Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis

The Lancet ^ | May 22, 2020 | Prof Mandeep R Mehra, MD Sapan S Desai, MD Prof Frank Ruschitzka, MD Amit N Patel, MD

[absalom01]

Summary Background Hydroxychloroquine or chloroquine, often in combination with a second-generation macrolide, are being widely used for treatment of COVID-19, despite no conclusive evidence of their benefit. Although generally safe when used for approved indications such as autoimmune disease or malaria, the safety and benefit of these treatment regimens are poorly evaluated in COVID-19.

Methods

We did a multinational registry analysis of the use of hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19. The registry comprised data from 671 hospitals in six continents. We included patients hospitalised between Dec 20, 2019, and April 14, 2020, with a positive laboratory finding for SARS-CoV-2. Patients who received one of the treatments of interest within 48 h of diagnosis were included in one of four treatment groups (chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide), and patients who received none of these treatments formed the control group. Patients for whom one of the treatments of interest was initiated more than 48 h after diagnosis or while they were on mechanical ventilation, as well as patients who received remdesivir, were excluded. The main outcomes of interest were in-hospital mortality and the occurrence of de-novo ventricular arrhythmias (non-sustained or sustained ventricular tachycardia or ventricular fibrillation).

Findings

96 032 patients (mean age 53·8 years, 46·3% women) with COVID-19 were hospitalised during the study period and met the inclusion criteria. Of these, 14 888 patients were in the treatment groups (1868 received chloroquine, 3783 received chloroquine with a macrolide, 3016 received hydroxychloroquine, and 6221 received hydroxychloroquine with a macrolide) and 81 144 patients were in the control group. 10 698 (11·1%) patients died in hospital. After controlling for multiple confounding factors (age, sex, race or ethnicity, body-mass index, underlying cardiovascular disease and its risk factors, diabetes, underlying lung disease, smoking, immunosuppressed condition, and baseline disease severity), when compared with mortality in the control group (9·3%), hydroxychloroquine (18·0%; hazard ratio 1·335, 95% CI 1·223–1·457), hydroxychloroquine with a macrolide (23·8%; 1·447, 1·368–1·531), chloroquine (16·4%; 1·365, 1·218–1·531), and chloroquine with a macrolide (22·2%; 1·368, 1·273–1·469) were each independently associated with an increased risk of in-hospital mortality. Compared with the control group (0·3%), hydroxychloroquine (6·1%; 2·369, 1·935–2·900), hydroxychloroquine with a macrolide (8·1%; 5·106, 4·106–5·983), chloroquine (4·3%; 3·561, 2·760–4·596), and chloroquine with a macrolide (6·5%; 4·011, 3·344–4·812) were independently associated with an increased risk of de-novo ventricular arrhythmia during hospitalisation. Interpretation We were unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or with a macrolide, on in-hospital outcomes for COVID-19. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19.

Funding

William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women's Hospital.

[absalom01]

Big international retrospective study, but without zinc.

Not what we would like to see, but an important data point, and one that the media will quickly politicize.

[glorgau]

Are there any actual clinical trials with zinc?

[absalom01]

I don’t think so.

[Ceebass]

The lancet recently published a piece urging the US to vote out Trump.

This study should be considered biased.

[Mom MD]

as will most freezers. Like it or not this is not an effective in hospital treatment

[Mom MD]

freepers. autocorrect is not your friend

[Mrs. Don-o]

Every one of these patients was hospitalized, which means that they were likely in the stages where there is a cytokine storm and are already experiencing lung tissue destruction. HCQ is of little use in such situations.

According to one of HCQ's earliest proponents, Dr. Vladimir Zelenko, HCQ + Zinc is to be used on high-risk patients (older, comorbidities) as early as possible, on the same day as the COVID-19 test or immediately upon the onset of symptoms. The whole idea is to prevent the cascading ARDS events which result in high-risk patients' hospitalization, not to intervene after ARDS and critical hospitalization.

Here's a group of Brazilian scientists and academics who charge that (some) doctors, using e.g. WHO guidelines, are using HCQ in such a way as to practically guarantee mortality:

https://conexaopolitica.com.br/ultimas/brazilian-scientists-and-academics-write-an-open-letter-on-the-science-of-the-coronavirus-pandemic/?idPost=59623

[hcqmonkey]

There is lack of critical disease indicators un-like in almost every other study, that’s why it looks so uniform: no CT scan, no body temp, no resp rate, no paO2/FiO2 ratio. Just above or below 94% sats and qSOFA . Now let me point out that using 94% spO2 as binary cut off will give you very wrong results, thats an example of just ONE misuse of an indicator. There is a very big difference between a patient with 93% O2 sat, and someone who is 80% but they are both under 94% cut off in this study! No other studies use so little and such coarse indicators, low-fidelity indicators of disease. Also pay attention that not only is the mortality almost double, the intubation and ventilator use is also more than double for HCQ group, that has nothing to do with HCQ - HCQ doesn’t affect respiratory function, it has to do with indicator bias, for which the Lancet study failed to control. Here are some links going in depth:
https://docs.google.com/document/d/e/2PACX-1vRJxr01VKOdUDSgXfGks6TMnhOF4csQ1sYhmlVGLpandXrhCi6nNV6Ig7wrBNcdril4izIGmpASAGuD/pub

https://threadreaderapp.com/thread/1264251404232855552.html

The evidence of mistakes are right there in the study, if you pay close attention! But neither media or officials, will they just take the Journal word for it.

[CharlesWayneCT]

Except for the ignoring zinc thing, which seems to be common in these treatments (wonder if they were testing for zinc and or not), this seems like it might be a rational study. If they properly controlled for other factors (and I thought it interesting that they specifically excluded treatment if it started after onset of serious conditions), it does seem that the HCQ isn’t helping much on it’s own anyway.

It is too bad that we couldn’t get people to do good studies of HCQ in March, that instead the media had to make it a big political fight.

[NonValueAdded]

Macrolide= Z-pack, etc. No mention of zinc. Anyone who has read up on HCQ knows it’s use is to open up the cells for zinc which does the dirty work. The macrolide is used to stave off pneumonia. No zinc means the trial is useless. And I’m betting they know this.

[lastchance]

Here’s what is never mentioned. Those risks of taking these drugs are present no matter the disease or ailment being treated. So does that mean these drugs should not be used to treat diseases such as Lupus based on these findings?

[CharlesWayneCT]

That is a good point, that HCQ’s “risk factors” are heart-related, and using HCQ wouldn’t lead to a greater pulminary response, so the fact that there WAS a greater response indicates that they did not appropriately control. They are aware that in many hospitals, the drug is given to the more serious cases, but they don’t seem to ahve controlled successfully for that.

[combat_boots]

IIRC, there’s zinc in red wine.

[iontheball]

For the Lancet to publish this misleading and deceptive study tells you all you need to know about the corruption in the U.S. medical industry. The researchers know full well you need to increase the availability of zinc for HCQ to do its job. They are afraid if they do a study with HCQ and zinc that this cure will become a universal treatment for all RNA viruses and that’s a kick in the head for the vaccine hounds. HCQ plus zinc treats a virus infected human cell, that’s why it’s unlike a vaccine that is geared to a specific virus. The industry wants this specific virus vaccine approach so they can market a new and different vaccine every time a different virus variant comes along.

[iontheball]

That is a good point, that HCQ’s “risk factors” are heart-related.
__________________________________
Every drug has side affects. While not denying that HCQ has side effects, the corona virus is a blood disease that causes a number of vascular problems all it own, including clots, which leads me to ask how many of the corona caused heart related problems are being blamed on HCQ?

[nwrep]

It’s over. We have lost this battle. We need to move on.

[ifinnegan]

Azithromycin is the macrolide usually used.

This is the most dishonest study (remember it is not a trial) I've ever seen. Here is the table..

Look at the last four in the table, the treatments. They associate them with higher mortality. But these are treatments. The others were pre-existing, not part of treatment or therapy.

Treatment is not independent but chosen specifically based on severity of the illness. Of course there will be a higher number of deaths in the treated cases because patients closer to death are treated. It is ludicrous to compare to body mass index or pre-existing medication history etc...which were independent of Covid-19 and not begun due to severity of disease.

This next table is doing the same thing. It presents treatment with the drugs as if treatment were a pre-existing condition.

Dishonest to the point of fraud. .

[ifinnegan]

And from the article, the bottom line where the authors say their study is meaningless, but they really really want to believe it's true:

"Our study has several limitations. The association of decreased survival with hydroxychloroquine or chloroquine treatment regimens should be interpreted cautiously. Due to the observational study design, we cannot exclude the possibility of unmeasured confounding factors, although we have reassuringly noted consistency between the primary analysis and the propensity score matched analyses. Nevertheless, a cause-and-effect relationship between drug therapy and survival should not be inferred."

[AndyTheBear]

Suspect the study is a failure due to a correlation vs cause effect problem. Whatever the attempts to account for confounding factors were, seems obvious they were overshadowed by real life doctors examining patients and deciding who needed treatmemt and who did not.

[Norski]

Welcome to Freerepublic.

Excellent start.

Norski