The Saga of Hydroxychloroquine and COVID-19: A Cautionary Tale
Authors: Neil W. Schluger
Journal: Annals of Internal Medicine (2020)

Editorials16 July 2020The Saga of Hydroxychloroquine and COVID-19: A Cautionary TaleFREENeil W. Schluger, MDNeil W. Schluger, MDNew York Medical College, Valhalla, New York (N.W.S.)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/M20-5041 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail The coronavirus disease 2019 (COVID-19) pandemic has stressed every component of our health care and public health systems with tremendous pressure to identify effective therapies. The saga of hydroxychloroquine should serve as a cautionary tale about the evaluation and promulgation of treatments during urgent situations; COVID-19 is not the first such situation and, unfortunately, will not be the last. We should examine carefully not only what we know about hydroxychloroquine but also how we learned it, disseminated it, and put it into practice.Early in the COVID-19 pandemic, hydroxychloroquine quickly came to be widely used on the basis of very thin evidence—a very small randomized trial (1) and a poorly done small observational study (2), both originally posted on a preprint server rather than published in the peer-reviewed literature. Professional societies, public health agencies, and many politicians with no expertise in science or medicine allowed, endorsed, or promoted the use of hydroxychloroquine. The hope was that, despite the very limited evidence, it was truly effective and the availability of promising treatment would reassure the public. The number of prescriptions for hydroxychloroquine in the United States skyrocketed.In early May 2020, two large observational cohort studies that found no association between administration of hydroxychloroquine and the rate of death or respiratory failure in hospitalized patients with COVID-19 were published in prominent journals (3, 4). These studies supported recommendations from the National Institutes of Health that hydroxychloroquine be used only in the context of clinical trials and not in routine care.To date, very few adequately powered, randomized controlled trials (RCT) of the effectiveness and safety of hydroxychloroquine in the management of COVID-19 have been published in the peer-reviewed literature. Press releases have reported negative results from 2 large RCTs sponsored by the National Institutes of Health and the U.K. National Health Service RECOVERY consortium (5, 6). The planned methods for these trials seem to be rigorous, but results have not yet appeared as preprints or in peer-reviewed journals. An RCT of hydroxychloroquine as postexposure prophylaxis failed to show any benefit in preventing progressing to disease (7), and a second RCT in patients with mild to moderate disease also failed to demonstrate faster conversion to negative viral status in hydroxychloroquine-treated patients (8).In this context, the study by Skipper and colleagues (9) is a welcome addition. The investigators set for themselves a challenging task. They sought to evaluate the utility of hydroxychloroquine in patients with very mild illness. This created significant operational hurdles related to conducting a trial at a time when in-person visits were difficult if not impossible and testing shortages made confirmation of a COVID-19 diagnosis quite difficult in patients with very mild illness. The study has clear limitations related to these issues. Although 82% of patients had laboratory-confirmed COVID-19 or documentation of close contact with a confirmed case, only 58% of study participants themselves received COVID-19 testing. The primary outcome, which was changed during the study with the permission of the data and safety monitoring board, relied on a novel and not previously validated tool for symptom assessment. However, the study did use a masked placebo, and follow-up was excellent. The investigators found no clinically or statistically significant difference in change in symptom severity over 14 days in persons who received hydroxychloroquine compared with those who did not. Medication side effects, although minor, were more common in the hydroxychloroquine-treated group. As expected in a relatively young population with mild illness and little comorbid illness, hospitalizations were uncommon overall and did not differ statistically between the 2 groups.Taken together with the other published RCTs, the current study by Skipper and colleagues (9) provides strong evidence that hydroxychloroquine offers no benefit in patients with mild illness. If the peer-reviewed findings confirm the preliminary reports of no benefit in sicker patients in the National Institutes of Health and RECOVERY trials, the saga of hydroxychloroquine and COVID-19 will likely reach its sad end.The apparent ineffectiveness of hydroxychloroquine as a treatment of COVID-19 should not come as a surprise. Of all novel drugs that enter clinical phases of testing, about 90% fail to demonstrate effectiveness and safety. More simply put, many good ideas in medicine do not work. There is no shame in acknowledging that. But there are deeper lessons to be learned from the hydroxychloroquine experience in the current pandemic.London and Kimmelman (10) have convincingly argued that research standards should not be lowered during a pandemic. However, there are enormous challenges to conducting and reporting research in such times as these. Hospitals overwhelmed with the provision of clinical care have had little spare capacity for conducting rigorous research. Patients, physicians, and politicians have been desperate for effective therapies and too willing to rely on thin scientific evidence. Individual groups and hospitals have launched scores of trials that will never meet their enrollment targets because of lack of coordination and cooperation among competing investigators and health care systems. The emergence of preprint servers, such as medRxiv, has allowed widespread dissemination of work that has not undergone careful review. Prestigious journals have worked feverishly to rapidly review studies that could have immediate impact but have occasionally fallen victim to deceit, damaging public confidence in their status as arbiters and presenters of objective facts. The scientific community needs to do a good bit of stock-taking and soul-searching about its performance in meeting the challenges of the pandemic and how it will meet these challenges in future pandemics that are certain to emerge.Unfortunately, the COVID-19 pandemic is far from over, but the emergence of data from well-done RCTs is a welcome development. Results of carefully done research, such as Skipper and colleagues' RCT, set an example for how we should search for effective therapies. It is time to move on from hydroxychloroquine.References1. Chen Z, Hu J, Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv. Preprint posted online 10 April 2020. doi:10.1101/2020.03.22.20040758 CrossrefGoogle Scholar2. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020:105949. [PMID: 32205204] doi:10.1016/j.ijantimicag.2020.105949 CrossrefMedlineGoogle Scholar3. Geleris J, Sun Y, Platt J, et al. Observational study of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med. 2020;382:2411-2418. [PMID: 32379955] doi:10.1056/NEJMoa2012410 CrossrefMedlineGoogle Scholar4. Rosenberg ES, Dufort EM, Udo T, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State. JAMA. 2020. [PMID: 32392282] doi:10.1001/jama.2020.8630 CrossrefMedlineGoogle Scholar5. National Institutes of Health. NIH halts clinical trial of hydroxychloroquine. 20 June 2020. Accessed at www.nih.gov/news-events/news-releases/nih-halts-clinical-trial-hydroxychloroquine on 12 July 2020. Google Scholar6. Nuffield Department of Population Health. No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19. 5 June 2020. Accessed at www.recoverytrial.net/news/statement-from-the-chief-investigators-of-the-randomised-evaluation-of-covid-19-therapy-recovery-trial-on-hydroxychloroquine-5-june-2020-no-clinical-benefit-from-use-of-hydroxychloroquine-in-hospitalised-patients-with-covid-19 on 11 July 2020. Google Scholar7. Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med. 2020. [PMID: 32492293] doi:10.1056/NEJMoa2016638 CrossrefMedlineGoogle Scholar8. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849. [PMID: 32409561] doi:10.1136/bmj.m1849 CrossrefMedlineGoogle Scholar9. Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in nonhospitalized adults with early COVID-19. A randomized trial. Ann Intern Med. 2020;173:623-31. doi:10.7326/M20-4207 LinkGoogle Scholar10. London AJ, Kimmelman J. Against pandemic research exceptionalism. Science. 2020;368:476-477. [PMID: 32327600] doi:10.1126/science.abc1731 CrossrefMedlineGoogle Scholar Comments 0 Comments Sign In to Submit A Comment John WalkerFormer clinical and molecular diagnostics laboratory medical director, Kalispell Regional Medical Center20 July 2020 Article makes unsupported conclusions Although 82% of patients had laboratory-confirmed COVID-19 or documentation of close contact with a confirmed case, only 58% of study participants themselves received COVID-19 testing." These facts essentially invalidate the study. There has been significantly more than "very thin evidence" supporting the efficacy of hydroxychloroquine for Covid19. There is abundant anecdotal evidence of significant efficacy from numerous large groups of Covid19 + (actually tested) patients. In addition, the Henry Ford hospital system study validated the use of HCL early in the disease. Therefore, the conclusions in this article appear completely unsupported. Is this due to some undisclosed bias by the author? Disclosures: Author does not have conflicts of interests. Clyde MeckelBryan Health System20 July 2020 Misinterpretation of study The study by Skipper and colleagues, weak in its own right, is being misinterpreted on these pages and in the press. This was a truncated (for logistical reasons noted in the study methods) randomized trial of very low risk patients with COVID symptoms, 58% of whom had a positive PCR test. Even in this low risk population (for which there is no support I know of for treating) there is a nonsignificant trend towards shortening symptoms and decreasing hospitalization. High-risk patients include: people over age 60, or obese (BMI>30), or with diabetes, hypertension, cancer history, immunocompromised, COPD or asthma or other chronic lung diseases etc., or presenting with shortness of breath in light activities such as walking around. Typically, there death and hospitalization rates are 3-5X what is seen in the very low risk population studied for this report. Skipper and colleagues admit in the conclusion section a study focused on high risk patients could demonstrate significant benefit. Dr. Schluger's editorial misinterprets the already weak study on very low risk patients and generalizes it to all COVID patients by declaring hydroxychloroquine therapy in COVID-19 dead. The study and editorial have been widely reported in the press today. This likely puts lives in danger by discouraging badly needed trials and early outpatient treatment of high risk patients who, from preliminary data available at this point, are very highly likely to benefit from the treatment. Disclosures: None Robert GatesNone3 August 2020 Zinc supplement Surprisingly this study failed to use a Zinc supplement that earlier studies had found to enhance the effect of hydroxychloroquine in inhibiting viral replication. Disclosures: None Andrea Carlo MangiagalliItalian GP NHS28 October 2020 Field use HCQ As italian GP, toghether with hundreds of other GP ( and many hosptital Colleagues) we widely used a treatment for covid 19 patients in the very fist "wave" of pandemia. Our scheme with Hydroxycloroquine, azitromicine and LMWE (enoxaparine) administred in the very first days of symptoms onset, almost impossible for patients admitted in most trial, as , probably, their first hospital consultation were scheduled not immediately as in our setting. We started at the end of March our treatment in a moment where all Milan area hospital were close to collapse and after days waiting emergency service to take people to ER with a very bad prognosis. After this field widespread use, the largest part of our patients ( mostly in Lombardia, Piemonte and Emilia) never reached any ER service, and in two or three day max achieved clinical remission on symptoms with good recovery outcome. This can be depicted as anecdotical medicine but, unless all of us have treated no covid patients (which by the way is not true, as many patients had a serological confirmation later of covid exposure..) none experienced any cardiac complication or bleeding disorder . At least one point must be undelined : all this "hyper" on the potential risk of these drugs was not seen in so many patients (even in hospital setting where this therapeutic scheme was fully used..) as italian GP has usually a deep medical story of all their patients, due to a long and strong relationship that can avoid administartion of potential risk drugs to well known patients with caridiac arrythmias ( i.e B Blocker or amiodarone users) . This accurate selection of patients to treat can explain the absence of any relevant life threatenig side effect of treatment in comparison to the very high risk at that moment to underwent mechanical ventilation with all the related problems and prognosis. In a pandemic situation real life study were neither proposed to us nor anyone designed one "field based". Nevertheless hydroxycloroquine is widespreadly use all over the world by thousand of doctors on thousand of patients (India, Cina still have this drugs in their field treatment) and surely we do not expect thaousand of death drug related as compared to ill realted death, especially where no public health service is guaranteed. Give us a chance to avoid at least a small amount of death. Raphael Stricker, MDUnion Square Medical Associates, San Francisco, CA 9410829 October 2020 Editorial Ignores HCQ PrEP The editorial by Dr. Schluger discusses failure of HCQ treatment in hospitalized patients and infected outpatients. It completely ignores HCQ pre-exposure prophylaxis (PrEP) for COVID-19. For a discussion of this rational and successful approach to prevention of serious COVID-19, see https://www.dovepress.com/flattening-the-risk-pre-exposure-prophylaxis-for-covid-19-peer-reviewed-article-IDR Neil W. Schluger, M.D.New York Medical College2 December 2020 Authors' response to Meckel Dr. Meckel posits that the study by Skipper could have failed to detect a beneficial effect of hydroxychloroquine (HCQ) in patients at high risk for bad outcomes. He also claims that there was in fact a trend towards a beneficial effect of HCQ in the study as reported that likely represented a true and significant clinical effect. He notes the study's limitations, and It is true that relatively few subjects had comorbid conditions of the type often associated with worse outcomes in patients with COVID-19 illness. But the idea that higher-risk patients would have benefitted cannot be simply inferred from the data as shown, and it is a truism that a non-significant result might have reached significance if the study had only been larger. Since the Skipper paper was published, many additional randomized trials of hydroxychloroquine in a variety of clinical settings—pre-exposure prophylaxis, post-exposure prophylaxis, mild illness, and moderate to severe illness—have been reported. All have been negative, and several included significant numbers of persons at high risk for bad outcomes. In a pre-exposure prophylaxis RCT of over 1400 subjects, 13% of whom were hypertensive, there was no statistically significant benefit to HCQ1. A randomized, controlled post-exposure prophylaxis study of over 800 subjects in which 12% of patients were hypertensive showed no benefit2. In a trial by Self and colleagues over half the study subjects had hypertension, and roughly a third were diabetic3. Most patients were only mildly ill to moderately ill, receiving no or little supplemental oxygen at the time of randomization. HCQ had no impact at all, across a range of important clinical outcomes. In the UK RECOVERY trial4, in which over 4500 patients were randomized, 27% were diabetic and 27% had heart disease. HCQ had no impact on mortality or any other important clinical outcome. It is unclear what the mechanism of purported benefit of HCQ might be in patients with COVID-19 illness. Lyngbakken and colleagues recently demonstrated in a randomized, controlled trial that HCQ administration did not result in any difference in viral kinetics, as assessed by decline in viral load in the oropharynx, compared to patients not receiving HCQ5. Most mildly ill or presymptomatic COVID-19 patients do not show evidence of a hyperinflammatory state and do not benefit from dexamethasone, so it is also difficult to imagine that HCQ might have benefit by tamping down inflammation. Is it possible that there could be a small benefit of HCQ in a subset of mildly ill COVID-19 patients? Anything is possible, but it seems unlikely. John Adams once said, "Facts are stubborn things; and whatever may be our wishes, our inclinations, or the dictates of our passions, they cannot alter the state of facts and evidence." Indeed. Neil W. Schluger, M.D. New York Medical College Valhalla, NY 10595 References Rajasingham R, Bangdiwala AS, Nicol MR, et al. Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthcare workers: a randomized trial. Clin Infect Dis 2020. Boulware DR, Pullen MF, Bangdiwala AS, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med 2020;383:517-25. Self WH, Semler MW, Leither LM, et al. Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial. JAMA 2020;324:2165-76. Group RC, Horby P, Mafham M, et al. Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med 2020;383:2030-40. Lyngbakken MN, Berdal JE, Eskesen A, et al. A pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics. Nat Commun 2020;11:5284. Author, Article, and Disclosure InformationAuthors: Neil W. Schluger, MDAffiliations: New York Medical College, Valhalla, New York (N.W.S.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-5041.Corresponding Author: Neil W. Schluger, MD, Department of Medicine, New York Medical College, 19 Skyline Drive, Valhalla, NY 10532; e-mail, nschluge@nymc.edu.This article was published at Annals.org on 16 July 2020. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoHydroxychloroquine in Nonhospitalized Adults With Early COVID-19 Caleb P. Skipper , Katelyn A. Pastick , Nicole W. Engen , Ananta S. Bangdiwala , Mahsa Abassi , Sarah M. Lofgren , Darlisha A. Williams , Elizabeth C. Okafor , Matthew F. 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