Saturday, September 26, 2020

Key benefit of hydroxychloroquine left out of RECOVERY trial report.

 Copyright 2020 Robert Clark

 Several studies have shown multiple different anti-inflammatories such as steroids can be beneficial against COVID-19. It is simply unreasonable then to suppose HCQ as one of the most effective anti-inflammatories is not. It’s probably the reason so many HCQ studies, including ones claiming “no benefit”, did show benefit.

 An astonishing instance of this last occurred in the RECOVERY trial. The RECOVERY trial was a randomized-controlled trial (RCT), which are called the "gold-standard" of medical studies. Because it was negative towards HCQ, it was frequently cited as evidence of HCQ having no benefit.

 RCT's aren't perfect of course. There can be flaws in interpreting the data, there may not be sufficient numbers of subjects to draw a strong conclusion. They can use the wrong dosage, etc. And unfortunately there can also be cases where researchers falsify data.

 I did not consider this last possibility to be likely with the RECOVERY trial. However, what I found did happen in the RECOVERY trial was nearly as bad in regards to accurately evaluating the effectiveness of HCQ. While the data was presented correctly, the way it was presented obscured the HCQ effectiveness. Note I am making no assertion on whether or not this was intentional.

 Here's the HCQ report from the RECOVERY trial:

Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial.

 Here's the relevant table, from page 24:

  You see instead of deaths on mechanical ventilation being given directly, it is combined with all deaths into one category. So, we need to do the calculation to find the proportion of the ventilated patients who died on HCQ and then calculate the proportion for those not on HCQ who died, since these are not given directly. Use the formula for counting the number of elements in the union of two sets with possible overlap:

which simply means you add together the number in each set, then subtract off the number in the overlap.

 First look at the cases on HCQ. Call A those within the HCQ group on "Invasive mechanical ventilation", at a count of 118. Call B those cases listed among the "Deaths", at a count of 308. Then the union of these two cases is listed in the "Receipt of mechanical ventilation or death" category at a count of 388. Let x equal the count of the cases that are in both "Death" and "Invasive mechanical ventilation", i.e., the intersection of the two sets. This is the number specifically in the ventilated group who died. Then using the formula we see: 388 = 118 + 308 - x. So x = 38. Then the proportion of the ventilated group who died on HCQ is 38/118 = .322, or 32.2%

 Now calculate it for the non-HCQ group, i.e., the usual care group. The numbers appear in the "Usual care" column in the table. Again let A be those on "Invasive mechanical ventilation", at a count of 215, and B those cases listed among the "Deaths", at a count of 572. Then the union of the two groups is the "Receipt of mechanical ventilation or death" category at a count of 696.

 Let x again be the number in the intersection of the two sets, i.e., the number on mechanical ventilation who died. Then using the formula again we get 696 = 215 + 572 - x. So x = 91. Then the proportion of the ventilated group who died not taking HCQ is 91/215 = .423, or 42.3%.

 This difference between the number of ventilated patients on HCQ who died of 32.2% and those not on HCQ who died of 42.3% is large enough that it should have been reported. 

  The RECOVERY trial made headlines world-wide when it sent out a news release on the "breakthrough" that the steroid dexamethasone could cut mortality for ventilated patients by 30%.

  Here is the published article on the discovery:

Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report.
The RECOVERY Collaborative Group   July 17, 2020

DOI: 10.1056/NEJMoa2021436

 In the Results section the mortality for ventilated patients on dexamethasone is given as 29.3%, while for those not on dexamethasone it's given as 41.4%. Note these numbers are quite close to those for HCQ. Yet the RECOVERY trial described HCQ as offering "no benefit" while dexamethasone was described as a "breakthrough".

  I want to reiterate I do not know if this obscuring of the HCQ effectiveness was intentional or not. However, there was another report which presented the data on ventilated patients in a similar way by combining the total number of deaths with the number on mechanical ventilation. That was the report by Geleris et. al. I discussed this report here:

About the article, “Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19”. UPDATED, 6/26/2020

 In this case as well presenting the data in this way obscured the benefits for patients on mechanical ventilation. In this study, the mortality for ventilated patients was cut 50% on HCQ. Yet this was not apparent because of the way the data was presented. 

 This was particularly unfortunate because the study was from patients in New York and in New York at the time the mortality for ventilated patients was in the range of 80%:

A bridge between life and death: Most COVID-19 patients put on ventilators will not survive.
John Bacon

USA TODAY       
Updated  April 10, 2020

 Again, I do not know if this was intentional or not. However, I have found there has been a pattern in which beneficial effects of HCQ were not included in the conclusions of papers that asserted that HCQ had "no benefit".

 In an upcoming article I'll discuss these papers where the final conclusion on HCQ was "no benefit", yet in the data in the paper themselves, HCQ did show benefit such as for ventilated patients for example. I don't know if this was intentional or not but the effect was to remove HCQ for consideration for treatment of COVID-19 particularly when it would be most beneficial.


  Robert Clark

  Department of Mathematics

  Widener University 

  Chester, PA 19013 USA



Gary Johnson said...

I'm not as sure of my facts as you seem to be, but I think I read in AAAS's "Science" that the Lancet report on HCQ not having benefit was withdrawn, for pretty much the faults you illustrated. The sense I get just "eyeballing-through" journals like "Science" is that there are several anti-inflammatories, and several anti-virals undergoing evaluation as treatments for Covid-19, as well as antibody-laden plasma. Those are not done yet, which is why the anti-viral and the antibody injections given to Pres. Trump are still considered "experimental". My understanding of the anti-inflammatories is limited (I am an engineer, not a "real" scientist), but I think the sense is that there are several such drugs with the benefits, while having fewer or milder side effects than the ones HCQ is known to have. All of these (including HCQ) are indeed available for doctors to use on an "experimental" basis. None of these would be allowed by any insurance companies, precisely because they are "experimental". That is just where we are. -- GW

Gary Johnson said...

According to the 18 December 2020 issue of AAAS's "Science" (volume 370, page 1382 there is some news to report about covid-19 therapies for hospitalized patients.

Azithromycin (antibiotic with anti-inflammatry properties - no benefit.

Article also says they previously found a similar no-benefit result for hydroxychloroquine in this scenario.

Article says others are still being tested: these include the gout medicine colchicine, the arthritis drug tocilizumab, aspirin, and blood plasma from recovered patients.

On page 1384, researchers have found that people with Down syndrome are at far higher risk from covid-19 than the rest of us.

This issue does not give the full list of things being studied and results already found. I know there are some steroids that have improved survival on ventilators. There are some other things now known that have improved hospitalization outcomes from abysmal to only "bad".


Robert Clark said...

Thanks for the comment. Use of AZT has always been recommended in concert with other drugs such as HCQ. For instance Dr. Didier Raoult recommends HCQ+AZT, with HCQ for antiviral and AZT for antibacterial.

And I’m still doubtful of the conclusion of “no benefit” of HCQ because of the data discussed in this blog post.

An interesting fact about AZT though I saw in this new report by the RECOVERY trial that I was not aware of is that it has antiviral effects not just antibacterial effects. Then it’s really unfortunate that the NIH has not promoted studies on various antivirals for *early* treatment. The studies that have been done were on *late* treatment where they were already expected to be less effective.

In this blog post I advised studies be done on the known antivirals for *early* treatment:

Bob Clark

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