Thanks to Twitter, you can now watch a doctor’s heart break in real time. Like everyone else, we’ve often made our feelings plain during the pandemic—our despondence over all the deaths, our anger over their preventability—but there’s another sort of public display that’s more special to our discipline. I like to call it publication humiliation. It comes out when you realize that the published data on a favored treatment just aren’t on your side.
There was plenty of publication humiliation to go around a couple years ago, when studies started coming out against the magical healing powers of Vitamin D. Researchers had noticed that people with low Vitamin D levels seemed to have a greater chance of developing a range of medical problems, and many serious physicians bought right in. Recent data from well-designed clinical trials suggested otherwise. Could taking Vitamin D prevent cancer or heart disease? Well, no. What about diabetes and depression? No, and no again. But heartbreak, as it often does, played out as denial. It wasn’t the treatment that was wrong; it was the science used to study it. If randomized controlled trials came out against the use of Vitamin D, that’s because they weren’t done correctly. Maybe the doses were too low to have an effect; or else, if the doses were high enough, then the timing wasn’t right. “If you are already too sick or have a disease, it is too late for Vitamin D,” one doctor tweeted when a major trial found the treatment wasn’t saving any lives. (Never mind the fact that prevention trials also come up short.)
If some doctors like to close their eyes in grief, others dig for deeper answers in the data. A “subgroup analysis”—for which you may end up picking out only the parts of a data set that happen to support your theory—is a useful tool in this regard. Doctors who were undeterred by the 26,000-person study on Vitamin D supplements and cancer quickly got to work on a second publication drawing from the same results. This one suggested that the vitamin could, at least, prevent more serious cancers … so long as you were only looking at the skinny patients. (If that hadn’t panned out, they might have tried dividing up the patients by eye color or favorite Seinfeld episode.)
The latest source of publication humiliation is convalescent plasma, the alleged Covid-19 wonder drug drawn through a needle from people who have recovered from infection. Last summer, former head of the Food and Drug Administration Stephen Hahn promised that recipients would see a “35 percent improvement in survival.” Experts quickly pointed out that he was looking at only the tiny subset of the data which was most favorable to plasma. Subgroup analysis strikes again! But still, doctors jumped at any chance to help their patients. In December alone, more than 100,000 units of convalescent plasma were given out in the US.
Our enthusiasm was not entirely unfounded. It’s reasonable to think that giving sick patients someone else’s naturally occurring antibodies might help their recovery along, even save their life, and doctors have tried convalescent plasma to treat viral illnesses at least as far back as the 1918 Spanish flu. Here’s the problem, though: The evidence for its benefit has never been very good. I can forgive those old-timey 1918 doctors, but a systematic review of published work as of 2013 drew from “predominately low-quality, uncontrolled studies.” Then this month, the most important medical study of the pandemic—the UK’s Recovery trial—put out its preliminary results on plasma, and they aren’t promising at all. Eighteen percent of hospitalized Covid patients who received the treatment died within 28 days, versus 18 percent of patients who didn’t receive plasma. You don’t need to be a scientist to understand the implication: Plasma didn’t help.
You might think this would be enough to change some minds. After all, Recovery’s simple, randomized design has been definitive for other drugs. Enrolling tens of thousands of participants, it has been able to answer our most important question about a number of potential Covid treatments: Does it actually prevent you from dying? For hydroxychloroquine or the antibiotic azithromycin, the answer was no. For the steroid dexamethasone, it was yes. Now, for convalescent plasma, it appears we have another no.
But alas, everybody knows that a broken heart is blind. Disappointed doctors have instead performed familiar parts, claiming that the dosage must have been too low or that the treatment must have been started at the wrong time. Michael Joyner, for example, was one of the leaders of the Mayo Clinic’s plasma initiative, which distributed plasma to almost 100,000 patients around the country starting last April; and he seems not at all convinced, let alone chastened, by the Recovery trial. He tweeted in response that the trial showed, at least, that plasma is safe, while the negative results were in his view “not unexpected.” Arturo Casadevall, an immunologist at Johns Hopkins and a collaborator of Joyner’s, agreed that the Recovery results “confirm what we already know from observational and other RCTs: that [convalescent plasma] has little or no effect on mortality when used late on hospitalized patients.”
To be fair, that’s been the prevailing wisdom among supporters of convalescent plasma as a Covid treatment. But if the need for early treatment had been “worked out in the early 20th century,” as Casadevall says, or known “since the 1930’s,” as Joyner claims, then why was the Mayo program itself willing to distribute plasma to late-stage patients around the country? And while the FDA did recommend high-antibody levels in its emergency use authorization of the treatment last summer, regulators put no time limits on how long after a patient becomes sick that plasma could be given. If we already knew that plasma wouldn’t work in advanced disease, then why did we give it to so many people with … advanced disease?
Now it’s true that the Recovery trial can’t answer every question that we might have about convalescent plasma. It doesn’t tell us for sure that it’s ineffective when given at the very first sign of Covid infection. It’s possible that future clinical trials, which are ongoing, will prove Joyner and Casadevall correct, that we can indeed help Covid patients by administering plasma early on. (One high-quality study did support this idea.) But at that point more practical matters will come into play: Blood transfusions will never be as easy to administer as a pill, and the treatment doesn’t easily scale. When doctors have to give a treatment early, they’re also more prone to giving it when it isn’t really needed. (Most healthy outpatients will recover from Covid on their own.) In any case, convalescent plasma is to this day authorized only for hospitalized patients, many of whom are far along in their illness. Despite the excuses we hear about the negative studies, regulators and many doctors haven’t given up on using convalescent plasma “late.”
Indeed, you don’t have to be on social media to see this pattern playing out. Doctors’ unwillingness to let go of treatments they hold dear may be just as apparent—and far more consequential—in their clinical practice. I once mentioned to an aging relative that he was now past the point when urologists typically recommend prostate cancer screening. But his own urologist would tell him otherwise: The issue wasn’t settled, that doctor said; and the benefit of screening might have been obscured in studies with insufficient numbers of older men. In fact, this urologist continued, he would personally continue to go in for prostate cancer screenings himself, for as long as he could.
For doctors, holding on can be an act of desperation. To set aside a once promising intervention—to commit to doing less for patients, instead of more—is often difficult, even heart-wrenching. But it’s important to remember that letting go is good medicine.
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