Hydroxychloroquine doesn’t work. But we know what does

It’s been a while since Donald Trump announced to the world the new good news: Hydroxychloroquine– a drug used to treat malaria and lupus. A magic cure to help the world fight against the COVID-19 pandemic (but don’t ask why). But then the evidence started coming in and it became increasingly obvious Hydroxychloroquine did not help patients with COVID-19. Since then, the question has gone from “does Hydroxychloroquine help patients” to “does Hydroxychloroquine harm patients”. We know it doesn’t help people with COVID-19 but could it add extra stress on the body and inadvertently harm them. Remember, even though Hydroxychloroquine is safe for healthy people it is not necessarily safe for those with a severe respiratory infection. 

Over the last four months there have been multiple studies of note. Most of them have been retrospective or observational studies. These studies aren’t as powerful as random controlled trials so we can’t infer causation but if they consistently suggest one outcome that outcome is probably accurate. 

The first study we are looking at compared outcomes in a 600 mg/day Hydroxychloroquine treated group to a non-Hydroxychloroquine treated group in four French hospitals:

In the weighted analysis, 20.2% patients in the HCQ group were transferred to the ICU or died within 7 days vs 22.1% in the no-HCQ group. In the HCQ group, 2.8% of the patients died within 7 days vs 4.6% in the no-HCQ group, and 27.4% and 24.1%, respectively, developed acute respiratory distress syndrome within 7 days… These results do not support the use of HCQ in patients hospitalised for documented SARS-CoV-2-positive hypoxic pneumonia.

The next study looked at patients in VA hospitals and has been published in the journal Med. It looked at the health records of  807 VA patients who were hospitalized within 24 hours of diagnosis. They were treated either with Hydroxychloroquine, Hydroxychloroquine and Azitromycin, or non-Hydroxychloroquine treatments. Mortality and ventilation use were compared. 

Compared to the no HC group, after propensity score adjustment for clinical characteristics, the risk of death from any cause was higher in the HC group but not in the HC+AZ group. Both the propensity-score-adjusted risks of mechanical ventilation and death after mechanical ventilation were not significantly different in the HC group or in the HC+AZ group compared to the no HC group. Among patients hospitalized with COVID-19, this retrospective study did not identify any significant reduction in mortality or in the need for mechanical ventilation with hydroxychloroquine treatment with or without azithromycin.

The third study was published in the Journal of the American Medical Association. The study retrospectively looked at the efficacy of Hydroxychloroquine alone, Hydroxychloroquine with Azithromycin, and Azithromycin alone in a random sample of 1,438 COVID-19 patients in 25 New York metropolitan hospitals. Their outcomes were compared to those that received standard treatment in terms of mortality, cardiac arrest, and electrocardiogram findings.

The probability of death for patients receiving hydroxychloroquine + azithromycin was 25.7%, hydroxychloroquine alone, 19.9%, azithromycin alone, 10.0%, and neither drug, 12.7%. In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in mortality for patients receiving hydroxychloroquine + azithromycin, hydroxychloroquine alone, or azithromycin alone. In logistic models, compared with patients receiving neither drug cardiac arrest was significantly more likely in patients receiving hydroxychloroquine + azithromycin, but not hydroxychloroquine alone or azithromycin alone. In adjusted logistic regression models, there were no significant differences in the relative likelihood of abnormal electrocardiogram findings.

The fourth study is an observational study in the New England Journal of Medicine. It looked at 1,446 patients in New York City hospitals. The study compared intubation and mortality rates between patients receiving Hydroxychloroquine and those not. 

In the main analysis, there was no significant association between hydroxychloroquine use and intubation or death.

In this observational study involving patients with Covid-19 who had been admitted to the hospital, hydroxychloroquine administration was not associated with either a greatly lowered or an increased risk of the composite end point of intubation or death. 

The fifth study we’re going to look at is a random controlled trial published in the British Medical Journal. The study looked at 150 patients with COVID-19 and compared the results of those treated with Hydroxychloroquine with those who received the standard treatment. 

The probability of negative conversion by 28 days in the standard of care plus hydroxychloroquine group was 85.4%, similar to that in the standard of care group 81.3%. 

Administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard of care alone in patients admitted to hospital with mainly persistent mild to moderate covid-19. Adverse events were higher in hydroxychloroquine recipients than in non-recipients.

The sixth and final study is another randomized trial, this time in the New England Journal of Medicine. The study was a “randomized, double-blind, placebo-controlled trial across the United States and parts of Canada testing hydroxychloroquine as postexposure prophylaxis.” Basically they tested Hydroxychloroquine as a preventative treatment against COIVD-19 using the gold standard scientific methodology. The study looked at 821 asymptomatic participants who had been exposed to someone confirmed to have COVID-19. The exposure has to be within six feet, for more than ten minutes, and with some type of facial exposure. The participants either got Hydroxychloroquine or a placebo. 

The incidence of new illness compatible with Covid-19 did not differ significantly between participants receiving hydroxychloroquine and those receiving placebo… Side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported.

After high-risk or moderate-risk exposure to Covid-19, hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure.

When it comes to studies that show Hydroxychloroquine works against COVID-19, they generally come in one of two groups. The first group of studies have some combination of flawed methodologies, obscure authors, aren’t published, or some other red flags. For example, the first study on Hydroxychloroquine was a study from France that purported to show it reduced the fatality of COVID-19. That study quickly came under massive scrutiny and the publishing society conceded it didn’t meet publishing standards. 

Multiple Hydroxychloroquine advocates have sent a link to this site as poof Hydroxychloroquine works. The problem is so many of the studies cited here have multiple red flags. Take this one for example. The red-flags are numerous. The authors are obscure and it doesn’t appear to be published anywhere. 

The site even includes a study that found “hydroxychloroquine did not prevent illness compatible with Covid-19” as positive for Hydroxychloroquine. This study was also cited above. 

The second group consists of the Henry Ford center study. Yes it was done well. I don’t know of any red flags or obvious flaws. But it’s simple in the minority of the evidence and we should expect a certain percentage of studies– especially lower quality studies– to provide biased results (in the statistical sense). We should consider it the context of all the studies above showing that it doesn’t work. There is no reason to put more stock in this study than any of the individual ones above– and certainly when the ones above are taken together. 

When you look at the evidence in totality, it shouldn’t be a surprise the FDA revoked Emergency Use Authorization. The evidence for Hydroxychloroquine is simply weak while the evidence against it is strong. 

Exit quote: “In early March, most doctors in the US had never seen a person sick with COVID19. 4 months later, nearly every ER and intensive care physician in the country is intimately familiar with the disease. In that time, they’ve learned a lot about how best to treat patients… Hospitals regularly change the drugs they use for conditions like flu and pneumonia as new data comes out. “What’s unusual is to change practice so quickly,” she says. “That’s just the reality of a global pandemic, with a disease we’ve never seen before.”

Update 1: I will try to include important updates periodically. First, that Henry Ford study. A STAT News article outlined some reasons to be skeptical of it.

The study that sparked the latest controversy was anything but randomized. Not only was it not randomized, outside experts noted, but patients who received hydroxychloroquine were also more likely to get steroids, which appear to help very sick patients with Covid-19. That is likely to have influenced the central finding of the Henry Ford study: that death rates were 50% lower among patients in hospitals treated with hydroxychloroquine.

Second, we have gotten two more random trial. The first study randomly assigned Hydroxychloroquine to 1,561 patients and standard care to 3,155 patients and compared 28-day mortality.

Overall, 418 (26.8%) patients allocated hydroxychloroquine and 788 (25.0%) patients allocated usual care died within 28 days… Patients allocated to hydroxychloroquine were less likely to be discharged from hospital alive within 28 days and those not on invasive mechanical ventilation at baseline were more likely to reach the composite endpoint of invasive mechanical ventilation or death.

In patients hospitalized with COVID-19, hydroxychloroquine was not associated with reductions in 28-day mortality but was associated with an increased length of hospital stay and increased risk of progressing to invasive mechanical ventilation or death.

The second study was a randomized, double-blind, placebo-controlled study in the US and Canada. The is limited by the fact it included both laboratory-confirmed COIVD-19 cases and probable COVID-19 cases. 491 patients were assigned to either a placebo or experimental group and their symptoms were compared over 14 days.

Change in symptom severity over 14 days did not differ between the hydroxychloroquine and placebo groups. At 14 days, 24% (49 of 201) of participants receiving hydroxychloroquine had ongoing symptoms compared with 30% (59 of 194) receiving placebo. Medication adverse effects occurred in 43% (92 of 212) of participants receiving hydroxychloroquine versus 22% (46 of 211) receiving placebo. With placebo, 10 hospitalizations occurred (2 non–COVID-19–related), including 1 hospitalized death. With hydroxychloroquine, 4 hospitalizations occurred plus 1 nonhospitalized death.

Hydroxychloroquine did not substantially reduce symptom severity in outpatients with early, mild COVID-19.

Neither are perfect but the add to the body of evidence.

Lastly, the New York Times is tracking the effectiveness of different COVID-19 treatments– including Hydroxychloroquine.

Update 2: There may be a third pharmaceutical on the way to help treat COVID!

A phase 3 clinical trial was also recently released looking at Hydroxychloroquine in 667 patients with suspected or confirmed COVID.

As compared with standard care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone or hydroxychloroquine plus azithromycin.

Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care.

And another RCT study on Hydroxychloroquine– this time in Clinical Infectious Diseases. Again, no effect. I’m sensing a pattern. 293 patients with mild COVID symptoms were randomly assigned either Hydroxychloroquine or a placebo.

No significant differences were found in the mean reduction of viral load at day 3 or at day 7. This treatment regimen did not reduce risk of hospitalization nor shortened the time to complete resolution of symptoms. No relevant treatment-related AEs were reported.

In patients with mild Covid-19, no benefit was observed with HCQ beyond the usual care.

Hydroxychloroquine advocates also recently launched a new offensive based off a Newsweek article from a Yale epidemilogist of chronic disease. Dr. David Gorski refuted it in detail here. The quick and dirty is Dr. Harvey Risch used a lot of poor quality studies to defend Hydroxychloroquine. Similarly, there was a rally of some quack doctors in DC supporting Hydroxychloroquine. They got a lot of attention. Dr. Gorski also talked about them in detail here. The Daily Beast also pointed out the headline doctor has some interesting beliefs.

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