Real-Life Data on Hydroxychloroquine or Chloroquine with or Without Azithromycin in COVID-19 Patients: A Retrospective Analysis in BrazilAbstract
Background Despite no evidence showing benefits of hydroxychloroquine and chloroquine with or without azithromycin for COVID-19 treatment, these medications have been largely prescribed in Brazil.
Objectives To assess outcomes, including in-hospital mortality, electrocardiographic abnormalities, hospital length-of-stay, admission to the intensive care unit, and need for dialysis and mechanical ventilation, in hospitalized COVID-19 patients who received chloroquine or hydroxychloroquine, and to compare outcomes between those patients and their matched controls.
Methods A retrospective multicenter cohort study that included consecutive laboratory-confirmed COVID-19 patients from 37 Brazilian hospitals from March to September 2020. Propensity score was used to select matching controls by age, sex, cardiovascular comorbidities, and in-hospital use of corticosteroid. A p-value <0.05 was considered statistically significant.
Results From 7,850 COVID-19 patients, 673 (8.6%) received hydroxychloroquine and 67 (0.9%) chloroquine. The median age in the study group was 60 years (46 - 71) and 59.1% were women. During hospitalization, 3.2% of patients presented side effects and 2.2% required therapy discontinuation. Electrocardiographic abnormalities were more prevalent in the chloroquine/hydroxychloroquine group (13.2% vs. 8.2%, p=0.01), and the long corrected QT interval was the main difference (3.6% vs. 0.4%, p<0.001). The median hospital length of stay was longer in the HCQ/CQ + AZT group than in controls (9.0 [5.0, 18.0] vs. 8.0 [4.0, 14.0] days). There was no statistical differences between groups in intensive care unit admission (35.1% vs. 32.0%; p=0.282), invasive mechanical ventilation support (27.0% vs. 22.3%; p=0.074) or mortality (18.9% vs. 18.0%; p=0.682).
Conclusion COVID-19 patients treated with chloroquine or hydroxychloroquine had a longer hospital length of stay, when compared to matched controls. Intensive care unit admission, invasive mechanical ventilation, dialysis and in-hospital mortality were similar.
Chloroquine; Hydroxychloroquine; Azithromycin; COVID-19
Resumo
Fundamento Apesar da ausência de evidência mostrando benefícios da hidroxicloroquina e da cloroquina combinadas ou não à azitromicina no tratamento da covid-19, esses medicamentos têm sido amplamente prescritos no Brasil.
Objetivos Avaliar desfechos, incluindo moralidade hospitalar, alterações eletrocardiográficas, tempo de internação, admissão na unidade de terapia intensiva, e necessidade de diálise e de ventilação mecânica em pacientes hospitalizados com covid-19 que receberam cloroquina ou hidroxicloroquina, e comparar os desfechos entre aqueles pacientes e seus controles pareados.
Métodos Estudo multicêntrico retrospectivo do tipo coorte que incluiu pacientes com diagnóstico laboratorial de covid-19 de 37 hospitais no Brasil de março a setembro de 2020. Escore de propensão foi usado para selecionar controles pareados quanto a idade, sexo, comorbidades cardiovasculares, e uso de corticosteroides durante a internação. Um valor de p<0,05 foi considerado estatisticamente significativo.
Resultados Dos 7850 pacientes com covid-19, 673 (8,6%) receberam hidroxicloroquina e 67 (0,9%) cloroquina. A idade mediana no grupo de estudo foi 60 (46-71) anos e 59,1% eram mulheres. Durante a internação, 3,2% dos pacientes apresentaram efeitos adversos e 2,2% necessitaram de interromper o tratamento. Alterações eletrocardiográficas foram mais prevalentes no grupo hidroxicloroquina/cloroquina (13,2% vs. 8,2%, p=0,01), e o prolongamento do intervalo QT corrigido foi a principal diferença (3,6% vs. 0,4%, p<0,001). O tempo mediano de internação hospitalar foi maior no grupo usando CQ/HCQ em relação aos controles (9,0 [5,0-18,0] vs. 8,0 [4,0-14,0] dias). Não houve diferenças estatisticamente significativas entre os grupos quanto a admissão na unidade de terapia intensiva (35,1% vs. 32,0%; p=0,282), ventilação mecânica invasiva (27,0% vs. 22,3%; p=0,074) ou mortalidade (18,9% vs. 18,0%; p=0,682).
Conclusão Pacientes com covid-19 tratados com cloroquina ou hidroxicloroquina apresentaram maior tempo de internação hospitalar, em comparação aos controles. Não houve diferença em relação a admissão em unidade de terapia intensiva, necessidade de ventilação mecânica e mortalidade hospitalar.
Cloroquina; Hidroxicloroquina; azitromicina; covid-19
Introduction
The COVID-19 pandemic caused an unprecedented global effort in the search for effective treatments to fight the disease. In this context, hydroxychloroquine (HCQ) and chloroquine (CQ) have caught the attention of the scientific community due to in vitro evidence showing an antiviral activity and immunomodulatory effect, which, in theory, could prevent cytokine storm.1 In vitro studies also showed that azithromycin (AZT) could have a synergic effect on the HCQ/CQ effects against SARS-CoV-2.2 On top of that, both medications are affordable, have a well-known safety profile, and are readily available all over the world, so they soon became potential treatments to the disease.2
Considering this encouraging preliminary information, important regulatory agencies, such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), granted permission for the use of HCQ and CQ outside clinical trials in March 2020, due to the emergency situation.3,4
Currently, even with robust findings from large randomized clinical trials (RCT), such as RECOVERY5 and SOLIDARITY-WHO,6 and several meta-analyses, showing no evidence to support this therapy and even evidence of harm,7,8 some physicians and Brazilian guidelines kept recommending the use of this medication for COVID-19 treatment.9 Therefore, this study aims to assess the clinical and electrocardiographic outcomes of hospitalized COVID-19 patients, who received CQ or HCQ, with or without AZT, from a large cohort of Brazilian hospitals, as well as to compare outcomes between those patients and their matched controls.
Methods
Study design
The present study is a part of the Brazilian COVID-19 Registry, a retrospective multicenter cohort study, which enrolled consecutive patients with laboratory-confirmed COVID-19.10,11 This study adheres to the STROBE guidelines (Strengthening the Reporting of Observational Studies in Epidemiology).12 The Brazilian National Commission for Research Ethics (CAAE 30350820.5.1001.0008) approved the development of this study and the need for individual consent was waived due to the pandemic circumstances and analysis based only on unidentified patient data.
The present analysis included patients admitted to 37 participant hospitals in 17 Brazilian cities, from March to September, 2020.10,11 There were no losses due to the retrospective nature of the study. Patients with missing values in the different variables were not excluded, and there were no missing values related to the exposure. We chose not to apply any further exclusion criteria, as our aim is to provide a real-life observational report.
Data collection
Trained researchers collected patient data from the medical records using the Research Data Capture (REDCap®) electronic data capture system,13,14 hosted at the Telehealth Center of the University Hospital of the Universidade Federal de Minas Gerais.14 Data included patients’ demographic and clinical characteristics, clinical evaluation at hospital presentation, laboratory, imaging, and electrocardiographic data, therapeutic interventions, and outcomes.10 To ensure reliability and monitor data quality, all information underwent an automatic verification periodically, to identify outliers and possible inconsistencies.
Outcomes
The primary outcome was COVID-19 in-hospital mortality. Secondary outcomes included electrocardiographic abnormalities (rhythm, heart rate, corrected QT interval, structural abnormalities, blocks, and tachycardias), hospital length-of-stay, admission to the intensive care unit (ICU), and need for dialysis and for invasive mechanical ventilation.
Statistical analysis
For the descriptive analysis, the demographic and clinical characteristics of the patients were represented by frequency distribution, using median and interquartile range for continuous variables, as they did not present normal distribution, and numbers and percentages for counts. Patients who received HCQ or CQ with or without AZT (HCQ/CQ + AZT) at any dosage were compared to matched controls (patients who did not receive this treatment) using the chi-square test and the Fisher’s exact test for categorical variables and the Wilcoxon rank sum test for continuous variables. In the latter case, the Kolmogorov-Smirnov test was applied to verify data normality.
For comparison purposes, a propensity score model (including age, sex, the number of cardiovascular comorbidities, hospital of origin, and corticoid use) was estimated by logistic regression to adjust potential confounding variables and match patients to controls. The control group was those who had the closest propensity score to those treated with CQ (within 0.17 standard deviations of the logit of the propensity score, on a scale from 0-1.00), using the MatchIt package, in R software.
For the outcomes admission to the ICU, and need for dialysis and mechanical ventilation, patients who used HCQ/CQ + AZT after the occurrence of these outcomes were excluded.
Results were considered statistically significant at a significance level of 5%. Statistical analysis was performed with the R program for statistical computing (version 4.0.2).
Results
From 7,850 hospitalized patients with a confirmed COVID-19 diagnosis, 725 (9.2%) patients received CQ/HCQ with or without AZT for COVID-19 treatment during hospital stay, 659 (90.9%) were treated with HCQ, 67 (9.2%) with CQ, and 640 (88.3%) received AZT simultaneously (Supplementary table 1). Of those, 673 patients who received CQ/HCQ could be matched, and the accuracy of the final propensity model was 0.91. The standardized mean differences of the key covariates before and after matching are shown in Supplementary table 2 and on the Central Figure.
The prevalence of comorbidities was similar between the two matched groups, as shown in Table 1, except for chronic kidney disease, which was more common in the controls. As for clinical characteristics at admission, the HCQ/CQ + AZT group had a slightly decreased SpO2/FiO2 ratio compared to controls. Characteristics of patients who were assessed for invasive mechanical ventilation, dialysis and ICU admission are described in Supplementary table 3.
With regards to the posology (Table 2), most patients used HCQ (90.1%) with or without AZT at a dose of 850 mg on the first day, followed by 450 mg daily for the duration of the treatment. The median length of the treatment was five days. Thirty patients presented side effects that were attributed to the medication by the attending medical team, with QT interval prolongation and gastrointestinal symptoms as the most common ones. The therapy was suspended in 15 patients due to concerns with side effects.
Less than half of patients on therapy had an electrocardiogram (ECG) recorded in the first 24 hours after admission. Most patients were on sinus rhythm and primary repolarization abnormality was the most common electrocardiographic finding.
For ECG outcomes (Table 3), patients in the study group were more likely to be diagnosed with a novel electrocardiographic abnormality during hospital stay. QT interval prolongation was the most frequent abnormality and its frequency was higher in patients on HCQ/CQ compared to controls. Supraventricular tachycardia was more frequent in controls. There were no other statistically significant differences in electrocardiographic abnormalities between the groups.
With regards to the outcomes (Table 4), the median hospital length of stay was longer in the HCQ/CQ + AZT group than in controls. There were no statistically significant differences in the need for admission to an ICU, mechanical ventilation or dialysis, and in-hospital mortality between groups.
Discussion
In the present study, COVID-19 patients treated with CQ or HCQ with or without AZT had a longer hospital stay and a higher frequency of long corrected QT interval compared to matched controls. Admission in ICU, dialysis, invasive mechanical ventilation support and in-hospital mortality were not statistically different between the groups.
As for the prevalence of underlying individual comorbidities, it is worth noting that more than 60% of patients on CQ or HCQ had at least one cardiovascular comorbidity, with hypertension as the most common one. The profile of patients receiving CQ and HCQ in our cohort differed considerably from patients enrolled in some of the largest RCTs on the topic, such as the RECOVERY5 trial, where only 27% of patients had cardiac comorbidities, and SOLIDARITY,6 in which 21% of patients were previously diagnosed with cardiac disease. This is possibly a selection bias as the ethical considerations for entering clinical trials excluded those patients with an additional risk of having serious adverse effects with the medication, such as those with cardiac comorbidities.5,6Thus, as these medications were largely used outside clinical trials, the analysis of real-life patients is warranted and appropriate to confirm the existing evidence from RCTs.
When receiving HCQ or CQ, especially associated with AZT, patients should be monitored for the development of cardiac adverse events. In the context of the COVID-19 in-hospital use of these medications, protocols advise that it is recommended to have an ECG recorded before the beginning of the therapy. This is even more important in patients with cardiac comorbidities (60% of our sample), for whom an ECG will exclude electrocardiographic abnormalities that may be a contraindication to therapy. However, even with such recommendations, only 42.3% of patients had an ECG recorded at admission. Among those who had an ECG recorded, 8.1% of patients in the HCQ/CQ + AZT group did not have a sinus rhythm on admission, seven patients had a diagnosis of atrial fibrillation or flutter and three had a pacemaker rhythm, which shows that even patients with serious ECG abnormalities were prescribed the treatment.
With regards to electrocardiographic outcomes during the hospital stay, QT interval prolongation was more common in patients using the therapy compared to controls (3.6 vs. 0.4, p<0.001). It is known that both HCQ and CQ have the potential of prolonging the QT interval and AZT has also been shown to impact cardiovascular outcomes and the incidence of sudden cardiac arrest. When administered simultaneously, the potential for cardiac toxicity seems to increase. Evidence from a systematic review that included 47 studies with a total of 13,087 patients showed that patients who had therapy with HCQ plus AZT had greater risk to be detected with QTc prolongation (relative risk [RR], 3.28; 95% CI, 1.16–9.30), which is in accordance with our findings. In our study, we were unable to identify differences in the occurrence of malignant arrhythmias between the study and control groups, which suggests that QT prolongation may serve as an early predictor of malignant arrhythmias. Consequently, it may be valuable as a surrogate marker in clinical practice, warranting further attention.
In our study, in-hospital mortality, ICU admission, need for mechanical ventilation and dialysis were not different between groups. Previous evidence agrees on the lack of benefit of the therapy for treating COVID-19, with studies showing even evidence of increased mortality (harm).7,15-17 A systematic review of 29 studies (three RCTs, one non-randomized trial, and 25 observational studies), with 11,932 patients found that the therapy with HCQ alone was not associated with improved survival (pooled RR, 0.83 [95% CI 0.65-1.06, n= 17 studies]), while among the 8,081 patients who had HCQ with AZT, a higher risk of death (RR= 1.27; 95% CI 1.04-1.54, n= 7 studies) was identified.16 However, this review was conducted before the publication of RECOVERY and SOLIDARITY.5,6 For that purpose, another systematic review was conducted including only RCTs; 28 studies (14 published and 14 unpublished RCTs) with 10,319 patients were included, comparing HCQ or CQ with standard care or placebo.18 This review found an increased mortality among patients receiving HCQ, with an pooled OR for all-cause mortality of 1.11 (95% CI: 1.02, 1.20; I2 = 0%; 26 trials; 10,012 patients), and no benefit from CQ, with a pooled OR of 1.77 (95% CI: 0.15, 21.13, I2 = 0%; four trials; 307 patients).18 However, this study did not evaluate the effect of the combination of AZT with HCQ/CQ on mortality.
A RCT was conducted in 504 Brazilian COVID-19 patients, who were assigned in a 1:1:1 ratio to receive standard care, standard care plus HCQ, or standard care plus HCQ and AZT. Those using HCQ with or without AZT showed a higher frequency of QT interval prolongation, and the therapy did not seem to be associated with an improvement of the patient’s status during hospitalization.19 Another Brazilian study, with non-randomized design, on COVID-19 outpatients showed that CQ was independently associated with higher mortality (OR 1.67 [95% CI 1.20-2.28]), but it was not associated with the occurrence of major electrocardiographic abnormalities (OR = 0.80 [95% CI 0.63-1.02)].20A retrospective analysis of COVID-19 inpatients who used HCQ also detected a higher rate of mortality (OR 3.3, 95%CI 1.1-9.6, p=0.03).21
Most of the robust evidence we have on HCQ/CQ and invasive mechanical ventilation comes from the RECOVERY trial,5 the largest published RCT to date, that alone represented 47% of the sample and 76% of the weight of the aforementioned systematic review that included 28 RCTs.18 In this study, that included 1,561 patients receiving HCQ compared to 3,155 patients receiving usual care, the HCQ group presented a higher frequency of the composite outcome of invasive mechanical ventilation or death (30.7% vs. 26.9%, RR = 1.14, 95% CI 1.03 - 1.27).5 However, this study differs from ours because it considers HCQ or CQ alone compared with standard care, while in our sample the most popular treatment scheme (received by 90.9% of patients in the sample) included the association with AZT. We hypothesize that the effect on mechanical ventilation (HCQ/CQ 27.0% vs. controls 22.3%, p=0.074) in the present analysis might not have been perceived due to the limited sample size (n = 559 patients). The possibility of a higher frequency of invasive mechanical ventilation is very relevant, not only due to a higher risk of immediate complications, such as nosocomial infection, but also due to resource depletion and risk of worse long-term outcomes. A recent multicenter Brazilian study followed 1,508 COVID-19 patients up to one year of hospitalization, and observed that those who needed mechanical ventilation during hospitalization had lower health-related quality-of-life utility scores, higher all-cause mortality (7.9% vs 1.2%; adjusted difference, 7.1% [95% CI 2.5%–11.8%]), major cardiovascular events (5.6% vs 2.3%; adjusted difference, 2.6% [95% CI 0.6%–4.6%]), and new disabilities in instrumental activities of daily living (40.4% vs 23.5%; adjusted difference, 15.5% [95% CI 8.5%–22.5]) at one year follow-up.22
This study provided a comprehensive overview of CQ or HCQ use in a large cohort of Brazilian hospitals. Even with its strengths, such as sample size, matched analysis, and multicenter design, the present study has limitations that should be addressed. As it includes retrospective data collected from medical records, the results are subjected to drawbacks inherent to the data. To minimize this, extensive training on how to collect data from medical records was mandatory for all health professionals and undergraduate students responsible for data gathering. Furthermore, as this is an observational and non-randomized study, it was not possible to establish cause-effect associations. Also, the study’s data reflect a time period before vaccination was offered to the Brazilian population and before effective antiviral therapies were available. Other treatments used during hospitalization, such as anticoagulation, steroids and monoclonal antibodies were not standardized. Although the results may not reflect the current profile and prognosis of in-hospital COVID-19 patients, the limitations do not invalidate the study’s results with regards to HCQ/CQ. At last, indication bias could be a limitation. As it was a compassionate use context, the drug could be given to highly selected individuals, such as patients who had a more severe condition and less prone to have adverse effects. However, it is likely that the successful matching between patients using HCQ/CQ and controls have lessened possible risks of indication bias, that the bias have not interfered or invalidated the study results.
Conclusion
In this study, patients treated with CQ or HCQ with or without AZT had a longer length of hospital stay, compared to matched controls. Electrocardiographic abnormalities were more prevalent in COVID-19 patients using CQ than in their controls. Nonetheless, no difference was observed in mechanical ventilation, ICU admission, dialysis and in-hospital mortality between the two groups. The study adds to the bulk of evidence not supporting the use of these medications for COVID-19 patients.
Acknowledgments
We would like to thank the hospitals involved in this project for the support. We also thank all the clinical staff of these hospitals, who cared for the patients, and all undergraduate students who helped on data collection.
References
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Study associationThis study is not associated with any thesis or dissertation work.Ethics approval and consent to participateThis study was approved by the Comitê Nacional de Ética em Pesquisa under the protocol number CAAE 30350820.5.1001.0008. All the procedures in this study were in accordance with the 1975 Helsinki Declaration, updated in 2013.
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Supplemental MaterialsFor additional information, please click here.
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Sources of funding: This study was partially funded by Minas Gerais State Agency for Research and Development (Fundação de Amparo à Pesquisa do Estado de Minas Gerais - FAPEMIG) [APQ-01154-21], National Institute of Science and Technology for Health Technology Assessment (Instituto de Avaliação de Tecnologias em Saúde – IATS)/ National Council for Scientific and Technological Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq) [465518/2014-1]. MSM was partially funded by CNPq [310561/2021-3]. DNP was partially funded by FAPEMIG [APQ-01154-21].
Publication Dates
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Publication in this collection
20 Oct 2023 -
Date of issue
Sept 2023
History
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Received
19 Jan 2023 -
Reviewed
03 July 2023 -
Accepted
17 July 2023
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