What Clinicians Should Know About the QT Interval (2024)

ContextOf the several factors implicated in causing QT interval prolongationand torsades de pointes, errors in the use of medications that may prolongthis interval deserve special attention.

ObjectiveTo systematically summarize the available clinical data on the QT intervaland to offer improved recommendations for the use of QT-prolonging medications.

Data SourcesWe searched MEDLINE from 1966 through 2002 for all English-languagearticles related to the QT interval. Additional data sources included bibliographiesof articles identified on MEDLINE, a survey of experts, and data presentedat a meeting of experts on long QT syndrome.

Study SelectionWe selected for review registries and case series examining clinicaloutcomes of patients with prolonged QT interval and the effect of differentmethods of measurement of the QT interval on patient outcomes. Ten studieswere identified, of which 6 were included in the analysis.

Data ExtractionData quality was determined by publication in the peer-reviewed literature.

Data SynthesisOptimal measurement of the QT interval is problematic because of lackof standardization and lack of data regarding the best way to adjust for heartrate. Reliable information on the proper use of QT-prolonging medicationsis scarce. Although a QT interval of at least 500 milliseconds generally hasbeen shown to correlate with a higher risk of torsades de pointes, there isno established threshold below which prolongation of the QT interval is consideredfree of proarrhythmic risk. The risk of torsades de pointes should be assessedin patients who are about to begin taking a QT-prolonging medication. Althoughinadequate clinical studies preclude prediction of absolute risk for individualpatients, particularly high-risk situations can be defined based on clinicalvariables. We propose recommendations on proper monitoring of the QT intervalin patients receiving QT-prolonging medications.

ConclusionAlthough the use of QT-prolonging medications can predispose to torsadesde pointes, there is a relative paucity of information that can help cliniciansand patients make optimal informed decisions about how best to minimize therisk of this serious complication.

The QT interval on the electrocardiogram (ECG) has gained clinical importance,primarily because prolongation of this interval can predispose to a potentiallyfatal ventricular arrhythmia known as torsades de pointes. Multiple factorshave been implicated in causing QT prolongation and torsades de pointes. Amongthese, improper use of QT interval–prolonging medications deserves specialattention. Recently, cisapride and grepafloxacin were removed from the USdrug market because of the risk for QT prolongation and fatal arrhythmias.^1,2 The need to remove these agents fromthe market was related not just to the inherent properties of the drugs butalso to the demonstrated failure of government-mandated black box warningsand "Dear Doctor" letters to mitigate inappropriate prescribing by physicians.³

To reduce the risk of torsades de pointes, health care providers mustunderstand what is known about the QT interval. In this article, we addressthe meaning and measurement of the QT interval, describe factors that affectthe QT interval, and assess the balance of risks and benefits of QT-prolongingmedications. We also evaluate the steps that have been taken to enhance propermanagement of risk emanating from the use of QT interval–prolongingmedications.

Literature for this review was systematically identified by searchingMEDLINE for all English-language articles published from 1966 through 2002related to the QT interval (search terms: long QT syndrome, death, outcomes, registries, case series, QT interval, and measurement),reviewing bibliographies of articles identified on MEDLINE, surveying experts,and reviewing data presented at a meeting of experts on long QT syndrome (LQTS).We selected for review registries and case series examining clinical outcomesof patients with prolonged QT interval and the effect of different methodsof measurement of the QT interval on patient outcomes. Ten studies were identifiedby the search, of which 6 were included in the analysis.^4-9 Dataquality was determined by publication in the peer-reviewed literature.

The QT interval on the surface ECG is measured from the beginning ofthe QRS complex to the end of the T wave. Thus, it is the electrocardiographicmanifestation of ventricular depolarization and repolarization. This electricalactivity of the heart is mediated through channels, complex molecular structureswithin the myocardial cell membrane that regulate the flow of ions in andout of cardiac cells. The rapid inflow of positively charged ions (sodiumand calcium) results in normal myocardial depolarization. When this inflowis exceeded by outflow of potassium ions, myocardial repolarization occurs.Malfunction of ion channels leads to an intracellular excess of positivelycharged ions by way of an inadequate outflow of potassium ions or excess inflowof sodium ions. This intracellular excess of positively charged ions extendsventricular repolarization and results in QT interval prolongation.¹⁰

In the clinical setting, it is now widely recognized that typical measurementof the QT interval is subject to substantial variability, which can cloudinterpretation.^11,12 This variabilityin QT interval measurement results from biological factors, such as diurnaleffects, differences in autonomic tone, electrolytes, and drugs; technicalfactors, including the environment, the processing of the recording, and theacquisition of the ECG recording; and intraobserver and interobserver variability,resulting from variations in T-wave morphology, noisy baseline, and the presenceof U waves. Interobserver variability also results from the lack of agreementamong experts about standardizing approaches to measure the QT interval.^11,12 Although experts on the QT intervalargue that intraobserver and interobserver variability and measurement errorare higher when the corrected QT (QTc) interval is taken from computerizedECG algorithms rather than from careful high-resolution manual measurements,automated readings may be useful for rapid assessment of patient safety.¹³ Unfortunately, there is no credible empirical evidenceto support this view. In addition, as demonstrated by a recent survey of healthcare practitioners, many clinicians simply do not know how to measure theQT interval. Whereas 61% of respondents were able to identify what the QTinterval represented on an ECG, only 36% correctly measured it.¹⁴

Although it is standard practice to measure the QT interval from thebeginning of the QRS complex to the end of the T wave, the actual methodsof measurement have not been standardized. Because the QT interval is prolongedat slower heart rates and shortened at faster heart rates, many formulas havebeen proposed to adjust for these variations. Yet differences of opinion existregarding the most useful correction for heart rate.^15-18 Oneof the commonly used formulas is the Bazett formula, in which the QT intervalis adjusted for heart rate by dividing it by the square root of the R-R interval(Figure 1, A). However, this formulahas been criticized for being inaccurate at fast heart rates.¹⁹ Otherformulas are the Fridericia cube-root correction (QT interval divided by thecube root of the R-R interval) and the Framingham linear regression equation.^16,17 From an epidemiological perspective,the Framingham approach is the most sound because it is based on empiricaldata from a large population sample rather than on hypothetical reasoning.Unfortunately, none of these corrections has been examined comparatively todetermine the most effective formula in predicting which patients are at greatestrisk for torsades de pointes.

A group of experts on LQTS recently acknowledged the lack of empiricaldata in determining the best approach to measuring the QT interval. This groupconvened in August 2000 to discuss the current knowledge of LQTS (see Acknowledgment).As a result of this meeting, the panel proposed the following 4 guidelines¹³ for measuring the QT interval, based on expert opinion:

1. The QT interval should be measured manually, preferablyby using one of the limb leads that best shows the end of the T wave on a12-lead ECG.

2. The QT interval should be measured from the beginningof the QRS complex to the end of the T wave and averaged over 3 to 5 beats.U waves possibly corresponding to the late repolarization of cells in themid myocardium should be included in the measurement only if they are largeenough to seem to merge with the T wave.

3. The QT interval should be measured during peakplasma concentration of a QT-prolonging medication.

4. The QT interval should be adjusted for heart rate.Because the best way to adjust for heart rate has not been determined by prospectivestudies, the panel could not make a definitive recommendation in this regard.

Measurement of the QT interval is particularly challenging if the patientis in atrial fibrillation because the QT interval varies from beat to beatdepending on the interval between successive R waves. Unfortunately, thereis no consensus on how to measure the QT interval in this circ*mstance. Someclinicians suggest using the same steps in the aforementioned recommendationsbut further advise averaging the measured QT interval over 10 beats. Othersprefer to measure the QT intervals that follow the shortest and longest R-Rintervals and divide each by the square root of the R-R interval precedingit. The average of these intervals would then be used as the adjusted QT interval(Figure 1, B).

Measurement of the QT interval is also difficult in the setting of awide QRS complex related to either ventricular conduction defects or a pacedQRS complex. This is primarily because of the lack of a standard method tomeasure the QT interval in this setting; data on the best way to make thismeasurement do not exist. The Pfizer Tikosyn program specifies that whilethe QTc should be no more than 440 milliseconds (ms) to start dofetilide inthe setting of a narrow QRS complex, the QTc should be no more than 500 msin the setting of ventricular conduction abnormality.²⁰ Thisguidance may be used with other QT-prolonging medications until a standardmethod to measure the QT interval in the setting of ventricular conductionabnormality is identified.

Some argue that the QT interval should be measured only by cardiologists,but this suggestion is impractical. In light of the number of medicationsthat could prolong the QT interval, other health care practitioners, especiallyinternists, family practitioners, and psychiatrists, should either learn howto measure the QT interval or develop systematic approaches to ensuring thataccurate measurements are being made at the appropriate time by specialists.Indeed, nurses, physician assistants, and clinical pharmacists may play animportant role in this regard; if properly trained, it is likely that theycan be relied on to measure the QT interval. However, the use of multiplehealth care practitioners in measuring the QT interval for clinical decisionmaking needs to be tested in prospective studies.

It is important to realize that the methods proposed to correct theQT interval have primarily been evaluated for their correlation with heartrate. The formula with the best correlation with heart rate is believed tobe the most accurate. It would be of great clinical importance if these formulaswere validated prospectively and then compared with each other in adequatelysized prospective studies. In this way, it could be determined which one moststrongly correlates with an increased risk of adverse clinical events (especiallydeath). However, this endeavor would be challenging because it might be difficultto identify a patient population with an event rate high enough to provideadequate statistical power. In the absence of such studies, practitionersmust be aware of the ongoing uncertainty about the best way to adjust theQT interval.

Although it is convenient to think of QT prolongation as occurring becauseof either congenital or acquired abnormalities, the phenomenon probably mostoften involves a gene-environment interaction. Pure congenital prolongationcharacterized by lifelong, ambient QT prolongation is rare but does carrya high risk of sudden death. Several forms of congenital LQTS have been reported,and 3 forms (LQT1, LQT2,and LQT3) have been well characterized in previousstudies.²¹ These forms have been found to havedistinctly different clinical outcomes and clinical manifestations, includingfactors that trigger clinical events and ECG features.^6,22 Forexample, physical activity tends to trigger events in LQT1, auditory stimuli in LQT2, and rest or sleepin LQT3.^7,23,24 Eachform has also been characterized electrocardiographically by a specific patternof T waves.²⁵ The T wave is of long durationin LQT1, is small and/or notched in LQT2, and has an unusually long onset in LQT3.²² More important, the genotype of LQTS seems to havea significant impact on outcome.⁴ In a studyusing a large international registry of LQTS, it was noted that although therisk of cardiac events was significantly higher among patients with LQT1 and LQT2 than with LQT3, the frequency of lethal cardiac events was significantlyhigher in the LQT3 group.⁶

When exposed to QT-prolonging medications, individuals without lifelongQT prolongation may develop QT prolongation with or without torsades de pointesor may not develop QT prolongation at all. Even after adjustment for otherfactors that could prolong QT interval, some patients seem to be more likelythan others to have QT prolongation at a given dose of a drug. This observationled researchers to hypothesize that patients with acquired QT prolongationmay have a genetic predisposition for it.^8,10,26 Recentinvestigations suggest that such patients may have clinically silent genemutations that lead to overt QT prolongation only with exposure to QT-prolongingmedications.^8,10,26

It is important to note that the majority of patients with documentedacquired LQTS never experience torsades de pointes, and many patients withtorsades de pointes have a normal QT interval shortly before the event. Itappears that a variety of coincident circ*mstances, including genetic predispositionand a prolonged QT interval (which may occur precipitously and transiently),are required to precipitate torsades de pointes.

Factors that predispose to QT prolongation and higher risk of torsadesde pointes include older age, female sex, low left ventricular ejection fraction,left ventricular hypertrophy, ischemia, slow heart rate, and electrolyte abnormalitiesincluding hypokalemia and hypomagnesemia.^5,27-34 Certaindrugs also predispose to QT prolongation (broach basic end-of-life issuesand to clarify goals of treatment (Box). An extensive list of these drugs can be found at http://www.torsades.org. Regarding antiarrhythmic QT-prolonging drugs, the risk of torsadesde pointes seems to be highest within the first few days of initiating therapy.^35-37 For this reason,physicians should consider admitting patients to the hospital when startingsuch drugs, a practice most warranted among patients with structural heartdisease. Hospitalized patients can be better monitored for the warning signsthat precede torsades de pointes. In a rigorous study of patients with supraventriculartachycardias, investigators reported that a 72-hour hospitalization for initiationof antiarrhythmic therapy appeared to be cost-effective.³⁸

VERY PROBABLE

Antiarrhythmics
Amiodarone
Disopyramide
Dofetilide
Ibutilide
Procainamide
Quinidine
Sotalol

Antipsychotics
Thioridazine

PROBABLE

Antipsychotics
Pimozide
Ziprasidone

POSSIBLE IN HIGH-RISK PATIENTS

Anti-infectives
Clarithromycin
Erythromycin
Gatifloxacin
Pentamidine
Sparfloxacin

Antipsychotics
Chlorpromazine
Haloperidol
Olanzapine
Risperidone

Antidepressants
Amitriptyline
Desipramine
Imipramine
Sertraline
Venlafaxine

Other
Droperidol

IMPROBABLE

Anti-infectives
Fluconazole
Levofloxacin
Trimethoprim-sulfamethoxazole

Antidepressants
Fluoxetine
Paroxetine

Migraine Drugs
Sumatriptan
Zolmitriptan

Other
Methadone

VERY IMPROBABLE

Anti-infectives
Azithromycin
Ciprofloxacin
Clindamycin

Other
Isradipine
Nicardipine

UNKNOWN

Antipsychotics
Mesoridazine
Quetiapine

Antidepressants
Doxepin

Other
Chloroquine
Domperidone
Felbamate
Foscarnet
Fosphenytoin
Indapamide
Moexipril/hydrochlorothiazide
Octreotide
Ondansetron
Quinine
Tacrolimus
Tamoxifen
Vasopressin

*"Very probable" indicates more than 50% of respondents stated theywould always check an electrocardiogram (ECG) when starting this medication;"probable," 40%-49% of respondents stated they would always check an ECG whenstarting this medication; "possible in high-risk patients," more than 40%of respondents stated they would always check an ECG in high-risk patients;"improbable," 40%-49% of respondents stated they would never check an ECGwhen starting this medication; "very improbable," more than 50% of respondentsstated they would never check an ECG when starting this medication; and "unknown,"survey responses did not fit any of the other categories.

Several noncardiac medications can cause torsades de pointes, eitherby directly blocking potassium currents or by interacting with other medications(Table 1). These interactionscould be purely pharmacodynamic (both drugs block outward potassium currents),purely pharmaco*kinetic (one drug interferes with the clearance of another),or of mixed pharmacodynamic and pharmaco*kinetic origin. An example of a purelypharmacodynamic interaction is that of quinidine and sotalol—both blockoutward potassium currents. The interaction between cisapride and ketoconazoleprovides an example of a purely pharmaco*kinetic interaction. Ketoconazoleinhibits the cytochrome P-450 3A4 isoenzyme that metabolizes cisapride, andthis inhibition results in increased cisapride levels that may augment QTprolongation and result in torsades de pointes. An example of a mixed interactionis that of erythromycin and cisapride. Not only do both drugs block potassiumcurrents, but erythromycin also inhibits cytochrome P-450 3A4.

When drugs that can prolong the QT interval are used, physicians shouldensure that the potential benefits are clinically important and the risksare minimized. Specifically, they should determine whether the likely benefitjustifies the potential risk and should do so in light of the treated condition,the specific circ*mstances of the patient, and other available therapeuticoptions. For example, a QT interval–prolonging medication is the appropriatechoice if it has a proven salutary effect on survival. However, the majorityof these medications have not been proven to improve survival. Another strongreason to use such a medication is if it will significantly improve symptomsand morbidity relative to other treatment options. In this regard, medicationsthat commonly cause significant QT prolongation must be used only if no othermedications have a comparable beneficial effect in treating the same condition,if they are known to be or are potentially superior to other available medications,or if other medications carry other more significant risks.

The benefit of antiarrhythmic therapy, for example, is clearest whenit results in the immediate termination of a sustained ventricular arrhythmia.When antiarrhythmic therapy is used for patients with symptoms of chronicarrhythmias, the risk may outweigh the benefit because few studies have showna significant effect of antiarrhythmic therapy in this situation.⁴³ The risks are particularly disconcerting with antiarrhythmicmedications that have been shown to worsen survival.^44-46

The risk of torsades de pointes should be assessed for patients whoare about to begin taking a QT-prolonging medication. Although inadequateclinical studies preclude prediction of absolute risk for individual patients,particularly high-risk situations can be defined based on clinical variables.This estimate requires knowledge of the drug's properties, including routeof elimination and drug interactions, familiarity with factors that predisposeto torsades de pointes, and baseline measurement of the QT interval. For example,sotalol and dofetilide are renally cleared; thus, it is important to monitorthe renal function of patients starting these medications and to reduce thedose if renal function is impaired. To avoid risk of torsades de pointes,physicians should be aware that dofetilide has significant interactions withcommonly used drugs such as verapamil and trimethoprim-sulfamethoxazole.

Among the factors that could predispose to torsades de pointes, hypokalemiaand hypomagnesemia are particularly significant and remediable. Physiciansshould monitor potassium and magnesium levels in patients who start antiarrhythmicQT-prolonging medications and supplement them as needed, especially in patientstaking other medications that can cause hypokalemia or hypomagnesemia.

Measurement of the baseline QT interval may also be of critical importancewhen assessing the risk of torsades de pointes in a particular patient. However,with many drugs that can cause QT interval prolongation, the risk of torsadesde pointes is so low that the majority of experts do not consider measurementof the QT interval to be cost-effective. For some of these drugs, the QT intervalmust be measured in thousands of patients to identify 1 person at risk ofsignificant QT prolongation. The cost of this practice, in our opinion, outweighsthe benefits. In a survey completed by LQTS experts, the majority would alwayscheck an ECG before and after starting an antiarrhythmic medication, one thirdto half would always check an ECG before and after starting an antipsychoticdrug, and less than one third would always check an ECG before and after startingan anti-infective or antidepressant (Box). Based on the results of this survey,we propose the following recommendations on the proper monitoring of the QTinterval in patients receiving QT-prolonging medications. First, an ECG shouldbe routinely checked before and after starting an antiarrhythmic agent thatcan prolong the QT interval (Table 1).If the patient has a prolonged QTc at baseline (>450 ms in men and >460 msin women in the absence of interventricular conduction defects), it is importantto try to avoid all QT-prolonging medications.⁴⁷ Althoughthis is not an absolute contraindication to starting QT-prolonging drugs,expert opinion should be sought before such drugs are started. If the patientis already taking an antiarrhythmic agent with this potential and anotherdrug needs to be added, it is important to know whether the new drug may alsoprolong the QT interval (Box) or can interact with the antiarrhythmic medication(Table 1). If one of these eventsis a possibility, an alternative agent should be considered. If no alternativeis available and the drug being added is necessary, an ECG should be performedto monitor the QT interval before and after starting the new drug. Indeed,concurrent prescribing of QT-prolonging drugs is common in the outpatientsetting; however, the clinical consequences of this practice are not known.⁴⁸

Second, an ECG should be checked before and after starting a drug ifthe drug is one that has been deemed by the LQTS experts to have very probable,probable, or possible potential for causing QT prolongation(Box). If thedrug was deemed by the LQTS experts to have improbable or very improbablepotential for causing QT prolongation, checking an ECG before and after startingthe drug, especially in low-risk patients, may not be necessary(Box).

Despite these recommendations, uncertainty remains regarding the specificrelationship between the degree of QT prolongation and the risk of life-threateningarrhythmias with each individual drug. A QT interval of at least 500 ms generallyhas been shown to correlate with a higher risk of torsades de pointes, butthere is no established threshold below which prolongation of the QT intervalis considered free of proarrhythmic risk.^9,49 Thus,physicians are left with great uncertainty regarding when to stop a QT-prolongingmedication. Respondents to the survey on LQTS were more likely to stop a QT-prolongingmedication for a QT of 520 ms than for a QT of 500 ms. However, it shouldbe emphasized that there is no clear-cut consensus on the degree of drug-inducedQT prolongation that should require drug discontinuation.

Despite the clinical importance of the QT interval, definitive informationon the clinical epidemiology of the QT interval and its prolongation by medicationsis surprisingly lacking. Few studies have evaluated the relationship betweenthe QT interval and patient outcomes. Even for commonly used antiarrhythmicdrugs like sotalol and amiodarone, this relationship has not been adequatelyexplored. The newly marketed compound dofetilide is the only medication forwhich such a relationship has been extensively explored and reported.^20,50 It has been demonstrated that a linearrelationship exists between the plasma concentration of dofetilide and themean change from baseline QTc. It has also been shown that a relationshipexists between the dose and concentration of dofetilide and its efficacy aswell as the risk of torsades de pointes associated with its use.²⁰ Adirect correlation between rate of torsades de pointes and increase from baselineQTc has also been proven for dofetilide.²⁰ Knowledgeof these relationships should enable an astute clinician to make a semiquantitativedecision about the use and dosing of dofetilide by weighing the risks andthe proposed benefits of preventing recurrent atrial fibrillation or flutter.Likewise, detailed dosing and monitoring recommendations are part of the productlabeling for the 2 most recently approved antiarrhythmic agents, dofetilideand sotalol. The product labeling for medications that could prolong the QTinterval contains warnings regarding their effect on the QT interval thatclinicians who prescribe these drugs should be aware of.

Some antipsychotic drugs have been shown to prolong the QT interval.^51,52 A recent clinical epidemiologicalstudy has demonstrated a direct relationship between the dose of the olderantipsychotic drugs and the risk of sudden death, but the QT interval wasnot measured in this study to examine its correlation with sudden death.⁵³ More recently, a population-based study confirmedthat antipsychotic drugs known to produce greater QT prolongation than otherantipsychotic drugs were associated with a higher risk of cardiovascular death.⁵⁴ Of note, no consensus exists about the relative likelihoodof torsades de pointes among patients treated with different antipsychoticdrugs, nor is there a prospective study delineating the absolute risk of arrhythmia.This paucity of data leaves the practitioner in a lurch concerning therapeutics:the need for antipsychotic therapy cannot be ignored, and the patients withthe most severe psychoses may need the highest doses of drugs. These samepatients are also at higher risk of nonadherence to prescribed therapies (includingomitting and taking excessive amounts of needed therapies) and to the developmentof other conditions, such as electrolyte depletion or sympathetic overactivity,that may predispose to torsades de pointes.

Furthermore, no data exist on how and when to monitor the QT intervalwhen various antipsychotic drugs are used. Until more data are obtained, theBox should provide some guidance in this regard. Of note, because of the concernraised about risk of QT prolongation with ziprasidone, a trial has been launchedthat will randomly assign more than 15000 patients with schizophreniato ziprasidone and olanzapine. This trial's primary end point is all-causemortality (Brian Strom, MD, unpublished data, 2002).

Quinolone antibiotics also pose a difficult dilemma. They are used ona wide scale for common infections without checking the ECG, an approach generallyagreed on by the aforementioned LQTS experts (Box). Yet, sporadic episodesof torsades de pointes have been reported in association with quinolones,⁵⁵ and there is evidence that quinolones are commonlycoprescribed with other QT-prolonging drugs.⁴⁸ Becauseof the immense uncertainly surrounding the effects of concurrent use of QT-prolongingdrugs, no preventive approach is currently recommended other than trying toavoid quinolones in patients taking other QT-prolonging drugs or with otherrisk factors.

We have thus far discussed the role of health care practitioners inmanagement of the risk of QT-prolonging medications in treating individualpatients. The scope of risk management, however, extends beyond health carepractitioners and includes regulators, pharmaceutical companies, and investigators.For example, regulators came to realize the potential of noncardiovasculardrugs to prolong the QT interval and potentially result in life-threateningarrhythmias. Thus, regulatory guidances on drug development advise that allnew drugs be evaluated for possible effects on cardiac repolarization.⁵⁶

Guidance in that regard had until recently been sketchy. The US Foodand Drug Administration's (FDA's) International Conference on Harmonization(ICH) S7A guidance included only a general mention of cardiovascular testingof new drugs, which led to a lack of standardization of preclinical and clinicalcardiovascular drug testing.⁵⁷ For example,it was not specified whether drug testing should explore the effect of thedrug on the QTc or the uncorrected QT interval. The label for dofetilide relieson the QTc (using the Bazett formula), whereas the label for sotalol usesthe uncorrected QT interval.

In February 2002, the ICHS7B guidance was proposed and, although ithas not been finalized, provides more specific direction for cardiac safetytesting of new drugs.⁵⁶ The ICHS7B specifiesthat new drugs should be tested in 3 preclinical assays: the human ether-a-go-go–relatedgene channel assay to check for blockade of the IKr channel, the action potentialduration (APD) assay that uses canine Purkinje fibers to check for significantAPD prolongation, and an in vivo rodent ECG with a detailed description oftest methods. The guidance also suggests that if the tested drug is shownin preclinical assays to cause some blockade of the IKr channel or prolongationof the APD, its potential clinical risks should be evaluated in carefullydesigned clinical trials. Those studies must have adequate sample sizes andshould ensure frequent recording of ECGs.

Although the preliminary ICHS7B guidance lacks data on the standardsof clinical evaluation, it is hoped that the final version will provide specificinformation on the clinical evaluation standards for compounds with and withouthazardous QT signals in preclinical testing. It is well known that many companiesare screening compounds and discontinuing those in which a flag is raisedat the preclinical level. The potential advantage of this approach is obvious:it prompts stopping the drug's development before the complex clinical manifestationsbecome an issue. However, the list of QT-prolonging drugs includes severalthat provide substantial health benefits, and it would be unfortunate if drugswith the potential for a highly positive overall impact were dropped earlyin development.

The ICHS7B is one of many initiatives recently developed to improvethe cardiac safety of new drugs. In November 2001, the FDA announced thatas of the fall of 2002, sponsors must submit ECG raw data in digital formatwith annotations to enable the FDA to independently assess the cardiac safetyprofile of new drugs.⁵⁸ The FDA is also workingwith Health Canada to develop guidance on the assessment of QT prolongationduring clinical trials.⁴⁷ The final guidanceis still pending. Through these initiatives, regulators are hoping to standardizepreclinical and clinical cardiovascular testing of all drugs, an importantendeavor in enhancing efforts at risk management of QT-prolonging medications.Equally important, however, is the clear dissemination of these guidelinesand clear labeling of drugs with QT-prolonging potential, specifically asthey relate to interactions that could augment prolongation.

In this article, we present an update of the current knowledge of theQT interval and proposed ways to enhance risk management of QT-prolongingmedications. As more knowledge about this important topic is gained, it iscritical that this knowledge be disseminated in a timely fashion and in astyle that is easily comprehended by clinicians. Perhaps the most surprisingfinding of our review is the relative paucity of information that can helpclinicians and patients make informed decisions about drugs that can prolongthe QT interval.