J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website http://www.jocmr.org

Original Article

Volume 10, Number 7, July 2018, pages 593-600

Malignant Ventricular Arrhythmias Resulting From Drug-Induced QTc Prolongation: A Retrospective Study

Figure 2. Drug-induced long QTc is a significant predictor of symptoms and arrhythmic events (TdP and ventricular fibrillation). diLQT: drug-induced long QT; QTc: heart rate-corrected QT interval.

Figure 3. Flowchart of diLQT case validation. diLQT: drug-induced long QT; QTc: QT corrected for heart rate.

Figure 4. Distribution of cases of diLQT of the present case-record in two groups: (a) Cases of diLQT accompanied by clinical symptoms (dizziness, near-fainting, syncope) or by occurrence of events (TdP on ECG, pulseless electrical activity from prolonged TdP, cardia arrest from ventricular fibrillation) (green bar). (b) Cases of diLQT not associated with clinical symptoms or events, (violet bar). diLQT: drug-induced long QT; QTc: heart rate-corrected QT interval.

Figure 5. Distribution of cases of diLQT of the present case-record in two groups according to the QTc durations: (a) Cases of diLQT with duration of QTc of ≤ 500 ms (yellow bar). (b) Cases of diLQT marked by a severely increased duration of QTc, i.e. with QTc > 500 ms (red bar). diLQT: drug-induced long QT; QTc: heart rate-corrected QT interval.

**Table1.** Patients’ Basic Information and Characteristics
	DiLQTc patients with symptoms (dizziness, near-fainting, syncope) or events(TdP, VF) (n = 46)	DiLQTc patients without symptoms or events (n = 27)	P-value
diLQTc: drug-induced long heart rate-corrected QT interval; TdP: torsade de pointes; VF: ventricular fibrillation; N/A: not applicable.
Age( mean ± SD), years	58 ± 10.5	62 ± 8.5	0.0972
Male sex, number (%)	23 (50 %)	13 (48% )	0.9285
Severe QTc ( > 500 ms)	34 (73.9 % )	20 (74%)	0.7940
Clinical signs/symptoms
Torsade de pointes	18 (39%)	0	N/A
Cardiac reanimation	15 (32.6%)	0	N/A
Syncope	15 (32.6%)	0	N/A
Severe dizziness	6 (13%)	0	N/A
Near-fainting	10 (21.7%)	0	N/A
Co-morbidities and risk factors
Chronic kidney disease	5 (10.8% )	3 (11% )	0.7217
Chronic heart failure	9 (19.5%)	6 (22.2%)	0.9770
Hypokalemia	19 (41.3%)	13 (48%)	0.7455
Bradycardia	9 (19.5%)	5 (18.5%)	0.8429
Alcoholism	9 (19.5%)	6 (22.2%)	0.9770

Table1. Patients’ Basic Information and Characteristics

DiLQTc patients with symptoms (dizziness, near-fainting, syncope) or events(TdP, VF) (n = 46)

DiLQTc patients without symptoms or events (n = 27)

P-value

diLQTc: drug-induced long heart rate-corrected QT interval; TdP: torsade de pointes; VF: ventricular fibrillation; N/A: not applicable.

Age( mean ± SD), years

58 ± 10.5

62 ± 8.5

0.0972

Male sex, number (%)

23 (50 %)

13 (48% )

0.9285

Severe QTc ( > 500 ms)

34 (73.9 % )

20 (74%)

0.7940

Clinical signs/symptoms

Torsade de pointes

18 (39%)

N/A

Cardiac reanimation

15 (32.6%)

N/A

Syncope

15 (32.6%)

N/A

Severe dizziness

6 (13%)

N/A

Near-fainting

10 (21.7%)

N/A

Co-morbidities and risk factors

Chronic kidney disease

5 (10.8% )

3 (11% )

0.7217

Chronic heart failure

9 (19.5%)

6 (22.2%)

0.9770

Hypokalemia

19 (41.3%)

13 (48%)

0.7455

Bradycardia

9 (19.5%)

5 (18.5%)

0.8429

Alcoholism

9 (19.5%)

6 (22.2%)

0.9770

**Table 2.** All Drugs Involved in Any Iatrogenic Cases of Prolongation of QTc Interval
QT prolongation	Symptoms	No symptoms
All drugs involved in any iatrogenic cases of prolongation of QTc interval, that had come to the observation of the two clinical institutes engaged in the retrospective study in the decade 2007 - 2017 are represented. Information is provided about the existence of a possible associated symptomatology. Of note, the involved 35 drugs were all marked by a “certain” or “probable” drug causality assessment, according to the respective definitions given in the text of Methods. Among the 73 validated adverse drug reactions consisting of drug-induced QTc lengthening, in 23 cases our retrospective investigation led to finding of two candidate drugs, as being equally involved as causative factors in the QTc prolongation.
Metoclopramide	3	0
Amiodarone	3	7
Dronedarone	0	2
Flecainide	1	1
Fluvastatin	1	1
Fosinopril + hydrochlorothiazide	1	1
Hydrochlorothiazide	1	2
Sotalol	0	2
Terlipressin	4	0
Aciclovir	2	1
Ceftriaxon	1	2
Ciprofloxacin	4	4
Clarithromycin	1	1
Cotrimoxazol	0	1
Ganciclovir	1	0
Levofloxacin	1	4
5-Fluorouracil	1	0
Oxaliplatin	1	0
Trastuzumab	0	1
Tacrolimus	2	0
Fentanyl	1	0
Tramadol	0	1
Carbamazepin	1	0
Valproic acid	1	0
Citalopram	6	0
Escitalopram	4	0
Fluoxetine	2	0
Haloperidol	6	0
Imipramine	1	0
Mirtazapine	2	0
Olanzapine	4	0
Promethazin	1	0
Quetiapin	2	1
Thioridazine	1	0
Methadone	2	0
	62	34

Table 2. All Drugs Involved in Any Iatrogenic Cases of Prolongation of QTc Interval

QT prolongation

Symptoms

No symptoms

All drugs involved in any iatrogenic cases of prolongation of QTc interval, that had come to the observation of the two clinical institutes engaged in the retrospective study in the decade 2007 - 2017 are represented. Information is provided about the existence of a possible associated symptomatology. Of note, the involved 35 drugs were all marked by a “certain” or “probable” drug causality assessment, according to the respective definitions given in the text of Methods. Among the 73 validated adverse drug reactions consisting of drug-induced QTc lengthening, in 23 cases our retrospective investigation led to finding of two candidate drugs, as being equally involved as causative factors in the QTc prolongation.

Metoclopramide

Amiodarone

Dronedarone

Flecainide

Fluvastatin

Fosinopril + hydrochlorothiazide

Hydrochlorothiazide

Sotalol

Terlipressin

Aciclovir

Ceftriaxon

Ciprofloxacin

Clarithromycin

Cotrimoxazol

Ganciclovir

Levofloxacin

5-Fluorouracil

Oxaliplatin

Trastuzumab

Tacrolimus

Fentanyl

Tramadol

Carbamazepin

Valproic acid

Citalopram

Escitalopram

Fluoxetine

Haloperidol

Imipramine

Mirtazapine

Olanzapine

Promethazin

Quetiapin

Thioridazine

Methadone

**Table 3.** Logistic Regression Analysis Including Patients With diLQTc
Dependent (Y) variable: event or symptom ( composite end-point)
In this series of patients with iatrogenic diLQT retrospectively collected and included in bivariate analysis, using as exposure variables both the duration of the QTc (continuous variable) and the duration of the QTc > 500 ms (categorical variable), the above-mentioned electrocardiographic abnormality is not independently associated with increased risk of events (cardiac arrest from TdP or ventricular fibrillation) or symptoms (dizziness, near-syncope, syncope). Please see also the Discussion for possible reasons underlying this finding. QTc: QT corrected for heart rate; Std. error: standard error; CI: confidence interval; diLQTc: drug-induced long QTc.
QTc interval duration on surface ECG	-0.00109	0.0074	0.998	0.984 to 1.013	0.8821
Presence of QTc > 500 ms on surface ECG	-0.62763	0.6063	0.533	0.162 to 1.752	0.3006

Table 3. Logistic Regression Analysis Including Patients With diLQTc

Dependent (Y) variable: event or symptom ( composite end-point)

Exposure variables

Coefficient

Std. error

Odds ratio

95% CI

In this series of patients with iatrogenic diLQT retrospectively collected and included in bivariate analysis, using as exposure variables both the duration of the QTc (continuous variable) and the duration of the QTc > 500 ms (categorical variable), the above-mentioned electrocardiographic abnormality is not independently associated with increased risk of events (cardiac arrest from TdP or ventricular fibrillation) or symptoms (dizziness, near-syncope, syncope). Please see also the Discussion for possible reasons underlying this finding. QTc: QT corrected for heart rate; Std. error: standard error; CI: confidence interval; diLQTc: drug-induced long QTc.

QTc interval duration on surface ECG

-0.00109

0.0074

0.998

0.984 to 1.013

0.8821

Presence of QTc > 500 ms on surface ECG

-0.62763

0.6063

0.533

0.162 to 1.752

0.3006