The Wall Street Journal just published a fascinating Op-Ed written by Joseph Ladapo, a physician at UCLA.
This is a provocative and thoughtful piece, in which Dr. Ladapo suggests that excessive caution has led physicians to avoid optimal treatments for patients with COVID, arguing that requiring too high a bar of evidence for our treatments does real damage to our vulnerable patients:
“The penchant for certainty is visible in the frequently updated treatment guidelines for Covid-19 from the National Institutes of Health. These guidelines were developed by scientists around the country, but because of a mentality that is biased toward virtually irrefutable evidence, no distinction is made for treatments with evidence for effectiveness that falls below the mark of certainty. This framework almost certainly has contributed to many avoidable deaths during this pandemic.”
Are we really harming our patients as a consequence?
Let’s take a look at his argument.
What does he claim we are doing wrong?
His major critique of the way doctors have been treating patients in the pandemic boils down to this: We are requiring too high a bar of evidence before deploying effective treatments for our patients.
Dr. Ladapo suggests that we should be using a few medicines more regularly for patients with COVID early in the course of disease:
Fluvoxamine (an antidepressant)
Ivermectin (a drug used to fight parasite infections)
Hydroxychloroquine (a drug used for autoimmune conditions)
By treating patients with these medicines early in the course of their illness, he argues, we could be doing something rather than the watchful waiting that we’ve been doing: “most physicians have been telling Covid-19 patients to quarantine and hope for the best rather than prescribing early treatment.”
Although this is a provocative and thought-provoking article, I don’t find it persuasive. The piece is filled with flawed arguments that ultimately don’t convince me of anything.
Let’s take a look at why.
Doctors actually aren’t withholding treatments that we think are useful
When it comes to this pandemic, most doctors have had the philosophy of “try first” rather than “trial first.”
Think about all of the hospital protocols giving everyone hydroxychloroquine and azithromycin at the beginning of the pandemic.
Think about the rush to use remdesivir before we had clinical trial data showing it was marginally helpful.
Think about the tens of thousands of patients who received convalescent plasma before a randomized trial showed it didn’t do much.
Think about all of the data published on giving blood thinners to COVID patients without blood clots without solid data to back up its use.
The argument he makes - quoted below - that we’ve had too high a bar for evidence strikes me as exactly the opposite of what I’ve witnessed and what has been reported/published:
“Because of a mentality that is biased toward virtually irrefutable evidence, no distinction is made for treatments with evidence for effectiveness that falls below the mark of certainty. This framework almost certainly has contributed to many avoidable deaths during this pandemic.”
So I just don’t buy that this is happening with COVID.
This argument isn’t just wrong about COVID, it’s wrong about doctors in general
Doctors aren’t exactly the most humble group of people that you will meet.
When doctors think that we know better than the guidelines, we almost always do what we think is the right thing for our patients.
That doesn’t mean we’re right - often the opposite - but fear of straying too far from the guidelines is simply not the way most doctors practice.
Professional societies have had to run massively expensive “Get with the Guidelines” campaigns to try to improve subpar adherence to guidelines among doctors who treat things like heart failure, heart attacks, and strokes.
But this isn’t the only reason that Op-Ed is wrong.
The trials he cites are incredibly flawed
He cites randomized clinical trials on fluvoxamine and ivermectin as well as a pre-print of a meta-analysis of hydroxychloroquine to make his points.
I read all of these papers.
I’m surprised that the conclusions that he drew from these is that we should be using these medications more based on the evidence that we have.
The evidence is just nowhere near as strong as he makes it sound.
Fluvoxamine
The fluvoxamine trial looked at patients with mild COVID infection given fluvoxamine and placebo and then followed for a month. They found that 6 patients in the fluvoxamine group had “clinical deterioration” as measured by clinical status on a 7 point scale. This is about 8% of patients in the study population.
A big problem here is the 20% of the patients were lost to follow up during the course of study. When the event rate of the bad outcome is lower than the percent lost to follow up, you need to take study results with a grain of salt.
With such a small sample size and such a small rate of clinical worsening, it’s a big leap of faith to say that there are any real conclusions we can draw here.
Ivermectin
The ivermectin trial that he cites is similarly weak.
In this study they took 200 health care workers and assigned 100 to receive only protective equipment and 100 to protective equipment plus ivermectin.
They found that 2 health care workers in the ivermectin group tested positive for COVID and 10 tested positive in the PPE-only group.
There was no placebo. There is no documentation about how frequently the groups were tested. There is no report about severe infections, hospitalizations, or deaths.
Since ivermectin is usually given as a single dose, even if we take these results at face value, we don’t learn anything about how long protection lasts.
I’m certainly not ready to start taking it myself based on this single, short term trial.
Hydroxychloroquine
I’ve gone over hydroxychloroquine more than once in this newsletter. I’m not impressed with the data.
It doesn’t seem to protect against COVID if you take it after you’re exposed. Really, it doesn’t.
It doesn’t seem to improve clinical status in patients already infected.
It doesn’t save lives when you’re sick enough to be hospitalized.
I will never understand the ongoing fixation with a medication that, at best, would have a marginal impact on the outcome of treating this disease. Yet the discourse on it continues.
Someday, when historians write about the COVID-19 pandemic, someone will tell the story about hydroxychloroquine. It’s sort of a perverse version of Godwin’s law, where the longer a COVID conversation goes on, the probability of hydroxychloroquine being mentioned approaches 100%.
The bottom line: a higher burden of proof is a good thing
I wouldn’t want to be treated by doctors who interpreted the evidence that loosely to give me hydroxychloroquine, ivermectin, and fluvoxamine with mild COVID infection.
Drugs that have small benefits and real side effects don’t always lead to a net positive in outcomes.
It’s tempting to want to prescribe medications to make people feel better or recover from illness more quickly because COVID makes us feel so helpless.
But I think that this piece is wrong about that.
I also think Dr. Ladapo makes a bit of a straw man argument when he says that this framework has led to many avoidable deaths but then provides evidence for treatments that only seem to have a role in treating mild disease.
This piece is certainly worth reading as an argument for liberalizing some outpatient COVID treatments. Ultimately, though, I simply disagree with his conclusions and looking at the weak evidence he cites doesn’t convince me otherwise.
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