Bax, Hannelore

Berge, M

Bokhizzou, N

Brinkman, K

Brohet, RM

Dofferhoff, A

el Moussaoui, R

Ellerbroek, J

Groeneveld, PH

Hassing, RJ

Hermanides, G

Koster, C

Lammers, AJJ

Postma, DF

Rood, R

Theunissen, REP

Verhagen, DWM

Visser, H

English

Lammers, A J J

Brohet, R M

Theunissen, R E P

Verhagen, D W M

Hassing, R J

El Moussaoui, R

van den Berge, M

Bax, H

Postma, D F

Groeneveld, P H P

University of Groningen

   University of GroningenResponse to correspondence concerning: "Early hydroxychloroquine but not chloroquine usereduces ICU admission in COVID-19 patients"Lammers, A J J; Brohet, R M; Theunissen, R E P; Koster, C; Rood, R; Verhagen, D W M;Brinkman, K; Hassing, R J; Dofferhoff, A; El Moussaoui, RPublished in:International Journal of Infectious DiseasesDOI:10.1016/j.ijid.2020.12.008IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Lammers, A. J. J., Brohet, R. M., Theunissen, R. E. P., Koster, C., Rood, R., Verhagen, D. W. M.,Brinkman, K., Hassing, R. J., Dofferhoff, A., El Moussaoui, R., Hermanides, G., Ellerbroek, J., Bokhizzou,N., Visser, H., van den Berge, M., Bax, H., Postma, D. F., & Groeneveld, P. H. P. (2021). Response tocorrespondence concerning: "Early hydroxychloroquine but not chloroquine use reduces ICU admission inCOVID-19 patients". International Journal of Infectious Diseases, 103, 478-479.https://doi.org/10.1016/j.ijid.2020.12.008CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.

Response to correspondence concerning: "Early hydroxychloroquine but not chloroquine use reduces ICU admission in COVID-19 patients"

NARCIS 

Response to correspondence concerning: “Early hydroxychloroquine but not chloroquine use reduces ICU admission in COVID-19 patients”

EUR Research Repository

International Journal of Infectious Diseases 103 (2021) 478–479Letter to the EditorResponse to correspondence concerning: “Earlyhydroxychloroquine but not chloroquine usereduces ICU admission in COVID-19 patients”We would like to thank all our colleagues for taking theopportunity to start a scientific discussion on the matter ofhydroxychloroquine in COVID-19. We feel that it is important inthe current climate, where politics and economics interfere withthe scientific domain, to have a calm and scientific discussion onthis topic. Below you will find our response to the letters.Authors’ reply:The first letter “Comparison of hospital treatment strategy orof treatment actually received in COVID-19?” asks us about ourmethodology. We understand the nature of the question quite well,since we have discussed this issue before deciding which analysisstrategy to choose. Clearly, this is an observational study that mightbe prone to potential bias. To avoid this, we used a two-stepprocedure. The first step encompasses the inclusion of patients.The second step involves the comparison of treated and untreatedpatients after their hospitalization.The inclusion of patients for our study was based on hospitaltreatment strategy. Patients were admitted to a HCQ, CQ or non-treatment hospital randomly; the hospital policy regarding the useof HCQ/CQ was not communicated to the patient beforehand,neither was it part of a selection procedure for the study. Thus, thefact that a patient was admitted to a HCQ, CQ or non-treatmenthospital was a random event and based on a random assignment,based on geographical loction only. That is the reason why webelieve that our study design and patient inclusion approaches theintention-to-treat strategy used in randomized-controlled trials.The assignment to receive HCQ or CQ treatment occurs afterhospitalization and is influenced by patient characteristics, such asco-morbidity. This means that the actual assignment of atreatment may lead to differences between treated patients anduntreated patients. Thus, to make accurate inferences, it is crucialto control for confounding by indication and for the differencesbetween treated and untreated patients. Since the assignment oftreatment occurs after hospitalization, it is independent of theactual hospital treatment strategy. Therefore, we believe that it isjustified in this second step to pool the data and compare alltreated and untreated patients directly. Subsequently, we used thepropensity score (PS) matching as a balancing score betweentreated and untreated patients, and to control for confounding byindication. PS matching is a proven tool to adjust a treatment effectfor measured confounders in non-randomized studies, such asours. At each value of the PS, the distribution of the consideredcovariates is the same in the treated and the untreated or controlmatching. In our study, after PS matching no significant statisticaldifferences were found between the baseline characteristics oftreated and untreated patients, including the differences betweenhospital strategies (as is shown in Table 1). Furthermore, the typeof hospital treatment was not a confounder in the definiteweighted regression model.In conclusion, we believe that with our two-step procedure(hospital treatment strategy at inclusion and actual treatmentreceived in the analysis), our study limits the influence of potentialbias and enables us to make correct inferences based on theavailable data.The second letter, by Asselbergs et al raises several questions onthe methodology as well.The authors stated: “in the presence of ICU restriction formedical reasons or patient preference, analyses on the outcome‘transfer to ICU’ are limited to patients without ICU restriction, aparticularly selected group. This might impact the generalizabilityof the results considerably”.Since patients with an ICU restriction cannot reach the endpoint“Transfer to ICU”, we started by computing the outcome asComposite Adverse Endpoint; taking the two endpoints (Mortalityand Transfer to ICU) together. This eliminates the bias of competingrisk between the two endpoints. We did not consider “Discharge”as a competing risk, since it was defined as discharge for cure only,discharge with the expectation of the patient to die for example ina hospice facility was considered “Death”. To adjust for potentialbias by ICU restriction, we performed stratified analysis for this“composite adverse endpoint” to reflect underlying potentialdifferences between the two groups with regard to adverseincidences and risk factor prevalence. In addition, multivariablecompeting risk analysis was conducted; including for ICUrestriction. The hazard ratio (HR) changed from 0.49 without, to0.47 with ICU restriction. This corresponds with a 4% change, whichis less than the 10% threshold, which is commonly used, if it were aconfounder. With the results of PS matching, competing multivar-iable risk analyses and stratified analyses, we do not believe thatICU restriction influenced the effect of HCQ/CQ that we havereported on ICU admission. Subsequently, we decided to report thetwo outcomes separately, after performing additional competingrisk analysis corrections. Here, we did not include patients with anICU restriction, therefore our data indeed only describe a possibleprotective effect of HCQ in patients without an ICU restriction. Aswe described in our discussion, prospective intervention studiesare needed to confirm our results. However, even in randomizedcontrolled trials generalizability can still be a problem toextrapolate from the results, although a causal effect has beenshown.Furthermore, the authors mention that the ICU-populationContents lists available at ScienceDirectInternational Journal of Infectious Diseasesjournal home page: www.elsevier .com/ locat e/ i j idgroup. The balance that a randomized experiment is expected tocreate by design, is in this way established through statisticalhttps://doi.org/10.1016/j.ijid.2020.12.0081201-9712/© 2020 The Authors. Published by Elsevier Ltd on behalf of International Slicense (http://creativecommons.org/licenses/by-nc-nd/4.0/).changed in the course of the pandemic. We did not include patientson the ICU in our study, for the patients on the ward we correctedociety for Infectious Diseases. This is an open access article under the CC BY-NC-NDfthDh“arabraausirSrlaiiBhhsCmtatpbH1outtCchFtLetter to the Editor International Journal of Infectious Diseases 103 (2021) 478–479or age (which was not different between the HCQ, CQ or no-reatment groups).It is suggested that regional differences in infection rates mightave caused different patient populations. This is unlikely, since 14utch hospitals participated (from Goes to Groningen, both ruralospitals as centers in large cities). Fortunately, we did not reachcode black” in the Netherlands, making large differences in ICUdmission rates unlikely. Obviously, all observational research is atisk for bias, including selection bias by leaving patients out of thenalysis that were transferred between hospitals.For an answer on the question on the methodology of inclusiony treatment center or treatment exposure, please see ouresponse to the letter by Peters et al. Patients that were directlydmitted to the ICU or patients that died within the first 24 h afterdmission, were excluded from the analysis. In addition, we havesed skimming as a routine procedure in our analyses. Separateensitivity analyses were performed to investigate whethermmortal bias or informative censoring could influence ouresults. First, there were no events before the start of the therapy.econd, time-dependent analysis shows no difference in oureported results (HRHCQ = 0.47; 95% = 0.27–0.81). Third, in aogistic regression analysis we found the same effect of HCQ on ICUdmission (ORHCQ = 0.40; 0.21–0.77). Thus, neither potentialmmortal bias nor informative censoring had a significantnfluence on the reported results.Finally, we would like to thank the authors of the letter byurger et al, ‘More gastro-intestinal adverse events in non-ICUospitalized COVID-19 patients treated with chloroquine versusydroxychloroquine’ for sharing the results of their interestingtudy. The authors show that HCQ has a better safety profile thanQ, with less gastro-intestinal adverse events, and suggest that thisay partially explain the difference in the risk of transfer to the ICUhat we found.We deliberately choose to refrain from collecting data ondverse effects, since symptoms of COVID-19 are possibly difficulto distinguish from treatment side-effects, especially in the elderlyopulation, so these results add valuable information on the use ofoth drugs.In their study,1.3% of the patients discontinued treatment in theCQ group due to gastro-intestinal adverse events, as compared to7% in the CQ group (a total of 2 patients on HCQ versus 13 patientsn CQ).We completely agree with the authors’ suggestion that since these of CQ is associated with a higher risk of discontinuation due tooxicity, more patients in the HCQ are able to complete theirherapy, possibly making it more effective.onflict of interestWe state on behalf of all the authors that there are no knownompeting financial interests, or personal relationships that couldave appeared to influence the work reported in this paper.unding sourceThere were no Funding Sources or Study Sponsors involved inhis study.sEthical approvalThe Medical Ethics Review Committee waived ethical Approvalfor this study.A.J.J. Lammers*Isala, Zwolle, The NetherlandsR.M. BrohetDepartment of Epidemiology and Statistics, Isala Academy, Zwolle,The NetherlandsR.E.P. TheunissenC. KosterIsala, Zwolle, The NetherlandsR. RoodDiakonessen Hospital, Utrecht, The NetherlandsD.W.M. VerhagenMedisch Centrum Jan van Goyen, Amsterdam, The NetherlandsK. BrinkmanOLVG, Amsterdam, The NetherlandsR.J. HassingRijnstate, Arnhem, The NetherlandsA. DofferhoffCanisius Wilhelmina Hospital, Nijmegen, The NetherlandsR. el MoussaouiMaasstad Hospital Rotterdam, The NetherlandsG. HermanidesRode Kruis Hospital, Beverwijk, The NetherlandsJ. EllerbroekReinier de Graaf Gasthuis, Delft, The NetherlandsN. BokhizzouBovenIJ Hospital, Amsterdam, The NetherlandsH. VisserBeatrix Hospital Gorinchem, The NetherlandsM. van den BergeAdmiraal de Ruiter Hospital, Goes, The NetherlandsH. BaxErasmus MC Rotterdam, The NetherlandsD.F. PostmaUniversity Medical Center Groningen, Groningen, The NetherlandsP.H.P. GroeneveldIsala, Zwolle, The Netherlands* Corresponding author at: Isala Hospital, Department of InternalMedicine and Infectious Diseases, Dr van Heesweg 2, 8025 ABZwolle, The Netherlands.E-mail address: a.j.j.lammers@isala.nl (A. Lammers).Received 3 December 2020479

ARTS repository - University of Groningen

Dissertations of the University of Groningen

Proceedings - University of Groningen

https://pure.rug.nl/ws/files/165247864/Response_to_correspondence_concerning_Early_hydroxychloroquine_but_not_chloroquine_use_reduces_ICU_admission_in_COVID_19_patients_.pdf

Response to correspondence concerning: “Early hydroxychloroquine but not chloroquine use reduces ICU admission in COVID-19 patients”

Abstract

Similar works

Full text

Available Versions

University of Groningen

NARCIS

EUR Research Repository

ARTS repository - University of Groningen

Dissertations of the University of Groningen

ARTS repository - University of Groningen

Dissertations of the University of Groningen

University of Groningen

Proceedings - University of Groningen

EUR Research Repository