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European Review for Medical and Pharmacological Sciences
2012; 16: 100-102
QTc prolongation and torsade de pointes
ventricular tachycardia in a small dose
voriconazole therapy
M.A. ELBEY, H. CIL, E. ONTURK, Y. ISLAMOGLU
Department of Cardiology, Dicle University Faculty of Medicine, Diyarbakır (Turkey)
Abstract. – Torsade de pointes (TdP) is a
life-threatening arrhythmia that can result from
long QT syndrome. Drug-induced QT prolongation is a potentially dangerous adverse effect
of some drug combinations. A 34-year-old
woman with history of nephrotic syndrome and
rheumatic mitral valve disease was admitted to
our Hospital because of high fever. The patient
continued to be febrile until antifungal treatment was switched to voriconazole. The electrocardiogram demonstrated sinus tachycardia
and a prolonged QTc interval of 580 ms. Patient was resuscitated with electrical cardioversion and had an emergent temporary pacemaker placed. We recommend careful monitoring
for QTc prolongation and arrhythmia in patients who are receiving voriconazole, particularly those who have significant electrolyte disturbances.
Key Words:
Voriconazole, QTc prolongation, Torsades de
pointes.
Introduction
Torsade de pointes (TdP) are a life-threatening
arrhythmia that can result from long QT syndrome. Many agents and medical conditions can
cause acquired long QT syndrome1. Azoles may
cause prolongation of the QT interval either directly or by inhibiting the hepatic metabolism of
other QT-prolonging agents2. Voriconazole is extensively metabolized by the liver, via the cytochrome P450 pathway, by the isoenzymes
CYP2C19, CYP2C9, and to a less degree by
CYP3A43. We report a rare case of voriconazoleassociated torsade de pointes (TdP) ventricular
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tachycardia followed by QT interval prolongation that occurred with a small dose of voriconazole in a patient with nephrotic syndrome.
Case Report
A 34-year-old woman with a 6 year history of
nephrotic syndrome was admitted to the intensive
care unit (ICU), due to high fever. Her medical
history was including uneventful rheumatic mitral valve disease in addition to nephrotic syndrome. Her family history showed no cases of
cardiac arrhythmia or sudden deaths. She presented with a fever (temperature, 39°C), blood
pressure of 110/70 mmHg, a regular heart rate
(96 beats per minute), and no other abnormalities. Laboratory studies were notable for potassium 3.5 mmol/L (RV: 3.5-5.5), magnesium 1.2
mg/L (RV: 1.3-2.1), calcium 7.4 mg/dL (RV: 8.410.2), albumin 2.3 mg/dL (RV: 3.5-5), WBC
13.700 cells/mm3, neutrophils 77%, CRP 18.5
mg/dL, and 66 mm/h. Echocardiography was
performed during the course of treatment because the patient’s unstable state. Rheumatic mitral valve and a moderate mitral regurgitation
were found. Three days later, while she was still
febrile, blood samples for culture were obtained,
and an empiric treatment with piperacillintazobactam and amikacin was started. Five days
after the beginning of the chemotherapy, vancomycin and systemic amphotericin B were
added to her regimen. The patient continued to
be febrile, and because of the dissemination of
her infection, the antifungal treatment was
switched to voriconazole [200 mg 2 × 1. given
intravenously (i.v.) for 4 days]. Therapy with i.v.
voriconazole with dose later adjusted according
to her renal function was started. An ECG
showed sinus tachycardia at a rate of 105, with
Corresponding Author: Mehmet Ali Elbey, MD; e-mail: [email protected]
QTc prolongation and torsade de pointes ventricular tachycardia in a small dose voriconazole therapy
Discussion
Figure 1. Electrocardiogram (ECGs) recorded on day 4 of
voriconazole treatment showing sinus tachycardia (heart
rate, 105 beats per minute) and QTc prolongation to 580 ms.
new non-specific T-wave abnormalities, and a
QTc interval of 580 ms. (Figure 1). On day 4 of
voriconazole treatment, nonsustained ventricular
tachycardia and torsade de pointes occurred (Figure 2). Her blood pressure was lowered to 85/60
mmHg. She was resuscitated with electrical cardioversion and had an emergent temporary pacemaker placed. Her QTc prolongation could be
considered depend on voriconazole, and treatment with all potentially arrhythmogenic medications including voriconazole were discontinued. Several ordinary echocardiograms demonstrated a normal cardiac function and structure
without evidence of any endocardial infection.
Furthermore, a transoesophageal echocardiography was performed. Cause of the high fewer, the
patient was started to treat with voriconazole for
a second time, but TdP recurred several days later, and then stopped it, TdP disappeared. Magnesium levels started to decrease in five days before
QT interval prolongation, and quickly returned to
normal with i.v. magnesium sulfate. Transvenous
pacing at a rate of 100 bpm was initiated, and
there were no recurrences of TdP. Subsequently,
the patient’s heart rate increased from 80 to 110
beats per minute with QTc normalization to 440
s after 48 h.
Figure 2. ECG recorded on day 4 of voriconazole treatment showing nonsustained polymorphic, ventricular tachycardia.
Antifungal agents of the azoles have been described as potentially arrhythmogenic drugs.
Cases of arrhythmia that develop after treatment
with itraconazole, fluconazole or ketoconazole,
alone have been reported, as well4-6. QT interval
prolongation and TdP were described as adverse
effects of treatment with azole family in combination with other arrhythmogenic drugs5. Female
gender is the most frequently associated risk factor for TdP7. Voriconazole is a potent blocker of
the P450 system, leading to increased hematic
concentrations of drug scarcely metabolized by
this system1.
In the literature, a few cases of nonsustained,
polymorphic ventricular tachycardia with QTc
interval prolongation associated with voriconazole have been reported, involving a 15-year-old
girl with acute lymphoblastic leukemia and a 14year-old girl with acute myeloid leukaemia. In
the first patient mentioned above 8 , the first
episode of QTc prolongation followed by torsade
de pointes was noted after 3 weeks of voriconazole treatment. She developed asymptomatic
bradycardia, QT interval prolongation and nonsustained, polymorphic ventricular tachycardia.
In addition voriconazole level and metabolism
were within expected normal values in that patient.
Another case of bradycardia with QTc interval
prolongation associated with voriconazole has
been reported: a 14-year-old girl with acute
myeloid leukemia and a suspected mucormucosis
infection was treated with intravenous voriconazole9.
In those cases the duration of the voriconazole
treatment was 3 weeks. However, in our case the
duration of voriconazole treatment was only 4
days. In our patient the first episode of QTc prolongation followed by TdP was noted after 4
days of voriconazole treatment, when she had a
combination of several risk factors. In this patient
predisposing factors identified were: i.v.
voriconazole, female gender, drug-interaction
and hypomagnesaemia, antifungal azoles and
amphotericin B treatment.
Polymorphic ventricular tachycardia and
QTc prolongation were dose independent and
recurred upon rechallenge with a very small
voriconazole dose in the absence of other
known proarrhythmogenic agents, thus suggesting a causal relationship with voriconazole
exposure.
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M.A. Elbey, H. Cil, E. Onturk, Y. Islamoglu
In this case we suggest that voriconazole may
induce QTc prolongation and polymorphic ventricular tachycardia independent of duration and
dose, in the absence of other arrhythmogenic factors. Physicians must be aware of multi-drug interactions potentiating QTc prolongation and
leading to torsade de pointes ventricular tachycardia. Patients receiving voriconazole should be
followed carefully for potential drug interactions
and electrolyte imbalance to minimize the possibility of proarrhythmia.
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