25 May: Stat Modeling (Columbia Uni): This controversial hydroxychloroquine paper: What’s Lancet gonna do about it?
Posted by Andrew
Lancet
A recent paper published in the famous/notorious medical journal Lancet reports that hydroxychloroquine and chloroquine increased the risk of in-hospital death by 30% to 40% and increased arrhythmia by a factor of 2 to 5. The study hit the news with the headline, “Antimalarial drug touted by President Trump is linked to increased risk of death in coronavirus patients, study says.” (Meanwhile, Trump says that Columbia is “a liberal, disgraceful institution.” Good thing we still employ Dr. Oz!)…
All this politics . . . in the meantime, this Lancet study has been criticized; see here and here. I have not read the article in detail so I’m not quite sure what to make of the criticisms; I linked to them on Pubpeer in the hope that some experts can join in...
Almost all the press coverage of this study seemed to be taking the Lancet label as a sign of quality...READ ON
FIRST COMMENT:
25 May: ETH: One additional important development: The WHO announced today that they would be temporarily pausing their trial of hydroxychloroquine, citing the results of The Lancet paper.
SECOND COMMENT:
26 May: Zach: It looks like they’ve already restarted it
https://statmodeling.stat.columbia.edu/2020/05/25/this-controversial-hydroxychloroquine-paper-whats-lancet-gonna-do-about-it/
26 May: RecoveryTrial.net: Recruitment to the RECOVERY trial continues as planned
Prof Peter Horby and Prof Martin Landray, Chief Investigators of the RECOVERY trial, said ‘We have been working over the weekend to understand the implications of the Mehra paper for the safety and welfare of patients randomised to hydroxychloroquine.
‘On Saturday 23 May, the independent Data Monitoring Committee conducted an urgent review of the data that we have collected so far on the effects of hydroxychloroquine on mortality among patients admitted to hospital with COVID-19. The Committee concluded that there is “no cogent reason to suspend recruitment for safety reasons.”
‘The Committee found that the effects of hydroxychloroquine on mortality reported in the analysis by Mehra were not consistent with those observed in the RECOVERY trial. The Committee therefore recommended that the trial continue recruitment without interruption, a recommendation that was endorsed on Sunday by the MHRA.
‘The conclusion of the Mehra paper is that “Randomised clinical trials will be required before any conclusion can be reached regarding benefit or harm of these agents in COVID-19 patients.” The RECOVERY trial is currently the largest randomised controlled trial of hydroxychloroquine and other potential treatments for COVID-19. Enrolment in this trial is the best way to provide definitive evidence on these drugs.’
https://www.recoverytrial.net/news/recruitment-to-the-recovery-trial-continues-as-planned
25 May: StatModeling: Hydroxychloroquine update
Posted by Andrew
The study only has 4 authors which is weird for a global study in 96,000 patients (and no acknowledgements at the end of the paper). Studies like this in medicine usually would have 50-100 authors (often in some kind of collaborative group). The data come from the “Surgical Outcomes Collaborative”, which is in fact a company. The CEO (Sapan Desai) is the second author. One of the comments on the blog post is “I was surprised to see that the data have not been analyzed using a hierarchical model”. But not only do they not use hierarchical modelling and they do not appear to be adjusting by hospital/country, they also give almost no information about the different hospitals: which countries (just continent level), how the treated vs not treated are distributed across hospitals etc. A previous paper by the same group in NEJM says that they use data from UK hospitals (no private hospitals are treating COVID so must be from the NHS). Who is allowing some random company to use NHS data and publish with no acknowledgments. Another interesting sentence is about patient consent and ethical approval:
We emailed them to ask for the data, in particular to look at the dose effect which I think is key in understanding the results. They got back to us very quickly and said
“Thanks for your email inquiry. Our data sharing agreements with the various governments, countries and hospitals do not allow us to share data unfortunately. I do wish you all the very best as you continue to perform trials since that is the stance we advocate. All we have said is to cease and desist the off label and unmonitored and uncontrolled use of such therapy in hospitalized patients.”
So unavailable data from unknown origins . . .
Another rather remarkable aspect is how beautifully uniform the aggregated data are across continents: ...
https://statmodeling.stat.columbia.edu/2020/05/25/hydroxychloroquine-update/
22 May: PubPeer: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis
The Lancet(2020) - 11 Comments
https://pubpeer.com/publications/71DA593B9943638F1ADE6F80696914#1
The Lancet: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis
Mandeep R Mehra, Sapan S Desai, Frank Ruschitzka, Amit N Patel
Declaration of interests
MRM reports personal fees from Abbott, Medtronic, Janssen, Mesoblast, Portola, Bayer, Baim Institute for Clinical Research, NupulseCV, FineHeart, Leviticus, Roivant, and Triple Gene. SSD is the founder of Surgisphere Corporation. FR has been paid for time spent as a committee member for clinical trials, advisory boards, other forms of consulting, and lectures or presentations; these payments were made directly to the University of Zurich and no personal payments were received in relation to these trials or other activities...
Research in context
Evidence before this study
We searched MEDLINE (via PubMed) for articles published up to April 21, 2020, using the key words “novel coronavirus”, “2019-nCoV”, “COVID-19”, “SARS-CoV-2”, “therapy”, “hydroxychloroquine”, “chloroquine”, and “macrolide”. Moreover, we screened preprint servers, such as Medrxiv, for relevant articles and consulted the web pages of organisations such as the US National Institutes of Health and WHO...
Acknowledgments
The development and maintenance of the Surgical Outcomes Collaborative database was funded by Surgisphere Corporation (Chicago, IL, USA). This study was supported by the William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women’s Hospital (Boston, MA, USA). We acknowledge Jide Olayinka (Surgisphere) for their helpful statistical review of the manuscript...
In the link above Didier Raoult addresses the Lancet article and also defends what they are doing in Marseille. It is in French so you can use google translate to read it. Some comments are negative saying in effect that he inflates the denominator by adding patients who would get well anyway. About that I don’t know, but Dr. Zelenko doesn’t inflate the denominator since he breaks patients into high risk and low risk groups, with symptoms, and then gives the meds to the high risk patients. And he says if someone is initially determined as a low risk patient, if symptoms worsen, he puts them into the high risk group and gives them the meds. So we know it works certainly from what Dr. Zelenko reports.
Zelenko’s presentation is essentially a report from an experimental group, in my mind, to be compared to the control group that consists of patients elsewhere who would have been assessed as high risk had Zelenko saw them. So we know what the general death rate is among those not getting Zelenko’s plan and the only question is what is the death rate of patients following Zelenko’s plan and it is immediately obvious that his plan is effective. Enough is determined that his strategy of early intervention should be applied at the lowest level of medicine, which is on an outpatient basis.
With respect to Lancet one commenter said the following (translated from French)
A shocking admission by the publisher of The Lancet, the world’s most esteemed medical journal, has been largely overlooked by mainstream and mainstream media. Dr. Richard Horton, editor of The Lancet, recently made an announcement saying that an outrageous number of study publications are at best, unreliable, if not completely false, in addition to fraudulent.
Horton said:
“A large part of the scientific literature, probably half, could be simply false. Afflicted with studies with reduced samples, tiny effects, invalid preliminary analyzes, and flagrant conflicts of interest, with the obsession to follow trends of dubious importance in fashion, science has taken the wrong turning to darkness. Putting it differently, Horton bluntly says that the big pharmaceutical companies are falsifying or faking tests on the health, safety and efficacy of their various drugs, taking samples too small to be statistically significant, or else, to the trials, hire laboratories or scientists with flagrant conflicts of interest, they must please the pharmaceutical company to obtain other subsidies. At least half of all these tests are worthless or are ...