HcQ is not an Information argument

[Giltil (Gilbert Thill)]

@Mercer

That’s just silly, because if HCQ works, it will work without death as the endpoint.

Are you serious?

@Mercer

Again, if HCQ works or does not work in an inpatient setting, one should see the same thing in an outpatient setting.

Are you serious?

@Mercer

That’s what those of us who do science describe as industrial-strength handwaving

Judging from your two above statements, one is forced to conclude that there are large gaps in your medical understanding.

[Michael_Okoko]

@Giltil

@Chris_Falter

Raoult’s recent study is retrospective, which means it is subject to selection bias and to recall bias. It is better to look to the several large prospective, random-controlled trials on HcQ, don’t you think?

Well, the first point I would like to make is that observational studies have a long track record of successes.

True. For example, the current consensus on the dangers of tobacco use was largely derived from well-designed observational studies.

However, confounding is a serious limitation of observational studies and RCTs were developed to overcome that (and other) limitation(s).

@Giltil

The second point is that it has been shown that RCT and observational studies don’t differ significantly in their conclusions

Observational studies that agree with the results of RCTs tend to be those that are designed to mimic RCTs as closely as possible. There is a reason why “adjustments” are done in observational studies and that’s to “pretend” like randomization was done. The authors in the second study you cited clearly state this as well:

Although the data we present are a challenge to accepted beliefs, the findings are consistent with three other types of available evidence. For example, previous investigations have shown that observational cohort studies can produce results similar to those of randomized, controlled trials when similar criteria are used to select study subjects.

First, there is evidence that observational studies can be designed with rigorous methods that mimic those of clinical trials and that well-designed observational studies do not consistently overestimate the effectiveness of therapeutic agents. An analysis19 of 18 randomized and observational studies in health-services research found that treatment effects may differ according to research design, but that “one method does not give a consistently greater effect than the other.” The treatment effects were most similar when the exclusion criteria were similar and when the prognostic factors were accounted for in observational studies.

A specific method used to strengthen observational studies (the “restricted cohort” design9) adapts principles of the design of randomized, controlled trials to the design of an observational study as follows: it identifies a “zero time” for determining a patient’s eligibility and base-line features, uses inclusion and exclusion criteria similar to those of clinical trials, adjusts for differences in base-line susceptibility to the outcome, and uses statistical methods (e.g., intention-to-treat analysis) similar to those of randomized, controlled trials. When these procedures were used in a cohort study9 evaluating the benefit of beta-blockers after recovery from myocardial infarction, the use of a restricted cohort produced results consistent with corresponding findings from the Beta-Blocker Heart Attack Trial20: the three-year reductions in mortality were 33 percent and 28 percent, respectively.

You have no case here Gil. In fact, you forget an important caveat stated by the authors which applies to Raoult’s poorly done study:

Despite the consistency of our results (involving five clinical topics and 99 separate studies), as well as the confirmatory evidence available in the literature, we believe that the appropriate role of observational studies may vary in different situations. For example, observational investigations of some kinds of treatments (e.g., surgical operations and other invasive therapies) may be more prone to selection bias than the observational studies of drugs and noninvasive tests that we examined in this study, and “softer” outcomes (e.g., functional status) may be more readily assessed in randomized, controlled trials. In addition, we are aware of the risk that the results of poorly done observational studies may be used inappropriately — for example,32 to promote ineffective alternative therapies.

@Giltil

This RCT [27] reported a non-significant but beneficial effect of HCQ (Table 3). However, new RCTs with medical quality crite- ria are not expected to change results since it has been shown that results from RCT and observational studies did not dif- fer significantly [37, 38].

Nobody bases clinical guidelines on a single RCT. When all high quality RCTs are pooled together, they show that HCQ offers no benefit in Covid-19 therapy.

@Giltil

Also relevant to your point, the following passage taken from the author’s discussion:
RCTs were excluded because of lack of systematic biologi- cal diagnosis or absence of death (Supplementary Table 9).

Seriously? There are several large, well-controlled, randomized trials where deaths were recorded and PCR diagnosis were done (all of whom show HCQ to be ineffective). We have to wonder why Raoult did not include them in his meta-analysis. Why would Raoult tell us he is conducted an observational study and go ahead to conduct a meta-analysis as well (with studies I can’t locate from the paper; do you have a link to the supplementary documents since the one provided keeps returning me back to the main article?).

@Giltil

However, new RCTs with medical quality crite- ria are not expected to change results since it has been shown that results from RCT and observational studies did not dif- fer significantly [37, 38].

Unfortunately for this expectation, the newer and better RCTs consistently show no benefits for HCQ (with other drugs like AZT or zinc). Raoult is saying nonsense and you have bought it.

[Giltil (Gilbert Thill)]

@Michael_Okoko

There are several large, well-controlled, randomized trials where deaths were recorded and PCR diagnosis were done (all of whom show HCQ to be ineffective).

Can you give some references of such RCTs for outpatient setting?

@Michael_Okoko

Raoult is saying nonsense and you have bought it.

I have bought it, as well as the editors and reviewers of Raoult’s paper.

[Michael_Okoko]

@Giltil

@Michael_Okoko

There are several large, well-controlled, randomized trials where deaths were recorded and PCR diagnosis were done (all of whom show HCQ to be ineffective).

Can you give some references of such RCTs for outpatient setting?

Here is one:

Effect of Hydroxychloroquine or Lopinavir-Ritonavir on Hospitalization for...

Need more?

@Giltil

@Michael_Okoko

Raoult is saying nonsense and you have bought it.

I have bought it, as well as the editors and reviewers of Raoult’s paper.

Junk science gets past journal peer-reviewers quite frequently. Community peer-review is on a different level and that’s where crappy studies like Raoult’s get pinned down. The overall body of evidence does not support HCQ usage for Covid-19 therapy.

[Faizal_Ali]

I’m not sure if you have forgotten or simply never understood the Cochrane article I linked a day or two ago. Regardless, here it is again to either jog your memory or so you can have it explained to you by someone who is able to understand it:

Is chloroquine or hydroxychloroquine useful in treating people with COVID‐19, or in preventing infection in people who have been exposed to the virus?

What is the aim of this review?

COVID‐19 is an infectious respiratory disease caused by a coronavirus called SARS‐CoV‐2. If the infection becomes severe, people may need intensive care and support in hospital, including mechanical ventilation.

Drugs used for other diseases were tried out in COVID‐19, and this included chloroquine, used for malaria; and hydroxychloroquine used for rheumatic diseases, such as rheumatoid arthritis or systemic lupus erythematosus. We sought evidence of the effects of these drugs in treating people ill with the disease; in preventing the disease in people at risk of getting the disease, such as health workers; and people exposed to the virus developing the disease.

Key messages

Hydroxychloroquine does not reduce deaths from COVID‐19, and probably does not reduce the number of people needing mechanical ventilation.

Hydroxychloroquine caused more unwanted effects than a placebo treatment, though it did not appear to increase the number of serious unwanted effects.

We do not think new studies of hydroxychloroquine should be started for treatment of COVID‐19.

What was studied in the review?

We searched for studies that looked at giving chloroquine and hydroxychloroquine to people with COVID‐19; people at risk of being exposed to the virus; and people who have been exposed to the virus.

We found 14 relevant studies: 12 studies of chloroquine or hydroxychloroquine used to treat COVID‐19 in 8569 adults; two studies of hydroxychloroquine to stop COVID‐19 in 3346 adults who had been exposed to the virus but had no symptoms of infection. We did not find any completed studies of these medicines to stop COVID‐19 in people who were at risk of exposure to the virus; studies are still under way.

The studies took place in China, Brazil, Egypt, Iran, Taiwan, North America, and Europe; one study was worldwide. Some studies were partly funded by pharmaceutical companies that manufacture hydroxychloroquine.

What are the main results of our review?

Treating COVID‐19

Compared with usual care or placebo, hydroxychloroquine:

· clearly did not affect how many people died (of any cause; 9 studies in 8208 people);

· probably did not affect how many people needed mechanical ventilation (3 studies; 4521 people);

· may not affect how many people still tested positive for the virus after 14 days (3 studies; 213 people).

We are uncertain whether hydroxychloroquine affected the number of people whose symptoms improved after 28 days.

Compared with other antiviral treatment (lopinavir plus ritonavir), chloroquine made little or no difference to the time taken for symptoms to improve (1 study; 22 people).

Compared with usual care in one study in 444 people, hydroxychloroquine given with azithromycin (an antibiotic) made no difference to:

· how many people died;

· how many needed mechanical ventilation; or

· time spent in hospital.

Compared with febuxostat (a medicine to treat gout), hydroxychloroquine made no difference to how many people were admitted to hospital or to changes seen on scans of people’s lungs; no deaths were reported (1 study; 60 people).

Preventing COVID‐19 in people exposed to it

We are uncertain whether hydroxychloroquine affected how many people developed COVID‐19, or how many people were admitted to hospital with COVID‐19, compared with those receiving a placebo treatment (1 study; 821 people).

Compared with usual care, hydroxychloroquine made no difference to the risk of developing COVID‐19, or antibodies to the virus, in people exposed to it (1 study; 2525 people).

Unwanted effects

When used for treating COVID‐19, compared with usual care or placebo, hydroxychloroquine:

· probably increases the risk of mild unwanted effects (6 studies; 1394 people);

· may not increase the risk of serious harmful effects (6 studies; 1004 people).

When given along with azithromycin, hydroxychloroquine increased the risk of any unwanted effects, but made no difference to the risk of serious unwanted effects (1 study; 444 people).

Compared with lopinavir plus ritonavir, chloroquine made little or no difference to the risk of unwanted effects (1 study; 22 people).

When used for preventing COVID‐19, hydroxychloroquine probably causes more unwanted effects than placebo, but may not increase the risk of serious, harmful unwanted effects (1 study; 700 people).

How confident are we in our results?

We are confident about our results for how many people died and moderately confident about how many needed mechanical ventilation. We are moderately confident about the unwanted effects of hydroxychloroquine treatment, but less confident about our results for serious unwanted effects; these results might change with further evidence.

How up‐to‐date is this review?

We included evidence published up to 15 September 2020.

https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013587.pub2/full

[Chris_Falter]

@Giltil

I have bought it, as well as the editors and reviewers of Raoult’s paper.

Your assertion that the editors and reviewers believe HcQ is efficacious is without question wrong.

Passing review does NOT imply that the reviewers agree that a particular outcome is proven correct. It means only that the paper conforms to the standards for a particular methodology.

Certainly you believe it, Gilbert, but you are accepting extremely dubious, low-quality evidence and rejecting a large amount of high-quality evidence. Why would anyone who understands statistical methods agree with you?

@Giltil

Can you give some references of such RCTs for outpatient setting?

I do not understand why you are asking for something that was already given to you.

The Cochrane Group meta-analysis incorporated 3 RCTs in ambulatory (outpatient) settings. Those RCTs showed no positive effect from using HcQ.

One of those RCTs was published in July 2020 here.

SUMMARY

A dozen high-quality random control trials of HcQ treatment have indicated that it has no positive effect for COVID outcomes. Three of those RCTs were in outpatient settings, and nine were in hospitals.

In addition, several studies have indicated dangerous side effects of HcQ during COVID treatment. These were described in the meta-analysis that @RonSewell linked in post 18 of this thread.

Based on the questions you are asking, I suspect you have read neither the Cochrane Group meta-analysis nor the meta-analysis on HcQ side effects. You are of course free to continue making conversation without any understanding of the relevant evidence, but you are likely not going to make a favorable impression if you do so.

On the other hand, if you would ask specific questions about those meta-analyses, I’m sure we can have a productive conversation.

Meilleures salutations,
Christophe

[Giltil (Gilbert Thill)]

@Chris_Falter

Your assertion that the editors and reviewers believe HcQ is efficacious is without question wrong.

My assertion was not that the editors and reviewers believe HCQ is efficacious, rather that they don’t opine that Raoult is saying nonsense.

@Chris_Falter

Certainly you believe it, Gilbert, but you are accepting extremely dubious, low-quality evidence and rejecting a large amount of high-quality evidence

I am skeptical about the high-quality evidence against Raoult’s protocol you are referring to here. For example, the RCT you linked to is about the effect of HCQ alone, which is not Raoult’s protocol, which is based on HCQ plus AZ. I also note that only 58% of participants in this study received SARS-CoV-2 testing, which the authors recognize as a limitation.

[Giltil (Gilbert Thill)]

@Michael_Okoko

Need more?

Yes, I need more, for the reference you’ve offered me is irrelevant for several reasons, the most obvious one being that the authors have assessed the effect of HCQ alone, whereas Raoult’s protocol includes AZ in addition to HCQ.

[Michael_Okoko]

@Giltil

@Michael_Okoko

Need more?

Yes, I need more, for the reference you’ve offered me is irrelevant for several reasons, the most obvious one being that the authors have assessed the effect of HCQ alone, whereas Raoult’s protocol includes AZ in addition to HCQ.

Cool. You have a lot of reading to do. The earlier RCT I cited used HCQ alone and found it ineffective for Covid-19.

The RCT below looked at orally administered azithromycin alone for Covid-19 in outpatients and found it ineffective.

Effect of Oral Azithromycin vs Placebo on COVID-19 Symptoms in Outpatients...

This RCT below investigated HCQ with or without azithromycin for Covid-19 in outpatients, and, drumroll, found it ineffective.

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00053-5

You would do well to look at the Cochrane article @Faizal_Ali cited to examine where the weight of evidence lies (and its not in favor of HCQ with or without AZT, zinc etcetera).

I have for inpatients as well, and it’s a meta-analysis too. Its more recent than the Cochrane article Faizal cited. Enjoy.

https://onlinelibrary.wiley.com/doi/10.1002/jmv.27259

[Michael_Okoko]

@Giltil

@Chris_Falter

Your assertion that the editors and reviewers believe HcQ is efficacious is without question wrong.

My assertion was not that the editors and reviewers believe HCQ is efficacious, rather that they don’t opine that Raoult is saying nonsense.

That Raoult study is subpar. Do you even know how to critically appraise medical studies?

@Giltil

@Chris_Falter

Certainly you believe it, Gilbert, but you are accepting extremely dubious, low-quality evidence and rejecting a large amount of high-quality evidence

I am skeptical about the high-quality evidence against Raoult’s protocol you are referring to here. For example, the RCT you linked to is about the effect of HCQ alone, which is not Raoult’s protocol, which is based on HCQ plus AZ. I also note that only 58% of participants in this study received SARS-CoV-2 testing, which the authors recognize as a limitation.

I have satisfied your request. I suspect you will shift the goal posts now.

[Giltil (Gilbert Thill)]

Chris, It seems that you give credence to well done meta-analyses. So I have a question for you. Given that at least 2 meta-analyses have found that Ivermectin is a useful drug for treating covi19 patients, should it be allowed to be freely prescribed by physicians ?

[Michael_Okoko]

@Giltil

Chris, It seems that you give credence to well done meta-analyses. So I have a question for you. Given that at least 2 meta-analyses have found that Ivermectin is a useful drug for treating covi19 patients, should it be allowed to be freely prescribed by physicians ?

No such meta-analysis exists. I suspect you will cite that Bryant et al. study and if you do it will indicate you haven’t kept up with events following the publication of that meta-analysis. Go ahead and cite it though, so that others who are unaware can know the latest.

[Mercer (John Mercer)]

@Giltil

@Mercer

That’s just silly, because if HCQ works, it will work without death as the endpoint.

Are you serious?

Very; people are dying horrible deaths because of misinformation like you are peddling here.

Are you serious? Your question is silly.

It should show very early effects since all the cellular evidence suggests that if they do anything, both HCQ and azithromycin work at the step of initial viral entry. Were you not aware of this?

@Giltil

@Mercer

Again, if HCQ works or does not work in an inpatient setting, one should see the same thing in an outpatient setting.

Are you serious?

Absolutely, for the same reason.

@Giltil

@Mercer

That’s what those of us who do science describe as industrial-strength handwaving

Judging from your two above statements, one is forced to conclude that there are large gaps in your medical understanding.

How are you qualified to judge, since you haven’t even reviewed the RCTs before claiming that HCQ works?

@Chris_Falter

@Giltil

Can you give some references of such RCTs for outpatient setting?

I do not understand why you are asking for something that was already given to you.

Not only already given to him, but would be necessarily a part of any attempt to examine the evidence. It’s clear that Gil is unwilling, or afraid, to dive into the relevant evidence.

[Mercer (John Mercer)]

@Giltil

My assertion was not that the editors and reviewers believe HCQ is efficacious, rather that they don’t opine that Raoult is saying nonsense.

Are those editors and reviewers experts in infectious diseases? Why was this published in Reviews in Cardiovascular Medicine?

How many infectious disease or general medical journals with a better fit rejected it before it was accepted? The study ended 7 months before publication; that’s a very long time for a COVID-19 paper. Why did it take so long to publish? Where are the more recent data?

[Chris_Falter]

B’jour Gilbert,

It seems you are conceding that HcQ is ineffective and want to start a new topic. I think several of us are willing to have the ivermectin discussion, but we need to know which meta-analyses you are referring.

Merci bien,
Christophe

[Dan_Eastwood]

@Giltil

I disagree. I think that the data of this study weigh in favor of HCQ.

The authors also acknowledge age differences. I’m not pulling your leg here.

I am offering my best professional opinion as a Biostatistician that works on analyses just like this one. The statistical methods used are flawed. That doesn’t necessarily mean the conclusions are wildly wrong, but they aren’t exactly correct either. We can’t know how wrong they are without doing the analysis correctly. I would not trust this for my personal health decisions, and I advise that you should not either. It would be irresponsible (and unethical) for me to say otherwise.

[Michael_Okoko]

@Chris_Falter

I think several of us are willing to have the ivermectin discussion, but we need to know which meta-analyses you are referring.

It will definitely include this one by Bryant et al., given below:

Ivermectin for Prevention and Treatment of COVID-19... : American Journal of...

The “Elgazzar” study (an RCT) analyzed in the study which drove the weight of evidence in favor of ivermectin was retracted because of data fraud concerns (just as the Surgisphere study). When the Elgazzar study is removed, ivermectin no longer shows any benefit.

Is Ivermectin for Covid-19 Based on Fraudulent Research? Part 3

High-quality meta-analysis such as the one below have shown there is still uncertainty as to whether ivermectin is suitable or not for Covid-19 therapy.

https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD015017.pub2/full

[Giltil (Gilbert Thill)]

@Chris_Falter

It seems you are conceding that HcQ is ineffective

No, I am not conceding this, and have offered some reasons why here

HcQ is not an Information argument

My assertion was not that the editors and reviewers believe HCQ is efficacious, rather that they don’t opine that Raoult is saying nonsense. I am skeptical about the high-quality evidence against Raoult’s protocol you are referring to here. For example, the RCT you linked to is about the effect of HCQ alone, which is not Raoult’s protocol, which is based on HCQ plus AZ. I also note that only 58% of participants in this study received SARS-CoV-2 testing, which the authors recognize as a limitation.

@Chris_Falter

but we need to know which meta-analyses you are referring

For example, this one:

Ivermectin for Prevention and Treatment of COVID-19... : American Journal of...

[Michael_Okoko]

@Giltil

No, I am not conceding this, and have offered some reasons why here

My assertion was not that the editors and reviewers believe HCQ is efficacious, rather that they don’t opine that Raoult is saying nonsense. I am skeptical about the high-quality evidence against Raoult’s protocol you are referring to here. For example, the RCT you linked to is about the effect of HCQ alone, which is not Raoult’s protocol, which is based on HCQ plus AZ. I also note that only 58% of participants in this study received SARS-CoV-2 testing, which the authors recognize as a limitation.

So you are going to pretend I did not show you a large RCT that compared HCQ to HCQ+AZT and placebo for Covid-19 in which HCQ and HCQ+AZT did no better than placebo?

[Witchdoc]

From your medium.com link

You see, the study has four authors, three of whom are in Argentina where the research took place*. They report no funding. And yet, these three Argentinian doctors managed to recruit 1,400 medical staff over a 1-month period from 4 different hospital sites which are an hour’s drive away from each other. They then got 80% of this huge numbers of clinicians to take a drug weekly and use a nasal spray 4-5 times a day, and report back every week for another month with a PCR test for Covid-19. Not a single person dropped out of the study. In one hospital, 0% of the treatment group got COVID-19 while over 90% of the control group got sick.

Roflmao.

Not one iota plausible.