Drug-Induced QT-Interval Prolongation: Considerations for Clinicians

Drug-Induced QT-Interval Prolongation:Considerations for Clinicians

Edward C. Li, Pharm.D., John S. Esterly, Pharm.D., Shaunte Pohl, Pharm.D.,Shane D. Scott, Pharm.D., and Brian F. McBride, Pharm.D.

Drug-induced proarrhythmia is a frequently encountered clinical problem anda leading cause for withdrawal or relabeling of prescription drugs.Suppression of the rapid component of the delayed rectifier potassiumcurrent, IKr, represents the principal pharmacodynamic mechanism leading toheterogeneous prolongation of the ventricular action potential andprolongation of the QT interval clinically. However, the risk of proarrhythmiaby QT-interval–prolonging drugs is variable and critically dependent onseveral factors leading to multiple reductions in the cardiac repolarizationreserve. As antiarrhythmic drugs that prolong the QT interval are usuallyaggressively managed with continuous electrocardiogram monitoring andscreening for drug interactions when administered to patients who have ahigh risk of sudden cardiac death, their risk of mortality is not increased.However, noncardiovascular QT-interval–prolonging drugs, which oftenproduce less QT-interval prolongation compared with antiarrhythmic drugs,are found to be associated with increased rates of death in patients who have amarkedly lower de novo risk of sudden cardiac death. Thus, it is importantfor clinicians, particularly pharmacists, to be cognizant of the levels of riskassociated with varying degrees of QT-interval prolongation caused by drugsso that they can develop strategies to either prevent or reduce the risk ofproarrhythmias.Key Words: antiarrhythmic agents, QT interval, QT prolongation, arrhythmia,atrial fibrillation, sudden cardiac death, torsade de pointes, pharmacogenomics.(Pharmacotherapy 2010;30(7):684–701)

OUTLINE

Physiology of Cardiac ConductionReduced Repolarization ReserveMonophasic Action PotentialVentricular Repolarization

Measurement and Heart Rate Correction of the QTInterval

Guidelines for QT or QTc Interval Prolongation:How Much Is Too Much?

Cardiovascular DrugsAntiarrhythmic Drugs That Primarily Suppress IKr

Multimechanistic AntiarrhythmicsProphylactic Strategies

Drugs for Mental Health DisordersMethadoneFirst-Generation Antipsychotics

Second-Generation AntipsychoticsAntimicrobial Agents

MacrolidesFluoroquinolonesAzole Antifungals

Antineoplastic AgentsTyrosine Kinase InhibitorsArsenic TrioxideSupportive and Emerging Agents

Conclusion

Arrhythmogenic syncope after starting quinidinetherapy has been recognized for nearly a century.In the early 1960s, a case series was publishedthat described patients with atrial fibrillationwho, after quinidine-induced conversion tonormal sinus rhythm, developed a drug-induced

DRUG-INDUCED QT-INTERVAL PROLONGATION Li et al

proarrhythmia characterized as a pause-dependent polymorphic ventricular tachycardia.1

In 1966, this rhythm was also identified byFrançois Dessertenne as torsade de pointes (TdP;literally translated as “twisting of the points”[Figure 1]) because of the alternating axis of theQRS complex during the arrhythmia.2 Since thattime, drug-induced proarrhythmia has evolvedinto a common cause of hospital admissions, hasresulted in withdrawals of prescription drugsfrom the market by the government, and hasbecome a significant barrier to new drugdevelopment.3, 4

Virtually all drugs that cause TdP do so byincreasing the time for electrical recovery ofmyocardial tissue (i.e., repolarization) betweenheartbeats. Most, but not all, drug-inducedincreases in repolarization are the result ofsuppression of the rapid component of thedelayed rectifier potassium current (IKr).

Suppression of IKr often leads to prolongation ofthe heart rate–corrected QT (QTc) interval on theclinical electrocardiogram (ECG).5–8 Despite thepresence of risk factors leading to exaggeratedQT-interval prolongation, the risk of drug-induced TdP is imprecise and remains highlystochastic even among patients with the samerisk profile and equivalent QT intervals.9–15

These risk factors for TdP are as follows:

• Hypokalemia• Hypomagnesemia• Bradycardia• Bundle branch block• Ion channel polymorphisms (e.g., KCNH2,KCNQ1, SCNA5A)

• Female sex• Cardiovascular disease (chronic heart failure,

previous myocardial infarction)• Conversion from atrial fibrillation to normal

sinus rhythm• Rapid infusion or overdose of QTc-interval–

prolonging drugs• Prolonged QT interval at baseline• Family history of long QT interval

Many QT-interval–prolonging antiarrhythmicdrugs are administered in the hospital wherepatients receive continuous ECG monitoring.Rigorous patient selection, ECG monitoring, andscreening for drug interactions contribute to thelow risk of TdP and lack of increased mortality inpatients receiving most QT-prolongingantiarrhythmic drugs.9, 16–20 However, registrydata suggest that noncardiovascular QT-prolonging drugs, which often produce less QT-

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From the National Comprehensive Cancer Network, FortWashington, Pennsylvania (Dr. Li); the Department ofPharmacy, Northwestern Memorial Hospital, Chicago,Illinois (Dr. Esterly); the Department of Pharmacy Practice,Midwestern University Chicago College of Pharmacy,Downers Grove, Illinois (Drs. Esterly and Pohl); theDepartments of Pharmacy and Psychiatry, North ChicagoVeterans Affairs Medical Center; Chicago, Illinois (Dr.Pohl); Baxter Healthcare, Deerfield, Illinois (Dr. Scott); andthe Marcella Niehoff School of Nursing and the StritchSchool of Medicine, Loyola University, Chicago, Illinois (Dr.McBride).

For reprints, visit http://www.atypon-link.com/PPI/loi/phco.For questions or comments, contact Brian F. McBride,Pharm.D., Marcella Niehoff School of Nursing, LoyolaUniversity Chicago, Building 102-4601, 2160 South FirstAvenue, Maywood, IL 60153; e-mail: [email protected].

Figure 1. Electrocardiogram of a patient with drug-induced QTc-interval prolongation and torsade de pointes.

PHARMACOTHERAPY Volume 30, Number 7, 2010

interval prolongation compared with antiarrhythmicdrugs, are associated with 2–3-fold increases inthe risk of sudden cardiac death.21, 22 The increasedrisk attributed to noncardiovascular QT-prolonging drugs is thought to be due to theconvergence of four main factors: clinical trialsthat are not designed to predict risk of TdP; atarget population that is large enough to producea significant proportion of cases of TdP despitelow estimates from clinical trials; pharmacokineticand pharmaco-dynamic drug interactions thatlead to an increased exposure of the drug; andprescription of these drugs by noncardiologistswho are less likely to be familiar with thepotential TdP risk conferred by them.23–26 Takentogether, these factors place an increasedimportance on the role of the clinical pharmacistin the prevention of drug-induced TdP. Pharmacistsmust understand the physiology of the cardiacconduction system and the degrees of acceptabledrug-induced QT-interval prolongation; theyshould also be aware of strategies for managingpatients who are receiving QT-prolonging drugs.

Physiology of Cardiac Conduction

Drug-induced QT-interval prolongationoriginates with either prolonged depolarization,reduced repolarization, or a combination of both.Prolonged depolarization is accomplished byadministering a drug that activates the latecomponent of the cardiac sodium current (INa).Reduced repolarization is accomplished throughsuppression of IKr or the simultaneoussuppression of IKr and the slowly activatingcomponent of the delayed rectifier potassiumcurrent (IKs).27–29 To our knowledge, there are nodrugs in clinical use that selectively suppress IKs.

Increases in late INa and/or reductions in IKrand IKs after drug block do not always predict thedegree of QT-interval prolongation. Indeed, thedegree of QT prolongation after exposure to aQT-prolonging drug is critically dependent onthe integrity of the redundant systems involvedin cardiac repolarization, such as IKs and post-translational modification of proteins involved inrepolarization.30 This redundancy is labeled“repolarization reserve” and considers the abilityof a drug to induce QT prolongation and/or TdPto be strongly dependent on the concomitantpresence of multiple reductions to the repolari-zation system including but not limited to thefollowing risk factors: hypokalemia, hypomagne-semia, female sex, bradycardia (or drugs slowingatrioventricular nodal conduction), and subclinical

mutations or polymorphisms in genes encodingcardiac ion channels that carry ion currents(mentioned above). However, the geneticgovernance of drug-induced QT prolongationand/or TdP remains unpredictable.5, 11–14, 31–32

Each of these risk factors either suppressesrepolarization directly or enhances drug-inducedsuppression of repolarization.

Although drugs and risk factors leading to QT-interval prolongation in patients decreaserepolarization reserve, decreases in repolarizationreserve are not the sole determinant forexaggerated QT prolongation and/or TdP.Multiple hypotheses regarding the genesis ofdrug-induced TdP have been proposed; however,one of the most well-described hypothesesincludes the convergence of three key electro-physiologic factors: decreased repolarizationreserve (i.e., QT-interval prolongation), increasedtransmural dispersion of repolarization, and theability to induce ectopic (i.e., premature)heartbeats caused by early afterdepolarizations.

Reduced Repolarization Reserve

With respect to reduced repolarization reserve,drug block of IKr and IKs and activation of late INado not represent the sole determinants of QT-interval prolongation. Indeed, an analysis of 249case reports of drug-induced TdP revealed thatthe convergence of multiple risk factors increasedthe risk for TdP.33 Serum potassium andmagnesium levels in the low or low-to-normalrange (potassium < 4 mEq/L and/or magnesium< 2 mg/dl) intensify IKr drug block and arepresent in approximately 40% of TdP cases.33–35

In addition, it was recently shown thatintracellular levels of these electrolytes correlatewith the duration of the QTc interval, thatpatients receiving diuretic therapy can haveintracellular electrolyte depletion despite normalserum levels, and that electrolyte repletion leadsto a shortening of the QTc interval.36, 37

Several studies have shown that compared withmale patients, female patients have dispropor-tionately longer QT intervals de novo and afterreceiving a QT-interval–prolonging drug and thatthis risk may be related to postpubescent sexhormones and is greatest during ovulation andmenstruation.12, 38–41 These factors may explainwhy 71% of all cases of drug-induced TdP occurin females.33

Bradycardia (heart rate < 60 beats/min) ordrugs slowing atrioventricular nodal conduction(e.g., �-blockers, digoxin, diltiazem, and

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verapamil) intensify drug block of potassiumchannels. This property is known as reverse usedependence and often occurs with drugs thatselectively suppress IKr.10

Finally, the importance of screening for drug-drug interactions cannot be understated. ManyQT-interval–prolonging drugs are substrates ofthe cytochrome P450 (CYP) enzyme system andwere identified in 39% of drug-induced TdPcases. The combination of multiple drugsblocking IKr or inhibition of the metabolism of IKrcan lead to high concentrations of the QT-prolonging drug, further reducing repolarizationreserve.33

Monophasic Action Potential

In the ventricular tissue, the QRS and QTintervals on the surface ECG approximate theventricular monophasic action potential (Figure 2).Each of the five sections (known as phases 0–4)of the monophasic action potential is producedby the synchronous action of cardiac ion channels,which transport ions across an electrochemicalgradient across the myocyte cell membrane.42

The balance of inward current and outwardcurrent activation, inactivation, and deactivationchanges as the cell undergoes depolarization andrepolarization; creating the monophasic actionpotential and thus allowing for the spontaneousbeating of myocytes.

When a selective IKr blocker such as ibutilideor dofetilide is used, these agents prolong theQTc by preferentially extending phase 3 of themonophasic action potential. This changes theshape of the action potential from the “spike anddome” morphology shown in Figure 2 to a moretriangular shape, referred to as “triangulation.”When triangulation occurs, the duration of timefor the monophasic action potential to reach 90%recovery from 40% recovery is prolonged,extending the vulnerable period where themyocytes are more susceptible to early after-depolarizations. Multimechanistic drugs, such asamiodarone, prolong the QTc by extending bothphases 2 and 3 of the monophasic actionpotential, preventing triangulation. Thisrepresents one possible explanation for whyamiodarone is associated with a markedly lowerrate of TdP compared with selective IKr blockerssuch as dofetilide, ibutilide, and sotalol.43

Ventricular Repolarization

Depolarization and repolarization of themyocardium act as electrical wavefronts, the

propagation of which may be visualized as thecrashing of two successive waves upon acoastline. The depolarization proceeds as awavefront, from the base of the ventricle, throughthe bundle of His and down the Purkinje fiberstoward the apex of the ventricle and outwardfrom the endocardium, through the midmyo-cardial layer and the epicardium. The repolar-ization wavefront, represented clinically by theQT interval, immediately succeeds the depolar-ization wavefront, following the same base toapex and endocardial to epicardial patterns.44

The QT-interval–prolonging drugs increase theduration of the repolarization wavefront andproduce a T wave that is not only prolonged buthas a reduction in the amplitude (i.e., T-waveflattening).

As the depolarization and repolarizationwavefronts progress through the myocardium,the monophasic action potential also exhibits asmall amount of heterogeneity in depolarizationand repolarization. This heterogeneity is

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Figure 2. Synchronous activation and deactivation ofcardiac ion channels produce a monophasic actionpotential, which is represented clinically as the QRScomplex and T wave from which the QT interval is derived.


commonly known as dispersion and exists in twoforms: temporal dispersion and spatialdispersion. Temporal dispersion is the variabilityin the velocity of the depolarization wavefront.At myocardial site A, depolarization begins at atheoretical time of 0 msec. At myocardial site B,depolarization begins 30 msec later. Althoughthe duration of the monophasic action potentialis the same, the two sites are activated at differenttimes. This difference in activation can create azone of myocardium that facilitates reentrantarrhythmias.28

Dispersion in repolarization, however, isaffected by the variability in basal to apicalrepolarization, as well as variability in transmuralrepolarization. Differences in basal to apicalrepolarization are measured as the differencebetween the minimum and maximum QTintervals on a 12-lead ECG, reported as QTdispersion; this is not considered a risk factor fordrug-induced TdP. The transmural dispersion ofrepolarization represents spatial heterogeneityacross the wall of the myocardium from theendocardial layer to the epicardial layer.28 This ismeasured from the peak of the T wave to the endof the T wave. Drug-induced increases in trans-mural dispersion of repolarization are consideredpart of a triad of arrhythmogenic propertiesassociated with the development of TdP.

Clinically used QT-interval–prolonging drugsthat increase spatial transmural dispersion ofrepolarization generally exhibit preferentialsuppression of IKr. Preferential suppression of IKrproduces a greater prolongation of the actionpotential in the midmyocardial layer of the hearttissue relative to the epicardial and endocardiallayers. One of the reasons that suppression of IKrincreases transmural dispersion of repolarizationis because the myocytes of the midmyocardium,known as M cells, have a reduced expression ofthe KCNQ1 potassium channel, which carries IKs.Reductions in IKs density in the M cells makerepolarization, and thus sensitivity to drug blockof the M cells, more dependent on IKr.28, 45

Therefore, pharmacologic suppression of IKr has agreater impact on M cells relative to epicardialand endocardial myocytes.

To illustrate the influence of transmuraldispersion of repolarization, consider the factthat amiodarone, dofetilide, and sotalol exertsimilar effects on the QT interval clinically.However, amiodarone is associated with amarkedly lower (< 2%) frequency of TdP.Because amiodarone exerts an effect on multipleinward and outward ion currents, it reduces

transmural dispersion of repolarization, makingthe prolongation of the action potential morehomogeneous.46–49 However, sotalol anddofetilide suppress only IKr, increase transmuraldispersion of repolarization, and are associatedwith a higher rate of TdP clinically. Exogenousand endogenous catecholamines can also increasetransmural dispersion of repolarization. Basicscience literature has identified a link between�2-adrenoreceptor stimulation, activation of IKs,and drug block of IKs.50 When IKs is activated inthe presence of drug block, the action potentialduration is paradoxically shortened in theendocardium and epicardium where IKs density ishigher.51, 52 This leads to a relatively longeraction potential duration in the M cells (whereIKs density is smaller) and thus increasedtransmural dispersion of repolarization.Therefore, the ability of a drug or combination ofdrugs to increase transmural dispersion ofrepolarization through suppression of IKr orenhancement of IKs should be considered as acomponent of the electrophysiologic principlesnecessary to develop drug-induced TdP becausein either instance, this inhomogeneity in theventricular action potential facilitates conductionof early afterdepolarizations.

The ability of a QT-interval–prolonging drug togenerate early afterdepolarizations represents thethird component of the torsadogenic triad. Earlyafterdepolarizations originate during phase 3 ofrepolarization, leading portions of the ventricularmyocardium to conduct the premature heartbeat.These activated myocytes will initiate a reentrantloop capable of stimulating the remainingventricular myocardium that failed to conduct theextra stimulus de novo.53–55 Thus, when theventricular myocardium experiences decreasedrepolarization reserve and increased dispersion ofrepolarization, the introduction of an earlyafterdepolarization can trigger a premature R waveemanating out of the preceding T wave (R-on-Tphenomenon) on the clinical ECG, with theensuing electrical reentry clinically observed asTdP.28 An emerging body of basic science evidencesuggests intramyocyte calcium overload as amechanism leading to the development of earlyafterdepolarizations and a role for the sodium-calcium exchange protein, NCX, which carries thesodium-calcium exchange current, INa-Ca.

The NCX protein can operate in two modes.In the forward mode, one calcium ion leaves thecell in exchange for three sodium ions enteringthe cell, creating a net inward current thatshortens the monophasic action potential. The

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reverse mode is where three sodium ions leavethe cell in exchange for one calcium ion enteringthe cell, which leads to intramyocyte calciumaccumulation, a prolongation of phase 3 of themonophasic action potential and therefore earlyafterdepolarizations. The NCX protein generallyoperates in reverse mode during myocardialischemia and heart failure due to an increasedintramyocyte sodium concentration.56 Multi-mechanistic antiarrhythmic drugs such asamiodarone and ranolazine inhibit NCX andsuppress early afterdepolarizations.29, 57 However,early afterdepolarization suppression bydronedarone is much less potent than that byamiodarone and thus permits genesis of TdP inanimal models.47, 58

Measurement and Heart Rate Correction of theQT Interval

Although guidelines for the clinical measure-ment of the QT interval are not yet adopted inthe United States, procedures used for theassessment of QT-interval prolongation in clinicaltrials can provide some direction.59 The reader isreferred to a detailed tutorial on the propermeasurement of the QT interval.59

The duration of the QT interval exhibits a greatdegree of variability with the heart rate. Therefore,correction factors are used to accurately predictdrug-induced changes in cardiac repolarization.This is particularly important since drugs thatreduce IKr and IKs exhibit reverse use dependence,a phenomenon in which their potency isincreased at slower heart rates. Although morethan a dozen correction formulas have beenproposed, the Bazett formula, QTc = QT/(RR)1/2,is the most commonly used in clinical practicedespite the fact that it overestimates the true QTinterval when the heart rate is greater than 60beats/minute.60 In 1992, a linear regressionformula developed from the Framingham HeartStudy, QTc = QT + 0.154(1 − RR), with the dataentered in seconds, was proposed and moreaccurately predicts drug-induced changes inrepolarization.60, 61 The disadvantage to clinicaluse of the Framingham correction formula,however, is that most drug-induced QTc prolon-gation is reported with the Bazett correctionformula. Thus, assessing the clinical risk ofdrug-induced TdP in patients approaching keycutoff points for QTc-interval prolongation (460,480, 500 msec) should include calculating theQTc by using both correction formulas, verifyingall interacting drugs (e.g., diuretics, �-blockers),

and identifying changes toward a more flattenedT-wave morphology and/or the presence of a Uwaves.27

The U wave is the sixth deflection observed onthe ECG, follows the T wave, and usually has thesame polarity as the T wave. In healthyindividuals, this is generally considered anincident finding as it usually represents an earlyafterdepolarization that did not result in apremature heart beat. In the context of drug-induced QT-interval prolongation, the presenceof the U wave (often referred to as the second Twave, T2) is concerning as it representsinterrupted repolarization resulting fromdiffering action potential duration in theepicardium, endocardium, and midmyocardiallayers.62 Further, the presence of U waves hasbeen associated with an increased frequency ofpremature ventricular contractions (an earlyafterdepolarization that conducts a prematureheartbeat) and is more common in patients whodevelop spontaneous ventricular tachycardiarelative to those patients who do not (39% vs8.7%, p<0.001).62–64 Therefore, it is generallyrecommended that U waves be included in themeasurement of the QT interval when QT-interval–prolonging drugs are administered.

The clinical trial guidelines, adopted by theEuropean Council for Proprietary and MedicinalProducts and under review by the U.S. Food andDrug Administration (FDA), recognize severalupper-limit values for drug-induced QTc-intervalprolongation. These values include absolute QTcintervals and changes in the QTc interval fromthe baseline (predrug) ECG. Absolute valuesinclude QTc intervals greater than 450, 480, and500 msec and changes from baseline greater than30 or 60 msec, with increasing upper-limit valuessignifying an increased risk for the developmentof TdP.51, 59 In fact, 92% of TdP cases occurredwhen the patient developed an antecedent QTcinterval greater than 500 msec.65–66 We thereforegenerally recommend that QTc-interval–prolonging drugs not be started in patients with abaseline QTc greater than 460 msec in theabsence of identifiable risk factors unlessprescribed by a cardiologist or if the patient is ona unit with 24-hour telemetry monitoring. Whenpatients reach the upper-limit values for QTcprolongation, the proarrhythmic risk associatedwith the regimen should be reevaluated andalternative treatment regimens considered.

Cardiovascular Drugs

Contrary to the notion that procedure-based

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therapy has supplanted antiarrhythmic pharmaco-therapy, both strategies are often used togetherfor two principal indications. The first isrestoration and maintenance of normal sinusrhythm in patients with a diagnosis of atrialfibrillation after electrical cardioversion or acatheter ablation procedure. The second is toreduce the frequency of device activation inpatients with an implantable cardioverterdefibrillator.16, 19, 67–79 In this section, we reviewantiarrhythmic drugs that predominantlysuppress IKr, multimechanistic antiarrhythmics,and prophylactic strategies to enhance rhythmcontrol and reduce the extent of QT-intervalprolongation and frequency of TdP.

Antiarrhythmic Drugs That Primarily Suppress Ikr

Ibutilide

One of the most effective agents for acutepharmacologic rhythm conversion, ibutilide alsomarkedly enhances the success rate of electricalcardioversion of atrial fibrillation or atrial fluttercompared with electrical cardioversion alone.80, 81

Ibutilide is administered as an 1-mg/50-mlinfusion over 10 minutes. A second 1-mginfusion may be administered if the patient hasnot converted to normal sinus rhythm within 20minutes of the start of the first infusion. As oneof the most potent antiarrhythmic compounds,ibutilide produces extensive QT-intervalprolongation, ranging from 60–100 msec inclinical trials, underscoring the need to monitorserum potassium and magnesium levels, inter-acting drugs, and heart rate after adminis-tration.82, 83 In addition, animal models indicate amarked increase in the development of earlyafterdepolarizations and transmural dispersion ofrepolarization.84, 85

Emerging evidence from the basic scienceliterature suggests that ibutilide is a substrate forthe drug efflux pump P-glycoprotein and thatpatients should be prescreened for use of drugsthat inhibit P-glycoprotein.86 In the absence ofclinical data for this interaction and out of anabundance of caution, we recommend discon-tinuation of P-glycoprotein inhibitors as soon aspossible before administration of ibutilide. Ifdiscontinuation is not possible, the clinicianshould be aware that the first dose of ibutilidemight be more likely to convert atrial fibrillation,exaggerate QT-interval prolongation, andpossibly increase the risk of TdP. The oneexception to this recommendation is concomitantadministration of amiodarone with ibutilide.

Early clinical trials of ibutilide enrolled patientswho were receiving concomitant long-termamiodarone therapy. Compared with patientswho did not receive amiodarone, no significantdifference was noted in the frequency of ven-tricular arrhythmias. This was due in large partto the multimechanistic nature of amiodarone. Forother compounds that inhibit P-glycoprotein,prophylactic administration of intravenousmagnesium may reduce the extent of QT-intervalprolongation. Taken together, it is not surprisingthat the 5% rate of TdP after ibutilide administra-tion is among the highest of any antiarrhythmicdrug.

Sotalol and Dofetilide

Sotalol is a racemic mixture in which thedextro-isomer suppresses IKr and the levo- isomeris a nonselective �-adrenoreceptor antagonist.On the other hand, dofetilide is the only pure IKrantagonist available for clinical use in the UnitedStates. For the treatment of atrial fibrillation,50–60% of patients receiving either sotalol ordofetilide remained in normal sinus rhythm after1 year. Either agent can be used safely in patientswith left ventricular dysfunction withoutaffecting survival.9, 70, 87–90

Sotalol and dofetilide have similar effects onthe QTc interval. Sotalol produces QTc-intervalincreases from baseline of 25, 40, and 50 msec inpatients receiving 80-, 120-, and 160-mg doses,respectively, which translates into an average4.3% risk of TdP.91 Furthermore, the �-adrenoreceptor antagonist properties of sotalolmay influence the occurrence of TdP byincreasing its reverse use–dependent properties.Dofetilide also has a linear dose–QTc-intervalrelationship of 25 msec for each ng/ml of plasmadofetilide concentration, which translates into a25–50-msec increase in QTc over the dosingrange in subjects free of renal impairment,decreases to 20–30 msec after 3 weeks of therapy,and an average 2% increase in TdP.92–94 Bothdrugs increase transmural dispersion ofrepolarization and induce early afterdepolar-izations at concentrations used in clinicalpractice.95, 96

Although the risk of TdP with sotalol isarguably higher than the estimates for dofetilide,the dosing protocol and restrictions on the latterare the result of the more stringent regulatoryenvironment after the withdrawal of thenoncardiovascular QT-interval–prolonging drugs,terfenadine and cisapride. Regardless, hospitalinitiation protocols and maintenance of sotalol

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therapy should be subject to the same restrictionsas dofetilide germane to prescriber access, druginteractions, electrolyte level management, andpostadministration QTc-interval prolongationmanagement.

Multimechanistic Antiarrhythmics

Amiodarone

Amiodarone, a multimechanistic ion channelantagonist and antiadrenergic compound,29, 97–99

is the most potent antiarrhythmic in terms of theproportion of patients remaining in normal sinusrhythm 12 months after cardioversion from atrialfibrillation and the reduction in ventriculartachyarrhythmia burden in patients who receivedan implantable cardioverter defibrillator. Thismarked clinical response to chronic therapy withamiodarone is the result of not only suppressionof a number of key ion currents, including INa,ICaL, INa-CaR, IKr, and IKs, but also downregulationof the ion channel proteins that carry thesecurrents.100 Although amiodarone prolongs theQTc interval by 30–60 msec, it reverses trans-mural dispersion of repolarization and suppressesearly afterdepolarizations induced by sotalol inanimal models of TdP. These features confer thelowest TdP risk of any antiarrhythmic drug (<0.5%).46–49 Its noncardiovascular adverse-effectprofile spawned the development of several newantiarrhythmic compounds including azimilide,ranolazine, and dronedarone.

Dronedarone

Dronedarone, a deiodinated congener toamiodarone with a nearly identical electro-physiologic profile, recently demonstratedincreased mortality among patients with heartfailure and the inability to suppress earlyafterdepolarizations, thus limiting the use of thisdrug despite a marked reduction in noncardio-vascular toxicity.47, 101, 102

Ranolazine

Ranolazine is used as a second-line adjunctivetherapy for chronic stable angina when standardof care with �-adrenergic antagonists, calciumchannel antagonists, and/or long-acting nitratesbecome suboptimal or fail. Initial use ofranolazine was limited because of concernsregarding QTc-interval prolongation of 6–12msec with FDA-approved dosages of 500–1000mg twice/day. During clinical development, amore complete electrophysiologic evaluation of

ranolazine was performed. A series ofelectrophysiology experiments using cellular andanimal models indicate that ranolazine preventedsotalol-induced transmural dispersion ofrepolarization, early afterdepolarizations, andsuppressed TdP through antagonism of INa, IKr,IKs, and activation of calcium efflux by NCXsimilar to amiodarone.29, 103–105 These data werefurther supported by data from the MetabolicEfficiency with Ranolazine for Less Ischemia inNon–ST-Elevation Acute Coronary Syndromes–Thrombolysis in Myocardial Infarction(MERLIN-TIMI) 36 trial that demonstrated thatpatients with an acute coronary syndrome eventand treated with ranolazine 2000 mg/day in anintravenous to oral hybrid regimen had signifi-cantly fewer episodes of ventricular tachycardia,supraventricular tachycardia, or new-onset atrialfibrillation.106 Furthermore, we found nopublished cases of TdP induced by sustained-release ranolazine in the 10 years since the drugbegan clinical development. These data have ledthe manufacturer to proceed with clinicaldevelopment of ranolazine as a potentialantiarrhythmic compound.

Prophylactic Strategies

Mexiletine

For more than 2 decades, electrophysiologistshave used mexiletine and/or magnesium inconjunction with QT-interval–prolongingantiarrhythmic drugs to improve control ofventricular arrhythmias and reduce the risk ofventricular proarrhythmia in patients receivingan IKr blocker.107, 108 Mexiletine is an orallyavailable lidocaine analog and suppresses INa.When coadministered with potassium channelantagonists such as quinidine or sotalol,mexiletine shortens the QT interval, reduces thefrequency of TdP, and improves control ofventricular arrhythmias relative to quinidine orsotalol alone.107 Animal models also indicate thatmexiletine reduces transmural dispersion ofrepolarization and early afterdepolarizations afterexposure to sotalol.52, 108, 109 Adverse effects withmexiletine were limited to nausea. Mexiletineshould be used in patients who have break-through arrhythmias while taking a maximallytolerated dose of dofetilide, sotalol, or amiodarone.

Magnesium

In one study, oral magnesium L-lactate 162 mgadministered with either sotalol or dofetilide to

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patients with implantable cardioverter defibril-lators shortened their QTc intervals, especially inthose receiving loop diuretics for advanced heartfailure.36 The strategy was associated with nomagnesium-related adverse effects except for onecase of diarrhea. No reduction in TdP frequencywas reported in this 72-hour study, and the long-term effects of oral magnesium supplementationon the frequency of drug-induced TdP have notbeen evaluated. Since the influence of oralmagnesium supple-mentation on the efficacy ofdofetilide or sotalol has not been established, thepractice of magnesium repletion in patientsreceiving dofetilide or sotalol is uncommon andshould be used only when patients have apotassium level less than 4 mEq/L or amagnesium level less than 2 mg/dl.

For patients receiving ibutilide, the data forcoadministration of prophylactic magnesium area bit more convincing. When coadministeredwith ibutilide, magnesium 2 g over 10 minutesbefore the first ibutilide infusion and 2 g over 60minutes after the first ibutilide infusionprevented QTc-interval prolongation, suppressedearly afterdepolarizations, and facilitatedibutilide-induced cardioversion, particularly inpatients with impaired left ventricular functionfor whom the rate of TdP can be higher.110, 111

There were no magnesium-associated adverseevents in this study, and a 38% reduction wasnoted in the frequency of TdP (p=0.338).112

However, the study was not powered to detect adifference in the frequency of TdP.112 Given thisevidence, prophylactic magnesium is not oftenused to prevent TdP but to enhance the efficacyof ibutilide and reduce cost by decreasing theneed for direct current cardioversion.112

Prophylactic magnesium is not listed in theAmerican Heart Association guidelines foradvanced cardiac life support.113

Propafenone and Amiodarone

In clinical practice, it is common to useelectrical or pharmacologic cardioversion foracute restoration of sinus rhythm whileintroducing a second agent for the maintenanceof sinus rhythm. Two options for maintenancetherapy, propafenone and amiodarone, can helpreduce the risk of QT-interval prolongation andTdP associated with acute cardioversion.82, 83 Inpatients with structurally normal hearts (e.g., nocoronary artery disease or left ventricularhypertrophy), the ability of propafenone tosuppress INa shortens the ventricular action

potential, prevents ibutilide-induced QT-intervalprolongation, suppresses premature beats (i.e.,early afterdepolarizations), facilitates cardioversionto normal sinus rhythm, and has one of thehighest rates of sinus rhythm at 1 year.114–116 Forpatients with structural heart disease who receivecardioversion, the addition of amiodarone tomaintain sinus rhythm reduces the frequency ofTdP because of its effects on multiple ioncurrents, reductions in transmural dispersion ofrepolarization, and suppression of earlyafterdepolarizations.117

Drugs for Mental Health Disorders

Psychiatric disorders for which drug therapy isprescribed include substance abuse, majordepressive disorder, and schizophrenia. Each ofthese disorders is associated with an increasedrisk of cardiovascular disease and thus higherbaseline QT intervals relative to those in healthysubjects.118–127 Drugs used in the treatment ofmental health disorders that increase the QTinterval include methadone, as well as first- andsecond-generation antipsychotics.

Methadone

Methadone is a µ-opioid–receptor agonist usedfor maintenance therapy in opioid-dependentpatients (including illicit drug abusers), as wellas for treatment of moderate-to severe pain. TheS-isomer of methadone suppresses IKr amplitudeand prolongs the QTc interval by 14.1 msec at amean ± SD dose of 80 ± 32 mg, and at least 18cases of TdP associated with S-methadone havebeen reported in the literature.128, 129

An independent multidisciplinary expert panelon the cardiac effects of methadone recentlypublished guidelines for QT-interval screening inmethadone treatment.130 These guidelinesrecommend a thorough history and physicalexamination, a pretreatment ECG, and a secondECG 30 days after start of treatment or a changein dosage. The panel specifically recommendsincreased monitoring when a patient has a QTinterval greater than 450 msec. Discontinuationof methadone in patients with a QT intervalgreater than 500 msec is advised. Since poornutritional status is a common comorbid disorderin this population, aggressive monitoring andrepletion of serum potassium concentration to 4mEq/L or greater and magnesium to 2 mg/dl orgreater are highly recommended.

Although buprenorphine is the only FDA-

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approved alternative to methadone, diacetyl-morphine has been shown to be more efficaciousthan methadone for the treatment of drug addic-tion. Like buprenorphine, diacetylmorphine, toour knowledge, does not prolong the QTinterval.131, 132

First-Generation Antipsychotics

First-generation antipsychotics are recom-mended for use in patients with schizophreniawho had a partial response or no response to asecond-generation antipsychotic.133 Haloperidolis also used in the setting of acute agitation.134

Thioridazine, chlorpromazine, and haloperidolsuppress IKr, prolong the QT interval by 15–30msec at therapeutic doses (similar to long-termdofetilide therapy), and are associated withTdP.135–140 Although thioridazine causes thegreatest QTc-interval prolongation, chlorpromazineand haloperiodol have also been reported toproduce TdP, particularly when combined withother compounds that prolong the QTc intervalor inhibitors of the CYP2D6 enzyme, the principalmetabolic pathway for these compounds.141–145

When used for in-hospital agitation, intravenoushaloperidol produced a dose-dependent increasein the risk of a QTc greater than 500 msec andthe risk of TdP.146 Alternatives to the use ofhaloperidol in the setting of acute agitationinclude verbal deescalation of the patient,parenteral second-generation antipsychotics (e.g.,olanzapine) that do not prolong the QT interval,and use of benzodiazepines. If alternatives tohaloperidol are not effective, patients receivingintravenous or intramuscular haloperidol shouldreceive continuous ECG monitoring as soon asthey are stabilized.134 As with the treatment ofaddiction, the prevalence of poor nutritionalstatus as a comorbid disorder requires thatclinicians monitor and replete serum potassiumlevels to at least 4 mEq/L and magnesium to atleast 2 mg/dl.

Second-Generation Antipsychotics

Second-generation antipsychotics includeclozapine, quetiapine, olanzapine, risperidone,paliperidone, ziprasidone, and aripiprazole. Allof these drugs suppress IKr to varying degrees,with clozapine, olanzapine, aripiprazole, andpaliperidone being the least potent and devoid ofsignificant QTc prolongation clinically.135, 137,

147–149 Quetiapine increases the QTc interval in adose-dependent fashion by an average of 15–20msec in the presence of CYP3A4 inhibitors.137, 150

Torsade de pointes was reported in patientstreated with quetiapine and who had concomi-tant risk factors (e.g., bradycardia, hypomagne-semia) for TdP.151 Risperidone increases the QTcby 10 msec, can induce early afterdepolariza-tions, increases transmural dispersion of repolar-ization, and has also been reported to causeTdP.135, 152 Risperidone is also metabolized by theCYP2D6 enzyme.153, 154 Inherent genetic vari-ability in the CYP2D6 enzyme leads to genotype-dependent effects on the QTc interval. Patientshomozygous for the wild-type CYP2D6 enzymehad a significantly lower QTc (400 vs 418 msec,p<0.05) compared with those who wereheterozygous for the *4 variant (i.e., presentingwith one copy of the wild-type [*1] CYP2D6gene and one copy of the variant CYP2D6gene).153 Ziprasidone prolongs the QT interval ina dose-dependent fashion, but the effect plateausat 20 msec.135, 137 The reason for this plateau isthought to be the concomitant suppression of INaat increasing doses, which can mitigate the effectof IKr suppression on the QT interval and has notbeen reported to cause TdP.135

In patients requiring treatment with a second-generation antipsychotic, treatment witholanzapine, paliperidone, and aripiprazole carriesthe least risk of TdP. However, each second-generation antipsychotic has differing affinitiesfor dopamine receptor subtypes, which maynecessitate the use of a QTc-interval–prolongingsecond-generation antipsychotic. In the casewhere a QTc-prolonging second-generationantipsychotic must be used, the QT intervalshould be verified before starting the drug, at 7days after initiation, and after any changes indosing. Adequate screening and prevention ofrisk factors for QTc-interval prolongation shouldbe mitigated aggressively.

Antimicrobial Agents

Prolonged QTc interval and TdP have beenassociated with multiple antimicrobial compounds.Macrolides, fluoroquinolones, azole antifungals,and pentamidine represent the most commonlyimplicated compounds.155, 156 Antimicrobialagents less commonly implicated includetrimethoprim-sulfamethoxazole, clindamycin,and metronidazole.33, 157 Drug interactions are ofparamount concern since many of theseantimicrobials implicated in the development ofTdP suppress not only IKr but also substrates ofthe CYP enzyme system. Therefore, coadminis-tration of inhibitors of the CYP enzyme system

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(predominantly CYP3A4 and CYP2C9 inhibitors)should be avoided since inhibition of CYPenzyme systems could raise plasma concentra-tions of antimicrobials, leading to suppression ofIKr, prolongation of the QTc interval, anddevelopment of TdP.158

Macrolides

Erythromycin and clarithromycin possessintrinsic QTc-interval–prolonging effects bysuppressing IKr.159, 160 Several animal studiesindicate that erythromycin and clarithromycinincrease transmural dispersion of repolarizationand facilitate the development of early afterdepo-larizations.161, 162 Macrolides produce a “doublehit” on cardiac repolarization reserve since theysuppress IKr and inhibit their own metabolismthrough CYP3A4. A retrospective case analysisrevealed that erythromycin and clarithromycinwere responsible for 53% and 36% of the cases ofantibiotic-associated TdP, respectively.156, 163

Further, sudden cardiac death associated witherythromycin was increased 5-fold whenerythromycin was coadministered with a CYP3A4inhibitor (incidence rate ratio 5.35, 95%confidence interval 1.72–16.64, p=0.004).22, 164–166

Similar evaluations of clarithromycin are inprogress, given these data and case reports of TdPwith clarithromycin.26, 167–173

Fluoroquinolones

Fluoroquinolones are widely used antibioticagents because of their broad spectrum ofantimicrobial activity and relatively safe adverse-effect profile.174–176 Ciprofloxacin, levofloxacin,and moxifloxacin are associated with case reportsof TdP. Based on published data, moxifloxacin isassociated with the greatest risk of QTc-intervalprolongation of all of the fluoroquinolones.33, 177, 178

Therefore, moxifloxacin, out of an abundance ofcaution, should be reserved for treatment inthose patients who fail therapy with anotherfluoroquinolone.

Azole Antifungals

Azole antifungal agents exert their effectthrough the inhibition of 14-�-demethylase.This fungal CYP enzyme is responsible forergosterol synthesis and is homologous to severalhuman CYP enzymes. As a result, all of thecurrently available azoles—ketoconazole,fluconazole, itraconazole, voriconazole, andposaconazole—inhibit CYP3A4 to varying

degrees, with ketoconazole being the most potentCYP3A4 inhibitor and fluconazole being a potentCYP2C9 inhibitor. We found no evidencesuggesting that members of this class, other thanketoconazole, directly suppress IKr to an appre-ciable extent. Indeed, this group of compoundsindirectly contributes to TdP by increasing theplasma concentrations of CYP3A4 substratesknown to prolong the QTc interval.179–185

Therefore, in the setting of concomitant QT-interval–prolonging drugs that are also CYP3A4or P-glycoprotein substrates, the offendingCYP3A4 or P-glycoprotein substrates should beremoved or, if sensitivities of the fungal pathogenpermit, a switch to fluconazole should beconsidered.

Antineoplastic Agents

The conventional focus of adverse effects dueto cancer pharmacotherapy has been on mini-mizing or managing myelosuppression, emesis,anemia, alopecia, and other adverse effectsconsistent with traditional cytotoxic chemotherapy.However, innovations in mapping the humangenome over the past decade have allowed theparadigm of cancer pharmacotherapy to shiftfrom traditional “cytotoxic” chemotherapy agentstoward a molecular “targeted therapy” approachby using biologics and small molecule receptorinhibitors. These agents are associated with adifferent adverse-effect profile compared withthat of older antineoplastics because of differentpharmacologic properties. Preclinical studiessuggest that prolongation of the QT interval is acommon thread among the targeted therapyagents. Consequently, cardiac rhythm monitoringhas become increasingly important in clinicaltrials that use these novel agents. Furthermore,clinicians will need to be aware of these cardiacmonitoring recommendations as these drugstransition from investigational agents into themarketplace.186 The National Cancer Institute(NCI) Common Terminology Criteria for AdverseEvents (CTCAE) standardizes the severity ratingof adverse events, including QTc-intervalprolongation, into five possible grades for clinicaltrial purposes.187 By definition, grade 1 is a mildadverse event, whereas a grade 5 event causesdeath. Table 1 shows a comparison between theNCI CTCAE standard for QT prolongation andthe proposed FDA standard.

Tyrosine Kinase Inhibitors

Of the novel types of anticancer therapy,

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tyrosine kinase inhibitors are the most proliferative.Since 2001, seven tyrosine kinase inhibitors havebeen introduced into the marketplace for thetreatment of a variety of cancers (e.g., breast,lung, kidney, pancreatic, and leukemia). The riskof QT-interval prolongation is mostly of concernwith tyrosine kinase inhibitors that target multipletyrosine kinase receptors—nilotinib, dasatinib,and sunitinib. In vitro studies suggest that themechanism of QT prolongation is suppression ofIKr in a concentration-dependent manner.186 Therate of QT prolongation from clinical trials is low(< 3%),188–190 but the potential for life-threateningTdP warrants consideration and strict monitoringin some cases.

In clinical trials, sudden deaths attributed toQT-interval prolongation have been reportedwith nilotinib, and the frequency of TdP inpatients receiving sunitinib has been reported tobe less than 0.1%.189, 191 The maximum QT-interval prolongation by nilotinib was 18 msec,and a black-box warning about QT-intervalprolongation and sudden death is included in theFDA-approved package labeling.189 Dasatinib,nilotinib, and sunitinib are also CYP3A4 sub-strates, and a dosage reduction should beconsidered if administration with a concomitantCYP3A4 inhibitor is necessary. In addition, foodinteracts with nilotinib by increasing thebioavailability, and therefore nilotinib should betaken on an empty stomach. There are clearECG monitoring requirements when a patientbegins therapy with nilotinib. The frequency ofmonitoring and specific dosage adjustmentsbased on these measurements can be found in theproduct labeling.189

Arsenic Trioxide

Infamously known as a poison, arsenic trioxideis an inorganic compound approved by the FDAfor the treatment of relapsed or refractory acute

promyelocytic leukemia displaying translocationbetween chromosomes 15 and 17 or promyelocyticleukemia–retinoic acid receptor-� gene expression.192

Arsenic trioxide is associated with many adversereactions and can affect many organ systems; itsproduct labeling carries a black-box warning forECG abnormalities, including QT-intervalprolongation and TdP, although the mechanismof action is unclear.

The risk of QT-interval prolongation and TdPwith this agent is clinically significant. In aphase II clinical trial, arsenic trioxide caused aQT prolongation of more than 500 msec in 16(40%) of 40 patients, with one patient experi-encing TdP.193 A case report describes threepatients who experienced TdP while receivingarsenic trioxide for the treatment of acutemyeloid leukemia or myelodysplastic syndrome.194

The doses of arsenic trioxide ranged from 10–20mg/day, and all three patients had coexisting lowserum potassium and magnesium levels. Despiterigorous electrolyte replacement and otherinterventions (including cardioversion), all threepatients died.

The National Comprehensive Cancer Networkguidelines recommend the following for arsenictrioxide–induced QT-interval prolongation:ECG, serum electrolyte levels (potassium,magnesium, calcium), and serum creatinineconcentration should be assessed for abnor-malities before arsenic trioxide therapy isstarted.192 If the absolute value of the QT intervalrises above 500 msec during therapy, immediatecorrective action should be taken. Discontinu-ation of arsenic trioxide should be stronglyconsidered. Reinitiation may be considered onlywhen the QT interval decreases below 460 msecand all other abnormalities have been corrected.

Supportive and Emerging Agents

In addition to tyrosine kinase inhibitors and

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Table 1. Standards for QTc-Interval Prolongation

Grade NCI CTCAE Standard187 Proposed FDA Standard59

1 (mild) QTc 450–470 msec QTc 450–479 msec or ≥ 30 msec above baseline

2 (moderate) QTc 470–499 msec or ≥ 60 msec above baseline QTc 480–499 msec or ≥ 60 msec above baseline

3 (severe) QTc > 500 msec QTc > 500 msec

4 (life-threatening QTc > 500 msec; life-threatening signs oror disabling) symptoms (e.g., arrhythmia, chronic heart

failure); torsade de pointes

5 (fatal) DeathQTc = heart rate–corrected QT; NCI = National Cancer Institute; CTCAE = Common Terminology Criteria for Adverse Events; FDA = U.S. Foodand Drug Administration.


arsenic trioxide, other agents are listed as havingthe potential to cause QT-interval prolongation.Some data exist in the form of case reports and/orin vitro experiments for other antineoplastics andsupportive care agents such as anthracyclines,antiemetics (such as serotonin receptor antago-nists, droperidol, metoclopramide), octreotide,and tamoxifen, but there is generally littleconcern for developing QT prolongation and TdPin day-to-day practice with these agents.195–198

Recently, a black-box warning for QT prolon-gation and TdP was added to droperidol’sproduct labeling, but it has been debated whetherthis addition was necessary.199–201

New anticancer agents are likely to continue tobe evaluated for QT-interval prolongation.Histone deacetylase inhibitors such as vorinostatand romidepsin (depsipeptide) have been shownto prolong the QT interval in clinical studies.195,

196, 198–202 Baseline magnesium and potassiumlevels should be assessed before starting therapywith romidepsin, and ECG monitoring may beconsidered for those at high risk for developingQT-interval prolongation. In addition, heat-shock protein 90 inhibitors are in clinical trialsand will likely cause clinically significant QTprolongation through blocking the maturationand trafficking of KCNH2.203 Other classes in theoncology pipeline that may induce QT prolon-gation include vascular disruption agents,farnesyl protein transferase inhibitors, andprotein kinase C inhibitors.186

Conclusion

Drug-induced QT-interval prolongation repre-sents a key component of drug management forpharmacists in all areas of practice. Recognizingthe important levels of risk associated with varyingdegrees of QT prolongation conferred by drugscan prevent or reduce the risk of proarrhythmia.To properly assign a level of risk and provide anappropriate intervention to improve patient care,pharmacists need to assess baseline risk factorsfor QT prolongation and place a special emphasison the convergence of the intensity of drug-induced suppression of IKr, the ability of the drugto increase transmural dispersion of repolarization,and the ability of the offending drug to induceearly afterdepolarizations.

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Drug-Induced QT-Interval Prolongation: Considerations for Clinicians