COMMENTARY

Hydroxychloroquine RCTs: 'Ethically, the Choice Is Clear'

F. Perry Wilson, MD, MSCE

Disclosures

August 05, 2020

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This transcript has been edited for clarity.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I'm Dr F. Perry Wilson, from the Yale School of Medicine.

This week, I am going against the advice of my loved ones who feel my pain as I read some pretty rough comments online to try to address the hydroxychloroquine issue.

I know, I know.

Whenever I discuss hydroxychloroquine (HCQ), people come out of the woodwork to tell me what a bad doctor I am. Even when I made a video simply demonstrating how searching pubmed.gov works, I got some pretty rough replies.

But I guess I'm a glutton for punishment, so I've set out today to collect — in one place — the randomized trials that have been conducted that form the centerpiece for why doctors like me and Anthony Fauci don't think HCQ works for COVID-19.

Now, before we get started:

I am not paid by any pharmaceutical company, nor do I hold a patent on any drug or device. My grant funding comes from the National Institutes of Health (NIH) and the Department of Defense (DOD). My NIH studies have nothing to do with drugs. My DOD study, in fact, is looking at repurposing an old, cheap, relatively safe drug (valproic acid) for the treatment of a certain type of kidney disease. I literally study whether old, cheap drugs can be repurposed for new benefit.

Which is to say that I am really, really interested in cheap, effective ways to fight COVID-19. Because — another thing I have to remind people — I'm not just a clinical researcher; I'm a medical doctor who has spent months caring for COVID-19 patients in the wards of Yale New Haven Hospital. I don't know what else to say. I'm really just trying to synthesize the data we have.

Now, when you look for HCQ studies in COVID-19, you will find a ton — roughly 900 published at last count. The vast majority of these are observational studies.

Why do people like me put so much more weight in randomized controlled trials (RCTs) than observational studies? It's simple.


 

In an observational study, the observed effect of the exposure of interest (HCQ) on the outcome of interest is due to both its true causal effect and the characteristics of who was selected for treatment.

In a randomized trial, because the selection is random, the observed effect is due solely to the true effect of the treatment.

That's why we put so much stock in RCTs. Before RCTs are available, observational data are okay; we can use them to generate hypotheses. But observational studies should be used to design RCTs, and RCTs should be used to guide therapy. Hence my focus today on the extant RCTs.

But to illustrate, I'll give one observational example, since I think 100 people have emailed it to me in the past week.

This is one of Didier Raoult's studies, appearing in Travel Medicine and Infectious Disease. They report on 3737 patients with COVID-19. These were mostly outpatients, and the study states that, barring contraindications, they were prescribed 200 mg of HCQ three times a day for 10 days, with 5 days of azithromycin. They then compared the 3119 people who took that regimen for at least 3 days with 618 who didn't.

In the observational setting like this, the key question is, why did they not take the medications? Looking at Table 1 in the paper, we can see that at baseline, these groups are quite different.


 

Those who took the standard therapy tended to be younger; 53% were under age 44 compared with 36.4% who got the other treatments. They had less cancer, less diabetes, less chronic heart disease, and lower NEWS scores, which is a measure of disease severity. In other words, this was a group poised to do well. The treatment wasn't assigned randomly; it was given to the healthiest. That's not unethical or anything, by the way. It's totally reasonable to be careful about who you give drugs to. It just makes it harder to interpret the results.

And the results were better in the group who got the HCQ regimen: 0.5% death rate compared with 3.1% death rate.

From Lagier JC, et al. Travel Med Infect Dis. 2020;36:101791. doi:10.1016/j.tmaid.2020.101791

Now, you can adjust for baseline differences. Here, they adjusted for that severity score and comorbidity score — not age or anything else — and still found significance. But let me highlight two issues with adjustment.

First, adjustment isn't magical. You have to adjust for all the factors that are different at baseline to get an unbiased estimate of treatment effect.

Second, you don't know all those factors. You can only adjust for what you measure. Unmeasured differences in the groups will always be present, with one exception.

You guessed it. If you randomize, you will balance not only measured differences but even unmeasured differences between the groups.

That's why clinical epidemiologists like me get so psyched about randomization.

Hopefully, I've convinced you that randomization is where it's at. And with that, I will present the five peer-reviewed randomized trials that (to date) have been published on HCQ and COVID-19. I'll also review one preprint, since it's by the same group that did the dexamethasone study. We'll do them in published chronological order, then the preprint.

Caveat: I may have missed a trial here or there, and more are coming. We are never done learning; we just let the evidence make our conclusions more or less firm.

Study number one: A study appearing in the BMJ.

One hundred and fifty hospitalized patients in three provinces in China were randomized to receive either 1200 mg of HCQ for 3 days followed by 800 mg daily for 2-3 weeks or usual care. There was no placebo in this study. The groups were well balanced because this was a randomized trial.

The primary outcome was absence of virus PCR on nasal swab at 28 days; 85.4% cleared the virus in the HCQ group compared with 81.3% in the usual-care group — not a statistically significant difference, with a P value of .34.

From Tang Wei, et al. BMJ. 2020;369:m1849

The adverse event rate was 30% in the HCQ group and 9% in the usual-care group.

Study number two: A study appearing in The New England Journal of Medicine.

Eight hundred twenty-one asymptomatic patients with a high-risk exposure to someone with COVID-19 were randomized to receive HCQ 800 mg once, followed by 600 mg 6-8 hours later, then 600 mg for 4 days vs placebo. The groups were well balanced because this was a randomized trial.

The primary outcome was the incidence of COVID-19 at 14 days: 11.8% of those receiving HCQ vs 14.3% of those receiving placebo hit the outcome, a nonsignificant difference with a P value of .35.

© The New England Journal of Medicine (2020)

The adverse event rate was 40% in the HCQ group and 17% in the placebo group.

Number three: a study appearing in the Annals of Internal Medicine.

Four hundred ninety-one nonhospitalized adults with COVID-19 or high-risk exposure were randomized to the same regimen from that New England Journal of Medicine trial or placebo. The groups were well balanced because this was a randomized trial. The primary outcome was change in symptom severity at 14 days.

From Skipper CP, et al. Ann Intern Med. 2020 Jul 16.

The HCQ group improved by 2.6 points and the placebo group by 2.3 points, a nonsignificant difference with a P value of .12. There was no difference in effect among the 24% of the study population who reported zinc supplementation, by the way. The adverse event rate was 43% in the HCQ group and 22% in the placebo group.

Number four: A study appearing in the journal Clinical Infectious Diseases.

Two hundred ninety-three nonhospitalized individuals with early COVID-19 were randomized to 800 mg HCQ on day 1 followed by 400 mg daily for 6 days vs usual care. There was no placebo in this study. The groups were well balanced because this was a randomized trial. The primary outcome was reduction of viral RNA load in nasal swabs at 3 and 7 days.

The viral load went down by 3.44 logs in the HCQ group and 3.37 logs in the usual-care group, a nonsignificant difference. The adverse event rate was 72% in the intervention arm and 8.7 % in the usual-care arm.

Number five: Another NEJM study.

Six hundred sixty-seven patients hospitalized with COVID-19 and on 4 L of oxygen or less were randomized to receive 400 mg HCQ twice daily, 400 mg HCQ twice daily plus azithromycin, or usual care for 7 days. There was no placebo in this study. The groups were well balanced because this was a randomized trial. The primary outcome was clinical status at 15 days on an ordinal scale.

© The New England Journal of Medicine (2020)

There was no significant difference in the outcome rates at day 15 for either of the treatment groups compared with usual care. The adverse event rate was 39.3% in the combined-therapy group, 33.7% in the HCQ group, and 22.6% in the usual-care group.

And finally, the preprint.

Again, I am showing this because this study, appearing (for now) on medRxiv , is from the RECOVERY trial group. They are the ones who published the randomized trial showing that dexamethasone (a cheap, widely available drug) reduced mortality in severe COVID-19. It's a talented group. They want to find cures. Anyway, they randomized 4716 hospitalized patients with COVID-19 to 800 mg of HCQ at entry and 6 hours, followed by 400 mg every 12 hours for the next 9 days or until discharge vs placebo. The groups were well balanced because this was a randomized trial. The primary outcome was all-cause mortality at 28 days.

From Horby P, et al. medRxiv 2020.07.15.20151852. doi: https://doi.org/10.1101/2020.07.15.20151852

At 28 days, 26.8% of the patients in the HCQ arm and 25% of those in the usual-care arm had died, a nonsignificant difference with a P value of .18.

Let's put these together:


 

I am not going to say that HCQ has no effect on COVID-19. We can never be 100% sure of that. But I am sure that if it has an effect, it is quite small. Think of a world where HCQ was a miracle cure for COVID-19. Think how different all of these randomized trials would look. It would be immediately obvious.

Straight talk: HCQ is unlikely to kill you. It will kill someone (rare cases of torsades de pointes occur), but it is unlikely to be you or your patients. It really is a relatively well-tolerated drug. But there are adverse effects, as all of these trials show. And given that, our ethical obligation to "first, do no harm" is paramount here. There simply is not good evidence that HCQ has a robust effect, and there is evidence of at least moderate harm. Ethically, the choice is clear.

A few final caveats. Yes, only one of these trials reported on the use of zinc with HCQ (no effect, by the way). But two things on that particular issue: First, we know that many individuals take zinc supplements, so if, as the argument goes, HCQ is a miracle cure when given with zinc, you'd still see a benefit in an HCQ trial because a subset of people — maybe 25% — are taking zinc.

The zinc issue falls into this "no true Scotsman" land of HCQ studies. Any negative study can be dismissed: "Oh, you didn't give it early enough, or late enough, or with zinc, or with azithromycin, or on Sunday," or whatever. That's not how science works. I'm not saying that any of these studies are perfect, just that they are the best evidence we have right now. The burden of proof is to show that the drug works. Though I'm sure that pharma would be stoked to be able to argue that their latest negative trial can be ignored because their billion-dollar drug wasn't given in concert with vitamin C or whatever.

Yes, I know that another Yale professor is saying that HCQ can save lives.

And to those of you who have pointed out that he is a full professor while I am a mere associate professor, you really know how to hurt a guy. I have no idea why he wrote that article and didn't mention any of the randomized trials. But I embrace the academic freedom that he and I both have to present our best interpretation of the data.

Science is ever-learning, ever-developing. More trials will come out and we need to integrate those results into these results to make decisions. We need to let new, high-quality evidence change our beliefs. I am willing to do that. I hope that you are too. But I want randomized trials. Because — if I didn't say it enough — randomization ensures that the treatment and control groups are well balanced, and that makes all the difference.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale's Program of Applied Translational Research. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @methodsmanmd and hosts a repository of his communication work at www.methodsman.com.

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