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Editor's Note
April 29, 2020

The Risks of Prescribing Hydroxychloroquine for Treatment of COVID-19—First, Do No Harm

Author Affiliations
  • 1Department of Medicine, University of California, San Francisco
JAMA Intern Med. 2020;180(8):1118-1119. doi:10.1001/jamainternmed.2020.1853

On March 21, 2020, President Donald Trump tweeted that hydroxychloroquine and azithromycin have “a real chance to be one of the biggest game changers in the history of medicine.”1 The president later said of hydroxychloroquine, “What do you have to lose? I’ll say it again: What do you have to lose? Take it.”2

Although the president acknowledged that physicians should be involved in the decision to use these medications, the message to patients with coronavirus disease 2019 (COVID-19), and people worried about becoming infected, was clear. Within days, a man in Arizona died after ingesting a chloroquine-containing aquarium product that did not require a prescription.3 Federal regulators facilitated use of prescription hydroxychloroquine and chloroquine by immediately issuing an Emergency Use Authorization.

One way of quantifying the influence of these high-profile statements is to examine internet search behaviors. In this issue of JAMA Internal Medicine, Liu and colleagues4 examined internet searches for purchasing chloroquine or hydroxychloroquine online. From March 16 to 29, 2020, searches increased 442% and 1389% for chloroquine and hydroxychloroquine, respectively, compared with the preceding 6 weeks.

Although testing of hydroxychloroquine for treatment of COVID-19 is underway, available data do not support its widespread use. The study5 referenced by President Trump may have methodologic flaws. A small randomized trial suggesting benefit was unblinded, and some patients received concomitant steroids or antivirals.6 Nevertheless, some physicians have begun prescribing hydroxychloroquine widely, which prompted at least 12 states to pass emergency prescribing restrictions.

The potential harms are substantial. Hydroxychloroquine is QT prolonging, which poses a risk of sudden cardiac death in certain populations. People with autoimmune conditions, disproportionately women and people of color, could face disease flares owing to medication shortages.7 The burden may fall hardest on the most vulnerable; low-income patients worldwide could be the first to lose access to hydroxychloroquine therapy.

Given the toll of COVID-19, the pressure to do something is enormous and understandable. But that must not prompt clinicians to jettison the tenets of evidence-based medicine and the admonition to do no harm. As health care providers, we should inform patients about the evidence behind experimental therapies, work to enroll patients in randomized clinical trials, and consider the needs of patients without COVID-19 who may be affected by drug shortages. It is vital that we do not give in to nonevidence-based calls to embrace unproven therapies. Although we may be tempted to bypass enduring principles in this time of uncertainty and fear, the best way to protect patients is to stay grounded in evidence and to fight misinformation.

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Article Information

Published Online: April 29, 2020. doi:10.1001/jamainternmed.2020.1853

Corresponding Author: Robert M. Wachter, MD, Department of Medicine, University of California, San Francisco, 533 Parnassus Ave, San Francisco, CA 94143 (robert.wachter@ucsf.edu).

Conflict of Interest Disclosures: None reported.

@realDonaldTrump. HYDROXYCHLOROQUINE & AZITHROMYCIN, taken together, have a real chance to be one of the biggest game changers in the history of medicine. The FDA has moved mountains - Thank You! Hopefully they will BOTH (H works better with A, International Journal of Antimicrobial Agents)… March 21, 2020. Accessed April 17, 2020. https://twitter.com/realdonaldtrump/status/1241367239900778501?lang=en
The White House. Remarks by President Trump, Vice President Pence, and members of the Coronavirus Task Force in press briefing. April 5, 2020. Accessed April 21, 2020. https://www.whitehouse.gov/briefings-statements/remarks-president-trump-vice-president-pence-members-coronavirus-task-force-press-briefing-19/
Vigdor  N. Man fatally poisons himself while self-medicating for coronavirus, doctor says. New York Times. March 24, 2020. Accessed April 17, 2020. https://www.nytimes.com/2020/03/24/us/chloroquine-poisoning-coronavirus.html.
Liu  M, Caputi  TL, Drezde  M, Kesselheim  AS, Ayers  JW.  Internet searches for unproven COVID-19 therapies in the United States.   JAMA Intern Med. Published online April 29, 2020. doi:10.1001/jamainternmed.2020.1764Google Scholar
International Society of Antimicrobial Chemotherapy. Statement on IJAA paper. April 3, 2020. Accessed April 10, 2020. http://www.isac.world/news-and-publications/official-isac-statement
Chen  Z, Hu  J, Zhang  Z,  et al  Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial.  Preprint. Posted online April 10, 2020. medRxiv. doi:10.1101/2020.03.22.20040758
Marsh  T. Live updates: which drugs are in shortage because of COVID-19? GoodRx website. Accessed April 13, 2020. https://www.goodrx.com/blog/covid-19-drug-shortages-updates/.
5 Comments for this article
Incidence of hydroxychloroquine-related cardiac arrhythmias in existing SLE & rhematoid arthritis patients on chronic therapy
Sam Mansour, MD | The George Washington University
Would be helpful to find out the latest data on the incidence of cardiac arrhythmias in patients taking this drug on a chronic basis for connective tissue disease related & autoimmune disorders.
FDA authorizes off-label treatment of COVID-19 with hydroxychloroquine
DAVID KELLER, MS, MD | Internal Medicine
"On March 28, 2020, FDA issued an EUA [Emergency Use Authorization] to allow hydroxychloroquine sulfate [HCQ] and chloroquine phosphate to be prescribed.... to adolescent and adult patients hospitalized with COVID-19, as appropriate, when a clinical trial is not available or feasible." [1]

FDA thus acknowledged that many physicians consider the existing information, flawed as it is, to favor treatment with HCQ over supportive care alone, in the face of a deadly pandemic with no proven therapy.

Prolongation of the QT interval sufficient to cause torsade des pointes is rare, and can be mitigated by
cardiac telemetry for hospitalized patients.

If randomized controlled trials eventually prove that HCQ does not improve outcomes in COVID-19, little will have been lost, but if HCQ is proven effective, physicians who scrupulously waited for solid proof before employing it may experience regret, or worse.


1: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization
"First Do No Harm" is impossible when doing nothing holds the possibility doing more harm.
Anthony Cusano, MD | Waterbury Health
"Medicine is a science of uncertainty and an art of probability".

"First, do no harm" was a wise missive when much of what physicians did had significant uncertainty and low probability of success. Its thoughtless application to a disease with a high probability of severe adverse outcomes does not follow any useful tradition of medical tradition.

Hydroxychloroquine is the fifth most widely prescribed drug in the world with exceedingly rare adverse effects documented. The prolonged QT interval it can cause has rarely been associated with sudden death, though it certainly warrants close attention when
using the medication.

A better way to approach this clinical dilemma is to review the benefits, risks, alternatives, and unknowns, and invite a shared decision by the patient or their family. That allows them to chose the potential harm of unclear action or the potential harm of no action at all.
The admonition to "Do No Harm"
John Simmons, MSed | Independent scholar
Although one appreciates "Do no harm" as an important aspiration, to cite it with reference to a possible but unproven therapy for COVID-19 in the context of President Trump's ad hoc remarks is a dubious admonition in the context of a global pandemic. The fact is that physicians frequently do harm; the really pertinent question concerns the costs and benefits of the decision and actions. The ability of physicians to think critically and evaluate clinical decision-making should not be hampered by unnecessary doubt. Inducing guilt where none is warranted is not useful.
Confusion on treatment protocols for experimental drugs
Jennifer Dankle, D.O. | cardiology
Hydroxychloroquine has had little evidenced basis for use against COVID-19. Having said that, experimental drugs are expedited and being utilized in relaxed regulations of studies in an effort to bring some hope of treatment for the critically ill, i.e., remdeisivr.

This article goes from talking about the irresponsibility of President Trump in supporting an experimental drug because of potential harms to concerns about providing enough of the drug for low income families.
Keeping medicine a non-partisan, objective, evidence base driven practice is crucial to our respected field of medicine.

Hope is never a bad thing
to provide to people.