key: cord-0889624-ljgo43ul
authors: Dauby, Nicolas; Hautekiet, Joris; Catteau, Lucy; Montourcy, Marion; Van Beckhoven, Dominique; Bottieau, Emmanuel; Goetghebeur, Els
title: Reply to the letter to the editor « The perceived efficacy of hydroxychloroquine in observational studies: The results of the confounding effects of "goals of care" »
date: 2021-02-17
journal: Int J Antimicrob Agents
DOI: 10.1016/j.ijantimicag.2021.106307
sha: d8146b3bc66ce01cbfb3a7f8b3d8be53b2d48027
doc_id: 889624
cord_uid: ljgo43ul

nan

We thank the authors for their letter (reference: original letter) regarding our analysis of inhospital mortality during the first wave of the COVID-19 pandemic and the impact of lowdose hydroxychloroquine (HCQ) therapy [1] .

The authors raise different points regarding our study: 1) the possible impact of "confounding by unmeasured goals of care"; 2) the need for a comprehensive competing risks analysis in the absence of follow-up data on death beyond hospital discharge alive; and 3) the absence of anti-viral activity of low-dose HCQ.

Regarding the impact of indication bias related to limitations of care such as do-notresuscitate orders, other authors have already raised this point in a previous letter to the editor [2] to which we responded [3] . Briefly, another study assessing the risk factors for mortality in patients admitted to intensive care unit in Belgium during the first wave of the pandemic also found an association between HCQ use and decreased mortality, including in patients on mechanical ventilation, i.e. a subcohort without any formal "do-not-escalate" orders [4] . The authors refer to guidelines for triaging patients based on short term survival chance. One of the tools used in Belgium was the Walter Prognostic Index [5] . It involves several variables that were entered in our model (age, male sex, cardiac disease, kidney function & cancer) but some were not available, such as dependency, a concept related to frailty.

For the competing risk analysis, we had calculated cause-specific hazards [using the corresponding Cox model] for both competing events, hence also for discharge alive. No meaningful difference in size nor significance emerged for the latter [the estimated adjusted effect size is cs-PH of .97, with p-value .57 -after adjusting for similar covariates to the ones we corrected for on the cs-PH of death analysis]. We then reported on the cause-specific hazard ratio for in-hospital death, as did prior studies, adding Figure 1 to showing cumulative incidence curves for COVID-19-specific death, integrating both types of cs-PHs. The accompanying Fine and Gray analysis gave similar results.

We fully agree that HCQ, at any dose, is unlikely to achieve anti-viral activity, as reported in different animal models & humans [6, 7] . It is now widely acknowledged that COVID-19 prognosis is driven by the host inflammatory response, which is associated with clinical deterioration, respiratory failure and diffuse thrombotic complications [3, 8, 9] . HCQ is a drug with well documented anti-inflammatory and anti-thrombotic properties, including modulation of platelet activity supporting biological plausibility for benefit in patients with COVID-19 [10] [11] [12] [13] .

In conclusion, we agree that one should use due vigilance and care in analysing and interpreting observational data. We believe we lived up to that rule when studying the observational data available on low dose HCQ for the first wave of the pandemic. Unlike studies published earlier on this topic [14] , we accounted for immortal time bias through trial emulation to the extent possible and analysed the competing risks outcomes. We further pointed to the hypothesis-generating nature of our causal effect examination due to inherent limitations of the observational study. We thank the authors and the journal for giving us the opportunity to underline the importance of this and engage in thoughtful peer discussions.

Funding: None

Lowdose hydroxychloroquine therapy and mortality in hospitalised patients with COVID-19: a nationwide observational study of 8075 participants

Low-dose hydroxychloroquine therapy and lower mortality in hospitalized patients with COVID-19: association does not mean causality

Reply to "Low-dose hydroxychloroquine therapy and lower mortality in hospitalized patients with COVID-19: association does not mean causality

The role of organizational characteristics on the outcome of COVID-19 patients admitted to the ICU in Belgium. The Lancet Regional Health

Development and validation of a prognostic index for 1-year mortality in older adults after hospitalization

Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates

Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2

Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19

Immune determinants of COVID-19 disease presentation and severity

Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology

The effect of hydroxychloroquine on platelet activation in model experiments

A pharmacological perspective of chloroquine in SARS-CoV-2 infection: An old drug for the fight against a new coronavirus?

The unfinished story of hydroxychloroquine in COVID-19: the right anti-inflammatory dose at the right moment?

Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19

Ethical Approval: Not required