Coronavirus, WHO “against” chloroquine. The researcher: “The Lancet study does not have the strength of a clinical trial”

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WHO has suspended testing on hydroxychloroquine, one of the drugs that had aroused greater interest in early treatments against Covid 19. And today, France is also stopping tests. The World Health Organization cited a retrospective observational study that appeared in The Lancet and we asked the researcher from the Istituto Superiore di Sanità for an opinion, Andrea Savarino. It was he, in 2003, who proposed hydroxychloroquine against Sars1, together with Roberto Cauda (Director of Infectious Diseases of the Gemini), and Antonio Cassone (former director of the Department of Infectious Diseases of ISS).

Dr. Savarino, WHO has suspended the Solidarity study on hydroxychloroquine, citing a study that appeared in The Lancet. What could you deduce from this publication?
Unfortunately, this research suffers from having been caught in the middle of a political battle. Donald Trump, a major supporter of hydroxychloroquine, recently suspended American funding for the WHO. Personally, I think it is really counterproductive that scientific research, especially those with a potential impact on public health, is being taken hostage by politics. Going into the merits of the publication: after conducting a retrospective analysis on 671 hospitals on six continents, the authors conclude that chloroquine and hydroxychloroquine, particularly in combination with macrolide antibiotics, would increase the number of deaths in patients hospitalized with Covid 19 and that this excess mortality would be associated with an increase in arrhythmias. The study, however, is influenced by a non-homogeneous distribution of pre-existing risk factors. Despite these limitations, the study supports the need for careful cardiological monitoring of patients receiving chloroquine / hydroxychloroquine, particularly those who have independent risk factors potentially associated with increased mortality from cardiovascular events. Many guidelines have existed for some time to try to prevent cardiac toxicity linked to those of kin / hydroxychloroquine, and should be implemented.

Does hydroxychloroquine increase mortality in treated patients?
From an analysis of the publication data it is not possible to draw this conclusion.

Randomization, in the Lancet article, by what criterion was it conceived?
Unfortunately, no randomization was performed. This is a retrospective observational study. It does not have the strength of a randomized clinical trial.

On a statistical level, in the article of The Lancet, were confounding variables weighted (which affect both dependent and independent variables)?
The study is influenced by a non-homogeneous distribution of pre-existing risk factors. For example, the groups treated with chloroquine / hydroxychloroquine contained, compared to controls, a higher prevalence of smokers, hypertensives and had on average a higher body mass index (BMI), a factor associated with obesity. All these factors are associated with poorer prognosis. According to the same analyzes by the same authors, some of these factors such as hypertension were found to be predictors of mortality in the entire cohort of patients considered, regardless of the use or not of chloroquine / hydroxychloroquine. Furthermore, it is not clear why only patients treated with Remdesivir but not those treated with other antivirals were excluded from the analysis. There were in fact other concomitant antiviral treatments and the distribution of the various antivirals in the groups with or without chloroquine / hydroxychloroquine was not reported. It is known that some antivirals such as Lopinavir, when administered in full doses, may increase the incidence of arrhythmias, and therefore this analysis should have been reported. Finally, the limitations of the study are evident from the fact that it has failed to demonstrate the contribution of cigarette smoking to the incidence of arrhythmias, an association widely documented in the literature, while it disappears here.

Savarino, you are working for a publication on hydroxychloroquine, taken at an early stage, what are the results of the research?
An antiviral effect of HCQ (hydroxychloroquine) is expected when the drug is administered early, before patients are hospitalized. Taking into account a mathematical model developed by Goncalves et al., Recent pharmacokinetic analyzes and some immunomodulating properties of the drug, we calculated that chloroquine / hydroxychloroquine could have a limited impact on complete suppression of the virus: this could only become evident inside a narrow window of drug concentrations in the tissues immediately below those causing toxicity.

Trump said a few days ago that he had been taking hydroxychloroquine for two weeks, on what grounds does the President of the United States take these drugs?
Trump sought advice from David Boulware, the doctor who is the principal investigator of a randomized, double-blind clinical trial of hydroxychloroquine as a preventive drug following exposure to infected people. The results of this clinical trial will be available shortly. If my theory that the earlier the drug is administered, the better the effects are correct, I expect at least that some positive effect has occurred; obviously I cannot predict if the effect is statistically significant. A couple of interim analyzes have already been carried out, i.e. preliminary studies in progress. Given the fairly high dosage of the drug, if this had had any unacceptable side effects, the clinical trial would have been stopped. Someone speculated that Trump already knew of the outcome of this ongoing clinical trial, given that hydroxychloroquine will be an important topic of debate for the race to the White House. This, however, remains in the field of mere speculation.

There are publications, as they say in the scientific field: with a high reference (authoritative), which report different data from The Lancet?
There are many of these trials, some randomized. Some report a beneficial effect of hydroxychloroquine, others do not, therefore further research is underway. But no such mortality disaster has been reported by anyone. In Europe, the DISCOVERY clinical trial is underway, conducted with all due chrisms. Here too, an interim analysis has already been carried out, and again, whether the drug had any unacceptable side effects, the clinical trial would have been stopped. Instead, the managers of the RECOVERY trial, born as an arm of DISCOVERY and then independent in the United Kingdom, decided to continue with the trial of hydroxychloroquine not considering the study published in Lancet sufficient evidence to prove the dangerousness of the drug.

The article in The Lancet

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Coronavirus, also the Italian Drug Agency suspends hydroxychloroquine use: “Risk of adverse reactions and benefits absent”

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