Ivermectin proponents point to in vitro studies as proof of efficacy
One problem: the dose required in vitro (IC50) to inhibit #COVID is 30-90x higher than the plasma or tissue levels (Cmax) achieved with a standard 12mg IVM dose
A 🧵 explaining & debunking this myth
1/
First some definitions:
- Cmax is the maximum concentration achieved after a medication is given; it is usually measured in healthy people
- IC50 is the concentration of a drug necessary to inhibit a particular enzyme or process by 50%; it is measured in vitro.
2/
Since the pandemic began, many studies looked at repurposing FDA approved drugs to treat COVID
Literally dozens of candidate drugs have been found that inhibit viral replication in vitro
One of these candidates is ivermectin
But as we will see the devil is in the details... 3/
The key study by Caly et al found that at a concentration of 5 μM ivermectin inhibited SARS-CoV-2 replication (IC50) in Vero cells (African Green Monkey Kidney cells)
🐒 kidney cells aren’t exactly proof of efficacy in humans but this is promising
Except there’s a problem... 4/
...the dose that inhibits SARS-CoV2’s replication (IC50) in vitro is MUCH higher than the concentration of ivermectin (Cmax) that’s actually achieved in humans taking the highest dose of the drug:
IC50 5 μM
vs
Cmax 0.05 μM (on 200 mcg/kg)
That’s 100x less drug than needed!
5/
Ivermectin proponents argue that the drug accumulates in lungs & therefore reaches an effective level.
This too has been debunked in this excellent paper by Schmith et al👇
Using measurements from cow lungs & serum, they calculate the tissue distribution of ivermectin.
Even though Cmax was higher for lung (0.08 μM vs 0.05 μM) it was still much less than the IC50 needed to inhibit SARS-CoV2 (5 μM).
That’s still 62x too low to be effective! 7/
What if we just use a 10x higher dose of Ivermectin (e.g. 120 mg instead of the standard 12 mg)?
We still come up well short!
Even at this dangerously high 10x usual dose, our lung specific Cmax is only 0.8 μM compared to an IC50 of 5 μM (still 6x too low to be effective). 8/
This brings us to another key point: toxicity.
Ivermectin proponents argue that the drug is safe & widely used. This is true, in healthy outpatients treated with a low *weekly* dose.
Critically ill inpatients on a high *daily* dose are much more likely to develop toxicity.
9/
Dr Carlos Chaccour wrote an excellent thread on Ivermectin a year ago👇
He points out that if ivermectin crosses the blood brain barrier it can interact with GABA receptors causing serious 🧠 side effects. This is more likely in inflamed patients on high dose ivermectin: 10/
The next time you hear that ivermectin is “perfectly safe” & “effective in COVID” remember:
- plasma or lung levels of ivermectin in vivo (Cmax) don’t get anywhere close to the IC50 required in vitro
- there ARE risks of potentially fatal neurological toxicity with ivermectin
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People are citing reports of declining #COVID cases or deaths after mass #ivermectin distribution.
This is the scientific equivalent of “the rain stopped after I bought an umbrella.”
A short thread about why these “studies” are NOT very compelling. 1/
As cases rise, schools & businesses close, people stay home, nursing homes restrict visitors, masks are mandated, etc
A few desperate governments worldwide distributed ivermectin too
In an uncontrolled situation, why should ivermectin get “credit” for reducing cases/deaths?
2/
This is a classic POST HOC ERGO PROPTER HOC ("after this therefore because of this") fallacy.
Ivermectin distribution is usually a last-ditch effort, like buying an umbrella as you are getting soaked.
But the natural history of pandemics is to peak, then decrease.
3/
A few years ago I wrote about the problem with vitamin C in sepsis.
It’s not that vitamin C is harmful (it probably isn’t) or that it’s ineffective (it almost certainly is) but that embracing pseudoscience undermines evidence based practice.
#INSPIRATION RCT comparing intermediate vs standard dose DVT prophylaxis, just published @jama:
-no benefit to additional anticoag in ICU patients w/ #COVID19:no reduction in mortality, MV, LOS or any 2° endpoint
-time to rethink COVID #anticoagulation? 1/ bit.ly/3vCluqK
INSPIRATION was a 10 site open-label RCT in 🇮🇷 comparing intermediate vs standard dose prophylaxis in ICU patients with PCR-confirmed #COVID19.
LMWH was the primary intervention (~40 mg vs 1mg/kg daily), dosed appropriately for weight; UFH was used if the GFR was too low.
2/
Overall the groups were balanced (total n=562) & were fairly representative of US ICU cohorts with COVID19.
The use of HFNC was very low (~3%) compared to in the US, which may reflect different practice patterns/availability.
Pre-print of the @remap_cap RCT of #anticoagulation for ICU patients w/ #COVID19 adds details but confirms what we learned from the press release:
- no improvement in survival or organ failure w/ therapeutic (TA) vs prophylactic anticoagulation (PA)
- medrxiv.org/content/10.110… 1/
This study is the amalgam of 3 large platform RCTs of TA in COVID19: @remap_cap@ACTIV4a & ATTACC.
Each trial was administered separately but as much as possible they harmonized the design so the results could be analyzed together. (a pragmatic way to enroll more pts faster) 2/
There were some differences:
-REMAP enrolled suspected & confirmed infxn; the others only enrolled confirmed
-choice of anticoagulant varied
-most importantly, the definition of prophylaxis: ~1/2 the sites used standard low-dose heparin, the remainder used “intermediate dose” 3/
Following @remap_cap & #RECOVERY#Tocilizumab results, @NIHCOVIDTxGuide has updated guidelines:
-#Toci + #Dexamethasone now recommended for all ICU pts on IMV, NIPPV, or HFNC
-Toci + Dex recommended for non-ICU pts w/ rapidly increasing O2 needs & elevated inflammatory markers 1/
There are some caveats:
-Toci must be combined with dexamethasone (not given alone; ? harm signal)
-It should be given early (w/i 3 days)
-Toci should NOT be given to people who are already immunosuppressed or who have “an uncontrolled” infxn (e.g. getting worse despite Abx) 3/
🚨Exciting results from the #RECOVERY trial #preprint of #Tocalizumab (Toci) in hospitalized people w/ #COVID19
-reduced 28-day mortality (29 vs 33%; NNT)
-decreased likelihood of requiring MV (33% vs 38%)
-shorter hospital stay (median 20 vs >28 days) medrxiv.org/content/10.110… 1/
They randomized 4116 pts to weight-based Toci vs usual care (UC):
-groups were balanced: mostly male (>65%), older (>60 yo), & w/ comorbidities (>55%)
-most patients (82%) also received dexamethasone
-they received Toci early in hospitalization but were 7-14 days after onset 2/
Notably, only 83% of patients in the Toci group actually received Toci (plus 2.6% randomized to the UC group got Toci); this would decrease the effect size and bias the towards null.
This means their ITT analysis is probably *underestimating* the true effect size somewhat.