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Managing Drug-Induced QT Prolongation in Clinical Practice Rani Khatib ,1,2,3 Fatima R N Sabir,1 Caroline Omari,1 Chris Pepper,3 Muzahir Hassan Tayebjee3

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Managing Drug-Induced QT Prolongation in Clinical Practice Rani Khatib ,1,2,3 Fatima R N Sabir,1 Caroline Omari,1 Chris Pepper,3 Muzahir Hassan Tayebjee3 Postgrad Med J: first published as 10.1136/postgradmedj-2020-138661 on 29 October 2020. Downloaded from Review Managing drug-induced QT prolongation in clinical practice Rani Khatib ,1,2,3 Fatima R N Sabir,1 Caroline Omari,1 Chris Pepper,3 Muzahir Hassan Tayebjee3 1Medicines Management & ABSTRACT been associated with increases in the QT interval.23 Pharmacy Services, Leeds Many drug therapies are associated with prolongation of Nonetheless, LQTS is typically rare, with an esti- Teaching Hospitals NHS Trust, – Leeds, UK the QT interval. This may increase the risk of Torsades de mated prevalence of approximately 1 in 2000 2500 4 2Leeds Institute of Pointes (TdP), a potentially life-threatening cardiac live births. Many patients are asymptomatic and Cardiovascular and Metabolic arrhythmia. As the QT interval varies with a change in thus congenital LQTS is often discovered inciden- Medicine, University of Leeds, heart rate, various formulae can adjust for this, tally on an ECG, by family history, or after even- Leeds, UK 2 3 producing a ‘corrected QT’ (QTc) value. Normal QTc Cardiology Department, Leeds tually experiencing symptoms such as syncope. Teaching Hospitals NHS Trust, intervals are typically <450 ms for men and <460 ms for Acquired QT prolongation is more prevalent than Leeds, UK women. For every 10 ms increase, there is a ~5% the congenital form and is often a result of structural increase in the risk of arrhythmic events. When heart disease (eg, myocardial infarction, heart fail- Correspondence to prescribing drugs associated with QT prolongation, ure, left ventricular hypertrophy) and drugs that Rani Khatib, Cardiology three key factors should be considered: patient-related prolong the QT interval.5 Many other individual Department, Leeds, UK; risk factors (eg, female sex, age >65 years, uncorrected [email protected] risk factors, detailed later, may also predispose to electrolyte disturbances); the potential risk and degree the prolongation of QT interval.6 of QT prolongation associated with the proposed drug; Received 11 July 2020 Whatever the underlying cause, prolongation Revised 14 September 2020 and co-prescribed medicines that could increase the risk of the QT interval is clinically significant. Accepted 24 September 2020 of QT prolongation. To support clinicians, who are likely Syncope, cardiac arrest and sudden death typi- to prescribe such medicines in their daily practice, we cally increase with increasing QT although assess- developed a simple algorithm to help guide clinical ment is complicated by the relationship being management in patients who are at risk of QT non-linear (figure 2).78QT prolongation may prolongation/TdP, those exposed to QT-prolonging be accompanied by arrhythmogenic after- medication or have QT prolongation. depolarisations, and predisposes patients to a condition known as Torsades de Pointes (TdP), a potentially life-threatening form of polymorphic ventricular tachycardia.910For INTRODUCTION some individuals, TdP may occur with modest The QT interval is the time from the onset of ven- QT prolongation, whereas others may experience 1 http://pmj.bmj.com/ tricular depolarisation to the end of ventricular no effects even with markedly prolonged QT. repolarisation; the latter accounting for the majority There are multiple factors that can increase the 11 of the interval as depolarisation in the absence of risk of TdP (table 1). Many are not modifiable and conduction disease is rapid (figure 1).1 The under- hence not amenable to specific medical interven- lying physiological processes are a result of move- tion. However, the most common environmental ment of sodium, potassium and calcium via specific stressor resulting in acquired LQTS is the use of receptors located in the cell membrane and endo- particular drug therapies,12 which can often be on September 26, 2021 by guest. Protected copyright. plasmic reticulum. Sodium channels are mainly modified to reduce the risk of QT interval prolonga- responsible for depolarisation; however, the late tion and hence of TdP. sodium current contributes to repolarisation. The mechanisms that underlie the impact of cer- Calcium channels are important in maintaining the tain drugs on the QT interval have not been fully plateau phase of the action potential, and potassium elucidated. However, in most instances, it is thought channels play a major role in repolarisation. to relate to effects on specific potassium channels 9 Abnormalities of these receptors can have profound known as rapid delayed rectifiers (IKr). These play ©Author(s)(ortheir effects on the cardiac action potential, for example, a crucial role in cardiac repolarisation and their employer(s)) 2020. Re-use abnormalities in the potassium channels can pro- inhibition extends individual action potentials and permitted under CC BY-NC. long repolarisation.1 The latter can result in QT hence prolongs the QT interval.9 For example, the No commercial re-use. See prolongation on the ECG. antipsychotic medication, haloperidol, is a more rights and permissions. Published by BMJ. Causes of QT prolongation can be divided into specific blocker of the IKr potassium channel and two categories: congenital or acquired. Congenital prolongs QT (by 15–30 ms) in a dose-dependent To cite: Khatib R, Sabir long QTsyndrome (LQTS) is an inherited disease, it manner; and it is known to cause TdP.13 FRN, Omari C, et al. has several forms, and is caused by mutations in the Antiarrhythmic agents such as quinidine and diso- Postgrad Med J Epub ahead genes encoding specific ion-channel subunits or reg- pyramide are known to block both the sodium and of print: [please include Day 2 Month Year]. doi:10.1136/ ulatory proteins. Polymorphisms in various other potassium channels, and are associated with QT postgradmedj-2020- genes—for example that encoding the nitric oxide interval prolongation. TdP was reported with these 138661 synthase 1 adaptor protein (NOS1AP)—have also drugs at therapeutic or subtherapeutic doses.13 Khatib R, et al. Postgrad Med J 2020;0:1–7. doi:10.1136/postgradmedj-2020-138661 1 Postgrad Med J: first published as 10.1136/postgradmedj-2020-138661 on 29 October 2020. Downloaded from Review Table 1 Patient risk factors for Torsades de pointes with drug-induced QT prolongation.10 14 15 Non-modifiable Potentially modifiable ► Congenital long QT syndrome* ► Bradycardia ► QT-prolonging drugs should not ► Uncorrected electrolyte distur- be used in these patients bances (hypokalaemia, hypo- ► Structural heart diseases, such magnesaemia, hypocalcaemia) as heart failure (low ventricular ► Recent cardioversion with ejection fraction), left ventricular a QT-prolonging drug hypertrophy, and myocardial infarction ► Thyroid disease (not treated); more common with hypothyroidism ► Impaired hepatic or renal func- tion (could affect drug metabolism) ► Female sex ► Age >65 years *Congenital long QT syndrome is rare (estimated prevalence: ~1 in 2000–2500 infants) but is associated with a risk of arrhythmia and premature sudden death.4 To reduce the risk of TdP, healthcare professionals should be aware of drugs that can prolong the QT interval. However, few recommendations exist for managing the risk of drug-induced QT prolongation in clinical practice. Many studies have intro- Figure 1 Measurement of the QT interval. duced risk models for predicting prolongation of the QT – interval/TdP,16 18 but these tools are often not generalisable across all populations. They also do not provide guidance on how to manage high-risk cases once identified. In this review, we provide guidance on what should be considered when prescrib- ing QT-prolonging medications in any speciality, in order to rationalise the associated risks and benefits and support clini- cians in making clinical judgements in a holistic manner. We also describe the recommended steps in managing QT prolongation if it arises. WHAT IS A NORMAL QT INTERVAL AND WHAT LEVEL OF http://pmj.bmj.com/ INCREASE IS SIGNIFICANT? The QT interval should be assessed from a good-quality ECG readout that is free from noise artefacts and has a stable baseline. It should be determined as a mean value based on at least 3–5 cardiac cycles.19 It is important to review the entire ECG before specifically on September 26, 2021 by guest. Protected copyright. assessing the QT interval, to ensure that other conditions such as bradycardia, myocardial infarction or cardiomyopathy are not responsible for any changes in QT. In addition, the QT interval cannot be assessed in the usual way in patients whose QRS dura- 19 Figure 2 Non-linear relationship in the estimated rate of patients being tion is abnormal (eg, those with bundle branch block). free of cardiac events at 40 years of age and QT interval corrected for Even in patients with an otherwise normal ECG readout, ana- heart rate (QTc). The study included 647 patients from families with lysis of the QT interval is made more difficult by substantial 1 long-QT syndrome divided into four quartiles based on QTc interval. natural variability. For example, it is typically prolonged at ‘Cardiac events’ were defined as the occurrence of syncope, cardiac arrest slower heart rates and shortened when heart rate is increased. or sudden death, and these increased non-linearly with increasing QTc. However, various formulae have been proposed to adjust for 1 Data were extracted from a Kaplan–Meier survival graph presented in these variations, thus producing a ‘corrected QT’ (QTc) value. Priori et al (2003)8 using WebPlotDigitizer v3.9. The most frequently
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