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Journal of Electrocardiology 62 (2020) 59–64
Contents lists available at ScienceDirect
Journal of Electrocardiology
j ourna l homepage: www. jecgon l ine .comThe effect of 5-day course of hydroxychloroquine and azithromycin
combination on QT interval in non-ICU COVID19(+) patientsNijad Bakhshaliyev, MD ⁎, Mahmut Uluganyan, MD, Asim Enhos, MD,
Erdem Karacop, MD, Ramazan Ozdemir, MD
Bezmialem Vakif University, Department of Cardiology, Turkey⁎ Corresponding author at: Bezmialem Vakif Univers
bulvari, Fatih, Istanbul 34093, Turkey.
E-mail address: bnijad@bezmialem.edu.tr (N. Bakhsha
https://doi.org/10.1016/j.jelectrocard.2020.08.008
0022-0736/© 2020 Elsevier Inc. All rights reserved.a b s t r a c ta r t i c l e i n f oKeywords:
Hydroxychloroquine
Azithromycin
Electrocardiography
Coronavirus disease 2019
QT intervalment for COVID-19 and is being used widely all around the world. Despite that those drugs are known to
cause prolongedQT interval individually there is no study assessing the impact of this combination on electrocar-
diography (ECG). This study aimed to assess the impact of a 5-day course of HCQ and azithromycin combinationBackground: The combination of Hydroxychloroquine (HCQ) and azithromycin showed effectiveness as a treat-
on ECG in non-ICU COVID19(+) patients.
Methods: In this retrospective observational study, we enrolled 109 COVID19(+) patients who required non-ICU
hospitalization. All patients received 5-day protocol of HCQ and azithromycin combination. On-treatment ECGs
were repeated 3-6 h after the second HCQ loading dose and 48-72 h after the first dose of the combination.
ECGs were assessed in terms of rhythm, PR interval, QRS duration, QT and QTc intervals. Baseline and on-
treatment ECG findings were compared. Demographic characteristics, laboratory results were recorded. Daily
phone call-visit or bed-side visit were performed by attending physician.
Results: Of the 109 patients included in the study, the mean age was 57.3 ± 14.4 years and 48 (44%) were male.
Mean baseline PR interval was 158.47 ± 25.10 ms, QRS duration was 94.00 ± 20.55 ms, QTc interval was
435.28 ± 32.78 ms, 415.67 ± 28.51, 412.07 ± 25.65 according to Bazett's, Fridericia's and Framingham Heart
Study formulas respectively. ΔPR was −2.94 ± 19.93 ms (p = .55), ΔQRS duration was 5.18 ± 8.94 ms
(p = .03). ΔQTc interval was 6.64 ± 9.60 ms (p = .5), 10.67 ± 9.9 ms (p = .19), 14.14 ± 9.68 ms
(p = .16) according to Bazett's, Fridericia's and Framingham Heart Study formulas respectively. There were
no statistically significant differences between QTc intervals. No ventricular tachycardia, ventricular fibrillation
or significant conduction delay was seen during follow-up. There was no death or worsening heart function.
Conclusion: The 5-day course of HCQ- AZM combination did not lead to clinically significant QT prolongation and
other conduction delays compared to baseline ECG in non-ICU COVID19(+) patients.
© 2020 Elsevier Inc. All rights reserved.Introduction
Since reporting of the first case on December 9 inWuhan, China, the
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread
swiftly in a short time throughout China and the outside [1]. In early
March World Health Organization (WHO) declared the SARS-CoV-2
outbreak a pandemic [2]. Due to the lack of specific antiviral medication
for treatment and vaccine for prevention “repurposing” drugs emergedity Hospital, Adnan Menderes
liyev).as a rescuer to deal with this problem. Several known molecules were
started to be tested in different countries [3–5]. Hydroxychloroquine is
an analogue of chloroquine and has been used as an antimalarial and
antirheumatic drug [6]. Antiviral effects of HCQ had been demonstrated
[7,8]. In a recent study HCQ reinforced by azithromycin was associated
significantly with viral load reduction in COVID19 (+) patients [3].
Chronic HCQ use demonstrated QT prolongation and refractory ven-
tricular arrhythmia [9], and azithromycin has been reported to be re-
lated to QT prolongation, sudden cardiac arrest, and increased cardiac
mortality [10,11].Since HCQ is metabolized by cytochrome P450 en-
zymes and azithromycin inhibits this enzyme [12,13], this adverse effect
brings about safety issues. Despite HCQ - AZM combination was found
60 N. Bakhshaliyev et al. / Journal of Electrocardiology 62 (2020) 59–64effective and well tolerable in the treatment of COVID19 there is no
study assessing the impact of this combination on ECG [14]. In this
study, we aimed to evaluate the ECG changes in COVID19(+) patients
taking HCQ -AZM combination.
Methods
Study population
Our study was designed as a retrospective observational study. We
screened the records of 196 COVID19(+) patients presented to our hos-
pital between March 31 and April 16 and who were followed in inpa-
tient wards and received HCQ - AZM combination therapy. Pregnancy,
patients under 18 years and patients who did not have control ECG
were exclusion criteria. After exclusion, we included 109 patients in
the study. The flowchart was described in Fig. 1. Patients who had
COVID19(+) with asymptomatic or mildly symptomatic (such as the
upper respiratory infection) and without comorbidity followed in the
outpatient clinic and excluded from the study. Patients with the lower
respiratory infection (such as pneumonia or bronchitis), 1 andmore co-
morbidity and age more than 64 years were hospitalized to inpatient
ward if SpO2 is more than %90 and hemodynamically stable.
Baseline and control ECG were obtained. Control ECGs were re-
peated 3-6 h after the second HCQ loading dose and 48-72 h after the
first dose of the combination. ECGs were assessed in terms of rhythm,
PR interval, QRS duration, QT and QTc intervals. Baseline and control
ECG findings were compared. Demographic characteristics, laboratory
results were recorded. Daily phone call-visit or bed-side visit were
performed by attending physician.
Treatment protocol
The treatment protocol was adopted by the national health system
and sent to all centers. According to this protocol,most patients after di-
agnosing COVID19(+) were started Hydroxychloroquine if not any
contraindication. Azithromycin was given if there is concomitant pneu-
monia. Oseltamivir was the part of the protocol until influenza was ex-
cluded. The contraindications for HCQ/AZM combination were:
1) QTc > 500 msn (or > 550 msn in bundle branch block) on the base-
line ECG; 2) Hypersensitivity.Fig. 1. Flow chart of the study population.On thefirst dayHCQwas loaded orally 400mgb.i.d then 200mgb.i.d
was given for following 4 days. After 500 mg loading dose on the first
day, AZM was continued 250 mg od for following 4 days. Enfluvir was
received 75 mg bid until influenza was excluded. Hydroxychloroquine
and azithromycin combination were given for 5 days if not any contra-
indications. After that, if the patient remained symptomatic other
medications can be given.
Laboratory testing
Blood samples from all patients who required hospitalization were
sent to the laboratory to check electrolytes, hemogram, acute phase re-
actants, kidney and liver functions, troponin I, creatinine kinase –myo-
cardial band (CK- MB), and D-dimer. Demographic characteristics,
concomitant diseases, medications were recorded.
ECG recordings
All ECGs were recorded using Mortara ELI 250 device (Welch Allyn,
Inc., Skaneateles Falls, NY, USA; standard 12‑lead resting ECG, paper
speed of 25 mm/s, the amplitude of 10 mm/V, and a sampling rate of
250 Hz). Patient's 12‑lead ECGs were evaluated before starting HCQ
and azithromycin combination. Control ECG was obtained 3 to 6 h
after the second HCQ loading dose. QT measurement was performed
in leads II, V5 or V6. Measured longest QT interval was used. To exclude
interobserver variability all measurements were completed by one car-
diologist (NB). In case of problems with measurement, the second car-
diologist (AE) measured blindly the QT interval to the first
cardiologist. If discrepancy between these two cardiologists was more
than %5, the third cardiologist (EK)were invited to resolve the problem.
The PR interval was described the interval measured from the onset of
the P wave to the beginning of the first point of deflection of the QRS
complex. The QRS durationwas the interval between the first deflection
of the QRS complex and the returning point to the baseline. The QT in-
terval was measured from the onset of the first deflection of QRS com-
plex to the end of T wave. The end of the T wave was determined by
the tangent method. QT measurement was performed according to
guideline proposed by expert panel [15]. The corrected QT (QTc) inter-
val was calculated by the Bazett's, Fridericia's and Sagie's (Framingham
Heart Study) formulas. All measurements were performed manually in
EP calipers software (EP Studios, Inc., Version 3.1).
Statistical analysis
Continuous variables were expressed as mean standard deviation,
categorical variables were expressed as median with interquartile
range. The data was tested by the Kolmogorov – Smirnov test or
Shapiro- Wilk test and a visual inspection of histograms for homogene-
ity. Changes in the baseline, after loading and during maintaining dose
were analyzed by Friedman test or repeatedmeasure ANOVAwhere ap-
propriate. Normally distributed continuous variables were expressed as
mean± standard deviation, non-parametric continuous variables were
expressed as median with interquartile range, while percentiles were
used for categorical variables. p< .05was considered as statistically sig-
nificant. Statistical analyses were performed using SPSS version 22.0
(IBM Inc. USA).
Results
A total of 109 patients eligible for analysis fulfilled the following in-
clusion criteria: 1) Patients who were in sinus rhythm; 2) Patients
>18 years and were followed in in-patient ward; 3) Patients who
were started HCQ and azithromycin combination; 4) Patients who had
at least 2 control ECGs during the treatment period. Exclusion criteria
were: 1) cardiac rhythm other than sinus; 2) Early discharged patients;
3) patients whose combination treatmentwas changed due to course of
the disease (other than cardiac or arrhythmic reasons); 4) Pregnancy.
One hundred and nine patients were included in the study. Of them,
N. Bakhshaliyev et al. / Journal of Electrocardiology 62 (2020) 59–64 61
Table 1
Baseline demographic characteristics of study population.
Patient characteristics Value
Gender, M, n (%) 48 (44)
Age, year, mean ± SD 57.3 ± 14.4
Hypertension, n (%) 49 (45)
DM, n (%) 32 (29.4)
CAD, n (%) 24 (22)
HFrEF or HFpEF, n (%) 10 (9.2)
COPD, n (%) 22 (20.2)
Cancer or taking chemoprophylaxis, n (%) 2 (1.8)
Tisdale risk score, n (%)
• low (< 7) 93 (85.3)
• moderate (7–10) 12 (11)
• high (≥11) 4 (3.6)
Medications which
ACEI or ARB, n (%) 31 (28.4)
CCB, n (%) 22 (20.2)
Diuretics, n (%) 27 (24.8)
Ivabradine, n (%) 0 (0)
Ranolazine, n (%) 1 (0.9)
Amiodarone, n (%) 1 (0.9)
Propafenone, n (%) 0 (0)
Favipiravir, n (%) 31 (28.4)
Oseltamivir. n (%) 68 (62.4)
SSRI, n (%) 7 (6.4)
Tocilizumab, n (%) 2 (1.8)
ACEI- angiotensin converting enzyme inhibitory; ARB- angiotensin receptor blocker; CAD-
coronary artery disease; CCB- calcium channel blocker; COPD- chronic obstructive pulmo-
narydisease; DM- diabetesmellitus; HFpEF- heart failurewith preserved ejection fraction;
HFrEF- heart failure with reduced ejection fraction; SSRI- selective serotonin receptor
inhibitor;
Table 2
Baseline laboratory findings of study population.
Parameters Variables
Hemoglobin, g/dL, mean ± SD 13.07 ± 1.85
Serum creatinine, mg/dL, mean ± SD 0.93 ± 0.38
BUN, mg/dL, mean ± SD 16.82 ± 12.18
eGFR, ml/min, mean ± SD 79.77 ± 24.34
Serum potassium, mmol/L, mean ± SD 4.07 ± 0.50
Serum calcium, mg/dL, mean ± SD 8.95 ± 0.70
Serum magnesium, mg/dL, mean ± SD 1.99 ± 0.23
Serum natrium, mmol/L, mean ± SD 137.12 ± 3.03
CRP, mg/dL, median (IQR) 31.10 (10.31–76.09)
Ferritin, mg/dL, median (IQR) 213.39 (68.43–417.59)
ESR, mm/h, median (IQR) 28 (18–46)
Procalcitonin, median (IQR) 0.21 (0.09–0.35)
Serum albumin, median (IQR) 3.90 (3.53–4.10)
BUN- blood urine nitrogen; CRP- C reactive protein; ESR- erythrocyte sedimentation rate;
IQR- interquartile range; SD- standard deviation;48 (44%) were male and the mean age was 57.3 ± 14.4 years (Table 1).
Laboratory findings were shown in Table 2. In the baseline ECG mean
heart rate (HR) was 86 ± 14 bpm, PR interval was 158.47 ± 25.10 ms,
QRS duration was 94.00 ± 20.55 ms, QT interval was 370.09 ±
37.15 ms. Corrected QT interval was 435.28 ± 32.78 ms, 415.67 ±
28.51 ms, 412.07 ± 25.65 ms according to Bazett, Frederica and Fra-
mingham Heart Study respectively. In the first on-treatment ECG
which was obtained 3–6 h after the second HCQ loading dose HR was
77 ± 12 bpm, PR interval was 156.35 ± 26.00 ms, QRS duration was
97.88± 21.73ms, QT interval was 389.68± 42.92ms. Corrected QT in-
terval was 459.68 ± 38.40 ms, 442.30 ± 40.42 ms, 440.97 ± 39.11 ms
according to Bazett, Frederica and Framingham Heart Study respec-
tively. In the second on-treatment ECG which was obtained on day 3
of hospitalization HR was 76 ± 12 bpm, PR interval was 155.53 ±
26.77 ms, QRS duration was 99.18 ± 20.99 ms, QT interval was
397.88 ± 55.66 ms. Corrected QT interval was 441.91 ± 38.71 ms,426.33 ± 41.19 ms, 426.21 ± 39.68 ms according to Bazett, Frederica
and Framingham Heart Study respectively (Table 3, 4). Compared
with baseline QTc interval, QT prolongation ≥50 msn and QTc inter-
val ≥ 500 msn was observed in 2 (1.8%) patients. We analyzed baseline
QTc interval and ΔQTc according to serum potassium level (serum
K+ < 4.0 mmol/L vs. serum K+ ≥ 4.0 mmol/L). In contrast to higher
serum potassium level (K+ ≥ 4.0 mmol/L), lower serum potassium
level (serumK+< 4.0mmol/L)were associatedwith statistically signif-
icantly longer QT interval. But no difference existed between ΔQTc in-
terval in this subgroup. This may be related to potassium replacement
in patients who had lower serum potassium level (serum
K+ < 4.0 mmol/L). Detailed results were demonstrated in Table 5. No
ventricular tachycardia, ventricular fibrillation or significant conduction
delay was seen during follow-up. There was no death or worsening
heart function.
Discussion
In our study, we showed that the 5-day course of HCQ-AZM combi-
nation does not cause significant QT prolongation and other conduction
delays and this protocol was safe in terms of malignant cardiac arrhyth-
mias. The changes in QTc interval (according to Bazett's formula) was
demonstrated in Fig. 2. Our results can be summarized as followings:
1) The risk for QT prolongation with this combination is not fre-
quent. 2) The QT prolongation that was seen after loading doses of
HCQ (800mg) and AZM (500mg) were shortened duringmaintenance
doses. Given that this trend in the QT interval, it may be suggested that
QT prolongation was the result of the acute effect of HCQ and this was
dose-related.We could not find a similar outcome in the previous stud-
ies. Tett et al. reported similar results with chloroquine [16]. 3) Serum
potassium level was lower who had QT prolongation >50 ms in com-
parison to whom QT prolongation <50 ms. 4) HCQ lowered serum po-
tassium level and this may exacerbate hypokalemia. Hypokalemia per
se with other QT-prolonging drugs can worsen myocardial
repolarization.
Two potassium ion channels, delayed rectifier K+ current (Ikr
(rapid) and Iks (slow)) primarily carry out myocardial repolarization.
Virtually Ikr was blocked by QT-prolonging drugs [17]. Ikr blockade pro-
duces prolongation of the action potential by delaying in phase 3. This
increased duration is reflected by QT prolongation. De Bruin et al.
established a clear correlation between the drug's ability to block Ikr
and its potential to induce malignant ventricular arrhythmias and sud-
den cardiac death [18].
Hydroxychloroquine is a chloroquine analogue. Its pharmacokinet-
ics vary widely in different diseases. Bioavailability can range from 25
to 100%. Mean absorption half-life is about 4 h and 40% of drug binds
to serum proteins (mostly to albumin). Hydroxychloroquine metabo-
lizes in the liver and excretes from the kidney as metabolites and un-
changed from [16]. Hydroxychloroquine impacts on the cell
membrane and causes potassium inflow [19]. Hypokalemia following
HCQ use can be interpreted by this effect [20]. During our study, we ob-
served a prominent decrease in serum potassium level after loading
dose compared to the maintenance dose. Baseline and control (after
the loading dose of HCQ dose) serum potassium were 4.13 ±
1.11 mmol/L and 4.0 ± 1.03 mmol/L respectively (p = .02).
QT prolongation, QRS widening was reported as a potential adverse
effect of HCQ. Profound bradycardia or advanced AV block and other se-
rious adverse effectswere rare [21]. Cardiomyopathywith azithromycin
has been reported [21].
Recently conducted chloroquine (CQ) study was stopped prema-
turely due to increased mortality rate with high dose CQ (the cumula-
tive dose 12 g) in comparison to low dose (the cumulative dose 2.7 g)
[22]. Hydroxychloroquine is less toxic than CQ [16]. In our study, there
were no significant cardiac adverse effects with HCQ and it waswell tol-
erated. Concomitantly, 75% of patients received oseltamivir and 8%
favipiravir.
62 N. Bakhshaliyev et al. / Journal of Electrocardiology 62 (2020) 59–64
Table 3
Changings in electrocardiographic findings during treatment course.
Baseline ECG On-treatment first ECG On-treatment second ECG
Heart rate, bpm, mean ± SD 86 ± 14 77 ± 12 76 ± 12
RR duration, ms, mean ± SD 739.06 ± 128.84 801.59 ± 140.49 816.06 ± 161.21
PR interval, ms, mean ± SD 158.47 ± 25.10 156.35 ± 26.00 155.53 ± 26.77
QRS duration, ms, mean ± SD 94.00 ± 20.55 97.88 ± 21.73 99.18 ± 20.99
QT interval, ms, mean ± SD 370.09 ± 37.15 389.68 ± 42.92 397.88 ± 55.66
QTc interval, ms, mean ± SD
• by Bazett 435.28 ± 32.78 459.68 ± 38.40 441.91 ± 38.71
• by Fridericia 415.67 ± 28.51 442.30 ± 40.42 426.33 ± 41.19
• by Framingham Heart Study 412.07 ± 25.65 440.97 ± 39.11 426.21 ± 39.68
LBBB, n (%) 4 (3.7) 4 (3.7) 4 (3.7)
RBBB, n (%) 3 (2.8) 3 (2.8) 3 (2.8)
NIVCD, n (%) 4 (3.7) 4 (3.7) 4 (3.7)
ECG- electrocardiogram; LBBB- left bundle branch block; NIVCD - Nonspecific intraventricular conduction delay; QTc- corrected QT; RBBB- right bundle branch block; SD- standard
deviation.
Table 4
Comparison of electrocardiographic findings during treatment course.
Parameters Δ1. on-treatment ECG vs. baseline ECG P value Δ2. on-treatment vs. P value Δ2. on-treatment ECG vs. baseline ECG P value
Δ1. on-treatment ECG
Heart rate, bpm, mean ± SEM 10 ± 1 < 0.001 1 ± 1 0.4 10 ± 1 <0.001
RR duration, ms, mean ± SD 62.53 ± 9.42 <0.001 14.47 ± 14.17 0.29 77 ± 24.95 0.009
PR interval, ms, mean ± SD −2.12 ± 18.90 0.65 −0.82 ± 9.79 0.73 −2.94 ± 19.93 0.55
QRS duration, ms, mean ± SEM 3.88 ± 8.37 0.074 1.29 ± 8.51 0.54 5.18 ± 8.94 0.03
QTc interval, ms, mean ± SEM
24.40 ± 2.99 <0.001 −17.76 ± 3.94 <0.001 6.64 ± 9.60 0.5
• by Bazett
26.64 ± 3.12 <0.001 −15.96 ± 3.94 0.001 10.67 ± 9.9 0.19
• by Frederica
28.90 ± 2.97 < 0.001 −14.76 ± 3.65 0.001 14.14 ± 9.68 0.16
• by FHS
SD- standard mean; SEM- standard error of mean;
*minus “- “indicates shortened duration. †Bold indicates statistically significant value. SE.Azithromycin is a macrolide. Oral bioavailability is low and affected
by foods. After taken 500 mg azithromycin orally it takes 2 h to reach
serum peak concentration. Binding to plasma protein is low. Similar to
other macrolides azithromycin interacts with the cytochrome P-450
and can influence other drugs metabolisms [23]. Hydroxychloroquine
metabolizes by the cytochrome enzymes partly and this rises concern
about drug interaction when used together. There were no significant
interactions before in clinical practice [24]. In our study, there was no
significant QT prolongation despite at least 68% of patients received
three QT-prolonging medications. Along with HCQ/AZM, 7 (6.4%) pa-
tients were received SSRI, 1 (0.9%) patient received amiodarone and 1
(0.9%) patient received ranolazine. No difference was observed on
ECGs of these patients compared to other patients.Table 5
Comparison of mean baseline QTc and ΔQTc interval according to baseline serum
potassium level.
Serum K+ < 4.0 mmol/L Serum K+ ≥ 4.0 mmol/L P value
N = 42 N = 67
QTc and ΔQTc, ms, Mean ± SD
QTc by Bazett 451.46 ± 33.44 435.82 ± 25.50 0.007
ΔQTc by Bazett 8.66 ± 37.03 7.26 ± 26.97 0.82
QTc by Fridericia 425.69 ± 30.64 410.23 ± 26.26 0.006
ΔQTc by Fridericia 13.43 ± 39.07 11.41 ± 27.77 0.75
QTc by FHS 423.46 ± 28.28 409.91 ± 2.98 0.009
ΔQTc by FHS 13.53 ± 37.85 10.91 ± 25.69 0.67
FHS- Framingham Heart Study.
Bold indicates significant value.*Azithromycin is known as the safest macrolide in terms of cardiac
events [25], this can be derived from unique monophasic action
potential configuration compared with clarithromycin and eryth-
romycin. But conflicting studies exist regarding the cardiovascular
safety of azithromycin [26]. The QT prolongation and
proarrhythmic effects that were reported previously were induced
by azithromycin [10,27–29]. Ray et al. reported the increased car-
diovascular mortality rate especially in patients who had cardio-
vascular risk factors with the 5- day course of azithromycin in
comparison to amoxicillin [11]. However, Mortensen et al. deter-
mined that in comparison to other antibiotics azithromycin was
safe and did not increase cardiac arrhythmias and heart failure
among older population [30]. In Danish adult cohort study,
azithromycin was not associated with increased cardiovascular
risk as compared with penicillin V in young and middle-aged
adults [31].
There are some limitations to our study. The sample size was small
and designed as a single center study. We could not compare our out-
comes with other protocols. The QT interval can be affected by several
factors including medications, metabolic status, hypoxia, ischemia and
underlying pathologies. Patients who were followed in the intensive
care unit and who was intubated can be susceptible to QT-prolonging
medications. Hence our results should not be generalized to all patients
who are a candidate for HCQ and azithromycin combination.We did not
perform a power analysis to calculate sample size that we need to pre-
dict the prevalence of significant QT prolongation following HCQ and
azithromycin combination. However, our study demonstrated that
prolonged QT interval after HCQ and azithromycin loading dose
N. Bakhshaliyev et al. / Journal of Electrocardiology 62 (2020) 59–64 63
Fig. 2. The changes in QTc intervals at the three times points (before starting HCQ/AZM combination, 3–6 h after the second HCQ loading dose and 48-72 h after the first dose of the
combination).generally shortened during the maintenance period. By increasing the
number of patients and centers attended the study, our results need to
be confirmed.
Conclusion
The 5-day course of HCQ -AZM combination did not lead to signifi-
cantQTprolongation and other conduction delays compared to baseline
ECG in non-ICU COVID19(+) patients.
Acknowledgement
I would like to express my special thanks to Sally SleimanMSc, MBA
and Patrick Schnegelsberg MD, PhD for making English proofreading of
my article and Hande Sisman for the assistance of data collecting.
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