An apology and an excuse
I want to start with another apology for being away from this blog for so long. At the beginning of the pandemic my time was occupied with the changing policies and procedures at the clinic, and preparing for a new reality. Of late we have opened a "respiratory clinic" where cases of respiratory illnesses can be assessed without going to the ER. The purpose of this was twofold: to keep our regular clinic somewhat isolated from possible COVID-19 cases and to help keep our ER open for more serious cases since these "moderate severity" cases were left with no where to go. And most of my online presence has been trying to bring an informed scientific perspective to a lot of the conversations on FB--that's not always welcome in this cultural climate.
Purpose of this post
So I want to try to provide insights into a few of the many articles that occupy the rest of my time at work. This one is about the recent news from Dr. Fauci about the positive results from a recent study on Remdesivir to treat COVID-19. With how fast the news cycle is these days, this is old news (it's only been a week?!). I didn't see the Task Force News Briefing that day, but I heard Dr. Fauci was almost giddy when he announced that Remdesivir had shown promise as an effective treatment in a preliminary study. Since then, it has come out that he released this information before the study had been peer-reviewed to get ahead of "leaks" in the White House. That rationale is beyond me, but this post is not about that. I just want to provide you with a synopsis of the study. It was published online in the The Lancet on 29 April 2020.
Skip this section if you don't care to read about the design.
It was a well designed study performed at multiple hospitals in Hubei, China. It was placebo controlled, meaning there was a treatment arm and an arm that received a placebo. It was double blinded, meaning that neither the patient nor the treating staff knew whether the patient was receiving a placebo or the treatment. This is the gold standard for scientific studies. Patients who had respiratory compromise (they had specific definitions of this) and tested positive for SARS-COV-2 (the virus that causes COVID-19) were admitted to the hospital and randomized (the other component of the Gold Standard) in a 2:1 ratio (there were twice as many patients in the treatment group as in the placebo group). 237 patients were enrolled. The treatment group received Remdesivir, a nucleoside analogue that had been developed by Gilead to treat Ebola and Marburg, but was not effective for either. I've read that it had some effect against SARS and MERS, but I have not read those reports myself. A nucleoside analogue gets incorporated into the RNA of the virus instead of adenosine (remember the A of AGTC/U from high school biology? see the movie GATACA) during replication and mucks everything up, with the anticipated result of less active virus being replicated.
The key results (go to Summary if you don't want the details)
On average, the treatment group recovered about 1 day more quickly than the control group. This was not a statistically significant difference.
The rate of improvement trended to be quicker in the treatment group, but this was not statistically significant.
There was no difference in mortality between groups 28 days after admission (Remdesivir did not improve survival).
The average length of time the treatment group required mechanical ventilation was less than the control group by about 4 days, but, again, this was not a statistically significant difference (although the number requiring ventilation was quite small in both groups).
The treatment group required an average of two fewer days on supplemental oxygen than control (again, not a statistically significant difference).
Length of stay in the hospital was no different between groups
Of those who died, the treatment group died more quickly by about a day (again, not statistically significant).
The viral load decreased steadily in both groups at the same rate; there was no difference in viral load at any time, whether treated or given placebo.
Interestingly, the few small differences in adverse effects reported occurred more commonly in the control group.
Summary
There was no appreciable difference between the treatment group and the control group. There might be a tendency to recover more quickly with treatment, but we cannot say that with certainty from this study. Additionally, the treatment did not affect the viral load (the putative mechanism of action for Remdesivir). So if Remdesivir does something in COVID-19, how is it exerting that effect?
What we really care about in finding a treatment for COVID-19 is a) does it save lives, b) does it save resources, c) does it improve other outcomes (like how quickly people recover or whether there are any long-term sequelae). This was a well done, albeit not large, study that provides no convincing evidence of any of those ultimate concerns. Indeed, it seems to be pretty good preliminary evidence that, barring larger studies that show more significant differences, Remdesivir is not what we are hoping for. We should (and are) looking elsewhere.
N.B.
Despite randomization, groups will sometimes have important differences. On admission to this study (after randomization), a slightly greater percentage of the patients required high flow oxygen or non-mechanical ventilation (e.g., CPAP or BiPAP) in the treatment group (18%) vs. the placebo group (12%). Otherwise, the severity of the disease was similar between groups (i.e., "no oxygen required" (0% vs. 4%), "supplemental oxygen (non-high flow) required" (82% vs. 83%), invasive mechanical ventilation or ECMO (0% vs. 1%), or death (1% vs. 0%)). Likewise, initial treatments (antibiotics, steroids, etc.) and initial viral loads were similar between groups. There were more patients with coronary artery disease (9% vs. 3%), diabetes (25% vs. 21%), and hypertension (46% vs. 38%) in the treatment vs. control group. This could suggest that the treatment group was "sicker" to begin with, and that the potential treatment differences were muted by these patients. It will take more studies to tease this possibility out.
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