Covid study question
- Dr. Stephen Smith
- Jun 9, 2021
- 4 min read
The most frequently asked question is "How do you know that people who got more HCQ, got more HCQ because they lived longer?" In other words, how do we know cumulative HCQ dose isn't a marker of survival instead of cause of survival.
You can read my response at MedRxiv or here -
First, the cumulative was not, for most pts, a measure of length of stay or determined by death. The most commonly used cumulative dose of HCQ = 2,400 mg. This dose/regimen was recommended, as noted in the manuscript by Yao et al., based upon computer modeling. The 2,400 mg dose was given over 5 days, 800 mg on Day and 400 mg on Days 2-5. The treating or consulting ID physician chose the cumulative dose. In late March, the French data came out and some switched to the French regimen, 600 mg of HCQ x 10 days plus azithromycin x 5 days. Most pts received the 800 mg first day dose, which was started by the ER docs and was a click in the computer ordering system. The ID docs saw the pt the next morning. Many continued the pt on 400 mg per day for 4 more days. Others switched to 600 mg per day. So, by Day 5 on the latter regimen, the cumulative HCQ dose = 3,200 mg or > 3 gm or the cut-off used in our paper. In other words, it took just as long to get to > 3 gm and as it took to get to 2,400 mg.
In a simplistic way to control for length of stay (LOS), we analyzed the effect of >3gHCQ/ >1gAZM on outcome after removing those patients, who had a LOS <= 5 days. All 49 patients with a LOS <= 5 days expired; none took > 3,000 mg HCQ and > 1,000 mg AZM. The 169 remaining patients serve as the "untreated" group and had a survival rate = 21.3%. The >3gHCQ />1gAZM group’s survival rate = 48.6%. This difference = 27.3%, which is still large and highly statistically significant (difference = 27.3%; 95% C.I. = 10.1-43.7%; p = 0.0006). In other words, even after eliminating all patients who had a LOS <= 5 days from the “untreated” group, the survival rate of the HCQ/AZM was more than 2.2-fold that of the "untreated" group. BTW, this type of analysis is heavily biased against showing a difference between treatment with HCQ, because the treatment may have an effect before Day 5. Remember, most of the "untreated" group did receive HCQ, just <= 3 gm.
In other words, cumulative dose of HCQ was not a marker of survival. The cumulative HCQ dose was determined by the ID doctor seeing the pt. Different ID doctors interpreted the available data on HCQ differently. Essentially, they chose between the 2,400 mg without AZM or the 6,000 mg total HCQ dose with AZM or no HCQ at all. A few ID doctors split the middle and used ~3 gm of HCQ with AZM. Many ID doctors did not use AZM with HCQ for fear or concern about prolonging the QTc interval on the ECG. We, instead, followed the QTc interval closely.
Lighter pts reached a weight-based cumulative HCQ dose well before heavier pts. If a pt weighed 50% of another pt, it took 50% of the days to reach a given weight-based HCQ cumulative dose. These pts typically received 800 mg HCQ on Day 1 and then 600 mg per day. A 60 kg pt reached 40 mg/kg by Day 4, while a 120 kg pt, didn't reach 40 mg/kg until Day 8.
Since weight-based HCQ cumulative dose was more strongly associated with survival than absolute cumulative dose, the association of HCQ dose and survival is not simply a marker of pts who lived longer.
And importantly, this subgroup with the high survival percentage also received >1 gm of AZM. There were 12 other pts, who received > 3g HCQ and ≤ 1 g AZM. Only 1 of these 12 survived. So, from these data, it’s not simply reaching a cumulative dose of >3 g HCQ.
If anything comes from these data, we hopes it’s this –
1. Weight-based and cumulative weight-based dosing of HCQ be considered in treatment of Covid pts and future HCQ-Covid trials;
2. AZM appears to have a synergistic effect and this needs to be further delineated, but for now used in severe Covid-19 treatment;
3. The studies, which concluded HCQ did prolong the QTc on the EKG even when given at low doses, need to be either retracted and/or re-analyzed, and;
4. The pharmacokinetics of any drug used to treat Covid need to be better understood than the PK of HCQ was understood before a clinical trial is designed. 2,400 mg HCQ over 5 days was used in many studies. This is a very small amount of HCQ. For pts weighing over 120 kg (264 lbs.), it’s a miniscule dose.
You know it’s weird, but in those QTc-EKG studies, the researchers didn’t even measure blood levels of HCQ. Maybe it’s because we are like Forrest Gump, Goddamn Geniuses. And it’s true, my son came up with the idea, so maybe he is. But are we really that much smarter than they are? I don’t think so. So, why didn’t they measure blood levels of HCQ? It’s a routine test.
SMS
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