were prescribed these medications at a lower rate than white patients, which is relevant given the population-level differences in COVID-19 deaths previously reported by race and ethnicity.The study sample likely included a small portion of patients from previous studies given overlapping observation periods and hospitals; however, data on hydroxychloroquine and azithromycin and associated outcomes have not been previously published.Strengths of this study include a large, random sample from 25 metropolitan New York hospitals. The sample was drawn early in the epidemic to include patients with long, complicated, and ongoing hospital stays.
Limitations
This study has several limitations. First, in sampling first hospitalizations, possible readmissions to other facilities may not be captured. Second, mortality was limited to in-hospital death, and patients discharged were assumed to still be alive during the study period. Third, some potential confounders such as inflammatory markers associated with severity of COVID-19 in prior studies were not frequently measured and thus not available for modeling.18 Fourth, the rapidity with which patients entered the ICU and underwent mechanical ventilation, often concurrently with initiating hydroxychloroquine and azithromycin, rendered these outcomes unsuitable for efficacy analyses. Fifth, adverse events were collected as having occurred at any point during hospitalization, potentially before drug initiation, although both medications were started on average within 1 day of admission; future studies should examine the onset of these events relative to drug timing. Sixth, it is likely that there is unmeasured residual confounding due to factors not included in the analysis. For the significant associations of hydroxychloroquine + azithromycin vs no drug with cardiac arrest and hydroxychloroquine alone vs azithromycin alone with cardiac arrest, the respective E-values for the lower bound of the OR’s CI of 1.31 and 1.81 suggest factors moderately associated with treatment and cardiac arrest could render these associations nonsignificant.Seventh, for the subsample of 211 patients receiving azithromycin alone, the HR point estimate for mortality was 0.56, but the confidence interval crossed 1.0. This suggests the possibility of a true protective association, but it may also represent unmeasured confounding; it may warrant additional study. Eighth, the confidence intervals for some of the findings are wide, reflecting limits in study power for some analyses
Clinical trials remain needed to provide definitive causal evidence of the effect of hydroxychloroquine and azithromycin on mortality, while also providing an opportunity to more finely control baseline patient severity and the dose and timing of drug administration. Nonetheless, the findings of the present study should be considered in concert with recent COVID-19 treatment guidelines from the National Institutes of Health and Infectious Diseases Society of America as well as the statement regarding safety concerning use of hydroxychloroquine from the US Food and Drug Administration.
Conclusions
Among patients hospitalized in metropolitan New York with COVID-19, treatment with hydroxychloroquine, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. However, the interpretation of these findings may be limited by the observational design.
Reference & source information: https://jamanetwork.com/
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