JAMA (jamanetwork.com) published online another confusing study on the use of hydroxychloroquine and azithromycin for the treatment of COVID-19 in New York State.
The authors, Rosenberg et al., 2020 (1), concluded that the use of hydroxychloroquine and azithromycin was not associated with a reduction in in-hospital mortality:
Among patients hospitalized with COVID-19, treatment with hydroxychloroquine, azithromycin, or both was not associated with significantly lower in-hospital mortality.
The study itself has serious flaws. First of all, it is not known for how long hydroxychloroquine alone or hydroxychloroquine in combination with azithromycin were administered to the patients. Hydroxychloroquine and azithromycin were administered for different durations to different patients. The exact dosage of hydroxychloroquine also differed for different patients and the exact dosages are also unknown. The supplementary material provided by Rosenberg et al., 2020 (1), contains a table that gives us some idea about the dosages, but it is not enough to have any reasonable clarity on the issue.
We can see, for example, that on the “initial prescription”, the most common dosage of hydroxychloroquine (90.3% of the patients) was 400mg. We also learn from the table that 24.6% of the patients took hydroxychloroquine once daily and 70.4% took it twice daily. Now, was 400mg a daily dosage, or was it taken twice a day? We can not understand this from the data provided by the authors. This is a serious flaw and it reflects an apparent chaotic state of mind of the study authors.
For how long hydroxychloroquine was administered to different patients? We can not understand this from the data submitted by Rosenberg et al., 2020 (1). What do “initial prescription”, “second prescription”, “third prescription” mean?
The number one goal in the treatment of a new disease with a drug is to discover the effective dose and duration. In the case of COVID-19 and hydroxychloroquine, Rosenberg et al., 2020 (1), are either not competent enough to understand this or deliberately present flawed data.
The very important data on the time between symptoms onset and the initiation of treatment with hydroxychloroquine is also unknown. Rosenberg et al., 2020 (1):
Nineteen patients initiated either medication prior to admission, including 12 who began medication use on the day prior, and another 3 began medication use 2 days prior to admission. Patients receiving neither drug also received few other abstracted medications; the most common were aspirin (38/192 [19.8%]) and lisinopril (13/193 [6.7%]) (eTable 2 inSupplement 2).
We only learn that 12 patients started hydroxychloroquine one day before hospital admission and 3 patients started hydroxychloroquine 2 days before hospital admission. In total, nineteen started hydroxychloroquine before hospital admission. Was it 19 out of 1006 or 19 out of 1721? And what was the time between symptoms onset and the start of hydroxychloroquine in these patients? How did they do? The answers to these questions can not be found in the study by Rosenberg et al., 2020 (1).
Another flaw of the study by Rosenberg et al., 2020 (1), is that patients in different study groups were not properly randomized, that is, there were significant statistical differences between the groups. Patients who received hydroxychloroquine alone, hydroxychloroquine and azithromycin, or azithromycin alone generally had higher clinical severity of COVID-19. Notably, they more often had abnormal chest imaging at any point of hospitalization, and more of them had low blood oxygen saturation within 24 hours of admission in comparison to the group of patients who received neither hydroxychloroquine nor azithromycin.
The full table with patients characteristics from the study by Rosenberg et al., 2020 (1), is inserted below.
Abnormal chest imaging at any point of hospitalization was identified by the study authors, Rosenberg et al., 2020 (1), as a strong predictor of in-hospital death. On one hand, it is not surprising that patients with higher severity of COVID-19 were at a higher risk of death. On the other hand, since it was “at any point of hospitalization” and not “at admission”, we do not know if hydroxychloroquine helped to prevent pathological changes in lungs.
There is one useful piece of data that we learn from the study by Rosenberg et al., 2020 (1). It is the way COVID-19 patients die. Thus, we see that in the hydroxychloroquine + azithromycin group, 119 of 609 patients (19.5%) died without ever being admitted to an ICU. The total number of deaths in the same group was 189 of 735 patients or 25.7%. We can see that a majority of patients die outside an ICU.
Given the 25.7% mortality in hospitalized patients on hydroxychloroquine, which is quite high, we should conclude that a chaotic administration of hydroxychloroquine did not influence in-hospital mortality downwards.
Conclusions.
The use of hydroxychloroquine alone or in combination with azithromycin in hospitals of the New York State can be described as chaotic. Apparently, no attempts do discover the appropriate dosage and duration of treatment with hydroxychloroquine have been attempted. Pharmacokinetics of hydroxychloroquine is also ignored in the study by Rosenberg et al., 2020 (1), and in other studies from the New York area.
Urso et al., 2012 (2):
Phamacokinetics is proposed to study the absorption, the distribution, the biotransformations and the elimination of drugs in man and animals.
Indeed, from other studies, we know that between 10 and 30% of patients can have low levels of hydroxychloroquine in the blood, which may reflect poor absorption.
In April 2020, many hospitals in the New York area started removing the recommendation to use hydroxychloroquine and azithromycin in COVID-19 patients from their guidances.
This was the case in the New York–Presbyterian Hospital (NYP)–Columbia University Irving Medical Center (CUIMC), a quaternary, acute care hospital in northern Manhattan. Geleris et al., 2020 (3).
A guidance developed by the Department of Medicine and distributed to all the house staff and attending staff at our medical center suggested hydroxychloroquine as a therapeutic option for patients with Covid-19 who presented with moderate-to-severe respiratory illness. The azithromycin suggestion was removed on April 12, 2020, and the hydroxychloroquine suggestion was removed on April 29, 2020. The decision to prescribe either or both medications was left to the discretion of the treating team for each individual patient.
Hydroxychloroquine is a drug that has been shown to be effective in the treatment of COVID-19. However, the effect of hydroxychloroquine is modest in severe COVID-19 and in some other cases. Hydroxychloroquine has also been a target of a disinformation war, which had an influence on many medical doctors.
In this situation, understanding what is the optimal hydroxychloroquine protocol for COVID-19 becomes a matter of personal responsibility and preparedness. Everyone needs to understand what the appropriate hydroxychloroquine dosage, duration of treatment and the time to start the treatment are. Also, it is a matter of personal responsibility to select a medical practitioner who is not influenced by disinformation and propaganda, and who is comptent in general.
If you need help with the above, do not hesitate to get in contact with us. In the meantime, do your best to avoid getting infected with SARS-CoV-2. Defy bureaucratic idiocy and lawlessness, but do not defy the disease.
Selected references:
1. Rosenberg ES, Dufort EM, Udo T, et al. Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State. JAMA. Published online May 11, 2020. doi:10.1001/jama.2020.8630
2. Urso R, Blardi P, Giorgi G. A short introduction to pharmacokinetics. Eur Rev Med Pharmacol Sci. 2002;6(2-3):33‐44.
3. Geleris et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19.
The article was published on May 7, 2020, at NEJM.org. DOI: 10.1056/NEJMoa2012410