key: cord-0929709-pprf18ml
authors: Özdemir, İbrahim Halil; Özlek, Bülent; Özen, Mehmet Burak; Gündüz, Ramazan; Çetin, Nurullah; Bilge, Ali Rıza
title: Hydroxychloroquine/azithromycin treatment, QT interval and ventricular arrhythmias in hospitalised patients with COVID‐19
date: 2020-12-15
journal: Int J Clin Pract
DOI: 10.1111/ijcp.13896
sha: e35539bd12260f46fc3f5254ad2738cbff222225
doc_id: 929709
cord_uid: pprf18ml

BACKGROUND: Hydroxychloroquine (HCQ) and azithromycin (AZM) are widely used in off‐label treatment of novel coronavirus disease (COVID‐19). However, cardiac safety of these drugs is still controversial in COVID‐19. Therefore, we aimed to evaluate association of HCQ or HCQ + AZM treatment regimens, corrected QT (QTc) interval and malignant ventricular arrhythmias in hospitalized patients. METHODS: This is a single‐center, retrospective and observational study. All data were extracted from the electronic medical records. The initial and post‐treatment mean QTc intervals were calculated and compared in patients with HCQ alone or HCQ + AZM therapy. Associated factors with QTc prolongation, the incidence of ventricular arrhythmia during treatment and in‐hospital mortality because of ventricular arrhythmias were evaluated. RESULTS: Our cohort comprised 101 hospitalized COVID‐19 patients (mean age of 49.60 ± 18 years, 54.4% men). HCQ + AZM combination therapy group (n = 56) was more likely to have comorbidities. After 5‐days treatment, 19 (18.8%) patients had QTc prolongation, and significant increase in the QTc interval was observed in both two groups (P < .001). However, HCQ + AZM combination group had significantly higher ΔQTc compared to HCQ group (22.5 ± 18.4 vs 7.5 ± 15.3 ms, P < .001). All of 101 patients completed the 5‐days treatment without interruption. Also, no malignant ventricular arrhythmia or death secondary to ventricular arrhythmia occurred during the treatment in both groups. CONCLUSIONS: The present study revealed that although HCQ + AZM treatment was independently associated with QTc prolongation, none of patients experienced malignant ventricular arrhythmia or death during treatment. Further prospective studies are needed to determine the exact implications of these drugs on arrhythmias in patients with COVID‐19.

the duration of infection in patients. 3 One small scale French study reported that the use of azithromycin (AZM), in combination with hydroxychloroquine (HCQ), was associated with a more rapid clearance of the virus compared to HCQ used alone. This promoted the worldwide use of that combination against COVID-19. 4 Initial hopes for these medications may have lead to the underestimation of serious cardiac side effects such as torsade de pointes (TdP) type arrhythmias. [5] [6] [7] [8] However, this combination should be interpreted with caution because of the potentially life threatening side effects associated with these molecules. Both HCQ and AZM are associated with corrected QT (QTc) prolongation, and the combined use may potentiate this adverse effect. 9 On the other hand, there is no consensus on the way to follow-up the QT interval prolongation related to HCQ and AZM treatment for COVID-19. Some authors suggested daily electrocardiogram (ECG) monitoring after obtaining a baseline ECG [10] [11] [12] ; others suggested daily monitoring for high risk patients only in order to avoid contagion to the healthcare personnel. 13 COVID-19 patients with pre-existing cardiovascular diseases are especially at risk to experience cardiac arrhythmias and sudden cardiac death. 14 However, few studies have investigated cardiac safety of HCQ and AZM treatment in patients with COVID-19. Therefore, we aimed to assess the implications of HCQ and HCQ + AZM treatment regimens on QTc interval and malignant ventricular arrhythmias in hospitalized patients with COVID-19.

This is a single-center, retrospective, observational study evaluating consecutive hospitalized adults with COVID- 19 Approval was also obtained from The Ministry of Health of Turkish Republic. 

• COVID-19 patients who were treated with HCQ or HCQ + AZM had a significantly increased QTc interval after treatment administration.

• QTc prolongation was more likely to occur in those received HCQ + AZM combination.

• Baseline QTc interval and HCQ + AZM treatment were independently associated with QTc prolongation.

• No patient experienced malignant ventricular arrhythmias during treatment.

• All of patients completed the 5-days treatment without interruption. method on the patients' initial ECG and post-treatment ECG. The current clinical standard is the most widely used Bazett's formula which provides a known overcorrection at high heart rates and undercorrection at lower rates. 17 Therefore, QTc was evaluated with the Framingham method in six patients who had an initial heart rate over 100 beats per minutes. The limits of QTc prolongation were considered over 470 ms for women and 450 ms for men. 18 A QTc interval >500 ms or an increase of more than 60 ms was defined as severely prolonged. Tisdale risk score was used to predict prognosis of QT prolongation in participants. [19] [20] [21] We monitored daily electrolyte levels of patients with high risk for arrhythmia according to Tisdale risk score. Malignant ventricular arrhythmias were defined as sustained or non-sustained ventricular tachycardia, ventricular fibrillation or TdP. Ventricular arrhythmia records were examined. Also, comorbid conditions and laboratory parameters were analysed.

The participants were divided into two groups: patients with treated only HCQ and patients with treated HCQ + AZM combination therapy. The initial and post-treatment mean QTc intervals were calculated and compared. Incidence of malignant ventricular arrhythmia during treatment, associated factors with QTc prolongation and in-hospital deaths secondary to ventricular arrhythmias were evaluated.

Categorical variables are shown as frequencies and percentages, and continuous variables as means with SDs or median with interquartile range. The Chi-square test was used to determine the correlation between the categorical variables. The Kolmogorov-Smirnov test was used to check whether the continuous variables were distributed normally. Non-parametric tests were used to analyse the data as the variables did not exhibit a normal distribution. A 1-sample t test (if samples were normally distributed) or a 1-sample Wilcoxon signed-rank test (if samples were not normally distributed) was performed to compare mean QTc interval before and after treatment in HCQ and HCQ + AZM combination groups. Mann-Whitney-U test was used to compare parameters if samples did not have normal distributions. Univariate and multiple regression analyses were used to calculate hazard ratio (HR) and 95% confidence interval (CI).

Multivariable analysis was performed to find associated factors with QTc prolongation. All analyses were performed with IBM SPSS Statistics for Windows, Version 21.0 (IBM Corp., Armonk, NY, USA).

A 2-sided P value of <.05 was considered statistically significant.

A total of 101 hospitalized COVID-19 patients (mean age of 49.60 ± 18 years, 54.4% men) were included. Patients were treated with HCQ alone or HCQ + AZM combination during 5 days. The maximum follow-up time was 7 days and ECG follow-up time was 5 days for all participants. Clinical characteristics of all population are presented in Table 1 . Twenty-nine patients (28.7%) were smokers and the mean body mass index was 27.3 kg/m 2 . 19.8% of patients had morbid obesity. Patients prescribed HCQ + AZM combination therapy were older and were more frequent smokers. The mean heart rate was similar in two groups and all of participants were in sinus rhythm at admission. Hypertension (38.6%) was the most common comorbidity in all population. HCQ + AZM combination therapy group was more likely to have hypertension (P = .002), coronary artery disease (P = .034), chronic heart failure (P = .020) and chronic obstructive pulmonary disease (P = .034). There were no significant differences in diabetes mellitus and hyperlipidemia between the two groups. Serum creatinine, sodium, potassium, calcium, magnesium, aspartate aminotransferase, alanine aminotransferase levels were also similar in between HCQ and HCQ + AZM groups. During follow-up, because of electrolyte deficiencies, potassium replacement was performed in two patients and magnesium replacement in three patients. Thereby, one of the well-known risk factors for arrhythmias were eliminated. COVID-19 patients who received HCQ + AZM combination had comparatively higher Tisdale risk score (6.64 ± 0.7 vs 4.26 ± 1.4, P < .001). The use of β-blockers and nondihydropyridine calcium channel blockers were similar in two groups. Arrhythmic events during follow-up are also given in Table 1 .

Sinus bradycardia was observed during follow-up in five (11.1%) patients in the HCQ treatment group, and seven (12.5%) patients in the HCQ + AZM group. However, no malignant ventricular arrhythmia or death because of ventricular arrhythmia was detected during the treatment in both groups. Of note, new-onset atrial fibrillation was not detected.

Individual QTc intervals before and after treatment are given in Figure 1 . The mean initial QTc interval was 416 ± 29.8 ms for all patients. As expected, women had longer initial mean QTc interval compared to men (423.9 ± 32.4 vs 409.3 ± 25.9 ms, P = 0,020). However, there was no significant difference after therapy in women and in men (436.9 ± 35.6vs 427.6 ± 27.1 ms, P = .213). Also, ΔQTc level was similar in women and in men (12.9 ± 18.9 vs 18.2 ± 18.1 ms, P = .153) ( Table 2 ). Before treatment, QTc interval was longer than 450 ms in three (2.9%) men, and was longer than 470 ms in four (3.9%) women patients. After treatment, QTc interval was longer than 450 ms in nine (8.9%) men, and was longer than 470 ms in 10 (9.9%) women patients. Three of these patients (2.9%) had severe QTc prolongation.

One (1.7%) patient in HCQ + AZM treatment group had an increase of more than 60 ms and two (3.5%) patients' QTc interval exceeded 500 ms on the fifth day of treatment, but no complaints such as syncope, palpitation and chest pain were noted. Further significant increase in the QTc was observed after treatment in all seven patients with prolonged QTc before treatment (P < .05). 

The largest report of adverse effects and safety of HCQ and AZM among patients with COVID-19 has recently been published by Rosenberg et al. 26 In this large scale, multicenter study revealed that among 1438 hospitalized patients with a diagnosis of COVID-19, treatment with HCQ, AZM or both, compared with neither treatment, was not significantly associated with differences in-hospital mortality. Additionally, there were no significant differences in the relative likelihood of abnormal ECG findings. 26 Some studies have recently reported that although HCQ + AZM combination therapy may induce increase in the QTc interval, this treatment is not associated with mortality because of ventricular arrhythmias. 27 , 28 Saleh et al prospectively analysed 201 hospitalized COVID-19 patients who received HCQ monotherapy or HCQ and AZM combination. 28 They found that the maximum QTc interval during treatment was significantly longer in the combination group vs the monotherapy group. Although participants experienced QTc interval prolongation, especially when combination therapy was used, the risk of arrhythmic death and TdP were not increased in this study. Therefore, authors suggested that though the beneficial effects of HCQ and AZM in patients with COVID-19 is unproven, the malignant arrhythmic risk appears to be low and may not warrant monitoring in most hospitalized patients. 28 Ramireddy et al studied 98 hospitalized COVID-19 patients. 29 Sixty-one of these patients received HCQ + AZM treatment, and they concluded that a total of 12% of patients manifested critical QTc prolongation, and the combination caused greater prolongation than either drug alone.

Also, no patients manifested TdP in this study. 29 In French prospective study, 30 for only patients with QTc interval longer than 500 ms seems to be an easy-to-feasible and plausible approach.

This study has several limitations. The retrospective design of the study and a relatively small sample size were major limitations. As patients needed intensive care unit were excluded from the study because of received oseltamivir, we could not evaluate the effects of HCQ/AZM therapy on QTc interval and arrhythmias in severe COVID-19 patients.

Another possible reason that more QTc prolongation was not seen was because of the fact that other drugs that prolong QTc were avoided. 

In this retrospective study, we observed a significant increase in the 

The authors declare that they have no conflict of interest.

The data that support the findings of this study are available from 

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