Ivermectin and Statistical Significance

By David Henderson.

"At the time this article was written, the website c19iver​mectin​.com listed 73 clinical trials of ivermectin and COVID-19, involving 56,774 patients, as having been conducted. Thirty‐​one of the studies (6,828 patients) were randomized, controlled trials. Fifty‐​two were peer‐​reviewed (18,768 patients).

A few of the studies have been challenged and even retracted for shoddy work (perhaps putting it kindly), but most have not; we will look more carefully at these studies below. Still, the aggregate results are noteworthy. The treatment group had 59% lower mortality than the placebo or standard therapy control group (examined in 34 studies involving 44,061 patients), 48% lower use of mechanical ventilation (12 studies; 2,316 patients), 57% fewer intensive‐​care‐​unit admissions (seven studies; 21,857 patients), 45% fewer hospitalizations (19 studies; 11,190 patients), 71% fewer cases (13 studies; 11,523 subjects), 52% faster recovery (23 studies; 3,664 patients), and 57% improved viral clearance (22 studies; 2,614 patients).

The FDA has approved many drugs based on less clinical research. When one of us (Hooper) worked at Merck three decades ago, the ACE inhibitor Vasotec (enalapril), one of the company’s biggest drugs, was tested in 2,987 patients before receiving FDA approval. The statin drug Mevacor (lovastatin), another of Merck’s big drugs at the time, was tested in 6,582 patients. Back then, that was considered to be a massive trial.

This is from Charles L. Hooper and David R. Henderson, “Ivermectin and Statistical Significance,” Regulation, Spring 2022.

 

On Scott Alexander

Last November, Scott Alexander, a psychiatrist and author of the science‐​heavy blog Astral Codex Ten (and, before that, Slate Star Codex), authored an extensive literature review of 11 ivermectin–COVID studies that he deemed to be of high quality. He tentatively concluded that, when ivermectin is given early in an infection, the studies indicate the drug reduces mortality by 40 percent, which is just barely statistically significant (significance: p = 0.04). Yet, he refrains from endorsing the use of the drug. Why?

To explain why, he presents a hypothesis and a prejudice (more on the prejudice below). The hypothesis is what we noted earlier: ivermectin’s benefit may come indirectly by ridding the body of parasites. The relationship isn’t direct. It has to do with corticosteroids, which are a common treatment for COVID. When patients don’t have parasites, giving them corticosteroids generally helps. But when patients do have parasites, giving the corticosteroids can cause a medical condition called hyperinfection syndrome. Hence, by removing the Strongyloides stercoralis worm infections, ivermectin may prevent potential problems with corticosteroid therapy, leading to the conclusion that ivermectin helps with COVID.

However, when the larger pool of studies is examined, they show a benefit to ivermectin of 72% in areas of low parasitic prevalence, while in areas with high prevalence the benefit is 55%. This is the exact opposite of what Alexander conjectured. Further, there is some evidence that the difference in the two areas can be partly explained by considering treatment delays — it’s better to give ivermectin early in the infection — and dosage size. In the geographic areas where the drug did better, it tended to be given earlier and at higher doses.

 

On Statistical Significance

Consider one COVID patient outcome: the need for invasive ventilation. In a randomized, double‐​blind, placebo‐​controlled clinical trial by Ranjini Ravikirti et al., of 55 patients in the ivermectin arm, only one patient needed invasive ventilation while five in the placebo group of 57 did. In other words, it appears that ivermectin reduced the need for ventilators by 80%. Yet, the study’s authors concluded, “This study did not find any benefit with the use of ivermectin in … the use of invasive ventilation in mild and moderate COVID-19.”

But one can reasonably conclude that the authors did find a benefit. A close look at their data shows 91.2% confidence that there was a difference. Because the authors used the 95% threshold, they stated that they had found no benefit.

Similarly, an observational controlled trial of 288 patients found that treatment with ivermectin allowed twice as many patients to improve and get off mechanical ventilators (36.1% vs 15.4%). But authors Juliana Cepelowicz Rajter et al. report no benefit to ivermectin because they were “only” 93% confident of the difference.

 

Scott Alexander Succumbs to Social Desirability Bias

He [Scott Alexander] further acknowledges that “if you say anything in favor of ivermectin, you will be cast out of civilization and thrown into the circle of social hell reserved for Klan members and 1/6 insurrectionists.” Not wanting to be relegated to this group of undesirables, he withholds his recommendation of ivermectin. In short, the scientific evidence led him to a tentative conclusion that he does not want to embrace because of social desirability bias. What happened to “follow the science?”

Read the whole thing."