May 24, 2020

COVID-19 Update: Just Say No to Hydroxychloroquine or Chloroquine With or Without Macrolides

This publication has now been retracted by Lancet (June 4, 2020)

Background: There is no conclusive evidence that chloroquine, or its derivative hydroxychloroquine, with or without a second-generation macrolide is effective in COVID-19 treatment or prophylaxis. Laboratory studies have shown antiviral and immunomodulatory properties in vitro. The small retrospective observational trials thus far have had mixed results in efficacy.  However, these medications are well known to have cardiovascular adverse effects via QT interval prolongation leading to ventricular arrhythmias. Despite the potential harms and the absence of convincing data to support treatment with these drugs, they are widely prescribed to COVID-19 patients.

This publication has now been retracted by Lancet (June 4, 2020)

Due to concerns with respect of the data and analyses conducted by Surgisphere Corporation, an independent third party peer review was launched to evaluate the origination of the database and to confirm the completeness of the database.  Surgisphere would not transfer the full dataset, as this would violate client agreements and confidentiality.  Therefore an independent peer review was not possible and the paper has been retracted.

Paper: Mehra MR et al. Hydroxychloroquine or Chloroquine With or Without a Macrolide for Treatment of COVID-19: A Multinational Registry Analysis. Lancet 2020. [Epub Ahead of Print]

Clinical Question: Is the use of hydroxychloroquine or chloroquine (used with or without macrolides) for treatment of COVID-19 associated with increased in-hospital mortality as compared to control patients not receiving these medications?

What They Did:

  • Multinational registry analysis from 671 hospitals across six continents using hydroxychloroquine or chloroquine with or without a macrolide for the treatment of COVID-19
  • Patients who received one of the treatments of interest ≤48hrs of diagnosis were included in one of 4 treatment groups:
    • Chloroquine Alone (CQ)
    • Chloroquine + Macrolide (CQM)
    • Hydroxychloroquine Alone (HCQ)
    • Hydroxychloroquine + Macrolide (HCQM)
  • Patients who received none of these treatments formed the control group (Control)

Outcomes:

  • Primary: In-hospital mortality
  • Secondary:
    • Occurrence of de-novo ventricular arrhythmias (non-sustained or sustained VT or VF)
    • Progression to mechanical ventilation
    • ICU LOS 

Inclusion:

  • Hospitalized patients with COVID-19
  • Either hospital discharge or death during hospitalization recorded
  • Receiving one or more of the test medications ≤48hrs

Exclusion:

  • Treatment initiated >48hrs after diagnosis
  • On mechanical ventilation
  • Received remdesivir

Results:

  • 96,032 patients included in analysis
    • 14,888 patients in one of 4 treatment groups
    • 81,144 patients were in the control group
    • Baseline severity of patients was overall pretty low (≈10% requiring O2)
    • Overall mortality rate of 11.1%
    • Median time form hospitalization to diagnosis of COVID-19 was 2 days (Range: 1 to 4d)
  • In-Hospital Mortality:
    • CQ: 16.4%
    • CQM: 22.2%
    • HCQ: 18.0%
    • HCQM: 23.8%
    • Control: 9.3%
    • All independently associated with increased risk of in-hospital mortality compared to control
  • De-Novo Ventricular Arrhythmia During Hospitalization:
    • CQ: 4.3%
    • CQM: 6.5%
    • HCQ: 6.1%
    • HCQM: 8.1%
    • Control: 0.3%
    • Also, all independently associated with increased risk of de-novo ventricular arrhythmia during hospitalization compared to control

Strengths:

  • Largest, most comprehensive data set to date evaluating the use of hydroxychloroquine and chloroquine (with or without a macrolide)
  • Evaluated patients from across multiple geographic regions which increases generalizability and is one of the most robust real-world pieces of evidence to date on these medications
  • Used propensity score matching analysis for each group individually compared with control group to approximate demographics, comorbidities, and disease severity
  • Hard, objective, patient centered outcome
  • Patients fairly well balanced between all groups
  • Performed additional analyses to evaluate the robustness of the initial results
  • All included patients completed their hospital course (discharged or died)

Limitations:

  • Observational data, which cannot account for unmeasured confounding factors
  • Due to lack of randomization, unable to control for other parts of management, minimal discussion of what was standard care
  • As this is an observational trial a causal relationship between drug therapy and survival cannot be inferred (i.e. association but not causation)
  • Results do not apply to outpatient setting

Discussion:

  • Overall, most common concurrent use of antivirals in this study were: lopinavir/ritonavir (31.6%), ribavirin (20.3%), and oseltamivir (13.1%)
  • Patients overall weren’t that sick (>80% with a SOFA score of 1 and only 10% with an oxygen saturation of <94%)

Author Conclusion: “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.”

Clinical Take Home Point: This study not only suggests an absence of efficacy for hospitalized patients with COVID-19, but a real signal of harm with increased ventricular arrhythmias with hydroxychloroquine or chloroquine (with or without macrolides) compared to a control population.  These medications should simply not be used outside of a randomized clinical trial.

Infographic Created By Mark Ramzy, DO (Twitter: @MRamzyDO)

References:

  1. Mehra MR et al. Hydroxychloroquine or Chloroquine With or Without a Macrolide for Treatment of COVID-19: A Multinational Registry Analysis. Lancet 2020. [Epub Ahead of Print]

For More on This Topic Checkout:

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)

Cite this article as: Salim Rezaie, "COVID-19 Update: Just Say No to Hydroxychloroquine or Chloroquine With or Without Macrolides", REBEL EM blog, May 24, 2020. Available at: https://rebelem.com/covid-19-update-just-say-no-to-hydroxychloroquine-or-chloroquine-with-or-without-macrolides/.
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Salim Rezaie

Emergency Physician at Greater San Antonio Emergency Physicians (GSEP)
Creator & Founder of REBEL EM
9 Comments
  • Magnim kadoua
    Posted at 09:53h, 24 May Reply

    – Point of interest : this study go well beyond evaluating the efficacy of chloroquine protocoles , they should expand their conclusions.
    -For the limitations : – No precision of dosage of medication / – no precision of time between onset of symptoms and treatment or No precision of the average time between blood sample taken and diagnostic of pcr / – History of arythmia and treatment
    are equally associated with De-Novo Ventricular Arrhythmia During Hospitalization

    • Salim Rezaie
      Posted at 10:03h, 24 May Reply

      All great and valid points. Although a large registry data set, there are tons of little details that need to be parsed out as you suggest with your comments. However, in the scheme of evidence and what we know thus far, I would argue that we should not be recommending these medications outside of an RCT, as the weight of evidence shows more harm than benefit at this time. No one, including me, can state causation here, only association and it remains to be seen if there is any role at all for these medications (i.e. dosing, duration, prophylaxis, etc…).

  • Michael Griesinger
    Posted at 11:44h, 24 May Reply

    Not at all a “fan” of plaquenil for covid but NYU retrospective study found a small benefit with hydroxychloroquine and zinc…

    • Salim Rezaie
      Posted at 12:01h, 24 May Reply

      Yup…it is a theory that the two can be synergistic, but does the incidence of adverse events trump that? Still remains to be proven.

  • Brendon Scott
    Posted at 14:41h, 24 May Reply

    For some reason there is more on chloroquine and various studies etc.

    Let’s say chloroquine bashing.

    My of officer commanding always had a saying, a rule, ‘if you come to me with a problem, come to me with a solution too.”

    So the problem is chloroquine…. What is the solution?
    In an article like this wouldn’t it be more beneficial to say “chloroquine sucks, but we have found drug regime consisting of “1X2Y”.

    Someone asked me yesterday on my opinion of chloroquine and my answer was o don’t know. There is people saying it works and others saying no. If we look into history, big pharma has always played a role in the flow or control of information.

    As it has been stated by so many experts, it is impossible to do the normal trials normal due would go through. From inception to distribution is on average 7 years. That’s not saving lives now but if this pandemic happens again in 7 years there would be an answer.

    At the end of the discussion I said to the person if I landed up needing treatment, chloroquine me and throw in some azithromycin. It least it is a drug were know, it is established, sand that means adverse effects can be negated and easier risk analysis patient dependant to whether the medication would be more harmful and therefore sell alternatives. The patients that don’t fall into the high risk after analysis, well let us use the devil we know.

    • Salim Rezaie
      Posted at 14:48h, 24 May Reply

      Hey Brendon,
      Everyone can interpret the evidence the way they like. The fact is, we don’t have an alternative at this time. Would be nice if we did. You say give me chloroquine, but that is assuming it is doing something beneficial, the evidence thus far, which is far from perfect, indicates that the harm > benefit. So in the same light, I would say, don’t give me chloroquine. The art of medicine is a balance of scientific evidence, clinical judgment, and patient values/preferences. The science is the science, we each have our own clinical judgment based on previous experiences, but none of us can speak for the patient. There may be some cohort that benefits from this med, but in order to find that, given the known harms, this should be done in a registered RCT and not just given willy nilly.

  • Soniya Sharma
    Posted at 07:10h, 30 May Reply

    Excellent post! We are linking to this particularly great article
    on our website. Keep up the good writing.

  • The RECOVERY platform trial: No benefit to Hydroxychloroquine in Covid-19. St Emlyn's • St Emlyn's
    Posted at 03:03h, 07 June Reply

    […] 10. Rezzaie S. COVID-19 Update: Just Say No to Hydroxychloroquine or Chloroquine With or Without Macrolides. REBEL EM. Published June 2020. Accessed June 2020. https://rebelem.com/covid-19-update-just-say-no-to-hydroxychloroquine-or-chloroquine-with-or-without&#8230; […]

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