key: cord-291272-srt08jh8
authors: Peters, E.J.G.; Collard, D.; Van Assen, S.; Beudel, M.; Bomers, M.K.; Buijs, J.; De Haan, L.R.; De Ruijter, W.; Douma, R.A.; Elbers, P.W.G.; Goorhuis, A.; Gritters van den Oever, N.C.; Knarren, G.H.H.; Moeniralam, H.S.; Mostard, R.L.M.; Quanjel, M.J.R.; Reidinga, A.C.; Renckens, R.; Van Den Bergh, prof, J.P.W.; Vlasveld, I.N.; Sikkens, J.J.
title: Outcomes of persons with COVID-19 in hospitals with and without standard treatment with (Hydroxy)chloroquine
date: 2020-10-14
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2020.10.004
sha: 
doc_id: 291272
cord_uid: srt08jh8

OBJECTIVE: To compare survival of subjects with COVID-19 treated in hospitals that either did or did not routinely treat patients with hydroxychloroquine or chloroquine. METHODS: We analysed data of COVID-19 patients treated in 9 hospitals in the Netherlands. Inclusion dates ranged from February 27(th) 2020, to May 15(th), when the Dutch national guidelines no longer supported the use of (hydroxy)chloroquine. Seven hospitals routinely treated subjects with (hydroxy)chloroquine, two hospitals did not. Primary outcome was 21-day all-cause mortality. We performed a survival analysis using log-rank test and Cox-regression with adjustment for age, sex and covariates based on premorbid health, disease severity, and the use of steroids for adult respiratory distress syndrome, including dexamethasone. RESULTS: Among 1949 included subjects, 21-day mortality was 21.5% in 1596 subjects treated in hospitals that routinely prescribed (hydroxy)chloroquine, and 15.0% in 353 subjects that were treated in hospitals that did not. In the adjusted Cox-regression models this difference disappeared, with an adjusted hazard ratio of 1.09 (95%CI 0.81-1.47). When stratified by actually received treatment in individual subjects, the use of (hydroxy)chloroquine was associated with an increased 21-day mortality (HR 1.58; 95%CI 1.24-2.02) in the full model. CONCLUSIONS: After adjustment for confounders, mortality was not significantly different in hospitals that routinely treated patients with (hydroxy)chloroquine, compared with hospitals that did not. We compared outcomes of hospital strategies rather than outcomes of individual patients to reduce the chance of indication bias. This study adds evidence against the use of (hydroxy)chloroquine in hospitalised patients with COVID-19.

The spread of SARS-CoV-2, leading to the current pandemic of COVID-19, has a profound global 128 impact on daily life, morbidity and mortality. Several preliminary studies have reported that the 129 antimalarial agents hydroxychloroquine and chloroquine, or (H)CQ, alone or in combination with the 130 antibiotic azithromycin, can have a suppressive effect on the viral replication, and might decrease the 131 mortality of COVID-19 1-5 . So far, clinical studies have been hampered by confounding by 132 indication 1,2,4,5 , monocentre setup 2,3 , and small numbers of included subjects 3 . A recently published 133 systematic review 6 , a published randomized controlled trial 7 and an RCT only available in pre-print 8 , 134 suggested that hydroxychloroquine is not effective in patients admitted to hospital. Side effects of 135 (H)CQ are well-known, and include fever and cardiac arrhythmias. While we are awaiting definite 136 results from more RCTs, cohort studies can provide quick closure of existing knowledge gaps. When 137 treatment assignment in cohort studies is based on prescriber discretion, the risk of indication bias 138 (even after covariate adjustment) remains high. However, our database of Dutch hospitals contains 139 data of subjects from hospitals that either routinely prescribed (H)CQ or did not prescribe it at all, 140 offering a unique opportunity to compare both strategies. The comparison of different treatment 141 strategies among hospitals leads to a significant reduction of (indication) bias. The objective of this 142 study was to compare the effect of hospital-wide COVID-19 treatment strategies with or without 143 routine (H)CQ use on all-cause 21-day mortality. We used data from the ongoing CovidPredict Clinical Course Cohort containing over 2,000 persons 150 with COVID-19 9 , from 9 hospitals in the Netherlands, including two university hospitals. Included in 151 the database were all subjects admitted to hospital with positive SARS-CoV-2 PCR of nasopharynx, 152 throat, sputum or bronchoalveolar lavage samples, or CT-scan abnormalities that were typical for 153 COVID-19 (CO-RADS 4 and 5) 10 , without another explanation for the abnormalities than Inclusion dates ranged from the first admitted case in the Netherlands on February 27 th 2020, to May 155 15 th , when the Dutch national guidelines no longer advised the use of (H)CQ. We excluded patients < 156 18 years and patients who were transferred to or from another hospital. Dosage of chloroquine base 157 was: loading dose of 600 mg, followed by 300 mg twice a day for a total of 5 days. Dosage of 158 hydroxychloroquine sulphate was 400 mg twice daily on the first day, followed by 200 mg twice daily 159 on days 2 to 5. Among the seven (H)CQ-hospitals, the timing of start of (H)CQ treatment differed; 160 three hospitals started at the moment of COVID-19 diagnosis, four started after diagnosis but only 161 when patients clinically deteriorated e.g., when there was an increase in respiratory rate or increase 162 in use of supplemental oxygen. The two hospitals that did not routinely treat subjects with (H)CQ 163 (i.e., the non-(H)CQ-hospitals), offered best supportive care, including oxygen therapy and 164 potentially antibiotic therapy, according to local guidelines and prescriber discretion. Participating 165 hospitals did not routinely prescribe other experimental medication (e.g., lopinavir/ritonavir, 166 remdesivir or steroids, see Table 1 ). Subjects who were incidentally treated with these drugs were 167 included in the study. Primary outcome was 21-day all-cause mortality, defined as hospital mortality, 168 or discharge to a hospice care facility. A waiver for the use of hospital record data was obtained 169 through the Institutional Review Board of Amsterdam UMC; however, patients were given the 170 opportunity to opt out. We collected data according to the collection protocol of the World Health 171

Organization. Missing covariates were imputed using multiple imputation with the MICE package 172 (version 3.8.0) and the outcomes were determined by pooling the results of 25 imputed datasets 11 . 173 J o u r n a l P r e -p r o o f

We performed a regression analyses and determined the pooled effect. Missing data range for all 174 covariates was less than 2.8%, except for obesity (missing data 6.2%) and use of corticosteroids 175 (22.3%). In the primary analysis, we compared effectiveness of (H)CQ versus non-(H)CQ hospital 176 strategies, irrespective of actual individual (H)CQ treatment. We performed a survival analysis using 177 log-rank test and Cox-regression with adjustment for age, sex, time in the pandemic (i.e., the number 178 of elapsed days after March 1 st 2020 at hospital admission),and covariates based on premorbid 179 health (i.e., history of lung, kidney and cardiovascular disease, diabetes mellitus, obesity, and 180 neoplasms or hematologic disease), disease severity during presentation (respiratory rate, oxygen 181 saturation) and the use of steroids, including dexamethasone, for adult respiratory distress 182 syndrome (ARDS) 12,13 . We repeated the analyses comparing actually received treatment, with (H)CQ. 183

In a secondary analysis, we used a composite endpoint (either mechanical ventilation or all-cause 184 mortality) at 21 days. As a sensitivity analysis, we performed a complete case analysis using inverse 185 probability weighting of propensity scores (determined using the same covariates). We performed a 186 subgroup analysis in (H)CQ hospitals that started (H)CQ directly from the moment of diagnosis versus 187 outcomes in non-(H)CQ hospitals. All statistical analyses were performed using R versions 3.6.3 (R 188 Table 1 . Follow-up data were missing for 20 (1.0%) subjects. The patients with missing 195 outcome data were included Table 1 saturation during admission were similar in both hospital groups (see Table 1 ). In (H)CQ-hospitals, 208 9.6% of subjects received corticosteroids for ARDS and 4.0 were in a study protocol of an 209 experimental SARS-CoV-2 directed antiviral (e.g., lopinavir/ritonavir) or immunomodulatory drug trial 210 (e.g., imatinib, anti-complement C5), versus 2.3% and 11.3% in non-(H)CQ-hospitals, respectively. 211 Table 2 ). When 215 stratified by actually received treatment, the use of (H)CQ was associated with an increased 21-day 216 mortality (HR 1.58; 95%CI 1.24-2.02, Table 3 ) in the full model. In the secondary analysis with either 217 mechanical ventilation or all-cause mortality at 21 days, there were no statistically significant 218 differences between the (H)CQ and non-(H)CQ hospitals (crude p=0.055, adjusted HR 0.87 (95%CI 219 0.68-1.10), Online Supplement 1). The complete analysis using propensity scores for treatment 220 strategy and actual treatment showed similar results (see Table 4 ). An overview of the distribution of The strength of this study is that data were collected in nine hospitals, including two university 248 hospitals, in the Netherlands during the COVID-19 epidemic. Data collection was set up prospectively 249 and the database included data on all consecutive subjects admitted to general medicine and 250 pulmonology wards, and to intensive care units. The database was set up according to the WHO 251 standards, which enabled data comparison and uniformity of data among the different participating 252 centres. The comparison of hospital-defined treatment strategies rather than the treatment actually 253 received led to a lower risk of indication bias compared with previous studies 1,2,4,5 . We roughly 254 estimate the extend of the effect of indication bias to be the difference in outcome between the 255 uncorrected and the corrected model. Further strengths include the multicentre setup 2,3 , as 256 mentioned above, and the relatively large numbers of included subjects 3 . 257

There are some limitations we need to address. Although health care in the Netherlands has a 259 homogeneous setup, there was some variability in standard protocols among the hospitals that could 260 J o u r n a l P r e -p r o o f have led to residual confounding. The two non-(H)CQ-hospitals were tertiary (university) centres, 261

whereas the (H)CQ-hospitals comprised both secondary and tertiary care hospitals. Before the 262 COVID-19 pandemic, the tertiary care hospitals and their intensive care units function as referral 263 centres for local secondary care hospitals. Since we excluded subjects transferred to and from other 264 hospitals, the referral role of the tertiary care hospitals, including the university hospitals, was 265 minimized. Furthermore, subjects in the (H)CQ hospitals were more likely to receive steroid 266 treatment, while subjects in the non-(H)CQ hospitals were more likely to receive other experimental 267 immunomodulatory drugs. The numbers of the individual types of medication were small, making it 268 impossible to draw conclusions from these differences. The results of the RECOVERY trial, suggested 269 a lower mortality in patients treated with dexamethasone 15 . Treatment with dexamethasone could 270 therefore have resulted in a lower mortality in the group of (H)CQ hospitals. We did not find such an 271 effect, even after correction in the full model. We also used extensive covariate adjustments, using 272 various methods to minimize influence of differences in patient population among hospitals, and the 273 similarity in outcomes between these methods is reassuring in this regard. show a benefit of (H)CQ treatment. This may be explained by the timing of the administration of the 282 drug and its specific working mechanism. Chloroquine binds in silico and in vitro with high affinity to 283 sialic acids and gangliosides of SARS-CoV-2. These bindings inhibit the interaction at non-toxic plasma 284 levels with ACE-2 receptors and could hypothetically stop the cascade from formation of pulmonary 285 infiltrations to full blown ARDS and death [17] [18] [19] . The antiviral activity might be more effective in the 286 pre-clinical setting as the deterioration in the hospital is more an effect of the cytokine storm 287 provoked by SARS-CoV-2 than an effect of the viral infection itself. This hypothesis might explain why 288 the clinical benefit for admitted subjects was absent in our study, although we did not observe a 289 difference in outcome among subjects treated early (at diagnosis) and among those treated later 290 upon clinical deterioration. J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f

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