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Does hydroxychloroquine work? Here’s what the studies say so far…

Kristen Panthagani, PhD

There has been lots of excitement about hydroxychloroquine as a treatment option for COVID-19; early on, this excitement was based on a few small studies and anecdotal reports from physicians. Since then, more studies have come out looking at the effectiveness of hydroxychloroquine in COVID-19 patients. Below is a summary of the study results so far.

For each study, I provide a simple Yes/No answer to did patients who got hydroxychloroquine do better than the patients who didn’t receive it? But this is very much an over-simplification: the type of study, details of the study population, details of the statistical analyses performed, and other strengths and weaknesses of the study should always be taken into account when interpreting the “Yes/No” conclusions (discussion of these is beyond the scope of this post.) Additionally, I only included studies that were (1) done in humans (not in cell lines) and (2) details of the results were made available.

First – a quick refresher on how to evaluate studies. More details are provided at the end of this post, but as you go through these studies, please remember two very important things:

1. Randomized >>> Observational

2. Big Sample Size >>> Small Sample Size

Hydroxychloroquine Study Results

(ordered by sample size) – last updated July 2020

Note: I have done my best to find all the studies to date, but I could have missed some. If you see one I missed, please send it to me and I’ll update this post.

Links to studies are provided in every title!

This is by far the best study we have to date, as it is the largest and it is randomized:

Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial

Type of Study: Randomized

Outcome: Death within 28 days

Sample Size: 4716 patients

Important notes: not yet peer-reviewed

Did patients who got hydroxychloroquine do better? No

Hydroxychloroquine with or without azithromycin and in-hospital mortality or discharge in patients hospitalized for COVID-19 infection: a cohort study of 4,642 in-patients in France

Type of Study: Observational

Outcome: Death within 28 days

Sample Size: 4642 patients

Important notes: not yet peer-reviewed, some patients got azithromycin

Did patients who got hydroxychloroquine do better? No*

*they did see a slight reduction in % of patients discharged with hydroxychloroquine, but no difference in mortality. They also saw a trending increase risk in mortality in hydroxychloroquine + azithromycin group.

 

Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis Type of Study: Observational

Outcome: Death / Hospital Stay ≥ 10 days / Transfer to ICU / Viral Shedding

Sample Size: 3737 patients

Important notes: patients also got azithromycin, patients who didn’t get drugs were older and sicker

Did patients who got hydroxychloroquine do better? Yes

 

Outcomes of Hydroxychloroquine Treatment Among Hospitalized COVID-19 Patients in the United States- Real-World Evidence From a Federated Electronic Medical Record Network

Type of Study: Observational

Outcome: Death / Need for Mechanical Ventilation

Sample Size: 3,372 patients (though main analysis is 1820 patients)

Important Notes: not yet peer-reviewed, some patients also got azithromycin

Did patients who got hydroxychloroquine do better? No

Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19

Type of Study: Observational

Outcome: In hospital mortality

Sample Size: 2541 patients

Important Notes: Some patients also got azithromycin, discussion of confounders here.

Did patients who got hydroxychloroquine do better? Yes

Hydroxychloroquine and Tocilizumab Therapy in COVID-19 Patients – An Observational Study

Type of Study: Observational

Outcome: Death

Sample Size: 2512 patients

Important Notes: Some patients got azithromycin and tocilizumab, not yet peer-reviewed.

Did patients who got hydroxychloroquine do better? No

Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State

Type of Study: Observational

Outcome: Death

Sample Size: 1438 patients

Important Notes: Some patients also got azithromycin

Did patients who got hydroxychloroquine do better? No

Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19

Type of Study: Observational

Outcome: Intubation or Death

Sample Size: 1376 patients

Important Notes: Patients who got hydroxychloroquine were already sicker prior to treatment.

Did patients who got hydroxychloroquine do better? No

Early Treatment of COVID-19 Patients With Hydroxychloroquine and Azithromycin: A Retrospective Analysis of 1061 Cases in Marseille, France

Outcome: Death, Clinical Worsening, Viral Shedding

Sample Size: 1061 patients

Important Notes: No Control Group

Did patients who got hydroxychloroquine do better? No evidence provided (no control group)

Empirical treatment with hydroxychloroquine and azithromycin for suspected cases of COVID-19 followed-up by telemedicine

Type of Study: Observational

Outcome: Hospitalization

Sample Size: 636 patients

Important Notes: Not all patients were confirmed to have COVID, and stats are weird.

Did patients who got hydroxychloroquine do better? Inconclusive*

*patients were not tested for COVID. also stats are funky in this paper. I do not trust it. not

Hydroxychloroquine application is associated with a decreased mortality in critically ill patients with COVID-19

Type of Study: Observational

Outcome: Death

Sample Size: 568 patients

Important Notes: not peer-reviewed

Did patients who got hydroxychloroquine do better? Yes

Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19

Type of Study: Observational

Outcome: Death, measures of inflammation

Sample Size: 550 patients

Important Notes: issues about statistics reported have been raised on pubpeer

Did patients who got hydroxychloroquine do better? Yes

COVID-19 Outpatients – Early Risk-Stratified Treatment with Zinc Plus Low Dose Hydroxychloroquine and Azithromycin: A Retrospective Case Series Study

Type of Study: Observational

Outcome: Hospitalization / Death

Sample Size: 518

Important Notes: No way to know if control group was comparable; no details provided

Did patients who got hydroxychloroquine do better? Inconclusive

Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19

Type of Study: Observational

Outcome: Use of Ventilator and/or Death

Sample Size: 368 patients

Important notes: Not yet peer-reviewed

Did patients who got hydroxychloroquine do better? No

Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial

Type of Study: Randomized

Outcome: viral RNA load in nose up to 7 days after treatment start, disease progression, time to complete resolution of symptoms

Sample Size: 293

Did patients who got hydroxychloroquine do better? No

Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data

Type of Study: Observational

Outcome: Transfer to ICU and/or Death

Sample Size: 181 patients

Did patients who got hydroxychloroquine do better? No

Early Hydroxychloroquine Is Associated with an Increase of Survival in COVID-19 Patients: An Observational Study

Type of Study: Observational

Outcome: Death

Sample Size: 166 patients

Important notes: Not yet peer-reviewed

Did patients who got hydroxychloroquine do better? Yes

Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial

Type of Study: Randomized Trial

Outcome: Positive for virus after 28 days

Sample Size: 150 patients

Did patients who got hydroxychloroquine do better? No

Compassionate use of hydroxychloroquine in clinical practice for patients with mild to severe Covid-19 in a French university hospital

Type of Study: Observational

Outcome: time to death, ICU admission, or withdrawal of supportive care

Sample Size: 89 patients

Did patients who got hydroxychloroquine do better? No

Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study

Type of Study: Observational

Outcome: Positive for Virus, Length of Hospital Stay, Clinical Outcome

Sample Size: 80 patients

Important notes: No control group

Did patients who got hydroxychloroquine do better? No evidence provided (no control group)

Clinical outcomes of hydroxychloroquine in hospitalized patients with COVID-19 : a quasi-randomized comparative study

Type of Study: Quasi-randomized (I would put this more as observational)

Outcomes: mortality, respiratory status

Sample Size: 63 patients

Important notes: this study was written in French and this is based off the google-translated abstract

Did patients who got hydroxychloroquine do better? Mixed Results (mortality was higher but improvement in respiratory status was better in the hydroxychloroquine group )

Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial

Type of Study: Randomized Trial

Outcome: Time to Clinical Recovery

Sample Size: 62 patients

Important notes: Not yet peer-reviewed

Did patients who got hydroxychloroquine do better? Yes (modest effect)

Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study. Type of Study: Randomized Trial

Outcome: Time to Clinical Recovery

Sample Size: 48 patients

Important notes: Not yet peer-reviewed, also included chloroquine group

Did patients who got hydroxychloroquine do better? Yes (modest effect)

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Type of Study: Observational

Outcome: Positive for Virus after 6 days

Sample Size: 36 patients

Important notes: major issues with study design

Did patients who got hydroxychloroquine do better? Mehhhhhh*

*the authors conclude there is an effect, but the study design had so many issues that I wrote a whole other post about it.

Hydroxychloroquine and azithromycin as potential treatments for COVID-19; clinical status impacts the outcome

Type of Study: Observational

Outcome: Positive for Virus

Sample Size: 36 patients

Important notes: I think they may have artificially inflated their statistical power in the way they did their analysis, but I’d have to dig into it more to be sure.

Did patients who got hydroxychloroquine do better? Yes

Hydroxychloroquine is associated with slower viral clearance in clinical COVID-19 patients with mild to moderate disease: A retrospective study

Type of Study: Observational

Outcome: Positive for Virus

Sample Size: 34 patients

Important notes: not yet peer-reviewed

Did patients who got hydroxychloroquine do better? No (those who got the drug did worse)

A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19)

Type of Study: Randomized Trial

Outcome: Positive for virus after 7 days of treatment

Sample Size: 30 patients

Did patients who got hydroxychloroquine do better? No

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

Type of Study: Observational

Outcome: Death (in the hospital)

Sample Size: 96,032 patients

Important Notes: Also includes analysis of chloroquine and macrolides (such as azithromycin)

Did patients who got hydroxychloroquine do better? No (those who got the drug did worse)

STUDY RETRACTED – leaving here for record purposes only.

So, does it work?

Most studies (13 studies) showed no improvement with hydroxychloroquine treatment, including the best designed study we have as well as 6 big studies (>1000 people). However, some studies (8) did show an effect of hydroxychloroquine (though these were often smaller studies, with only 2 studies with >1000 people). How do we interpret this? One way is to go back and do a meta-analysis — where someone pulls all the available data from the studies and re-analyzes the data from multiple studies together. This study did just that, here is what they found:

The Role of Hydroxychloroquine in the Age of COVID-19: A Periodic Systematic Review and Meta-Analysis Sample Size: 21 studies, 103,486 patients

Important Notes: not yet peer reviewed, some patients also received azithromycin

Did patients who got hydroxychloroquine do better? No

Studies of Hydroxychloroquine as Prophylaxis

(ordered by sample size)

prophylaxis: a treatment that is given to prevent a disease from developing (rather than treat a disease that somebody already has)

A Cluster-Randomized Trial of Hydroxychloroquine as Prevention of Covid-19 Transmission and Disease

Type of Study: Randomized Trial

Outcome: PCR-confirmed symptomatic Covid-19 within 14 days

Sample Size: 2314 patients

Important notes: not yet peer-reviewed

Were patients who got hydroxychloroquine less likely to develop COVID? No

A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19

Type of Study: Randomized Trial

Outcome: laboratory-confirmed COVID-19, or illness compatible with COVID-19, within 14 days

Sample Size: 821 patients

Were patients who got hydroxychloroquine less likely to develop COVID? No

Pre exposure Hydroxychloroquine Prophylaxis for COVID-19 in healthcare workers: a retrospective cohort

Type of Study: Observational

Outcome: positive for COVID-19

Sample Size: 106

Important notes: not yet peer-reviewed

Were patients who got hydroxychloroquine less likely to develop COVID? Yes

What do all these words describing studies mean?

Type of Study: All of the studies reported here are some form of either an observational or randomized trial. What’s the difference? An observational study is a study that is done by looking back at what happened organically in the hospital. These studies usually use hospital records to see who got the treatment, who didn’t, and how these groups of patients did over the course of their hospital stay. These studies are important and provide much better evidence than anecdotal reports by physicians, but there are down sides — the main one is that there is no guarantee that those who got the treatment and those who didn’t are truly comparable groups of patients. For example, maybe patients who got hydroxychloroquine were already sicker than those who didn’t — this would effect the differences in outcomes between the treatment and control groups. There are some fancy statistical methods to help correct for these differences, but they are not perfect. Observational studies also are prone to the placebo effect, where patients improve because of the hope of treatment (and possibly other more complicated reasons), and not due to the actual effect of the drug. A randomized study takes care of one of these problems — patients are randomized to either the treatment or control group at the beginning, which usually takes care of differences in populations between the two groups. The control group in these cases is usually the standard-of-care (everything the hospital would normally do for a COVID-19 patient). If it is a randomized placebo-controlled study, then that study also takes care of the placebo effect problem by giving the control group a placebo in addition to the standard-of-care. So if randomized placebo-controlled studies are clearly the best, why don’t we do that for every study? Because they are much harder to do (they take time to get up and running, they cost more, they require much more time on the part of the researchers, etc.)

Outcome: This is simply the patient outcome (positive for virus after 7 days, fever, transfer to ICU, death, etc.) the study used to measure if there was an effect of the treatment. All of these in some way measure how sick the patient is.

Sample Size: How many patients were included in the study (more is always better).

Disclaimer: This post is not intended to provide medical advice or guide treatment decisions. Please consult your physician for questions about medical treatments. COVID-19 treatment guidelines provided by the CDC can be found here.

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