Drs. Vladimir Zelenko and Stephen Smith: Abandoning evidence-based medicine to promote unproven drugs for COVID-19

If there’s one thing that the coronavirus pandemic has revealed, it’s just how weak physicians’ dedication to science- and evidence-based medicine truly is. Facing COVID-19, doctors have embraced protocols to treat the virus based in the thinnest of evidence, or even no evidence. I discussed this phenomenon yesterday, using as my example the rapid, near universal embrace of the anti-malaria drugs (which are also used to treat rheumatoid arthritis, lupus, and some other autoimmune diseases) chloroquine and hydroxychloroquine, even though the evidence base for them is anecdotal and the existing clinical evidence is either negative or very, very weak. It’s worse than that, though. Now we have doctors like Dr. Vladimir Zelenko and Dr. Stephen Smith promoting the use of hydroxychloroquine and azithromycin, even though the evidence for this drug combination comes entirely from a truly awful study by French “brave maverick scientist” Didier Raoult. Worse still than even that, these two physicians are actively feeding the right-wing quackery promotion machine touting all manner of “miracle cures” for COVID-19. Before I discuss these doctors, here’s a bit of background.

How did these drugs even come to be studied? To recap, based on the observation of 80 patients, Chinese doctors in Wuhan noted that no patients with lupus erythematosis became ill with COVID-19 and hypothesized that the chloroquine or hydroxychloroquine that they were taking might be the reason. (These drugs are also mildly immunosuppressive, hence their use to treat autoimmune diseases.) Of course, during a pandemic, it is people who are immunosuppressed are the very people who most rigorously obey orders to practice social distancing and self-quarantine and thereby protect themselves from infection. Be that as it may, the Chinese doctors started using the antimalarial drugs, and anecdotal evidence of success was reported, leading to randomized clinical trials that were announced by the Chinese government to have been “promising.” (None have been published yet, other than a study published as a preprint last week with so many issues that it shows, in essence, nothing.) None of this stopped China from incorporating these drugs into its recommended regimen. The World Health Organization followed suit, as did several countries, and thus was born a new de facto standard of care for COVID-19 based on, in essence, no evidence other than some in vitro evidence that the drugs inhibit replication of SARS-CoV-2, the virus that causes COVID-19, anecdotes, and incredibly weak clinical trial evidence.

As for the combination of azithromycin/hydroxychloroquine combination, its rise is directly traceable to Didier Raoult, a scientist with a history of data fabrication and irresponsible self-promotion to a level that he has been described as “Trumpian.” He published one study that claimed that the combination of these drugs eliminated SARS-CoV-2 (the virus that causes COVID-19) from the body. It was a study so riddled with methodological flaws as to demonstrate nothing, and his followup study was a singularly uninformative case series. The widespread adoption of drugs that have significant toxicities to treat COVID-19 before there anything resembling adequate evidence has been a massive failure of science-based medicine. Worse, given that the FDA granted emergency use authorization to use hydroxychloroquine and chloroquine to treat COVID-19, we might never know if these drugs are clinically effective because no patient is going to want to risk being randomized to the placebo group in the randomized clinical trials doctors are scrambling to try to complete right now.

Enter Dr. Vladimir Zelenko, who was featured in the New York Times yesterday:

The source was Dr. Vladimir Zelenko, 46, a mild-mannered family doctor with offices near the village. Since early March, his clinics had treated people with coronavirus-like symptoms, and he had developed an experimental treatment consisting of an antimalarial medication called hydroxychloroquine, the antibiotic azithromycin and zinc sulfate.

After testing this three-drug cocktail on hundreds of patients, some of whom had only mild or moderate symptoms when they arrived, Dr. Zelenko claimed that 100 percent of them had survived the virus with no hospitalizations and no need for a ventilator.

“I’m seeing tremendous positive results,” he said in a March 21 video, which was addressed to President Trump and eventually posted to YouTube and Facebook.

Here’s an example of the sorts of videos that Dr. Zelenko has been posting to social media:

Meanwhile, Dr. Zelenko has been making claims like this:

Zelenko is one of a handful contending it should be in widespread distribution to people at higher risk of having a serious case of Covid-19 with mid-level symptoms, most often without even confirming their illness is in fact connected to coronavirus.

He wrote in the emails sent on Friday that his clinic had so far given 669 outpatients the drug cocktail, and that none had died. He attached a spreadsheet in which he listed 54 high-risk cases, including three who required hospitalization.

In an interview Friday, Zelenko encouraged doctors to resist calls from infectious disease experts to prescribe the drug only as part of clinical trials and to critical patients.

“This is a World War III situation — it’s the virus versus humanity,” he said. “If we were to adopt their approach, there would be an extra million dead people.”

There is, of course, zero evidence that withholding hydroxychloroquine from mild cases of COVID-19 will result in an extra million deaths. Dr. Zelenko’s actions and words have been truly irresponsible and unethical. It’s made him very famous, though:

Sean Hannity, the Fox News host, quickly promoted Dr. Zelenko’s claims on his TV and radio shows. Mark Meadows, the incoming White House chief of staff, called Dr. Zelenko to ask about his treatment plan. And Rudolph W. Giuliani, Mr. Trump’s personal lawyer, praised him in a podcast interview this week for “thinking of solutions, just like the president.”

And:

In a phone interview from his home, where he has been in self-isolation, Dr. Zelenko, who goes by Zev, described a dizzying week filled with calls from media and health officials from countries including Israel, Ukraine and Russia, all seeking information about his treatment. Some world leaders, including Brazil’s president, Jair Bolsonaro, are also talking up some of the same drugs as a cure.

“It’s a very surreal moment,” said Dr. Zelenko, who has been practicing medicine for 16 years. “I’m a simple country doctor, you know. I don’t have connections.”

I love the whole “simple country doctor” shtick. Dr. Zelenko is anything but. He has, if anything, shown himself to be a master of Trumpian self-promotion, having become a social media (and old media) star almost overnight by promoting Didier Raoult’s cocktail (plus zinc). He’s even appeared on Rudy Giuliani’s video podcast. There is, however, an interesting update in the NYT article. In earlier videos, Dr. Zelenko has bragged that none of his patients had required a ventilator. In this article:

While dealing with his newfound fame, Dr. Zelenko, who has been practicing telemedicine from his home office, is working to keep his coronavirus patients alive. He said his team had seen about 900 patients with possible coronavirus symptoms, treating about 350 with his regimen. None had died as of Thursday, he said, though six were hospitalized and two were on ventilators.

Can you say “selection bias”? Sure, I knew you could. I predict that, as the pandemic continues, more and more of Dr. Zelenko’s patients will wind up hospitalized, with more winding up on ventilators. He’s been treating patients with mild disease, and, as time goes on, more of those will progress to severe disease.

Here’s the thing. All Dr. Zelenko has is a spreadsheet of some of his patients. I found an image of it, and, as data, it’s a joke. The lack of detail, specifically whether a patient tested positive for COVID-19 or was “clinically diagnosed,” is woeful. Basically, you can’t tell anything from it. It doesn’t even qualify as a well-documented case series. Worse, the combination of azithromycin and hydroxychloroquine can cause fatal cardiac arrhythmias. Dr. Zelenko’s actions are profoundly unethical, as he is prescribing drugs willy-nilly to everyone with COVID-19-like symptoms that are not without risk. That spreadsheet is also a major violation of patient privacy. (HIPAA violation, anyone?)

For a case series testing drugs like these on COVID-19 patients to be even minimally informative, there need to be: rigorous diagnostic criteria, rigorous criteria for who is treated, close followup with objective parameters measured (in this case, time to clear the virus would be useful information), and careful data analysis. Even then, observational case series provide the weakest form of evidence. There are rare cases when they can demonstrate efficacy of a treatment, for instance a normally 100% fatal disease in which a high percentage of the treated patients survive, but these sorts of situations are quite uncommon. The vast majority of the time, case series, even well-done and rigorously reported ones, are not very useful for answering the question of whether a treatment is efficacious, and Dr. Zelenko’s case series is anything but rigorous or well-reported. To my mind, it’s no different than Dr. Mayer Eisenstein’s claim that he observed no autism in his unvaccinated patients.

Unfortunately, Dr. Zelenko is not alone. Wednesday night, an infectious disease specialist named Dr. Stephen Smith, founder of the Smith Center for Infectious Diseases and Urban Health, appeared on right wing Fox News propagandist Laura Ingraham’s show to make similar exaggerated claims for hydroxychloroquine, going so far as to call it an “absolute game changer” and the “beginning of the end of the pandemic.”

I will credit Dr. Ramin Oskoui, a cardiologist, for starting out by sounding a cautious note about how chloroquine and hydroxychloroquine can cause dangerous cardiac arrhythmias in a small percentage of patients and recommending a baseline EKG and regular EKGs during the treatment. Then Dr. Smith launched into his uncontrolled case series:

He notes that in his practice that nearly all of the patients who were intubated were diabetic or prediabetic. One thing that stood out is that two out of “over forty” patients developed EKG changes, which he seemed to view as unimportant. Consider this: that’s as much as 5% of patients. Scale that up to giving the drug to thousands of patients, and there will be a lot of cardiac toxicity; so the drug had better work if you’re going to recommend it, particularly to asymptomatic healthcare workers as a prophylactic or as prophylaxis after exposure to COVID-19.

Here’s another excerpt:

He pointed out that not a single COVID-19 patient of his that has been on the hydroxychloroquine and azithromycin regimen for five days or more has had to be intubated.

“The chance of that occurring by chance, according to my sons Leon and Hunter who did some stats for me, are .000-something,” he said, adding that “it’s ridiculously low.”

I call bullshit here. Dr. Smith dismisses the possibility that his reported results are due to selection bias, but he doesn’t show his work. Your sons did a “statistical analysis”? Show it! And what are the qualifications of your sons to do such a “statistical analysis,” anyway? Such a statistical analysis would depend very much on the assumptions made regarding the endpoints examined. Without knowing those, it’s impossible to judge whether the statistical analysis has any validity whatsoever. I say that Dr. Smith is pulling figures out of his nether regions.

Sadly, if there’s anything that the COVID-19 pandemic has revealed, it’s how weak physicians’ dedication to science- and evidence-based medicine is. I understand. Fear will do that. Many of my colleagues who are on the frontlines and lack adequate personal protective equipment are desperate for anything that will help keep them safe as they take care of COVID-19 patients. There is also a profound feeling of helplessness that overwhelms us as physicians when we face a disease for which we have nothing to offer other than supportive care and hope that patients can ride out the disease and emerge alive at the other end. It’s a humbling and terrifying combination. Moreover, it is all too often ingrained in the culture of medicine that we must “do something” at all costs. Physicians do not tolerate helplessness well.

I’m sure that Dr. Zelenko and Dr. Smith believe they’re helping patients, but they also strike me as, like Didier Raoult, having come to like their newfound fame just a wee bit too much. (In the case of Raoult, it’s clearly a way bit too much.) To be sure, in an emergency like a pandemic, there is a role for trying treatments for which the evidence is less than robust in the name of rushing potentially effective treatments to dying patients. Unfortunately, we already know enough about hydroxychloroquine, chloroquine, and combinations with azithromycin to know that these treatments are almost certainly not “game changers” or the “beginning of the end of the pandemic.” They might have some efficacy, but if they were truly “game changers,” we’d already have evidence of it by now. It is indeed still possible that these drugs impact the course of COVID-19, but it is also possible that, being immunosuppressive and having well-known effects on the heart, they could result in harm without benefit. After all, the history of these drugs as antivirals is checkered and mixed, at best. We will never know for sure if trials are not completed, and, right now, doctors like Drs Zelenko and Smith are hindering progress towards that end, which in the end is far more likely to harm large numbers of patients than help them.

Doctors also need to remember: There’s a political purpose behind the promotion of these drugs by the right wing, and it’s most definitely not to help patients. Rather, the purpose is to weaken the FDA, decreasing its authority and lowering the bar for drug approval as part of an ideological opposition to government regulation, and divert attention from the Trump administration’s criminally incompetent response to the COVID-19 pandemic. To the degree that Drs. Zelenko and Smith participate in that propaganda campaign, they will be complicit in the deaths of far more people than these drugs could potentially save, even if randomized clinical trials ultimately demonstrate them to be effective.