To the Editor
Cavalcanti et al. (Nov. 19 issue)1 stated in the originally published Supplementary Appendix of their article (a corrected version is available at NEJM.org) that the use of “hydroxychloroquine and macrolides rapidly became part of the routine care of patients with Covid-19 [coronavirus disease 2019] in Brazil” during their trial, such that, as they stated in the originally published version of their article, “enrollment of patients with no previous use of these medications was challenging.”2 Preenrollment use of these medications was not an exclusion criterion until a change in their trial protocol (available at NEJM.org) was made 5 days before the last patient underwent randomization, yet only 7.5% of the patients in the modified intention-to-treat analysis had received hydroxychloroquine before enrollment (Table S3 in their Supplementary Appendix). In contrast, 35.8% of the patients had received azithromycin. Consecutive eligible patients were not recruited.2 Instead, an active-screening process was used that was not defined. The number of patients who underwent screening and the number who were excluded from the trial, as well as the reasons for exclusion, are important data that are not included in the CONSORT (Consolidated Standards of Reporting Trials) diagram (Fig. S1).
Furthermore, it is not clear whether “previous use” systematically included data on prehospital use of these medications. Hydroxychloroquine use was reported to be widespread, yet only 0.3% of the patients received 48 hours or more of treatment. The authors report that this was primarily because patients were required to be enrolled in the trial within 48 hours after hospital admission and because outpatient use of these drugs was infrequent; this information suggests that “previous use” represented in-hospital use only. How were retrospective data on the incidence and duration of prehospital use of these medications obtained?
Michael J. Keane, B.M., B.S.
Swinburne University of Technology, Melbourne, VIC, Australia
[email protected]
Dr. Keane reports serving on the medical advisory board of Cannvalate. No other potential conflict of interest relevant to this letter was reported.
This letter was published on December 2, 2020, at NEJM.org.
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1. Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19. N Engl J Med 2020;383:2041-2052.
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2. Correction: Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19. N Engl J Med. DOI: 10.1056/NEJMx200021.
To the Editor
Cavalcanti at al. conclude that the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status among patients who had been hospitalized with mild-to-moderate Covid-19. However, the median number of days from symptom onset to randomization in the hydroxychloroquine-alone group was 7 (interquartile range, 5 to 8). The use of this drug starting 1 week after symptom onset might diminish its possible effectiveness, given that the postulated pathophysiology of Covid-19 consists of an initial viral infection phase followed by a hyperimmune response, which suggests a potential benefit of early administration of hydroxychloroquine.
In addition, hydroxychloroquine and azithromycin were used in 8.4% and 39.8%, respectively, of the patients in the control group before randomization. Furthermore, 11.6% of the patients in the control group received at least one dose of hydroxychloroquine during the 7-day treatment period. The possible effect of even a single dose of hydroxychloroquine given early in the course of the disease cannot be ruled out.
Finally, the percentage of patients with in-hospital use of glucocorticoids was higher in the control group than in the hydroxychloroquine-alone group (4.8% vs. 2.8%). This finding is relevant, considering the results of the recent Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial, which showed lower mortality with dexamethasone therapy than with usual care among patients hospitalized with Covid-19.1
Rahul Choudhary, M.D., D.M.
Gopal K. Bohra, M.D.
Deepak Kumar, M.D.
All India Institute of Medical Sciences, Jodhpur, India
[email protected]
No potential conflict of interest relevant to this letter was reported.
This letter was published on December 2, 2020, at NEJM.org.
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1. The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19 — preliminary report. N Engl J Med. DOI: 10.1056/NEJMoa2021436.
Response
The authors reply: We agree with Keane that data on the screening process are important. Although it was the aim of the researchers to screen all the patients who presented to the hospital with known or suspected Covid-19 for enrollment in the trial, increased health care demands during the peak of the pandemic, coupled with limited human resources dedicated to research, impeded us from systematically registering the screening data. Instead, we prioritized efforts to ensure protocol adherence and data collection among the patients who had undergone randomization. Therefore, the screening process was not presented in the corrected trial flowchart (Fig. S1 in the Supplementary Appendix of our article).
With regard to previous use of hydroxychloroquine or azithromycin, starting on April 13, 2020, our baseline case-report form included the following questions: “Was the patient using azithromycin before randomization?” and “Was the patient using hydroxychloroquine before randomization?” For patients who had been enrolled before that date, we sent emails to investigators asking them to review patients’ charts and to provide information regarding previous use and duration.
Choudhary et al. have concerns regarding the time that elapsed between symptom onset and enrollment, the potential effects of crossover, and between-group differences in glucocorticoid use. The question of whether very early use of hydroxychloroquine (e.g., ≤3 days since symptom onset) may improve outcomes was not addressed in our trial. Among the 59 patients who were enrolled with no more than 3 days since symptom onset, the number of patients who were at home without limitations at day 14 was 6 of 16 (38%) in the hydroxychloroquine-plus-azithromycin group, 10 of 19 (53%) in the hydroxychloroquine-alone group, and 14 of 24 (58%) in the control group. So far, other trials have not shown a benefit of hydroxychloroquine in this scenario.1,2
The possibility that the 11.6% of the patients with hydroxychloroquine use in the control group could explain the null treatment effect is addressed in our per-protocol sensitivity analysis (Table S10); the findings were consistent with those of the modified intention-to-treat analysis. Finally, only 18 patients in the modified intention-to-treat population (5 patients in the hydroxychloroquine-alone group, 5 in the hydroxychloroquine-plus-azithromycin group, and 8 in the control group) received glucocorticoids. Exclusion of these patients did not change the overall results (odds ratio for the ordinal outcome for hydroxychloroquine plus azithromycin vs. control, 0.92; 95% confidence interval [CI], 0.58 to 1.47; odds ratio for hydroxychloroquine-alone vs. control, 1.17; 95% CI, 0.73 to 1.86).
Alexandre B. Cavalcanti, M.D.
HCor Research Institute, São Paulo, Brazil
[email protected]
Otávio Berwanger, M.D., Ph.D.
Hospital Israelita Albert Einstein, São Paulo, Brazil
Fernando G. Zampieri, M.D., Ph.D.
HCor Research Institute, São Paulo, Brazil
Since publication of their article, the authors report no further potential conflict of interest.
This letter was published on December 2, 2020, at NEJM.org.
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1. Mitjà O, Corbacho-Monné M, Ubals M, et al. Hydroxychloroquine for early treatment of adults with mild Covid-19: a randomized-controlled trial. Clin Infect Dis 2020 July 16 (Epub ahead of print).
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2. Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial. Ann Intern Med 2020;173:623-631.
December 03, 2020 at 05:03AM
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