Published: December 2010
Publications
Drug-induced QT prolongation and Torsades de Pointes - the facts
Prescriber Update 31(4): 27-29
December 2010
Prescribers are advised to consider the possibility of drug-induced QT prolongation or Torsades de Pointes (TdP) in patients presenting with new onset syncope, palpitations, seizures or resuscitated cardiac arrest.
QT prolongation, a surrogate marker for the risk of developing TdP, is an established side effect of Class I and Class III anti-arrhythmic medicines. It is also a rare side effect of a wide range of non-cardiac medicines including some antibiotics, antihistamines, opioid analgesics and complementary medicines.
What is QT prolongation?
QT prolongation is a measure of delayed ventricular repolarisation. Excessive QT prolongation can predispose the myocardium to the development of early after-depolarisations, which in turn can trigger re-entrant tachycardias such as TdP.
Although the relationship between QT interval duration and the risk of TdP is not fully understood, a corrected QT interval (QTC) of >500ms1 or an increase in the QTC of >60ms2 is generally considered to confer a high risk of TdP in an individual patient.
Table 1: QTC values for normal and prolonged QT interval after correction with Bazett's formula3
| QTc values by Age and Sex (ms) | |||
|---|---|---|---|
| 1-15 years (ms) | Adult males (ms) | Adult females (ms) | |
| Normal | <440 | <430 | <450 |
| Borderline | 440-460 | 430-450 | 450-470 |
| Prolonged (top 1%) | >460 | >450 | >470 |
QTC = corrected QT interval which corrects for heart rate. It is often derived using Bazett's formula (QTC = QT interval/vR-R interval), which can be unreliable at HR<50 bpm or >90 bpm.
What medicines cause QT prolongation/TdP?
An up-to-date database of medicines with the potential to cause QT prolongation/TdP, including a separate list of medicines to be avoided by patients with congenital long QT syndrome, is available on-line at www.qtdrugs.org.
The database, which is maintained by the Arizona Center for Education and Research on Therapeutics, groups medicines according to the level of evidence supporting an association with QT prolongation/ TdP (see Table 2 and Table 3 below).
Table 2: Examples of non-cardiac medicines that are generally accepted to have a risk of QT prolongation/TdP (see www.qtdrugs.org for a complete list)
| Anti-infectives | Anti-emetics/gastric motility agents |
Anti-psychotics | Opioid analgesics | Antihistamines |
|---|---|---|---|---|
| Clarithromycin Erythromycin Chloroquine Pentamidine |
Domperidone Cisapride# |
Haloperidol Chlorpromazine |
Methadone | Terfenadine# |
# these medicines have been withdrawan wordwide due to risk of QT prolongation/TdP
Table 3: Examples of non-cardiac medicines that are possibly associated with a risk of QT prolongation/TdP (see www.qtdrugs.org for a complete list)
| Anti-infectives | Anti-emetics | Antipsychotics | Antidepressants | Anti-cancer |
|---|---|---|---|---|
| Azithromycin Roxithromycin Telithromycin Moxifloxacin Amantadine |
Ondansetron Dolasetron Granisetron |
Risperidone Quetiapine Sertindole Ziprasidone Lithium Clozapine |
Escitalopram Venlafaxine |
Tamoxifen Nilotinib Lapatinib |
What are the risk factors for drug induced QT prolongation/TdP?
The available evidence suggests that additional risk factors must be present before drug-induced QT prolongation/TdP will occur. In most reported cases at least one additional risk factor was present and in 70% of cases two risk factors were present.1
Most risk factors are continuous variables, for instance the risk from hypokalaemia increases as potassium levels fall.
Table 4: Risk factors for the development of drug induced QT prolongation/TdP 1,4,5,6,7
| Unmodifiable risk factors | Potentially modifiable risk factors |
|---|---|
| Female gender (present in 70% of cases) | Hypokalaemia or severe hypomagnesaemia |
| Increasing age | Absolute or relative bradycardia (including recent conversion from AF) |
Genetic predisposition
|
Drug interactions
|
| Structural heart disease/LV dysfunction | Starvation or obesity |
| Impaired elimination due to renal or hepatic disease | High drug concentrations due to overdose or rapid IV administration |
What should you do before prescribing a QT prolonging medicine?
- Screen for other risk factors for QT prolongation, including possible medicine interactions and electrolyte abnormalities. Correct any modifiable risk factors.
- Baseline ECGs should be performed in high risk patients, or in patients receiving more than one QT prolonging medicine. A non-QT prolonging medicine should be considered in these patients if possible.
- Do not prescribe a QT prolonging medicine to patients already receiving a Class I or Class III anti-arrhythmic medicine.
- Patients should be advised to avoid consuming grapefruit juice, liquorice or any complementary medicines in addition to a QT prolonging medicine.8
What monitoring should be undertaken?
- All patients should be advised to report symptoms of arrhythmia or any conditions that could lead to hypokalaemia or renal dysfunction.9,10
- ECGs should be performed in all patients with symptoms of arrhythmia and periodically in patients at high risk of QT prolongation/TdP.
- If there are risk factors for electrolyte disturbance, electrolytes should be measured periodically. Hypokalemia or hypomagnesaemia should be corrected.
What should you do if QT prolongation occurs?
- If QT prolongation (i.e. QT >500ms or an increase of >60ms) or symptomatic arrhythmia occurs, the medicine should be stopped unless there are compelling reasons to continue.
- Specialist advice from a cardiologist should be sought. Investigation for congenital long QT syndrome may be appropriate, particularly if the QTC fails to normalise after the medicine is discontinued.
What should you do if TdP occurs? 9,11
- Sustained episodes or unstable patients require DC cardioversion.
- Intravenous magnesium sulphate should be given immediately.
- The suspect medicine should be withdrawn and any electrolyte abnormalities corrected.
- Cardiac pacing or isoprenaline infusion should be considered for refractory cases.
References
- Heist EK and Ruskin JN (2005). Drug-induced proarrythmia and use of QTc prolonging agents: Clues for clinicians. Heart Rhythm 2(11):S1-S8.
- Barnes BJ and Hollands J M (2010). Drug-induced arrhythmias. Crit Care Med 38(6 Suppl): S188-S197).
- Yap YG and Camm AJ (2003). Drug induced QT prolongation and torsades de pointes. Heart 89:1363-1372.
- Viskin S (1999). Long QT syndromes and torsades de pointes. The Lancet 354; 1625-1633.
- Morissette P et al (2005). Drug induced long QT syndrome and torsade de pointes. Canadian Journal of Cardiology 21(10):857-864.
- Al Khatib SM et al (2003). What Clinicians Should Know About the QT interval. JAMA 289 (16): 2120-2127.
- Fraley MA et al (2005). Obesity and the electrocardiogram. Obesity Reviews 6: 275-281.
- Personal communication. 18 November 2010. Cardiologist. Auckland.
- Gowda RM et al (2004). Torsade de pointes: the clinical considerations. International Journal of Cardiology 96:1-6.
- Roden DM (2005). Drug-Induced Prolongation of the QT interval. NEJM 350;10:1013-1022.
- Zipes et al (2006). ACC/AHA/ESC Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death. Journal of the American College of Cardiology 48(5)e247-e346.
