Hyperventilating About Hydroxychloroquine

Today’s subject is a contentious one - hydroxychloroquine. But we’re not investigating whether it’s a miracle cure for The Covid. Instead our not-really-impromptu adventure has been prompted by a Politico story about the use of hydroxychloroquine with the exciting headline:

“Hydroxychloroquine could have caused 17,000 deaths during Covid, study finds”

Here’s a brief summary of the relevant points of the article: someone published a study and you goobers need to stop thinking for yourselves and do what The Experts tell you. Because if you don’t PEOPLE WILL DIE.

For anyone who’s been living under a rock and doesn’t know what we’re talking about:

The anti-malaria drug was prescribed to some patients hospitalized with Covid-19 during the first wave of the pandemic, "despite the absence of evidence documenting its clinical benefits," the researchers point out in their paper, published in the February issue of Biomedicine & Pharmacotherapy.

You know what other drugs were prescribed during the “first wave of the pandemic” despite an absence of evidence of clinical benefit? All of them. If this whole thing was caused by a “novel” virus then there could hardly be drugs with proven clinical effectiveness against it.

It’s not hard to guess why Politico decided to run this story - because it’s Politico, and everything has to be about Trump.

It was also considered something of a “miracle cure” by the then-U.S. President Donald Trump, who said: “What do you have to lose? Take it.”

They provide a link to The Guardian, secure in the knowledge that few people check references and no one reads The Guardian.

Except us of course, because we’re gluttons for punishment. The article doesn’t include any quotes from Trump calling the drug a “miracle cure” for The Covid but the drug is associated with all sorts of bad people: anti-vaxxers, conspiracy theorists, and ultra-conservatives who don’t want the government dictating health care decisions.

The idea that hydroxychloroquine is “the cure” has taken off within certain online communities, including among anti-vaxxers and followers of QAnon, a rightwing conspiracy theory. The drug has also found support from the Association of American Physicians and Surgeons, a small, ultra-conservative organization that advocates against government involvement in medicine.

[There’s no way I’m typing hydroxychloroquine a hundred times, so from now on it’s HCQ. All remaining full spellings of the name are purely the result of my copy-pasting text because I’m super lazy.]

As is typical, everyone has an opinion but no one has read the research. But reading research is what we do here, so let’s end the boring introduction and move on to the even more boring scientific papers.

Did use of HCQ to treat The Covid increase mortality?

Here’s the paper being referenced in the crappy article from Politico:

Deaths induced by compassionate use of hydroxychloroquine during the first COVID-19 wave: an estimate. (Pradelle et al. 20241)

The authors tell us that an analysis of clinical trials showed an increase in mortality and they are using the results of this analysis to estimate deaths caused by use of HCQ.

During the first wave of COVID-19, hydroxychloroquine (HCQ) was used off-label despite the absence of evidence documenting its clinical benefits. Since then, a meta-analysis of randomised trials showed that HCQ use was associated with an 11% increase in the mortality rate. We aimed to estimate the number of HCQ-related deaths worldwide.

The authors are making their estimate by looking at the number of people hospitalized and treated with the drug, then applying the 11% increase to come up with excess deaths. Here’s the formula given in the paper:

Number deaths = Number hospitalized patients × mortality rate × HCQ exposure × Odds Ratio of using HCQ

That 11% increase is another way of describing the Odds Ratio, and it’s the critical part of this equation. If the ratio is greater than 1, the intervention (HCQ, in this case) increased mortality. If it’s less than 1, the intervention decreased mortality. The rest of their calculation determines how large the change in mortality was. But whether that number is positive or negative depends on that Odds Ratio. So where did the authors get their Odds Ratio?

We used the odds ratio (OR) for HCQ-related mortality estimated from a previous meta-analysis of RCTs (i.e. OR=1.11).

The Pradelle paper is brand new (2024) but the Odds Ratio number comes from a paper published back in 2021.

That sounds like something I made up, but It’s Real. (Quite ironically, I’m listening to It’s Real by Real Estate while typing this sentence.)

Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials. (Axfors et al. 20212)

Of course the actual paper was only written by three of the 94 authors (Axfors, Schmitt and Hemkens) and most of the credited authors were just submitting data.

This is a meta analysis of clinical trials of HCQ conducted in various countries around the world. Unfortunately most of those trials were quite small so two of them dominate the data.

Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size).

The Odds Ratio from RECOVERY was 1.11, and from WHO SOLIDARITY it was 1.21. We can see the large impact these two trials have on the final OR.

In the meta-analysis, the combined odds ratio (OR) was 1.11 (95% confidence interval (CI), 1.02–1.20, p = 0.02)...

So based on the published trials, patients treated with HCQ were more likely to die. But having two trials provide 2/3 of the data is important. Why?

The RECOVERY and WHO SOLIDARITY trials used HCQ in comparatively higher doses than all other trials except REMAP-CAP. There was no evidence for an effect modification by dose (p for interaction = 0.29), and the combined effect of all the trials with lower dose did not indicate a benefit of HCQ but tended to a null effect (OR 0.97; 0.73–1.30) with wide CIs, compatible with the main effect estimate.

The two big trials that weigh most heavily in the Odds Ratio used high dosages, while the trials at lower dosage showed no net impact.

Axfors says specifically that they didn’t review any individual trials - but of course we will. The RECOVERY trial provided nearly half the data by itself so let’s start with that one and look at the dosage schedule.

RECOVERY is actually a very large study of multiple interventions, generating multiple papers. For the RECOVERY results on HCQ, this is the paper being referenced by Axfors:

RECOVERY Collaborative Group; Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19. (RECOVERY Collaborative Group 20203)

The HCQ part of the study was in the UK and involved patients spread among 176 hospitals.

The RECOVERY trial is an investigator-initiated platform trial to evaluate the effects of potential treatments in patients hospitalized with Covid-19. The trial is being conducted at 176 hospitals in the United Kingdom.

The RECOVERY trial used the following dosage schedule: 800 mg to start and again at 6 hours, then 400 mg at 12 hours and 24 hours, followed by 400 mg every 12 hours for 9 days.

Total dosage: 9,600 mg over 10 days. (with 2,400 mg in the first 24 hours.)

What is normal dosage? For prophylaxis against malaria the dosage is 400 mg per week (so this is the dosage to prevent getting malaria). For treatment of malaria, the recommended dosage is 800 mg for an initial dose, then 400 mg at 6 hours, followed by 400 mg at 24 and 48 hours.4

Total dosage: 2,000 mg over 2 days.

The trial used almost 5x as much HCQ as would normally be prescribed to treat malaria. What are the potential risks from HCQ? The RECOVERY paper tells us.

The primary concern with short-term, high-dose 4-aminoquinoline regimens is cardiovascular toxicity. Hydroxychloroquine causes predictable prolongation of the corrected QT interval on electrocardiography, which is exacerbated by coadministration with azithromycin, as widely prescribed in Covid-19 treatment.

Or more simply: HCQ can affect the timing of the valves of the heart in some patients, which can lead to fatal ventricular fibrillation. This is exacerbated when used in combination with a common antibiotic.

Grab hold of that big horizontal bar they put on the roller coaster, because we’re plunging deeper into this mess.

RECOVERY is a very large study (70,000 subjects) called a master protocol5 and is still on going. The study is looking at 18 different treatments for The Covid, plus a few more for influenza and pneumonia (for a total of 22 trials plus one control arm). The investigators also registered the trial with the NIH at ClinicalTrials.gov.

[ClinicalTrials.gov is a database of trials maintained by NIH, and studies seeking FDA approval for a drug are registered here. This study, like many others, is also registered with the NIH because the database itself is useful.]

The use of a master protocol like this is a recent innovation, and in fact the RECOVERY study is specifically mentioned as an example in this paper about the use of them.

RECOVERY is an example of the most complex type of master study, called a platform trial, in which there are multiple diseases and multiple treatments being evaluated. The use of a platform trial comes with its own set of issues when interpreting results (but we’re going to leave that discussion for another day).

The whole shebang is being run by Oxford and even has its own website, which you can find here. HCQ was added in version 2 of the test protocol (they’re up to version 27 as of now).

The test protocol tells us that hydroxychloroquine is essentially a safer version of chloroquine, a drug that has been in use for a very long time.

Hydroxycholoroquine: Chloroquine (CQ), an antimalarial drug discovered in 1934 and introduced generally in 1947, is the drug to which humans have been most exposed, with an annual global consumption of hundreds of metric tonnes for over 50 years. It is inexpensive, simple to administer, and, at the appropriate doses, has an excellent safety profile in all age groups and has been the prophylactic drug of choice in pregnancy... HCQ is reported to have better safety profile than CQ, better gastrointestinal tolerability, and less retinal toxicity.

Notice that the authors consider the drug to be very safe at the appropriate doses. But as we already know, this trial is using much more than the standard dose. The authors describe how they arrived at the dosage schedule based on laboratory testing of the drug on SARS-CoV-2, and decided that the standard dose would probably not be sufficient.

So the loading dose in RECOVERY is twice the normal dose for treating malaria... Given the significant mortality in patients hospitalised with COVID-19, this dose is felt to be justified. This is the schedule that is likely to be adopted by the World Health Organisation.

They know their protocol is using a dosage schedule that carries some risk, but are accepting that risk because the mortality rate for The Covid is so high. But was this same dosage schedule recommended by the WHO? Did doctors actually do this in practice?

In early 2020 the WHO began publishing a clinical management guide for The Covid with specific recommendations on treatments. The original link is gone but here’s an archive of the page.

The original version is dated 13 March 2020 and doesn’t mention HCQ. The first big update is 27 May 2020 and at that time the WHO was recommending against using HCQ to treat The Covid outside of clinical trials. As far as I can tell the WHO never recommended HCQ, and so never adopted the dosage schedule used in the RECOVERY trial.

What does all this mean? The team running the RECOVERY trial chose a dosage schedule that they knew carried some risk, but felt it was justified because per their analysis the standard dosage would not be effective.

But as we’ll see, there’s no evidence this dosage was used outside of clinical trials.

Just to be complete, here’s the paper from the WHO trial on HCQ.

Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. (WHO Solidarity Trial Consortium 20216)

Just like RECOVERY this is a large, platform trial of multiple treatments. And just like RECOVERY they have a home page for the master protocol7. They also provide an abstract for the whole trial.

We’re not going to waste a lot of time here - the important detail for us is the dosage schedule, which was exactly the same as the RECOVERY trial. Per the abstract they found no benefit from HCQ, and although there was an unfavorable Odds Ratio it was not statistically significant.

Now that we have some understanding of the trials that determined the Odds Ratio, let’s climb back up to the Pradelle paper and look at one of their actual calculations for excess deaths. The authors used hospitalization data from six countries (Belgium, France, Italy, Turkey, Spain, USA) to arrive at their estimate of 16,990 excess deaths in those countries.

The results of the calculations are given in Table 2 and Table 3, and the first country listed is Belgium. The authors use the following inputs:

Number of deaths: 19,644

Mortality rate: 0.218 (21.8 %)

HCQ exposure: 0.51 (51%)

Odds Ratio: 1.11

To find the excess deaths we need to run the formula once without the Odds Ratio (to get total deaths without HCQ) then again with the 1.11 OR (to get total deaths with HCQ), then subtract the first number from the second to get the estimated excess deaths.

Estimated number of deaths among those treated with HCQ, if they had not been given the drug:

19,644 x 0.218 x 0.51 = 2,184

Estimated number of deaths using HCQ with an Odds Ratio of 1.11:

19,644 x 0.218 x 0.51 x 1.11 = 2,424

And the difference between these two is 240, therefore compassionate use of HCQ resulted in an estimated 240 excess deaths in Belgium (per Pradelle).

Except it didn’t - per their own source. Pradelle obtained the Odds Ratio from Axfors, but the mortality rate estimates for each country come from other papers. In this case the mortality rate estimate comes from the following paper published by researchers in Belgium.

Belgian Collaborative Group on COVID-19 Hospital Surveillance. Low-dose hydroxychloroquine therapy and mortality in hospitalised patients with COVID-19: a nationwide observational study of 8075 participants (Catteau et al. 20208)

This is a retrospective study, meaning the authors looked into the hospital data in Belgium to determine how many people were and were not given HCQ and what the outcomes were.

We conducted a retrospective analysis of in-hospital mortality in the Belgian national COVID-19 hospital surveillance data.

This is where Pradelle obtained the 0.218 estimate for mortality rate from The Covid.

The observed in-hospital mortality rate (~21.8%).

At the time of writing their report, the Belgian researchers had mortality data on 8,075 patients - and guess what? A significantly lower percentage of the patients on HCQ died than those not given HCQ.

Of 8075 patients... 4542 received HCQ in monotherapy and 3533 were in the no-HCQ group. Death was reported in 804/4542 (17.7%) and 957/3533 (27.1%), respectively.

The Pradelle paper calculated 10,018 people were given HCQ in Belgium (19,644 x 0.51) and this resulted in 240 excess deaths. But the actual (not calculated) outcomes for 4,542 of those patients, as recorded in the Belgian health care system, are reported in this paper - and the mortality rate was lower than for those who didn’t receive HCQ.

Pradelle has extracted the part of the Catteau paper needed for their calculation (the overall mortality rate from The Covid) while apparently not bothering to address the rest of the paper. In doing so they have contradicted the conclusions of the authors of their own reference.

Is there a possible explanation for this? Well yes, it could be the dosage. Per Catteau:

On 13 March 2020, a task force... coordinated by Sciensano, published a guidance for the management of patients hospitalised with COVID-19. Based on the above described rationale, the ‘low-dose’ HCQ regimen (2400 mg in total over 5 days) was recommended as a reasonable emergency therapeutic option for hospitalised patients and was centrally provided for free.

Patients in Belgium were receiving 1/4 the total dosage of HCQ when compared to RECOVERY and SOLIDARITY. But the Pradelle paper has reduced the subject to a one-dimensional view of medicine: using drug X will either increase mortality or decrease mortality.

Belgium isn’t the only example of this issue among the six countries analyzed in the Pradelle paper. For example, here’s a paper referenced by Pradelle that reports a reduction in mortality in New York state hospitals.

Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19 (Arshad et al. 20209)

In this multi-hospital assessment, when controlling for COVID-19 risk factors, treatment with hydroxychloroquine alone and in combination with azithromycin was associated with reduction in COVID-19 associated mortality.

Another Pradelle reference, this paper from Italy also reports lower mortality among patients given HCQ.

COVID-19 RISK and Treatments (CORIST) Collaboration. Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: Findings from the observational multicentre Italian CORIST study (202010)

HCQ use was associated with a 30% lower risk of death in COVID-19 hospitalized patients. Within the limits of an observational study and awaiting results from randomized controlled trials, these data do not discourage the use of HCQ in inpatients with COVID-19.

This discrepancy in calculated deaths versus counted deaths in their own references is a serious contradiction, and it’s one that the authors of the Pradelle paper don’t address - or even mention. In fact, Pradelle tells us:

Finally, the results of observational studies and randomized trials in May and June 2020, respectively, convincingly demonstrated that HCQ was ineffective and led to an increase in adverse events.

The references they give us for the quote above are the Axfors paper, three of the trials used in that paper, and a paper about calculating Number Needed to Treat (NNT). They’ve added observational studies to this statement despite (as we have just seen) their own references contradicting it.

This is so moronic it bears repeating: Pradelle claims that observational studies show use of HCQ led to increased deaths. Observational studies being used as references by Pradelle say the exact opposite. Can the Pradelle authors read? Were they distracted by a squirrel?

So why do the retrospective studies report reductions in mortality while the randomized controlled trials show either no benefit or negative benefit? It sure would be nice to know, but no one is discussing it.

The retrospective studies are reporting on actual use of the drug by individual medical doctors making decisions with regard to specific patients. They aren’t blindly following a pre-written protocol. Is it possible they actually learned something valuable in medical school? (Primum non nocere - “first, do no harm”)

For Pradelle to be correct, the observational studies must not just be wrong, but have the result completely in the opposite direction of reality (harm instead of benefit).

Were some people killed by compassionate use of HCQ? It certainly appears so - in the RECOVERY trial in the UK. They reported 27.0% mortality in the HCQ group and 25.0% mortality in the control group. Based on those numbers, about 40 extra people died in the HCQ group. This isn’t surprising given that the people who designed the RECOVERY trial were taking a deliberate risk with the dosage.

But Pradelle’s own references indicate that the dosage schedule from the two large trials is not representative of how HCQ was normally prescribed.

The issue at question here is whether compassionate use of HCQ caused excess deaths. Here’s as concise a summary as I can manage of the key points:

1. The Pradelle paper does not address the issue of dose-dependent response to HCQ, despite clear evidence of drastically different dosage schedules between treatment centers.

2. The source for the 1.11 Odds Ratio (Axfors et al. 2021) sates that 2/3 of the data came from just two studies using very high dosages (9,600 mg), and that trials using lower dosages showed no net difference.

3. Pradelle applies the 1.11 Odds Ratio to all patients but provides no evidence that the 9,600 mg dosage schedule was typical practice. Available evidence indicates the opposite is likely true.

4. Pradelle’s calculated numbers of excess deaths are contradicted by their own references of retrospective studies in the countries they are analyzing. Pradelle provides no explanation for this or even an acknowledgment of the discrepancy.

Two large trials of HCQ were conducted as parts of even larger, platform trials. Those two trials reported an increase in mortality but used very high doses. There’s no evidence this was common practice, so the excess deaths may be just those reported in the trials.

At normal dosages, some retrospective studies show a correlation between HCQ use and lower mortality while small randomized controlled trials have failed to show a benefit. We currently have no explanation for this difference.

Based on the available evidence, it appears that most doctors who prescribed HCQ did so in a safe manner. Therefore we have no reason to believe they caused excess deaths through use of HCQ.

In my generally unsought-after opinion the Pradelle paper should never have been written. Their key reference (the Axford paper) was published more then two years ago and contains a very limited set of data.

The authors of the Axford paper were drawing together results from both published and unpublished studies in an attempt to generate some useful information as quickly as possible. These calculations shouldn’t be taken as the definitive answer to a complicated question. If no one else has published a more comprehensive analysis, including studies not available two years ago, then the Pradelle authors should have been doing that first.

Instead they took the Odds Ratio number and published a headline-generating paper from very little actual substance. It’s an effective way to get attention with a dry scientific paper but it’s not adding anything of value to the discussion.

Hidden in the data reported by Axfors et al. is an incredible gem, and may give us a hint about why this entire discussion is even happening. Here’s the bombshell from the paper:

In 12 trials including a total of 1282 patients (representing 12.8% of the total sample size for HCQ), there were zero deaths in both arms.

The authors of the Axfors paper included a chart of 26 trials and in this chart they report the overall mortality in each study, for both the control arms and treatment arms together. Here’s a sample of the bigger trials with number of subjects and mortality rate:

• RECOVERY: 4,716 subjects, 25.67% mortality

• WHO SOLIDARITY: 1,853 subjects, 10.15% mortality

• Coalition 1: 448 subjects, 2.90% mortality

• COVID-PEP: 471 subjects, 0.42% mortality

• BCN PEP CoV−2 Study: 293 subjects, 0% mortality

• NCT04491994: 500 subjects, 0% mortality

That’s not the mortality from HCQ, it’s the TOTAL MORTALITY RATE FROM THE COVID in those trials. So in some of the clinical trials no one died at all. Keep in mind these trials occurred in 2020, during the “first wave.”

Here’s a quote from Noam Chomsky that may be very relevant to what is happening here:

The smart way to keep people passive and obedient is to strictly limit the spectrum of acceptable opinion, but allow very lively debate within that spectrum – even encourage the more critical and dissident views. That gives people the sense that there’s free thinking going on, while all the time the presuppositions of the system are being reinforced by the limits put on the range of the debate.

I would like to put to everyone the possibility that we are being encouraged to argue about the efficacy and risks of drugs like HCQ to keep us from asking more important questions. Why did patients in the UK have a 1 in 4 chance of dying, while at exactly the same time in other countries the odds of dying were close to zero - regardless of the treatment?

How can these wildly varying mortality rates be caused by the same, “pandemic” virus?

It’s like saying Ebola has a 50% mortality rate in Kenya but 0% in Brooklyn. either someone in Kenya is screwing up, or you’re lying about the mortality rate of Ebola. (Or no one in Brooklyn had Ebola!)

As long as we’re arguing about whether HCQ could have saved lives, caused more harm than good, etc. we’re not questioning the central narrative that a worldwide pandemic of a novel human coronavirus caused mass deaths. What if most/nearly all of the deaths were caused by our interventions instead? (Both pharmaceutical and non-pharmaceutical.) If so, the only pandemic was one of greed and stupidity.

If you’re curious about that, a nice lady named Jessica Hockett has asked a lot of interesting questions that no one seems able to answer. Here’s a link to her index of articles about mortality in New York hospitals in the spring of 2020:

Follow the White Rabbit

She’s far from the only person discussing anomalies in mortality data but it’s a good place to start.

The Pradelle paper has been retracted11 by the journal. The retraction notice gives two main reasons for the retraction:

1. Reliability of the data and choice of the data. The Belgian dataset in particular was found to be unreliable, based on estimates.

2. The assumption that all patients that entered the clinic were being treated the same pharmacologically was incorrect.

That second item is the issue being highlighted in this Substack post. The Pradelle authors based their analysis either on everyone receiving the same dosage, or the assumption that dosage has no impact on the safety of the drug.

Reviewing the Belgian paper in detail is outside the scope of this post, and with or without that paper the analysis remains the same. It is interesting, however, that the editor of Elsevier chose to list this first as though it were the more important issue with the Pradelle paper. If the same analysis were done without the Belgian paper, it would still be garbage and still need to be retracted.