Chloroquine and hydroxychloroquine (HCQ) have been touted as promising and effective treatments for patients with COVID-19 infection. The drugs are often recommended to be used together with azithromycin, an antibiotic.
On March 21, 2020, President Trump claimed that these drugs were "one of the biggest game-changers in the history of medicine." On March 30, under considerable political pressure, the for these drugs for COVID-19.
The U.S. government , and HCQ is being routinely prescribed for patients with COVID-19. As a result, the drug has been in short supply, and who require HCQ have had .
Enthusiasm for these drugs was fueled by statements from the Oval Office. Referring to HCQ, : "It's a very strong, powerful medicine." He strongly encouraged its use: "What do you have to lose? Take it." "It doesn't kill people."
I am a cardiologist and a clinical trialist, and during the last 2 months, physicians have sought my advice about the design of clinical trials with chloroquine and HCQ for the prevention and treatment of COVID-19. During these discussions, I asked my colleagues two questions: "What evidence do you have that the drugs might work?" "Are you not worried about their known adverse effects on the heart?"
Sadly, I did not receive any reassuring answers.
First question: what evidence exists that these drugs might work?
On Feb. 17, the State Council of China held a news conference claiming that chloroquine had demonstrated efficacy in treating COVID-19-associated pneumonia. The findings were , and to my knowledge, the actual data underlying the claim have never been published. HCQ has been in vitro, but such laboratory reports are notoriously unreliable in correctly predicting the benefits of a drug in animals or human beings.
On March 17, Didier Raoult, MD, PhD -- a with a long history of controversy -- announced in an online video that HCQ and azithromycin had been in 24 patients in France. A appeared in a journal three days later; the first author was Philippe Gautret, MD, PhD.
Gautret and Raoult evaluated 42 patients with COVID-19. The data in six patients (all treated with HCQ) were excluded and never reported. The 36 remaining patients had all been hospitalized, but inexplicably, six had been asymptomatic and 22 had had only upper respiratory symptoms before treatment. Why would nearly 80% of the patients have been hospitalized with a nonserious COVID-19 infection? Of the 36 patients, 14 received HCQ, six received a combination of HCQ and azithromycin, and 16 received neither drug. Treatment was not randomized or blinded. The investigators did not explain why they chose to prescribe the drugs to some patients and not others.
According to the Gautret-Raoult paper, after a week of therapy, the proportion of patients with SARS-CoV-2-negative swabs was greater in the active treatment groups than in the nontreated group. However, it is not clear that patients in the three groups had the same viral burden before therapy. For unknown reasons, the authors did not report the baseline level of virus in 10 of the 16 patients in the untreated group. This information was always provided in the 20 patients treated with HCQ with or without azithromycin.
Importantly, in this report, the authors made no claims that patients treated with HCQ and azithromycin actually experienced any clinical benefits, as compared to untreated patients. Clinical responses were , but in a study that had no control group.
The conclusion? Those of us who have spent decades critically examining studies of drug efficacy would refer to the Gautret-Raoult paper as representing "uninterpretable data," We would not refer to their observations as "evidence."
Might HCQ work in patients with COVID-19 pneumonia? An reported no difference in a clinical course of patients who received HCQ and those who did not.
At this time, there is that chloroquine or HCQ has meaningful clinical benefits in patients with COVID-19. Well-designed trials are in progress.
Second question: is HCQ safe?
Both chloroquine and HCQ can change the electrical activation of the heart in a way that increases its susceptibility to life-threatening rhythm disturbances. Use of the two drugs have been linked to increases in cardiac vulnerability (as measured by the QTc interval), which may worsen the effects of COVID-19 on the electrical properties of the heart. These effects can persist for a meaningful time after the drugs are discontinued. In one report, the QTc interval increased more than the critical level of 500 milliseconds in 20% of treated patients. Lengthening of the QTc interval was who received azithromycin in addition to HCQ. One patient treated with the drug combination developed torsade de pointes. These associations may or may not be causal, but they are disconcerting.
Have chloroquine and HCQ actually hurt people?
These drugs have been given to millions of people, but this experience has not involved the use of high doses in acutely ill patients who are likely to have meaningful underlying cardiac dysfunction, which may predate or be caused by COVID-19.
Only in COVID-19 has been carried out to date. In that trial, patients received high doses or low doses of chloroquine. The trial planned on enrolling 440 patients, but it was terminated early by the study's ethical committee after only 81 patients had been enrolled -- because of the finding of an increase in mortality in the high-dose group. After 2 weeks, the high-dose group had a mortality rate of 39% and the low-dose group had a mortality rate of 15% (P=0.03). The investigators expressed concern about cardiac toxicity.
Can high doses of HCQ increase the risk of death other than causing serious arrhythmias?
Chloroquine is widely used by basic research scientists to experimentally inhibit autophagy, a critically important adaptive cellular pathway that underlies the ability of organs to fight viral infection and preserve function under states of stress. the ability of the heart to respond appropriately to stress, thus . Heart failure due to chloroquine-induced cardiomyopathy is a .
Why is this important? About 15%-20% of patients with COVID-19 show evidence of significant cardiac injury, which is manifest by increases in troponin, the same biomarker that is elevated in patients with a heart attack. The increases in troponin in COVID-19 patients are often quite marked and can . COVID-19 patients with cardiac injury are far more likely to require ICU care, mechanical ventilation and die.
Does chloroquine and HCQ worsen COVID-19-related cardiac injury? We do not know, but I am worried.
What do physicians know? First, there are no reliable observations indicating that chloroquine or HCQ favorably influences the clinical course of COVID-19. Second, there is evidence that these drugs are capable of causing serious toxicity.
Many physicians share both my skepticism about the benefits and my concern about the risks of these drugs.
When asked if there was evidence supporting the use of chloroquine and HCQ, NIAID Director Anthony Fauci, MD, "
At a White House briefing on April 21, FDA Commissioner Stephen Hahn, MD, emphasized that the agency wanted data from randomized clinical trials before considering the drugs as a "valid" treatment. On April 24, the that recommended close supervision of patients receiving chloroquine and HCQ for "off-label" use due to concerns about cardiac toxicity.
An against the use of both chloroquine and HCQ for the treatment of COVID-19, due to a lack of evidence supporting efficacy and important concerns about cardiac toxicity.
Even the French Minister of Health, Dr. Olivier Veran, , which was carried out in France with the apparent support of the French government: "Dr. Raoult's study involves 24 people. What kind of health minister would I be if, on the basis of a single study conducted on 24 people, I told French people to take a medicine that could lead to cardiac complications in some people?" A French hospital has because of concerns about lethal cardiac arrhythmias.
Furthermore, on April 3, the International Society of Antimicrobial Chemotherapy, which oversees the journal that published the Gautret-Raoult study, that the study did not meet the Society's expected standard.
The medical community has raised concerns that chloroquine and HCQ cause a form of cardiac toxicity that can be detected on an electrocardiogram. Additionally, I am worried that chloroquine and HCQ (especially at high doses) may exert serious adverse effects on the heart that are above and beyond those that can be detected by an electrocardiogram.
Might advocacy of chloroquine and HCQ for COVID-19 serve a political purpose? Since I am not a politician, I will not comment on the moral hazards of disseminating highly problematic information to millions of vulnerable medically-naive people who are desperate for a breakthrough.
I am a cardiologist who has spent his entire professional life as a strong advocate for upholding standards of evidence that should validly drive medical decision-making. And I have spent my career reporting on the adverse cardiac effects of drugs.
My message is simple. Any physician who feels compelled to prescribe chloroquine and HCQ for the treatment of COVID-19 should carefully examine the evidence that informs the balance of the risks and benefits of using these drugs in these critically ill patients. Advocating unproven and risky drugs for a serious illness during a tumultuous time is , not practicing medicine.
Disclosures
Packer has recently consulted for Amarin, AstraZeneca, Boehringer Ingelheim, Novartis, and Relypsa on issues unrelated to COVID-19. Novartis is one of several companies that manufactures hydroxychloroquine, and is conducting clinical trials with the drug for COVID-19. Packer has no financial relationship with Gilead Sciences, which is developing remdesivir for COVID-19.