After writing about remdesivir last week, I had a number of people email me and ask what there is to lose by trying remdesivir in patients before a randomized trial has shown that it has benefit. It’s easy to think, “well, this compound seems to work against the virus, so how can we afford not to give remdesivir to patients? After all, didn’t those doctors in Chicago see amazing effects from the drug, with fevers dropping and rapid clinical improvement? Weren’t other doctors able to take their patients off ventilators and ECMO after giving remdesivir for compassionate use?”
So what the hell do we have to lose?
A plausible biologic mechanism doesn’t mean a treatment works or is safe
The medical literature is filled with examples of treatments and medications that either failed to fulfill their initial promise or were actually harmful to the people who took them when studied in a rigorous way.
Take a look at heart disease. The cholesterol ester transfer protein inhibitors (CETP) were supposed be to medications that completely changed the face of how manage cholesterol to prevent heart attacks. Torcetrapib is a drug that raised good cholesterol (HDL) and lowered bad cholesterol (LDL). In 2006, the CEO of Pfizer publicly announced that it would be “one of the most important compounds of our generation.” But when tested in a randomized clinical trial, we found that even though it impacted cholesterol in the way it was supposed to, torcetrapib increased deaths in patients who took it compared to placebo.
Take a look at diabetes. The drug Avandia (rosiglitazone) lowered blood sugar and increased the effectiveness of a patient’s own insulin without the use of frequent injections and no risk of low blood sugar. But then we found that in randomized trials that it increased risk of congestive heart failure and heart attacks compared to other diabetes medications.
Take a look at high blood pressure. Atenolol was one of the most popular antihypertensive drugs for years. It lowered blood pressure effectively without risks of dehydration and electrolyte problems. But then a randomized trial showed treatment of high blood pressure with atenolol had a higher risk of heart attacks and strokes compared to other blood pressure medications.
You can also look at Vioxx for treating arthritis, vitamin E for prevention of cancer, surgery to repair a torn meniscus, or suppressing irregular heart beats after cardiac surgery as other treatments that seemed to make sense and then were shown to either be ineffective or frankly harmful. Medical reversal is a real thing, and it causes real harm.
In other words, the road to hell is paved with biologic plausibility.
The danger of using surrogate markers to evaluate success
Another important point to note is that how a clinical trial is designed matters. Look at some of the examples above - lots of treatments seem to work when we look at a surrogate endpoint but fail when tested with a real endpoint that we care about. Just because it makes sense that something would work based on our understanding of the biology doesn’t mean that it works in reality. And there can be unintended consequences with any intervention, which is why doing trials is vital!
I tell my patients a version of this all the time. I don’t actually care what your blood pressure is, I care whether you have a stroke. It doesn’t matter if you have low cholesterol if you’re going to have a heart attack anyway. Does anyone consider a diabetes drug a success if it lowers blood sugar but leads to congestive heart failure and a higher risk of death?
Just because remdesivir works in a test tube to inhibit a virus and seems to bring down fevers in patients with COVID-19 doesn’t mean that it’s life saving.
So the recent protocol change in the remdesivir trial to adjust endpoints matters because it impacts how we interpret the trial. In COVID-19, we don’t actually care about improving on a 7 point scale - what is now being evaluated - we care about getting off a ventilator and surviving.
The opportunity cost of these cycles of hype
We’ve had over 750,000 confirmed COVID-19 infections in America and over 40,000 deaths to date (as of 4/20/20). We still have no idea whether any of the treatments that we’re using have any impact over placebo.
I know that a lot of brilliant researchers are actively designing trials and enrolling patients to see if different treatments work in COVID-19. We need to give them time to conduct trials and figure out what works. These media cycles of attention, first for hydroxychloroquine and now for remdesivir, take our eye off the ball. There’s reason to be optimistic, but there isn’t reason to believe that we already have the solutions available if only we would start using them more.
I certainly hope that remdesivir is a miracle drug! But there’s a difference between hoping something works and hyping it as though we already know that it does.