April 12th, 2020

IDSA’s COVID-19 Treatment Guidelines Highlight Difficulty of “Don’t Just Do Something, Stand There”

Winner, 1923 White House Easter Egg Roll

The Infectious Diseases Society of America (IDSA) gathered a series of experts for what were undoubtedly many late-night calls, reviews of published and pre-print literature, and revisions (of revisions), and admirably generated a set of treatment guidelines for COVID-19.

The problem — there is no proven effective treatment for COVID-19.

That is, there’s no proven treatment based on our usual highest standard metric for efficacy, the randomized clinical trial — nor the next-best thing, a carefully done observational study that meticulously accounts for potential confounders.

Which means these guidelines have a Groundhog Day-like quality. In a series of clear and comprehensive sections, they review the available evidence, then repeatedly conclude the same thing:

The IDSA guideline panel recommends the use of [insert putative COVID-19 treatment here] in the context of a clinical trial. (Knowledge gap.)

Well, not exactly the same thing — for some of these treatments they insert the word “only”, yielding “… only in the context of a clinical trial.”

Here’s the difference between the two, according to the lead author:

For interventions with certainty regarding risks and benefits, the expert panel recommended their use “in the context of a clinical trial”. The guideline panel used “only in the context of a clinical trial” for interventions with higher uncertainty and/or more potential for harm.

But the message is clear. We don’t have sufficient evidence now to recommend any specific treatment.

That’s right — for chloroquine/hydroxychloroquine (HCQ), hydroxychloroquine with azithromycin, tocilizumab, corticosteroids for acute respiratory distress syndrome (ARDS), lopinavir/ritonavir — all are readily prescribable by clinicians (each is FDA-approved for other indications), yet none is proven to work for COVID-19.

That might be hard to believe given the publicity surrounding some of the approaches, in particular hydroxychloroquine. But those are the facts as of today.

So where does that put clinicians on the front lines managing this new disease?

Highly conflicted.

Those favoring the use of hydroxychloroquine for COVID-19 say that there is at least some evidence that hydroxychloroquine helps — enough so that controlled studies are ongoing. We certainly don’t have anything else to offer, and people are sick!

Plus, there’s a plausible mechanism of action, with in vitro antiviral activity. Maybe even two mechanisms if we consider the anti-inflammatory effect.

In addition, there’s this comment, posted by a critical care specialist in response to my poll:

Yes. No idea if it works, but it’s plausible, and it’s part of the YNHH [Yale New Haven Hospital] treatment algorithm for now. Wonder if those on the only-clinical-trials high horse have ever prescribed Haldol for agitated delirium?

High horse, ivory tower, unconnected to “real practice” — these are common charges levied at academic medicine, with some justification. Certainly not everyone has access to clinical trials.

And even when clinicians do have access to these studies, not all patients meet inclusion criteria, and some others might choose not to participate.

Indeed, at our hospital — which, like many academic medical centers, both has clinical trials for COVID-19 and prides itself on following evidence-based medicine — approximately a third of our COVID-19 cases have received hydroxychloroquine.

(Thanks to our crack ID PharmD Jeff Pearson for the quick data review.)

But why just a third? Why not all of them?

Let’s take up the nay-sayers view. They cite the weakness of the data. One study was, on further scrutiny, so flawed the journal publishing it raised concerns about the low quality of the study.  How often do we see that?

Another trial has not yet been published in a peer-reviewed journal, was quite small, and showed improvement in some minor endpoints only — with tremendous heterogeneity in other treatment approaches.

Furthermore, people already receiving hydroxychloroquine for rheumatologic indications have already acquired COVID-19 — how effective can it be? Plus, there’s an abstract of a study (inadvertently circulated before publication) that not only shows no benefit, but also suggests harm.

If we have questions about clinical benefit, all must acknowledge that any treatment can cause harm. Of particular concern with hydroxychloroquine for elderly patients — those at greatest risk of severe COVID-19 disease — is QT prolongation, a problem worsened with concomitant azithromycin, many other medications, and underlying heart disease.

Is it any wonder the poll results are so split? This is a real tough one.

Often in such circumstances, it’s helpful to ask what one would do for a loved one — or yourself — if having to make the decision.

Personally, I would not take hydroxychloroquine for COVID-19, concerned about side effects and not so sanguine about its potential antiviral activity. The road is littered with drugs that have in vitro activity for respiratory tract infections, and yet do nothing when given to people.

In fact, our list of effective antiviral treatments for these infections is very short! For common respiratory tract infections, we have only the influenza drugs — and even with the flu, some argue the benefits are marginal.

I do understand the opposite view. I would listen carefully to a patient who strongly wanted treatment and go forward with prescribing it, provided they understood the risks and there were no contraindications.

But a well-designed clinical trial? Sign me up. We’ve got to learn more about this disease, and fast.

So take it away, Mabel and Olive. You two are giving me great pleasure at a time when we all really need it.

 

74 Responses to “IDSA’s COVID-19 Treatment Guidelines Highlight Difficulty of “Don’t Just Do Something, Stand There””

  1. Laura Weymers says:

    So if there are no clinically supported treatments showing positive outcomes…and no vaccines for SARS or MERS which Covid is quite similar to…..how can we expect a vaccine to work? There are already different strains…and even influenza vaccines are only about 60% effective. What glimmer of hope is there? I’m still waiting for statistics showing how anti rheumatic medications…in my case hydroxychloroquine and a JAK inhibitor may provide a protective effect for people like me with RA….

  2. Amudhan Azhahan says:

    Needful discussion of the time. In India mist forums they advocate the prophylactic use of HCQ for HCW and dentist too who plan to do aerosol generating procedures. But no advice or guidelines given how it should be taken. At the same time we hear news of HCW died of cardiomyopathy and some affected with retinopathy. After the president of USA advertised the usage of HVQ in an open press meet the stocks in the pharmacy got dried up. It should have been propagated through safe medium.

  3. Fernando Ramos says:

    What would D.L. Sackett say at this time? “Good doctors use both individual clinical expertise and the best available external evidence, and neither alone is enough”. Let’s forget the cookbook and practice real EBM. DOI: 10.1136/bmj.312.7023.71

  4. Beth says:

    Some correction, clarification to previous blog: Hydroxychloroquine allows zinc ions to enter the cells, which is a powerful healing agent. In addition to other studies, a Korean study also had some positive outcomes using hydroxychloroquinie.

  5. Mauro Schechter says:

    On the contrary. There is plenty of evidence. I suggest you start by looking at Molina et al, who repeated exactly what was done by Didier Raoult in the retracted (and most likely fraudulent) paper that started all the controversy. He showed not only no virologic impact, but also no clinical benefit.

  6. ali hassoun says:

    I’m sick and tired to hear these comments from academic , IDSA leadership, CDC and NIH
    we studied medicine like you, we understand statistics, study method and results
    the reality the keep talking about clinical trials but we cant be part of clinical trials study study sites even though we tried different way, different channels, different drugs studies while the big academic centers have many options to their patients like Dr Sax saying his running multiple clinical trials I think its unethical and not professional in the current situation of what these big centers doing with NIH, IDSA and CDC, because all of them remain silent

    The IDSA president stated after the guideline issued that it does not need randomized clinical trial but on local level we can collect and monitor our data if we use any medication not approved which I agree with

    The safety of HCQ been shown for a long time when used for Malaria and autoimmune diseases, recent study from NYC to look at QT prolongation with combination of Zithromax/HCQ showed no significant cardiac toxicity , it was renal failure and use of amiodarone is the main factors

    as there is evidence of possible benefit vs non, I think we can cont monitor closely these patients with using these medication till we get more data

  7. jesus insuasty says:

    Attention is drawn to the tendency of COVID-19 to be more present in places with a high population density, and in highly developed countries. It would be worthwhile to further investigate this aspect

    jesus Solier Insuasty-Enriquez

  8. Dr Robert L. Beckman says:

    Hyperbaric Oxygen Therapy (HBOT) for COVID-19 pneumonia and respiratory failure. HBOT is being used and considered in multiple worldwide sites. Five studies are underway in the US. [clinicaltrials.gov] HBOT appears to be treating the hypoxemia and underlying pathology (lung inflammation) in COVID-19. Hyperbaric physicians in France, Italy, China, Pakistan, Iran, Thailand, and Japan have also begun treating COVID-19 patients. The studies uniformly show safety and efficacy in treating infection, inflammation and oxygen deprivation.

    https://hbot.com/hbot-for-covid-19-pneumonia-and-respiratory-failure/

  9. Young kim says:

    Exellent your presentation,but HCQ alredy having been using for RA,LUPUS,MALARIA for long time,trial is better than none. If dervellope adverse effect ,you can stop,once patient consented. Science is not
    Methmetic ,especially medicine. Old traditional medicine has been utilizing more now,although we do not know its mechanism,just by long history of using.
    Science and medicine are also trial and error historical sequence. We only learn through trial and error,since human being is not GOD. Do it try it HCQ,since nothing avaiable now for COVID19 treatment,once patient has no othet choice,Better than nothing except Death.

  10. Anderson Magalhaes Junior says:

    I do agree with doctor Ali Hassoun. If the patient does not have a favorable course and is going to the hole, why not use these drugs ? Wait for him to go into respiratory failure and go the mechanical ventilator where they will no longer be effective ?

  11. Tim Bohn MD says:

    I can’t believe that we are investing so much time and energy in an argument that I had to address as a high school senior at Bishop Dubourg in 1969. For his novel Arrowsmith, Sinclair Lewis won the Pulitzer Prize not the Nobel Prize for Medicine in 1926. If you don’t want to follow the rules of science, you need to question whether you belong in medicine.

  12. karim azmy says:

    yes why not giving patient severely ill a chance for hyperbaric oxygen and hydroxy chloroquin

    this has definit role in saving patients

  13. Doug Krakower says:

    Hi Paul, with health care workers at high risk of COVID-19, the dichotomy between provider and patient feels less clear than usual, so I agree that it feels very relevant to ask what we would do for our patients and for ourselves. Interestingly, even for health care workers who have not been diagnosed with COVID-19, there is an opportunity to consider using investigational treatments in the context of prophylaxis with hydroxychloroqiune. U. Minnesota is conducting two national studies of PEP and PrEP with this medication for providers on the frontlines: see https://covidprep.umn.edu/ for the PrEP study, led by our ID colleague Radha Rajasingham. Will health care workers be interested in being in a study – and thus advancing clinical sciende – while providing care for patients with COVID-19?

  14. David Boulware says:

    We continue to run nationwide, double-blind randomized placebo-controlled hydroxychloroquine trials for:
    1) Prevention in exposed household contacts or healthcare workers without PPE to someone with COVID-19 diagnosis;
    2) Early preemptive treatment of symptomatic COVID+ persons who are not hospitalized or among persons with known exposure as household contact or healthcare worker;
    3) Pre-exposure prophylaxis for HCWs with 1x or 2x weekly HCQ led by Dr. Radha Rajasingham

    We have no idea whether this works or not, and we are attempting to rapidly perform trials to determine the answer. What we most need are volunteers. Anyone US nationwide as well as in Quebec, Manitoba, or Alberta can participate. No need to live on one of 10,000 lakes in MN. Participation is online, and we’ll ship study meds overnight. Just go to http://www.covidpep.umn.edu for prevention / treatment trials or for COVID PREP to http://www.covidprep.umn.edu

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HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

Biography | Disclosures | Summaries

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