April 13 2020
On April 10th, The New England Journal of Medicine (NEJM), arguably, the most influential medical journal in the World, published original article “Compassionate Use of Remdesivir for Patients with Severe Covid-19”.
Here are the highlights and some critique of the study:
Clinical improvement was observed in 36 of 53 patients (68%); this is good;
There are multiple limitations to the study although:
The first factor undermining significance of the data is “compassionate” use of medications;
It is not clear how patients were selected. It is well-known that the total of several hundred patients received the drug on compassionate use basis. What happened to the rest, beyond these 53 patients?
Absence of randomization;
Absence of the control group;
Lack of information of what happened to 8 patients whose date were not analyzable and the absence of explanations why;
Inclusion of patients with very different prognosis at the baseline: from those who were on low dose oxygen who were likely to survive without intervention, while 57% of patients were receiving mechanical ventilation;
The cut off for the patients who were not on mechanical ventilation was quite generous: oxygen saturation of 94% or less on ambient air. Every clinician knows that there is a big difference between patients with formally low oxygen saturation - <89%, and those who are hovering in “low 90s”;
There is no information on the oxygen flow rate, use of masks vs. nasal cannulas, etc.;
The age brackets were <50 y.o., 50-70 y.o, and >70 y.o., approximately 30% in each category. We all know that mortality increases multifold with age. Not surprisingly, patients who were <50 y.o. did better than 50-70 y.o. and those who were >70 y.o. did worse than the first two groups. We do not need a study to come to this conclusion;
Viral load was not measured. This would be important to confirm the antiviral effects of remdesivir or any association between baseline viral load and viral suppression, if any, and clinical response;
The duration of remdesivir therapy was not entirely uniform in our study, largely because clinical improvement enabled discharge from the hospital. This means that some patients received the drug on compassionate use basis despite improving without it;
There is no accounting for difference in treatment protocols between multiple institutions in several countries involved;
There is no data on co-morbidities and pre-hospitalization baseline performance of the patients;
18 out of 56 authors work for the manufacturer.
Dr. Why: in conclusion, the publication of this compassionate use data is premature and serves no scientific or practical purpose. It will also worsen the frenzy amongst patients and clinicians in the effort to obtain the drug while distracting them from what matters most: supportive and thoughtful medical care. The only reasons to publish this in the rush is to promote manufacturer interest and to get authors a credit for publication in a peer-reviewed journal.
This makes me question judgement of NEJM editors who allowed this to happen.