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Current Medical Research & Opinion Vol. 29, No. 12, 2013, 17191726
0300-7995 Article ST-0277.R1/840568
doi:10.1185/03007995.2013.840568 All rights reserved: reproduction in whole or part not permitted
ReviewQT interval prolongation and the risk of torsadesde pointes: essentials for clinicians
Katy E. TrinkleyRobert Lee Page IIHoang LienKevin YamanouyeUniversity of Colorado, Skaggs School of Pharmacy
and Pharmaceutical Sciences, Aurora, CO, USA
James E. TisdaleCollege of Pharmacy, Purdue University, West
Lafayette, IN, USA
Address for correspondence:Katy E. Trinkley PharmD, Assistant Professor,
Department of Clinical Pharmacy, Skaggs School of
Pharmacy and Pharmaceutical Sciences, University of
Colorado, Anschutz Medical Campus, 12850 E
Montview Blvd., Mail Stop C238, Aurora, CO 80045,
Tel.: +1 303 724 6563; Fax: +1 303 724 0979;
Keywords:Drug-induced Mitigation Prevention QT interval
prolongation Risk factors Torsades de pointes
Accepted: 30 August 2013; published online: 20 September 2013
Citation: Curr Med Res Opin 2013; 29:171926
QT interval prolongation signifies an increased risk of the life-threatening arrhythmia torsades de pointes
(TdP). The purpose of this paper is to review the diverse methods for assessing and monitoring the risk of
TdP, discuss risk factors for TdP, and recommend interventions that may mitigate the risk of TdP.
A non-systematic search of PubMed (through March 2013) was conducted to determine the optimal
approach to assessing and monitoring QT interval, prevention of TdP, and to identify risks factors for
TdP. Papers known to the authors were included, as were scientific statements. Articles were chosen
based on the judgment of the authors.
Risk factors for drug-induced TdP include hypokalemia, female sex, drugdrug interactions, advancing age,
genetic predisposition, hypomagnesemia, heart failure, bradycardia, and corrected QT (QTc) interval
prolongation. Many risk factors, including hypokalemia, use of QT-interval-prolonging drugs, and drug
interactions are potentially modifiable and should be corrected in persons at risk for QT interval
prolongation. Given the variable onset of TdP following initiation of QT-interval-prolonging drugs, careful
and regular monitoring of electrocardiography (EKG) and electrolytes are necessary. Patients at risk for QT
interval prolongation should be educated to go directly to the emergency room if they experience
palpitations, lightheadedness, dizziness or syncope. When the QTc interval is 470500 ms for males, or
480500 ms for females, or the QTc interval increases 60 ms or more from pretreatment values, dose
reduction or discontinuation of the offending drug should be considered where possible, and electrolytes
corrected as needed. Furthermore, if the QTc interval is 500 ms, the offending drug should bediscontinued, and continuous EKG telemetry monitoring should be performed, or the 12-lead EKG should
be repeated every 24 hours, until the QT interval has normalized.
Close monitoring for QTc prolongation is necessary to prevent TdP. The recommendations in this paper are
limited by the available evidence and additional studies are needed to better define the approach to
QT interval prolongation can lead to the ventricular arrhythmia known as tor-sades de pointes (TdP), which can result in sudden cardiac death. In recent years,the potential for QT interval prolongation and TdP has received increasedattention, partly owing to increased recognition of the risks and catastrophicnature of this disease13. Although the risk of QT interval prolongation andresultant life threatening TdP may be present in both outpatients and inpatients,hospitalized patients are thought to be at a greater risk, given they are more likelyto have a larger number of risk factors, such as electrolyte abnormalities, kidney
! 2013 Informa UK Ltd www.cmrojournal.com QT interval prolongation and torsades de pointes Trinkley et al. 1719
disease, and cardiovascular disease1. A prospective, obser-vational study of patients admitted to cardiac critical careunits found nearly 30% of patients had QT interval pro-longation upon admission, and of those, 35% were subse-quently administered a QT-interval-prolonging drug4.Administering a QT-interval-prolonging drug to aperson with known QT prolongation greatly increasesthe risk of TdP, especially in the presence of other riskfactors1.
Within the past 1520 years, numerous medications,including terfenadine, astemizole and cisapride havebeen removed from the United States (US) market as aresult of inducing deaths from TdP. However, many drugswith the potential to cause QT interval prolongationremain available5. In view of the large number of medica-tions available that may prolong the QT interval, and thefrequency of QT interval prolongation, clinicians shouldbe aware of the risks associated with QT interval prolonga-tion and TdP. The purpose of this paper is to review thediverse methods for assessing and monitoring the risk ofTdP, discuss risk factors for TdP, and recommend inter-ventions that may mitigate the risk of TdP.
A non-systematic search of PubMed (up to March 2013)was conducted to determine the optimal approach toassessing and monitoring QT interval, prevention ofTdP, and to identify risks factors for TdP. Papers knownto the authors were included, as were international recom-mendation statements. Articles were chosen based on thejudgment of the authors.
QT interval prolongation and TdP
A prolonged QT interval is defined by AHA/ACCF as arate-corrected QT (QTc) interval greater than the 99thpercentile for females and males, which is 4480 ms and
4470 ms, respectively1. However, many standard EKGscontinue to label a QTc interval of4440 ms as borderlineQTc interval prolongation1. A prolonged QTc intervalrepresents the prolongation of the repolarization phase ofthe ventricular action potential6. TdP is a polymorphicventricular tachycardia characterized by a pattern of twist-ing of the peaks (or points) of the QRS complexes1.Figure 1 is an example of EKGs indicating a normal andprolonged QT interval. A prolonged QTc on an EKG is anindicator of prolonged ventricular repolarization1, whichincreases the risk of TdP and resultant sudden cardiacdeath. Prolonged repolarization can be mediated via sev-eral subtypes of sodium and potassium channels in cardiacmyocytes. Most commonly, acquired prolongation of repo-larization is caused by inhibition of the rapid component ofthe delayed rectifier potassium current (IKr)
Measuring QT interval prolongation as apredictor of TdP
Progressive prolongation of the QTc interval increases therisk for TdP, and the risk increases markedly when the QTcinterval exceeds 500 ms7. Despite this, limitations existwhen using QTc interval prolongation as a surrogatemarker for TdP, complicating monitoring and risk stratifi-cation. Not every patient that develops QTc interval pro-longation, even beyond 500 ms, experiences TdP.Therefore, while progressive increases in QTc intervalincrease the risk, QTc interval prolongation is an imper-fect predictor of TdP. In addition, obtaining an accurateQTc measurement is difficult, and measurement and ratecorrection of QTc intervals is often performed incor-rectly8. Many factors influence QTc interval measure-ments, including interindividual variability inperforming measurements, diurnal variability and heartrate. Diurnal variability in QT intervals can be as muchas 100 ms3. Although the influence of heart rate on the QTinterval can be minimized by calculations that correct for
Normal EKG Prolonged QT EKG
QT Interval Prolonged QT Interval
Figure 1. EKG of a normal QT interval and a prolonged QT interval.
Current Medical Research & Opinion Volume 29, Number 12 December 2013
1720 QT interval prolongation and torsades de pointes Trinkley et al. www.cmrojournal.com ! 2013 Informa UK Ltd
RR interval, there are many different calculations for cor-recting the QT interval that each result in different values.The most commonly used equation for calculating the cor-rected QT interval is Bazetts formula (QTcQT inter-val/[RR interval]), which was developed in 19209.Although most EKG machines automatically correct theQT interval using Bazetts equation, it is prudent for clin-icians to manually measure and calculate the QTc, as tech-nologies are not fail-proof10. Bazetts formula is accepted asthe correction factor for use in clinical practice; however,this method is known to overcorrect the QT interval at fastheart rates and undercorrect at slow heart rates, leading tofalsely prolonged or shortened QTc intervals, respectively.Other QT interval corrections exist (e.g., Fridericia, Vande Water), and, while used for research purposes, are notcommonly used in clinical practice11. Despite the limita-tions of Bazetts formula, it continues to be that which ismost commonly used for QT interval correction in clinicalpractice12.
QTc interval prolongation as a predictor of TdP
Despite inconsistency in the predictive ability of the QTcinterval, the lack of a better predictive method of detect-ing TdP warrants its continued use. To increase reliabilityof the QTc interval measurement, only highly trainedindividuals should perform the measurement, or the meas-urement should be automatically generated by the EKGmachine using a universally accepted definition for QTcinterval prolongation. When using the QTc interval as apredictor of TdP, the magnitude of the QTc interval andthe magnitude of the QTc interval increase can be usefulin understanding the risk of TdP. For each 10 ms increasein the QTc interval, there is roughly a 57% increase inthe risk of developing TdP7,13, and every 20 ms increase inQTc substantially increases the risk of TdP14. QTc intervalprolongation is generally defined as greater than 480 ms inwomen and greater than 470 ms in men, and a QTc inter-val 500 ms is widely considered the point at which therisk of TdP is very high and intervention is needed1.
Risk factors for TdP
Prolonged QTc interval can be the result of extrinsiccauses (e.g., drugs, hypokalemia, bradycardia) or a geneticpredisposition (the congenital long QT syndrome, orLQTS). Table 1 lists common risk factors for TdP. Thereis a risk of sudden cardiovascular death regardless ofwhether QTc interval prolongation resulted from anextrinsic cause or LQTS, warranting caution in both scen-arios. Further, all potential causes for QTc interval pro-longation are considered to be risk factors for TdP. Riskfactors for acquired QTc interval prolongation includeelectrolyte disturbances, structural heart disease,
bradycardia, female sex, advanced age, history of QTc pro-longation, genetic polymorphisms, and drugs6.Hypokalemia inhibits IKr, leading to prolongation of repo-larization. Hypomagnesemia impairs the function of thesodiumpotassium ATPase pump, leading to reducedintramyocyte potassium concentrations15. Females aremore susceptible to drug-induced inhibition of IKr andhave inherently longer QTc intervals than adult males,which predisposes females to QTc interval prolongationand TdP. Structural heart disease, including myocardialinfarction and heart failure, is a risk factor for TdP16.
Genetic risk factors for TdP
Genetic mutations and polymorphisms also increase therisk of QTc interval prolongation. Numerous such poly-morphisms have been identified, and multiple types ofcongenital LQTS have been identified, with LQTS 1and 2 the most common. LQTS 1 and 2 comprise morethan 60% of congenital LQTS cases and are the result ofpolymorphisms in genes that encode for IKr, KCNQ1 andKCNH21,17. Patients with these polymorphisms havedecreased IKr function, which may lead to LQTS, increas-ing the risk of TdP and possible sudden death. There issome evidence that 1015% of patients who experiencedrug-induced TdP may have a genetic predisposition in theform of mutations or polymorphisms of genes that are asso-ciated with the congenital LQTS18. Although QT-inter-val-prolonging drugs can increase the risk of QTc intervalprolongation and TdP, QT-interval-prolonging drugsrarely cause TdP in the absence of other TdP risk factors.Nearly all cases of drug induced QTc interval prolongationoccur in the presence of at least one known risk factor andover 70% occur in the presence of 2 risk factors16.
The risk of drug-induced QTc interval prolongation variesby drug and presence of risk factors. The drugs of greatestconcern are those that not only increase the QTc interval,but that have also been associated with TdP, compared todrugs that have only demonstrated an increase in the QTcinterval. Although most drugs that prolong the QTc inter-val have documented reports of TdP, not all drugs that
Table 1. Non-drug risk factors for QT interval prolongation.
Hypokalemia Structuralheart disease
History of QTcprolongation
Bradycardia Bradycardia Genetic polymorphismsCongenital long
QT syndromeFemale sex Hypomagnesemia
Long QT syndrome Advanced age Hypocalcemia
QTc corrected QT.
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prolong the QTc interval have yet been associated withTdP in published reports. The risk of QTc interval pro-longation is often greater in association with intravenousadministration, presumably as a result of higher plasmadrug concentrations and greater cardiovascular exposure1.Similarly, the dose of a QTc prolonging drug also influ-ences the risk of QTc prolongation. Although not alwaysthe case, higher doses are often associated with increasedrisk of QTc prolongation. Drugs for which doses are notappropriately adjusted for kidney or liver disease canincrease the risk of QTc interval prolongation if plasmaconcentrations become supratherapeutic. In addition,drugdrug interactions leading to supratherapeuticplasma concentrations of a QTc-interval-prolonging drugcan be an important risk factor for QTc interval prolonga-tion. In particular, cytochrome P450 (CYP450) mediateddrug interactions can lead to clinically significant plasmadrug concentration changes. Strong CYP450 inhibitorsmay increase the area under the curve (AUC) of the sub-strate by five-fold o...