CLINICAL CARDIOLOGY CLINICIAN’S CORNER What Clinicians Should Know About the QT Interval Sana M. Al-Khatib, MD, MHS Context Of the several factors implicated in causing QT interval prolongation and Nancy M. Allen LaPointe, PharmD torsades de pointes, errors in the use of medications that may prolong this interval deserve special attention. Judith M. Kramer, MD, MS Objective To systematically summarize the available clinical data on the QT interval Robert M. Califf, MD and to offer improved recommendations for the use of QT-prolonging medications. HE QT INTERVAL ON THE ELEC- Data Sources We searched MEDLINE from 1966 through 2002 for all English- trocardiogram (ECG) has language articles related to the QT interval. Additional data sources included bibliog- gained clinical importance, raphies of articles identified on MEDLINE, a survey of experts, and data presented at primarily because prolonga- a meeting of experts on long QT syndrome. Ttion of this interval can predispose to Study Selection We selected for review registries and case series examining clini- a potentially fatal ventricular arrhyth- cal outcomes of patients with prolonged QT interval and the effect of different meth- mia known as torsades de pointes. Mul- ods of measurement of the QT interval on patient outcomes. Ten studies were iden- tified, of which 6 were included in the analysis. tiple factors have been implicated in causing QT prolongation and torsades Data Extraction Data quality was determined by publication in the peer-reviewed de pointes. Among these, improper use literature. of QT interval–prolonging medica- Data Synthesis Optimal measurement of the QT interval is problematic because of tions deserves special attention. Re- lack of standardization and lack of data regarding the best way to adjust for heart rate. cently, cisapride and grepafloxacin were Reliable information on the proper use of QT-prolonging medications is scarce. Al- removed from the US drug market be- though a QT interval of at least 500 milliseconds generally has been shown to corre- late with a higher risk of torsades de pointes, there is no established threshold below cause of the risk for QT prolongation which prolongation of the QT interval is considered free of proarrhythmic risk. The 1,2 and fatal arrhythmias. The need to re- risk of torsades de pointes should be assessed in patients who are about to begin tak- move these agents from the market was ing a QT-prolonging medication. Although inadequate clinical studies preclude pre- related not just to the inherent prop- diction of absolute risk for individual patients, particularly high-risk situations can be erties of the drugs but also to the dem- defined based on clinical variables. We propose recommendations on proper moni- onstrated failure of government- toring of the QT interval in patients receiving QT-prolonging medications. mandated black box warnings and Conclusion Although the use of QT-prolonging medications can predispose to tor- “Dear Doctor” letters to mitigate inap- sades de pointes, there is a relative paucity of information that can help clinicians and propriate prescribing by physicians.3 patients make optimal informed decisions about how best to minimize the risk of this To reduce the risk of torsades de serious complication. pointes, health care providers must un- JAMA. 2003;289:2120-2127 www.jama.com derstand what is known about the QT interval. In this article, we address the METHODS 2002 related to the QT interval (search meaning and measurement of the QT Literature for this review was system- terms: long QT syndrome, death, out- interval, describe factors that affect the atically identified by searching comes, registries, case series, QT inter- QT interval, and assess the balance of MEDLINE for all English-language ar- val, and measurement), reviewing bib- risks and benefits of QT-prolonging ticles published from 1966 through liographies of articles identified on medications. We also evaluate the steps Author Affiliations: Duke Center for Education and Johnson & Johnson, Pfizer, and Eli Lilly, which all sell that have been taken to enhance proper Research on Therapeutics, Duke Clinical Research In- QT-prolonging drugs described in the article. None management of risk emanating from stitute, Durham, NC. of these research grants pertain to QT-prolonging Financial Disclosures: AstraZeneca and GlaxoSmith- drugs. the use of QT interval–prolonging Kline (GSK) have contributed unrestricted funds to Corresponding Author and Reprints: Sana M. Al- medications. projects of the Duke Center for Education and Re- Khatib, MD, MHS, Duke Clinical Research Institute, search on Therapeutics. Dr Al-Khatib is involved in a PO Box 17969, Durham, NC 27715 (e-mail: alkha001 research project sponsored and funded by GSK. This @mc.duke.edu). See also p 2041 and Patient Page. project is not related to the QT-prolonging drugs made Clinical Cardiology Section Editor: Michael S. Lauer, by GSK. Dr Califf has received research funding from MD, Contributing Editor. 2120 JAMA, April 23/30, 2003—Vol 289, No. 16 (Reprinted) ©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 THE QT INTERVAL MEDLINE, surveying experts, and re- Figure. Measuring the QT Interval in Different Clinical Scenarios viewing data presented at a meeting of experts on long QT syndrome (LQTS). A Normal Sinus Rhythm B Atrial Fibrillation We selected for review registries and case series examining clinical out- RR RR comes of patients with prolonged QT 1 2 interval and the effect of different meth- ods of measurement of the QT inter- RR val on patient outcomes. Ten studies R were identified by the search, of which P T 6 were included in the analysis.4-9 Data Q quality was determined by publica- S QT 1 QT 2 tion in the peer-reviewed literature. QT QT1 QT2 QT QTc = QTc = WHAT IS THE QT INTERVAL QTc = 1 √ 2 √ RR1 RR2 AND HOW SHOULD IT BE √RR Bazett Formula MEASURED? QTc + QTc = 1 2 QTc The QT interval on the surface ECG is 2 measured from the beginning of the QRS complex to the end of the T wave. Thus, it is the electrocardiographic QTc indicates corrected QT interval; RR, R-R interval. A, Normal sinus rhythm; the Bazett formula is used to correct the QT interval for the heart rate. B, Atrial fibrillation; QT interval is calculated by taking the average of manifestation of ventricular depolar- QT intervals with shortest and longest preceding R-R intervals. ization and repolarization. This elec- trical activity of the heart is mediated through channels, complex molecular ity, resulting from variations in T-wave longed at slower heart rates and short- structures within the myocardial cell morphology, noisy baseline, and the ened at faster heart rates, many formulas membrane that regulate the flow of ions presence of U waves. Interobserver vari- have been proposed to adjust for these in and out of cardiac cells. The rapid ability also results from the lack of variations. Yet differences of opinion ex- inflow of positively charged ions (so- agreement among experts about stan- ist regarding the most useful correc- dium and calcium) results in normal dardizing approaches to measure the tion for heart rate.15-18 One of the com- myocardial depolarization. When this QT interval.11,12 Although experts on the monly used formulas is the Bazett inflow is exceeded by outflow of po- QT interval argue that intraobserver and formula, in which the QT interval is ad- tassium ions, myocardial repolariza- interobserver variability and measure- justed for heart rate by dividing it by tion occurs. Malfunction of ion chan- ment error are higher when the cor- the square root of the R-R interval nels leads to an intracellular excess of rected QT (QTc) interval is taken from (FIGURE, A). However, this formula has positively charged ions by way of an in- computerized ECG algorithms rather been criticized for being inaccurate at adequate outflow of potassium ions or than from careful high-resolution fast heart rates.19 Other formulas are the excess inflow of sodium ions. This in- manual measurements, automated Fridericia cube-root correction (QT tracellular excess of positively charged readings may be useful for rapid assess- interval divided by the cube root of ions extends ventricular repolariza- ment of patient safety.13 Unfortu- the R-R interval) and the Framingham tion and results in QT interval prolon- nately, there is no credible empirical linear regression equation.16,17 From gation.10 evidence to support this view. In addi- an epidemiological perspective, the In the clinical setting, it is now widely tion, as demonstrated by a recent sur- Framingham approach is the most recognized that typical measurement of vey of health care practitioners, many sound because it is based on empirical the QT interval is subject to substan- clinicians simply do not know how to data from a large population sample tial variability, which can cloud inter- measure the QT interval. Whereas 61% rather than on hypothetical reason- pretation.11,12 This variability in QT in- of respondents were able to identify ing. Unfortunately, none of these cor- terval measurement results from what the QT interval represented on an rections has been examined compar- biological factors, such as diurnal ef- ECG, only 36% correctly measured it.14 atively to determine the most effective fects, differences in autonomic tone, Although it is standard practice to formula in predicting which patients are electrolytes, and drugs; technical fac- measure the QT interval from the be- at greatest risk for torsades de pointes. tors, including the environment, the ginning of the QRS complex to the end A group of experts on LQTS re- processing of the recording, and the ac- of the T wave, the actual methods of cently acknowledged the lack of em- quisition of the ECG recording; and in- measurement have not been standard- pirical data in determining the best ap- traobserver and interobserver variabil- ized.