Friday, May 22, 2020

Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis

Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis

In summary, this multinational, observational, real- world study of patients with COVID-19 requiring hospitalisation found that the use of a regimen containing hydroxychloroquine or chloroquine (with or without a macrolide) was associated with no evidence of benefit, but instead was associated with an increase in the risk of ventricular arrhythmias and a greater hazard for in-hospital death with COVID-19. These findings suggest that these drug regimens should not be used outside of clinical trials and urgent confirmation from randomised clinical trials is needed...end

Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis

Mandeep R Mehra, Sapan S Desai, Frank Ruschitzka, Amit N Patel

Summary

Background Hydroxychloroquine or chloroquine, often in combination with a second-generation macrolide, are being widely used for treatment of COVID-19, despite no conclusive evidence of their benefit. Although generally safe when used for approved indications such as autoimmune disease or malaria, the safety and benefit of these treatment regimens are poorly evaluated in COVID-19.

Methods We did a multinational registry analysis of the use of hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19. The registry comprised data from 671 hospitals in six continents. We included patients hospitalised between Dec 20, 2019, and April 14, 2020, with a positive laboratory finding for SARS-CoV-2. Patients who received one of the treatments of interest within 48 h of diagnosis were included in one of four treatment groups (chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide), and patients who received none of these treatments formed the control group. Patients for whom one of the treatments of interest was initiated more than 48 h after diagnosis or while they were on mechanical ventilation, as well as patients who received remdesivir, were excluded. The main outcomes of interest were in-hospital mortality and the occurrence of de-novo ventricular arrhythmias (non-sustained or sustained ventricular tachycardia or ventricular fibrillation).

Findings 96 032 patients (mean age 53·8 years, 46·3% women) with COVID-19 were hospitalised during the study period and met the inclusion criteria. Of these, 14 888 patients were in the treatment groups (1868 received chloroquine, 3783 received chloroquine with a macrolide, 3016 received hydroxychloroquine, and 6221 received hydroxychloroquine with a macrolide) and 81 144 patients were in the control group. 10 698 (11·1%) patients died in hospital. After controlling for multiple confounding factors (age, sex, race or ethnicity, body-mass index, underlying cardiovascular disease and its risk factors, diabetes, underlying lung disease, smoking, immunosuppressed condition, and baseline disease severity), when compared with mortality in the control group (9·3%), hydroxychloroquine (18·0%; hazard ratio 1·335, 95% CI 1·223–1·457), hydroxychloroquine with a macrolide (23·8%; 1·447, 1·368–1·531), chloroquine (16·4%; 1·365, 1·218–1·531), and chloroquine with a macrolide (22·2%; 1·368, 1·273–1·469) were each independently associated with an increased risk of in-hospital mortality. Compared with the control group (0·3%), hydroxychloroquine (6·1%; 2·369, 1·935–2·900), hydroxychloroquine with a macrolide (8·1%; 5·106, 4·106–5·983), chloroquine (4·3%; 3·561, 2·760–4·596), and chloroquine with a macrolide (6·5%; 4·011, 3·344–4·812) were independently associated with an increased risk of de-novo ventricular arrhythmia during hospitalisation.

Interpretation We were unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or with a macrolide, on in-hospital outcomes for COVID-19. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19.

Snip...

In summary, this multinational, observational, real- world study of patients with COVID-19 requiring hospitalisation found that the use of a regimen containing hydroxychloroquine or chloroquine (with or without a macrolide) was associated with no evidence of benefit, but instead was associated with an increase in the risk of ventricular arrhythmias and a greater hazard for in-hospital death with COVID-19. These findings suggest that these drug regimens should not be used outside of clinical trials and urgent confirmation from randomised clinical trials is needed.

Funding William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women’s Hospital. Copyright © 2020 Elsevier Ltd. All rights reserved. Published Online



Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School, Boston, MA, USA

(Prof M R Mehra MD); Surgisphere Corporation, Chicago, IL, USA (S S Desai MD); University Heart Center, University Hospital Zurich, Zurich, Switzerland (Prof F Ruschitzka MD); Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA (A N Patel MD); and HCA Research Institute, Nashville, TN, USA (A N Patel)

Correspondence to: Prof Mandeep R Mehra, Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School, Boston, MA 02115, USA mmehra@bwh.harvard.edu


https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31180-6/fulltext

UPDATE! THE ABOVE PAPER HAS BEEN RETRACTED!

Published Online June 4, 2020 https://doi.org/10.1016/ S0140-6736(20)31324-6

Retraction—Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis

After publication of our Lancet Article,1 several concerns were raised with respect to the veracity of the data and analyses conducted by Surgisphere Corporation and its founder and our co-author, Sapan Desai, in our publication. We launched an independent thirdparty peer review of Surgisphere with the consent of Sapan Desai to evaluate the origination of the database elements, to confirm the completeness of the database, and to replicate the analyses presented in the paper. Our independent peer reviewers informed us that Surgisphere would not transfer the full dataset, client contracts, and the full ISO audit report to their servers for analysis as such transfer would violate client agreements and confidentiality requirements. As such, our reviewers were not able to conduct an independent and private peer review and therefore notified us of their withdrawal from the peer-review process.

We always aspire to perform our research in accordance with the highest ethical and professional guidelines. We can never forget the responsibility we have as researchers to scrupulously ensure that we rely on data sources that adhere to our high standards. Based on this development, we can no longer vouch for the veracity of the primary data sources. Due to this unfortunate development, the authors request that the paper be retracted. We all entered this collaboration to contribute in good faith and at a time of great need during the COVID-19 pandemic. We deeply apologise to you, the editors, and the journal readership for any embarrassment or inconvenience that this may have caused.

MRM reports personal fees from Abbott, Medtronic, Janssen, Roivant, Triple Gene, Mesoblast, Baim Institute for Clinical Research, Portola, Bayer, NupulseCV, FineHeart, and Leviticus. FR has been paid for time spent as a committee member for clinical trials, advisory boards, other forms of consulting, and lectures or presentations; these payments were made directly to the University of Zurich and no personal payments were received in relation to these trials or other activities since 2018. Before 2018 FR reports grants and personal fees from SJM/Abbott, grants and personal fees from Servier, personal fees from Zoll, personal fees from Astra Zeneca, personal fees from Sanofi, grants and personal fees from Novartis, personal fees from Amgen, personal fees from BMS, personal fees from Pfizer, personal fees from Fresenius, personal fees from Vifor, personal fees from Roche, grants and personal fees from Bayer, personal fees from Cardiorentis, personal fees from Boehringer Ingelheim, other from Heartware, and grants from Mars. ANP declares no competing interests.

*Mandeep R Mehra, Frank Ruschitzka, Amit N Patel mmehra@bwh.harvard.edu

Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School, Boston, MA 02115, USA (MRM); University Heart Center, University Hospital Zurich, Zurich, Switzerland (FR); Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA (ANP); and HCA Research Institute, Nashville, TN, USA (ANP) 1 Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet 2020; published online May 22. https://doi.org/10.1016/S0140-6736(20)31180-6


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