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We read with interest the study by Graef et al,1 who mentioned about the treatment and safety of hydroxychloroquine (HCQ) for the current COVID-19 pandemic. They described that decades of research strongly support the well control of disease activity and survival benefit of HCQ use in rheumatic diseases, such as systemic lupus erythematosus and rheumatoid arthritis (RA). They also highlight that HCQ should be used with caution in patients with COVID-19, including the safety concern, especially when combined with administration of azithromycin because both of them are known corrected QT interval (QTc) prolongation agents.
During early outbreak, HCQ, combined with azithromycin, has been used as a treatment option for COVID-19.2 3 Recently, an observational study with 1446 patients with COVID-19 reported that HCQ administration was not associated with a lower risk of intubation or death.4 However, the reasons for mortality were not illustrated. Multiple confounding factors like histories of ischaemic heart disease, heart failure and cardiac arrhythmia were not well adjusted. The main functional site of HCQ in COVID-19 is the entry via ACE2 preceptor.5 6 We believe that patient selection in early phases of COVID-19 infection would be more appropriate than well-established pneumonia or cytokines storm cases.
The risk of cardiac arrhythmias is an important safety issue. HCQ inhibits the ‘funny’ current of sinoatrial node and rapid component of the delayed rectifier potassium current, causing lengthening of the action potential and QTc prolongation, which results in potential life-threatening ventricular arrhythmias such as torsades de pointes.7–10 Nevertheless, previous reports showed limited and inconsistent arrhythmia risk of HCQ treatment.11 12
We investigated a report to clarify whether HCQ increased the new onset of arrhythmia in patients with RA by using a large population-based dataset from the National Health Insurance Research Database in Taiwan from 1999 to 2013. We enrolled all people aged 20 years or more who were newly diagnosed with RA (International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM)=714.0)13 14 with at least ≥3 outpatient clinic or once admission. Patients with previous arrhythmia history (ICD-9-CM=426–427) or usage of antiarrhythmic agents such as amiodarone, propafenone and dronedarone were excluded. The end point was set as the first cardiac arrhythmia or 1 year from the index date. To minimise the effect of confounding factors, we used propensity score matching (PSM) to obtain 1:1 ratio matched by age and gender, and comorbidities such as hypertension, hyperlipidaemia, chronic liver disease, chronic kidney disease, diabetes mellitus, chronic obstructive pulmonary disease, ischaemic heart disease, heart failure, stroke, history of β-blocker usage and antibiotic macrolide treatment. χ2 test for categorical variables and independent t-test for continuous variables were used. The Kaplan-Meier method was applied to obtain the cumulative incidences of newly diagnosed arrhythmia and log-rank test to determine the significance. We used a Cox proportional hazard model to estimate crude HRs, adjusted HRs (aHRs) and 95% CIs between the two groups.
A total of 8564 patients with newly diagnosed RA were selected to participate in the study. We excluded 1559 patients who had arrhythmia before their RA diagnosis and those using antiarrhythmic agents. After PSM, 2111 patients were enrolled in both HCQ and non-HCQ groups, respectively (see online supplementary figure 1). Table 1 shows the baseline patient demographic and clinical characteristics. The mean age of the patients was 52.7 (SD 14.1) years in the HCQ group and 53.6 (SD 14.4) years in the non-HCQ group. The cumulative risk of arrhythmia was not significantly higher in the HCQ group than in the non-HCQ group (log-rank test, p=0.99) (figure 1).
The incidence of arrhythmia did not increase when a combination of HCQ with or without a macrolide antibiotic was taken (aHR 2.7, 95% CI 0.73 to 9.97, p=0.114). Age above or below 50 years, gender and β-blocker usage also did not increase the risk of arrhythmia in patients either using HCQ or not using HCQ (see online supplementary table 2). We found that the risk of arrhythmia for HCQ was not significantly different regardless of the daily dose of <400 mg (aHR 1.0, 95% CI 0.65 to 1.53) or ≥400 mg (aHR 0.85, 95% CI 0.52 to 1.4), and follow-up duration of <3 months (aHR 1.0, 95% CI 0.52 to 1.91) or ≥3 months (aHR 0.98, 95% CI 0.62 to 1.53) compared with non-HCQ usage (see online supplementary table 3).
This report may represent the first cohort study that used nationwide population-based data to assess the risk of arrhythmia with HCQ usage in patients with RA. The main results indicate that patients with RA using HCQ did not have a higher risk of cardiac arrhythmia. Larger daily HCQ dose, longer follow-up duration and combination therapy of HCQ with macrolides also did not increase any arrhythmia. Our result provides safety evidence of HCQ for rheumatic diseases. It may indirectly support the safety of HCQ therapy for other diseases such as COVID-19. Further prospective randomised controlled trial is required.
The authors thank all the patients and staff who made this study possible.
Contributors CHL designed the study, generated the figures and wrote the manuscript. Y-HW analysed the data and generated figures. CFT, KCC, LCL and THL performed bioinformatics analysis and wrote the manuscript. CHS and JC-CW made substantial contributions to the design of the study, conducted the data analysis and figure generation, and wrote the manuscript. All authors read and approved the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Patient consent for publication Not required.
Ethics approval This study was approved by Chung Shan Medical University Hospital (IRB, CS17114).
Provenance and peer review Not commissioned; internally peer reviewed.
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