Preprint Article Version 2 This version is not peer-reviewed

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

Version 1 : Received: 2 May 2020 / Approved: 5 May 2020 / Online: 5 May 2020 (03:32:22 CEST)
Version 2 : Received: 6 May 2020 / Approved: 9 May 2020 / Online: 9 May 2020 (04:45:37 CEST)

How to cite: Membrillo, F.J.; Ramírez-Olivencia, G.; Estébanez, M.; de Dios, B.; Herrero, M.D.; Mata, T.; Borobia, A.M.; Gutiérrez, C.; Simón, M.; Ochoa, A.; Martínez, Y.; Aguirre, A.; Alcántara, F.D.A.; Fernández-González, P.; López, E.; Valle, P.; Campos, S.; Navarro, M.; Ballester, L.E. Early Hydroxychloroquine Is Associated with an Increase of Survival in COVID-19 Patients: An Observational Study. Preprints 2020, 2020050057 (doi: 10.20944/preprints202005.0057.v2). Membrillo, F.J.; Ramírez-Olivencia, G.; Estébanez, M.; de Dios, B.; Herrero, M.D.; Mata, T.; Borobia, A.M.; Gutiérrez, C.; Simón, M.; Ochoa, A.; Martínez, Y.; Aguirre, A.; Alcántara, F.D.A.; Fernández-González, P.; López, E.; Valle, P.; Campos, S.; Navarro, M.; Ballester, L.E. Early Hydroxychloroquine Is Associated with an Increase of Survival in COVID-19 Patients: An Observational Study. Preprints 2020, 2020050057 (doi: 10.20944/preprints202005.0057.v2).

Abstract

Background: Although no specific treatment for COVID 19 has been proven effective yet, some drugs with in vitro potential against SARS-CoV-2 virus have been proposed for clinical use. Hydroxychloroquine has in vitro anti-viral and immunomodulatory activity, but there is no current clinical evidence of its effectiveness on the outcome of the disease. Methods: We enrolled all 18-85 years old inpatients from Central Defense Hospital, Madrid, Spain, who were hospitalised due to COVID-19 and had a definitive outcome (either dead or discharged). We used a statistical survival analysis. Results: We analysed 220 medical records. 166 patients met the inclusion criteria. 48,8 % of patients not treated with HCQ died, versus 22% in the group of hydroxychloroquine (p=0,002). According to clinical picture at admission, hydroxychloroquine increased the mean cumulative survival in all groups from 1,4 to 1,8 times. This difference was statistically significant in the mild group. Conclusions: in a cohort of 166 patients between 18 to 85 years hospitalised with COVID-19, hydroxychloroquine treatment with an initial loading dose of 800mg improved patient survival when admitted in early stages of the disease. There was a non-statistically significant trend towards survival in all groups, which will need to be clarified in subsequent studies.

Subject Areas

COVID-19; treatment; drug; survival; antiviral; hydroxychloroquine

Comments (7)

Comment 1
Received: 9 May 2020
Commenter: Francisco Javier Membrillo de Novales
Commenter's Conflict of Interests: Author
Comment: English style improvedNew author added (Valle P.)
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Comment 2
Received: 13 May 2020
Commenter: Frank Conijn
The commenter has declared there is no conflict of interests.
Comment: Table 2 shows that the mean D-dimer levels at baseline were 558 (HCQ) versus 1511 (NHCQ), with a p value of 0.168. I'm guessing that the p value is caused by the large range, because D-dimer values in some Covid-19 patients can be extremely high.

However, it was determined that the cut-off value of between physiological and pathological level in patients > 50 yrs should be age x 10 mcg/l (or ng/ml). See https://pubmed.ncbi.nlm.nih.gov/20354012/ . That means that the HCQ group had a physiological level, whereas the NHCQ group had a clearly pathological level at baseline. And high D-dimer levels have shown to be a powerful predictor of mortality in Covid-19, see https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.14859 .

Also, the percentages in table 2 should add up vertically, not horizontally.
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Response 1 to Comment 2
Received: 13 May 2020
Commenter: Frank Conijn
The commenter has declared there is no conflict of interests.
Comment: The values mentioned in the second-linked article need to be converted. That's easily done here: https://unitslab.com/node/83 .
Response 2 to Comment 2
Received: 14 May 2020
Commenter: Nicolo de Groot
The commenter has declared there is no conflict of interests.
Comment: It looks to me that a normal distribution is assumed in calculating the SD and consequently the p-value for the D-dimer test (table 2). For asymmetric distributions with a long tail this would lead to the wrong p-value.
Comment 3
Received: 13 May 2020
Commenter: Francisco Javier Membrillo
The commenter has declared there is no conflict of interests.
Comment: Thank you for the feedback. In the first days of the pandemic, our ER Department didn't perform D-dymer test systematically. As we analysed the analytical values only at admission, we had over 50% of this data missed. This issue is discussed in v2.
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Response 1 to Comment 3
Received: 14 May 2020
Commenter: Frank Conijn
The commenter has declared there is no conflict of interests.
Comment: Thank you for the reply.

However, if the (100 - 46.9 =) 53.1% of the patients with D-dimer value determined were more or less evenly divided over the two groups, you should still have a representative statistic. And even if not, it still is not correct to state that a difference of 558 versus 1511 is insignificant.

Clinically, it's very significant, as I already explained, and that's what matters. You should present the D-dimer values as a dichotomous-numerical or categorical variable (physiological/pathological as per the study I referred to). You should then get a very significant p value.

Furthermore, the no-HCQ group also had significantly more cardiopathy, dementia and - as the text tells but not the table - lymphopenia. So, the no-HCQ group probably just was a lot sicker than the HCQ group. Which invalidates your conclusion.

As a former editor-in-chief, I'd suggest withdrawing this paper. In stead, I'd write one on your remarkable finding that the patients with severe covid had a shorter time from symptom onset than the patients with mild/moderate. I'd do some more research on what could have caused that, including prior use of medication and whether symptom onset was really symptom onset.

That will eventually produce a much more productive article. This one will only generate a stack of letters to the editor, and it will be ignored in any review.
Comment 4
Received: 23 May 2020
Commenter: Martin Nelwan (Click to see Publons profile: )
The commenter has declared there is no conflict of interests.
Comment: The authors describe the use of hydroxychloroquine for treating COVID-19. They stated that hydroxychloroquine is more potent than chloroquine to inhibit SARS-CoV-2 in vitro . The authors suggested that this disease consists of three levels: mild, moderate and severe. The COVID-19 has three clinical pictures. Clinical pictures of mild infection consist of no hypoxemia, no respiratory insufficiency. Moderate consists of hypoxemia and/or moderate respiratory insufficiency, while clinical pictures of severe COVID-19 include severe hypoxemia, severe respiratory distress, and poor overall status. To treat COVID-19, the authors suggested the use of hydroxychloroquine for the loading dose of 800 mg + 400 mg, followed by a maintenance dose of 400 mg a day (for one day only?). This treatment increased the mean cumulative survival if patients treated early, first week since symptoms onset. This is a promising manuscript. However, this manuscript needs revisions. It raises at least two questions. Globally, a mild infection is 80% of cases, moderate and severe cases can lead to death. Is mild infection treated with hydroxychloroquine all cured? Is moderate infection all cured either?

Others,

For example, spell ARDS in the first time use.

The Ethics Committee on Clinical Investigation on the Ministry of Defense of Spain approved the research protocol. Moreover, the authors stated that they conducted a systematic review related to this manuscript. Did the authors register this study with PROSPERO? If registered, put the registration number.
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