key: cord-0786123-7efvbsoe
authors: Abdulrahman, A.; AlSayed, I.; AlMadhi, M.; AlArayedh, J.; Mohamed, S. J.; Sharif, A. K.; Alansari, K.; AlAwadhi, A. I.; AlQahtani, M.
title: The efficacy and safety of hydroxychloroquine in COVID19 patients : a multicenter national retrospective cohort
date: 2020-11-30
journal: nan
DOI: 10.1101/2020.11.25.20234914
sha: efdd400dc0189736ab60d7b4c0d08c3396b64dca
doc_id: 786123
cord_uid: 7efvbsoe

Background Hydroxychloroquine is an antimalarial drug that received worldwide news and media attention in the treatment of COVID-19 patients. This drug was used based on its antimicrobial and antiviral properties despite lack of definite evidence of clinical efficacy. In this study, we aim to assess the efficacy and safety of using Hydroxychloroquine in treatment of COVID-19 patients who are admitted in acute care hospitals in Bahrain. Methodology We conducted retrospective cohort study on a random sample of admitted COVID19 patients between 24 February and 31 July 2020. The study was conducted in four acute care COVID19 hospitals in Bahrain. Data was extracted from the medical records. The primary endpoint was the requirement of non-invasive ventilation, intubation or death. Secondary endpoint was length of hospitalization for survivors. Three methods of analysis were used to control for confounding factors: logistic multivariate regression, propensity score adjusted regression and matched propensity score analysis. Results A random sample of 1571 patients were included, 440 of which received HCQ (treatment group) and 1131 did not receive it (control group). Our results showed that HCQ did not have a significant effect on primary outcomes due to COVID-19 infection when compared to controls after adjusting for confounders (OR 1.43 95% CI 0.85 to 2.37, P value=0.17). Co-administration of azithromycin had no effect on primary outcomes (OR 2.7 95% CI 0.82 to 8.85 P value =0.10). HCQ was found to be associated with increased risk of hypoglycemia (OR 10.9 95% CI 1.72 - 69.49, P value =0.011) and diarrhea(OR 2.8, 95% CI 1.4-5.5, P value =0.003), but not QT prolongation(OR=1.92, 95% CI 0.95-3.9, P value =0.06) or cardiac arrhythmia.(OR=1.06, 95% CI 0.55-2.05, P value =0.85). Conclusion Our results showed no significant beneficial effect of using hydroxychloroquine on the outcome of COVID-19 patients. Moreover, the risk of hypoglycemia due to hydroxychloroquine would possess a significant risk for out of hospital use.

An outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), 66 causing the coronavirus disease 2019 (COVID19) started in December 2019, and 67

almost a year later, we seem to be at the brink of an imminent second wave. Since it 68 was declared a pandemic by the World Health Organisation (WHO) in March 2020 (1), 69 it infected more than 52 million people and lead to the death of 1.3 million others (2). 70

With no cure or vaccine identified yet, the health sector moved to repurposing available 71 drugs. 72

One of the first and most rapidly identified was Hydroxychloroquine (HCQ), which was 73 considered due to its antiviral activity. It was initially developed as an antimalarial drug, 74

and is currently widely used to treat autoimmune diseases like systemic lupus 75 erythematosus and rheumatoid arthritis (3). The efficacy of HCQ against SARS-CoV-76 2 was first confirmed in vitro and was reported to mediate its inhibition through the 77 blockage of angiotensin-converting enzyme (ACE) II receptors which facilitate SARS-78

CoV-2 entry into cells (4). In addition, HCQ reportedly also disrupted the transport of 79 SARS-CoV-2 from endosomes to endolysosomes, which is necessary for viral release 80 (4, 5). HCQ also has immunomodulatory effects such as inhibition of antigen-81 presenting cell activity, in turn blocking the activation of T cells (6). This prevents the 82 release of inflammatory cytokines, which causes the "cytokine storm" observed in 83 COVID19 patients (6-8). The Food and Drug Administration issued an "emergency 84 use authorization" for the use of HCQ for COVID19 patients, based on these limited 85 results (9), which lead to an increase in HCQ use. The first clinical trial studying the 86 use of HCQ to treat COVID19 was an open-label, non-randomized trial conducted in 87

France. A total of 36 patients received HCQ and 16 controls, with results showing a 88 drop in viral load amongst the HCQ group compared to the controls by day 6 of the 89 trial (10). Observational studies that followed failed to report a therapeutic advantage 90 of the magnitude seen in the French study, instead showing that HCQ has no effect 91 on intubation or mortality amongst COVID19 patients (11, 12) . 92

Soon after, studies showing adverse effects of HCQ use started appearing. Concerns 93 regarding safety and efficacy increased after the infamous, and not retracted, study 94

Labeling patients as "receiving HCQ" depended on whether they were received the 152 drug at our study baseline -defined as within 72hrs of admission. 153

The National Bahrain treatment protocol, developed by the national task force medical 154 team, was issued to all COVID19 facilities as guidance to health care workers for the 155 management of COVID19. HCQ was suggested for patients with COVID19 as a 156 therapeutic option. The suggested HCQ regimen was a loading dose of 600 mg twice 157 on day 1, followed by 400 mg daily for 4 additional days. Azithromycin at a dose of 158 500 mg on day 1 and then 250 mg daily for 4 more days in combination with HCQ was 159 an additional suggested therapeutic option. However, the suggestion of HCQ and/or 160 Azithromycin was removed in April after several manuscripts showed lack of benefit 161 from HCQ and a potential risk. Prescribing either or both medications was a decision 162 left to the judgment of the treating team based on individualization of the patient care. 163

We obtained data from the "I-SEHA" electronic medical records. The I-SEHA is a 165 doctor station which provides access to patient records and has all the clinical details 166 of the hospital stay as text files. Data was manually extracted from the electronic 167 records. 5 physicians who were assisted by 10 senior medical students reviewed all 168 the cases and filled in an electronic form developed to collect data for this study. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.25.20234914 doi: medRxiv preprint Safety outcomes: the development of any of the adverse events during hospital stay, 180 after the prescription of medications. Adverse event included were cardiac arrythmia, 181

QT prolongation (>500ms), diarrhea and hypoglycemia (defined as glucose levels less 182 than 3.6 mmol/L) 183

Secondary outcome was length of stay in days for survivors. 184

The distribution of treatment groups was summarized. Bivariate associations between 186 the treatment group and the measured patient characteristics were analyzed using 187

Chi-squared (χ2) tests for categorical variables and t-test for continuous variables. We is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint 

The protocol and manuscript for this study were reviewed and approved by the Ethics Committee for this study due to its retrospective and observational nature and 223 the absence of any patient identifying information. 224

A total of 1849 cases were reviewed. Of those, 278 were excluded; 57 due to 227 duplicates, 79 due to age less than 18 years, and 34 cases were excluded due to 228 insufficient information. A further 56 patients were excluded due to endpoint (of 229 ventilatory support or death) being achieved within 1 day, 7 were excluded due to 230 transfer/discharge within 1 day, and 45 were excluded as they received HCQ out of 231 study baseline. 1571 cases were included in the study. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.25.20234914 doi: medRxiv preprint Among the patients who received HCQ. The median time to start HCQ was 1 day from 236 admission (IQR 0-2). 237

Patients' baseline characteristics (demographic and clinical) according to HCQ 238 exposure is shown in Table 1 and 2. A propensity matched analysis was conducted to 239 balance the two groups and their characteristics are also shown in Table 1 and 2. 240

In the unmatched sample, patients who received HCQ had a significantly higher mean 241 age (43.4 years), were more likely to be Bahraini and had more comorbidities. 242

Diabetes and hypertension were more common in patients receiving HCQ. The HCQ-243 receiving patients were more likely to be symptomatic (68.9% compared to 61.8%). 244

Symptoms of fever, cough, body ache, nausea and vomiting were more predominant 245 in patients who received HCQ. The HCQ-receiving patients were also more severely 246 ill on admission, as 12.3% received supplemental oxygen on admission (through 247 nasal cannula, face mask and Nonrebreather mask). 248

The Propensity score 250

The distribution of the estimated propensity scores for receiving HCQ among patients 251 who did and did not receive HCQ is shown in Appendix B. The C-statistic of the 252 propensity-score model was 0.83 . In the matched analytic sample, 223 patients were 253 exposed to HCQ and 223 were not exposed. The differences between HCQ and 254 pretreatment variables were attenuated in the propensity-score-matched samples as 255 compared with the unmatched samples. Table 3 summarizes outcomes in each treatment group. 263

The difference between the two groups was not significant across the different 264 methods used to control confounders. The primary analysis using multivariate model 265

showed an odds ratio of 1.43 with a 95% CI 0.85 to 2.37, P value=0.17. Other methods 266 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.25.20234914 doi: medRxiv preprint of confounding adjustment showed similar and non-significant results. Table 4  267 summarizes the analysis results. 268

There was a significant effect modification in COVID-19 patients receiving HCQ and 270 requiring supplemental oxygen on admission. Significant effect modification was also 271 noted on in cases exposed to azithromycin. Appendix C shows the detailed effect 272 modification analysis. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.25.20234914 doi: medRxiv preprint arrhythmias (OR=1.06, 95% CI 0.55-2.05, P value =0.85) however these findings were 298 non-significant. Table 7 summarizes the safety endpoints. 299 300 Secondary outcome: Length of stay in survived cases 301

The mean length of stay of discharged patients in the study cohort was 10.0 days (+/-302 5.54 days). The minimum stay was 2 days, and the maximum was 57. Patients who 303 received HCQ had a mean stay of 11.3 days (5.65 days) while patients in the control 304 group had mean stay of 9.5 days (5.41 days). The difference was statistically 305 significant in a two-sided t-test (p<0.001). After adjustment for confounders using a 306 multivariate model, HCQ had a higher length of stay by 0.63 days, however this 307 difference was non-significant (95% CI ranged from -0.02 to 1.29). The results of this study show that, for our studied sample and models used, HCQ did 313 not have a significant effect on primary outcomes (requirement for ventilation or death) 314 due to COVID-19 infection. 315

Analysis of the demographics of our studied sample showed that patients who 316 received HCQ were significantly of older age, which could be associated with a more 317 severe HCQ-requiring presentation. Although this is an extrapolation from our data, 318 age has reportedly been associated with a more severe progression of the disease 319 (25-28). However, a recent study quantifying the isolated effect of age on severity of 320 COVID-19 outcomes concluded a minimal influence of age after adjusting for 321 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.25.20234914 doi: medRxiv preprint course and progression of the disease, with strong correlations with hypertension, 327 diabetes and CVD (30). However, there was no difference in rates of CVD presentation 328 between the HCQ-receiving and control groups, which may be due to increased 329 prevalence of CVD in the country (31). The HCQ receiving group had significantly less 330 G6PD deficiency, stemming from management guidelines contraindicating HCQ in 331 patients with G6PD deficiency due to increased risk of hemolytic crisis (32, 33). 332

Patients who received HCQ had a higher presentation of symptoms on admission and 333 scored significantly higher on baseline clinical severity scale. Creatinine levels were 334 significantly elevated amongst patients who received HCQ, indicating COVID-19-335 mediated acute kidney injury (34). A significantly higher proportion of HCQ receiving 336 patients presented with chest x-ray findings of pneumonia compared to control 337 patients. All these presentations on admission indicate a more severe progression of 338 the disease that is a risk of poor prognosis (28, 34, 35), increasing risk of developing 339 composite outcome and hence indicating HCQ requirement. This may also explain the 340 higher incidence of composite outcomes seen amongst patients receiving HCQ. 341

Interestingly we found no difference in requirement of oxygenation on admission 342 between the HCQ and control groups in our studied sample. This was not expected 343 as requirement of supplemental oxygenation on admission has been associated with 344 increased risk of severe illness (36), and hence expected to be prescribed HCQ. 345

However, this could be interpreted alongside the increased G6PD deficiency amongst 346 the control groups. With a high prevalence of G6PD in Bahrain (37), it may be that 347 many severe COVID-19 admission, that potentially required oxygen on admission, 348 were contraindicated to receive HCQ. Yet, more patients required oxygenation on 349 baseline in the hydroxychloroquine group. This indicates that physicians tends to 350 prescribe HCQ in the sicker patients. 351

Almost all factors were insignificant after propensity score matching analysis. 352

However, it is important to note that to conduct matched analysis, the sample size was 353 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.25.20234914 doi: medRxiv preprint There was no significant difference in the clinical outcome between HCQ and control 356 groups of patients with mild to moderate disease who did not require oxygen at 357 baseline. Therefore, there is insufficient evidence to suggest benefit of using HCQ to 358 treat patients with low risk of developing severe disease. This finding was consistent 359 across several reports (38, 39) . 360

Patients in our study who received HCQ while on oxygen therapy had lower rates of 361 developing the primary outcome, yet this as still non-significant. 362

Our study showed no clinical benefit from using HCQ in COVID19 patients. Moreover, 363 the effect remained non-significant across different subgroups: room air/oxygen 364 therapy and with and without azithromycin cotreatment. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.25.20234914 doi: medRxiv preprint HCQ in diabetic patients and showed a decreased requirement in insulin (42, 43). As 385 for diarrhea, it is a known adverse effect of HCQ as well (44). The increased risk of 386 hypoglycemia is alarming, as it would potentially be of a significant risk if patients 387 prone to hypoglycemia or are receiving HCQ outside hospital setting. 388

The surprising result was the insignificant association between QT interval 389 prolongation and the use of HCQ. It was difficult to find a study that supported our is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.25.20234914 doi: medRxiv preprint both, compared with neither treatment, was not significantly associated with 416 differences in in-hospital mortality in COVID19 patients (11). 417 418 Interpreted along with these prior studies, the results of this study provide additional 419 evidence that HCQ is not beneficial for adults hospitalized with COVID-19. Admitted 420 and on Oxygen support 421

The study has several strengths. It involved majority of hospitals which provide acute 423 care for hospitalized COVID19 cases. Moreover, our study included all hospitals that 424 use HCQ as part of the treatment regimen. The data collection process was done 425 manually and hence all patients files were reviewed carefully and all documented 426 details were collected. The outcomes and adverse were collected after the 427 medication starting date, any event occurring within 24hour of admission or prior to 428 starting the study drug were excluded. 429

The study main limitation is its design, being a retrospective observational study. 431

Secondly, given the retrospective design, information that wasn't documented 432 weren't available for analysis, and these can be potential confounders. These 433 included : time from symptom onset, inflammatory markers. It is also likely that there 434 is still unmeasured residual confounding due to factors not included in the analysis. 435

Our results showed no significant beneficial effect of using HCQ on the outcome of 437 COVID-19 patients. Moreover, the risk of hypoglycemia due to HCQ would possess a 438 significant risk for out of hospital use. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.25.20234914 doi: medRxiv preprint

Conflict of interest: The authors have declared that no conflict of interest exists. 576

Ethics approval and consent to participate: The study was approved by the National 577 COVID-19 Research and Ethics Committee. 578

Consent for publication: All authors gave their consent for publication. 579

Availability of data and materials: All the data for this study will be made available 580

upon reasonable request to the corresponding author. 581 Acknowledgements: 593 We would like to express our gratitude towards our colleagues: Ammar Kheyami, 594

Mujtaba Mal Alla, Abdulla AlMuharraqi, Zeyad Mahmood, Narjis Ali AlSheala, Ola 595

Husain AlHalwachi, Maryam Ghazi Alarayedh, and Amna Mohamed Buheiji who 596

played an essential role in the data collection process related to this paper. Our 597 thanks and appreciation goes to them for their hard, dedicated work. Wishing them 598 all the best in the future. We would also like to extend our appreciation to Dr 599

Simone Perna who dedicated time and effort to review and help us improve the 600 manuscript. 601 602 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.25.20234914 doi: medRxiv preprint TABLES 603 604 605 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.25.20234914 doi: medRxiv preprint 607 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.25.20234914 doi: medRxiv preprint 614 615 616 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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WHO Declares COVID-19 a Pandemic

Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and 446 rheumatoid arthritis patients

Hydroxychloroquine, a less toxic 448 derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro

Ebola virus and severe acute respiratory syndrome coronavirus display late cell entry 452 kinetics: evidence that transport to NPC1+ endolysosomes is a rate-defining step

COVID-19: a recommendation to examine the effect of 455 hydroxychloroquine in preventing infection and progression

Clinical features of patients infected 458 with 2019 novel coronavirus in Wuhan

Mechanisms of action of hydroxychloroquine and 460 chloroquine: implications for rheumatology

Covid-19: US gives emergency approval to hydroxychloroquine despite lack 462 of evidence

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label 465 non-randomized clinical trial

Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital 468

Mortality in Patients With COVID-19 in New York State

Observational Study of 470 Hydroxychloroquine in Hospitalized Patients with Covid-19

RETRACTED: Hydroxychloroquine or 473 chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry 474 analysis. Lancet. 2020. 475 14. WHO

Effect of 480 Hydroxychloroquine in Hospitalized Patients with Covid-19

Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract 483 Illnesses in Preschool Children With a History of Such Illnesses: A Randomized Clinical Trial