Drug Induced QTc Prolongation

Publication: 03/05/2017  --
Last review: 16/07/2019  
Next review: 16/07/2022  
Clinical Guideline
CURRENT 
ID: 5011 
Approved By: LTHT Drug and Therapeutics Group and Leeds Area Prescribing Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2019  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Drug Induced QTc Prolongation

Introduction

Prolongation of the QTc (corrected QT) interval can cause a potentially life threatening form of polymorphic ventricular tachycardia termed “torsades de pointes” (TdP).While this can be self-limiting and transient it may degenerate into potentially fatal ventricular fibrillation. Whilst the risk of TdP increases with increasing QTc the relationship is imperfect and TdP can occur even with modest QTc prolongation or not at all despite a markedly abnormal QT. The risk is further influenced by a variety of additional factors detailed below.

In recent years the Medicines and Healthcare products Regulatory Agency (MHRA) has released a number of warnings relating to drug-induced QTc prolongation for some commonly used drugs (e.g. domperidone, ondansetron and hydroxyzine). Some drugs (e.g. amiodarone) can markedly prolong QTc but rarely cause TdP.

Healthcare professionals should be aware of drugs which prolong the QTc interval. Few recommendations exist for managing the risk of drug-induced QTc prolongation in clinical practice. This document provides general guidance of what should be considered when prescribing medicines which prolong QTc. Prescribers need to individually assess the risk for each patient and exercise clinical judgment when initiating QTc prolonging medicines.

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Basic Considerations

The following should be considered and taken into account when assessing the risk of the QTc prolongation and action needed:

1) What is a normal QTc interval and what change is considered significant?

  • Normal QTc intervals are <440ms for men and <460ms for women
  • Changes of less than 20ms are generally considered NOT to increase the risk of arrhythmic events.
  • In general, for every 10ms increase in the QT interval there is a 5% increase in the risk of arrhythmic events
  • A change over baseline of >20ms should raise concern. A change of >60ms very significantly increases the risk of an arrhythmic event.
  • Any change to over 500ms, regardless of the level over baseline, would also be a significant concern.

2) Individual patient’s risk factors which increase the risk of TdP with QTc prolonging drugs include:

Non-modifiable

  • Congenital Long QT Syndrome (CLQTS)
    • CLQTS is associated with a risk of arrhythmia and premature sudden death. CLQTS is rare, with an estimated prevalence of approximately 1 in 2,000 infants.
    • QTc prolonging drugs should not be used in patients with CLQTS.
  • Structural heart disease such as heart failure, left ventricular hypertrophy and myocardial infarction
  • Thyroid Disease (not treated) more common with hypothyroidism.
  • Impaired hepatic/renal function (due to effects on drug metabolism)
  • Female gender
  • Increased age (>65 years old)

Potentially Modifiable

  • Bradycardia
  • Uncorrected electrolyte disturbances (hypokalaemia, hypomagnesaemia, hypocalcaemia)
  • Recent cardioversion with QT-prolonging drug

Most clinical cases of drug-induced QTc prolongation occur in the presence of at least one of these risk factors, and over 70% occur in the presence of two or more risk factors.

3) The degree of the potential risk and degree of QTc prolongation that can be induced by the drug.

  • The extent of drug induced QTc prolongation varies between drugs and individuals. (e.g. citalopram 20 mg daily has been shown to cause a mean change in baseline QTc of 7.5 ms, whereas clarithromycin increased QTc interval by of less than 5ms).
  • QTc prolongation is generally dose dependent.
  • For some drugs the level of risk is categorised (e.g. “high risk”, “some risk” or “potential to cause QTc prolongation and/or TdP”). However, for some drugs it is necessary to review original reports to assess level of risk.
  • Information on the potential for medicines to cause prolongation can be found in:
    • Stockley’s Drug Interactions (limited access via www.medicinescomplete.com) see table below.
    • CredibleMeds® (American resource) (www.crediblemeds.org). It categorised risk as follows:
      • Known Risk of TdP
        Drugs that prolong the QTc interval AND are clearly associated with a known risk of TdP, even when taken as recommended.
      • Possible Risk of TdP
        Drugs that can cause QT prolongation BUT currently lack evidence for a risk of TdP when taken as recommended
      • Conditional Risk of TdP
        Drugs that are associated with TdP BUT only under certain conditions of their use (e.g. excessive dose, in patients with conditions such as hypokalaemia, or when taken with interacting drugs) OR by creating conditions that facilitate or induce TdP (e.g. by inhibiting metabolism of a QT-prolonging drug or by causing an electrolyte disturbance that induces TdP.)
      • Drugs to Avoid in Congenital Long QT
        Drugs that pose a high risk of TdP for patients with CLQTS and include all those in the above three categories (KR, PR & CR) PLUS additional drugs that do not prolong the QT interval per se but which have a Special Risk (SR) because of their other actions
    • manufacturer’s information (www.medicines.org.uk)
    • Individual MHRA alerts in Drug Safety Update (https://www.gov.uk/drug-safety-update?keywords=QT), for example citalopram, ondansetron, domperidone, hydroxyzine

4) Drug interactions can increase the risk of QTc prolongation by:

  • Pharmacodynamic Interaction - Co-prescribing more than one drug that prolongs the QTc interval.
  • Pharmacokinetic Interaction - by affecting the metabolism of drugs that are known to increase risk of QTc prolongation.
  • Electrolyte changes - drugs that lead to hypokalaemia and hypomagnesaemia thereby increasing the risk of QTc prolongation. e.g. diuretics causing hypokalaemia.

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Practical Approach

Before starting a medicine that may prolong the QTc interval, the prescriber should consider the degree of risk posed by the drug, individual patient risk factors and other medicines that patient is already prescribed, and balance it against the individual benefits of treatment with that particular drug.

The concurrent use of drugs that have a high risk of prolonging the QTc interval should be avoided.

If a QT prolonging drug is considered appropriate, then consider the following (see Figure 1):

  • Correct modifiable risk factors as much as possible in all patients (e.g. correct hypokalaemia, stop medicines that are not needed) and aim for potassium closer to the higher end of the range.
  • Drug carries a low risk of QTc prolongation and no other drugs that prolong QTc were co-prescribed
    • Treat, no monitoring
  • QTc prolongation from the drug is possible (e.g. listed as a potential side effect)
    • No patient risk factors or co-prescribing of other medicines that prolong QTc - treat, no monitoring
    • Patient risk factors present (including pre-existing QTc prolongation) - treat, but monitor baseline
      ECG and repeat once drug reaches steady state.
    • Patient has congenital long QT syndrome - seek alternatives
  • Drug carries a high risk of QTc prolongation (e.g. listed as a caution or contraindication in product information)
    • No patient risk factors - treat, check baseline ECG, may repeat once drug reaches steady state, no regular ECG monitoring is needed if patient is asymptomatic.
    • Patient risk factors present - treat, check baseline ECG, repeat once drug reaches steady state ECG, and as appropriate.
    • Patient has pre-existing QT prolongation or congenital long QT syndrome - seek alternatives
  • Patients should be educated on the common symptoms of cardiac arrhythmias such as dizziness, palpitations and syncope, and advised on when to seek medical attention.
  • Any patient who presents with palpitations, light headedness or dizziness whilst on a medicine with the potential to prolong the QT interval should be offered an ECG, regardless of their risk factors

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Monitoring

It is not practical to recommend an ECG every time a QTc prolonging medicine is prescribed. Currently, there are no published guidelines on when to undertake ECG monitoring and follow-up for those patients. Where monitoring is recommended:

1. Carry out a baseline ECG, repeated when drug levels are likely to be at steady state (generally around 4-5 half-lives).

2. Consider repeating the ECG after dose changes.

3. Be sure it is clear who is responsible for monitoring the ECG, and that they understand how to interpret any QTc changes.

4. If there is a significant change in a patient’s QTc interval (i.e. an increment >50ms or absolute value >500ms), check (and correct) any electrolyte imbalances. If this does not resolve the prolonged QTc, consider a dose reduction or stopping the drug.

5. Cardiology need only be consulted when there is uncertainty about the ECG (e.g. persistent prolongation that is not resolved with the above measures) or in the presence of ventricular arrhythmia.

Figure 1. The practical considerations when initiating patients on QTc prolonging drugs

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Measuring the QT Interval

  • The QT interval should be measured from a good quality ECG with a stable baseline and free from noise artefact.
  • Most modern automatically reporting ECG machines will report the QT and QTc intervals. These can only be relied upon if the ECG is of good quality.
  • The QT is measured from the initial inflection of the Q wave to the point at which the terminal T wave returns to baseline. If a U wave is present, the tail of the T-wave should be interpolated and the point at which it would reach baseline estimated (see Figure 2).
  • A number of formulae exist to calculate the QT interval. All have their limitations, however the most widely used in Bazett’s formula:

Figure 2. Measurement of the QT interval

 

Drugs causing QT prolongation and torsade de pointes
(Adopted from Table 9.2 in Stockley’s Drug Interactions. Last updated 08-Jul-2016. Accessed via www.medicinescomplete.com)

High risk

Some risk

Risk not categorised

Antiarrhythmics, class Ia (ajmaline, cibenzoline, disopyramide, hydroquinidine, procainamide, quinidine)

Antiarrhythmics, class III (amiodarone, azimilide, cibenzoline, dofetilide,† dronedarone, ibutilide,† sotalol,† vernakalant)

Arsenic trioxide (40% of patients had a QTc interval greater than 500 milliseconds)

Artemisinin derivatives (artemisinin, artemether/lumefantrine, artenimol - 5% of patients had an asymptomatic prolongation of QTc intervals by greater than 30 milliseconds, with an actual QTc of greater than 450 milliseconds in males and greater than 470 milliseconds in females)

Halofantrine†

Haloperidol (risk increased in high doses and with intravenous use)

Ketanserin (30% of patients had an increase of greater than 30 milliseconds in a clinical trial)

Mesoridazine†

Pimozide†

Sertindole†

Thioridazine†

Vandetanib (QTcF prolonged by 35 milliseconds, with greater than 60 millisecond increase in QTcF interval in 36% of patients)

Amisulpride

Bedaquiline (QTcF interval prolonged by 15.7 to 23.7 milliseconds)

Bosutinib (QTcF interval greater than 500 milliseconds reported in some patients, with greater than 60-millisecond increase in 0.9% of patients)

Chlorpromazine

Citalopram (dose-dependent increase in QTcF interval of 7.5 to 18.5 milliseconds).

Crizotinib (QTcF interval greater than 500 milliseconds reported in some patients, with greater than 60-millisecond increase in 5% of patients)

Dasatinib (increase in QTcF interval of 7 to 13.4 milliseconds)

Delamanid (QTcF interval increased by 7.6 to 12.1 milliseconds, with greater than 60-millisecond increase in 3% of patients)

Domperidone (In one study (Br J Clin Pharmacol. 2012 Mar;73(3):411-21) maximum mean increase in QTc compared with placebo was > 5 milliseconds at some time points but never exceeded 12 milliseconds). Use the lowest possible dose of domperidone, and be cautious when prescribing domperidone to patients at high risk of developing abnormal heart rhythms.

Dolasetron* (increase in QTcF interval of 14.1 milliseconds, larger increases have been seen in overdose; not all studies have found an increase)

Droperidol†

Eribulin (QTcF interval prolonged by 11.4 milliseconds on day 8 of use)

Escitalopram (QTcF interval prolonged by 10.7 milliseconds with 30 mg daily)

Gatifloxacin (increase in QTc interval less than 10 milliseconds)

Iloperidone (12 mg twice daily increased QTc interval by 9 milliseconds; greater increases if metabolism inhibited)

Hydroxyzine

Levomepromazine

Methadone (in doses greater than 100 mg)

Moxifloxacin (increase in QTc interval less than
10 milliseconds)

Nilotinib (QTc interval prolonged by 5 to 15 milliseconds)

Ondansetron* (dose-related prolongation of
QTcF interval of up to 20 milliseconds)

Paliperidone (dose-dependent prolongation of
6.8 to 12.3 milliseconds)

Pasireotide (QTcF interval prolongation that equates to a 17.5 millisecond increase over placebo)

Pazopanib (QT interval of greater than
500 milliseconds in some patients)

Quinine (greater risk with higher doses and intravenous use)

Ranolazine (dose-related QTc interval prolonged by up to 15 milliseconds, or more if metabolism inhibited)

Romidepsin (QTc interval prolongation of 14.4 milliseconds in lymphoma patients)

Saquinavir boosted with ritonavir (QTcS
interval increased by 18.9 milliseconds with
1 g/100 mg twice daily)

Sildenafil (QT interval prolonged by
6 milliseconds with 50 mg dose; not all studies
have found an increase)

Sorafenib (QTcF interval prolonged by
9 milliseconds)

Sparfloxacin (QTcF interval prolonged by
10 milliseconds in clinical studies)

Sultopride†

Sunitinib (QTcF interval prolonged by 9.6 milliseconds)

Telaprevir (QT interval prolonged by 8 milliseconds)

Tolterodine (QTcF interval prolonged by up to
11.8 milliseconds)

Toremifene (Dose-related effect; QT interval prolonged by 21 to 26 milliseconds with 80 mg dose)

Tricyclics (prolongation of QTc interval greater than 10 milliseconds, most notable risk occurs with clomipramine, risk with other tricyclics largely seems to be in overdose)

Vardenafil (QTcF interval prolonged by 8 milliseconds with 10 mg dose)

Ziprasidone (QTc interval prolonged by about 10 milliseconds with 160 mg dose)

Amifampridine (no data but because of the arrhythmogenic potential of amifampridine other drugs that prolong the QT interval are contraindicated)

Androgen antagonists (abiraterone, bicalutamide, enzalutamide, flutamide, nilutamide - lack of direct evidence but note, low testosterone concentrations are associated with an increase in the QT interval)

Asenapine (QTc interval increased by 2 to 5 milliseconds with 5 to 20 mg daily; nevertheless some advise caution or avoiding other QT prolonging drugs)

Atomoxetine (No significant change in QTc interval from baseline in a study; however because of post-marketing reports of QT interval prolongation, some advise caution with other QT prolonging drugs)

Azithromycin (because of post-marketing reports of QT interval prolongation, some advise caution with other QT prolonging drugs)

Boceprevir (no effect seen in studies; nevertheless UK manufacturer advises caution with other drugs that prolong the QT interval)

Clarithromycin (increase in QTc interval of less than 5 milliseconds but because of rare case reports of torsade de pointes some advise caution with other QT prolonging drugs)

Clozapine (because of post-marketing reports of QT interval prolongation, some advise caution with other drugs that prolong the QT interval)

Erythromycin (greater risk with intravenous use)

Gonadorelin analogues (buserelin, goserelin, histrelin, leuprorelin, triptorelin - lack of direct evidence but note, low testosterone concentrations are associated with an increase in the QT interval)

Gonadorelin antagonists (degarelix - lack of direct evidence but note, low testosterone concentrations are associated with an increase in the QT interval)

Lapatinib (small, dose-dependent prolongation of the QTc interval; magnitude not stated)

Lithium (can increase the QT interval particularly if concentrations increased therefore some advise caution with other QT prolonging drugs)

Lofexidine (because of post-marketing reports of QT interval prolongation, some advise caution with other QT prolonging drugs)

Olanzapine (studies suggest no effect but UK manufacturer advises caution on the basis that other antipsychotics have QT prolonging effects)

Pentamidine (intravenous) Piperaquine (appears to cause dose-dependent prolongation of the QTc interval)

Quetiapine (the available data neither proves nor disproves an effect, therefore some advise caution with other QT prolonging drugs)

Rilpivirine (dose-related QT-prolongation occurs, which is considered unlikely to be clinically relevant at the recommended dose; however, because of the limited information manufacturers advise caution)

Risperidone (lack of direct evidence but note, paliperidone is a metabolite of risperidone and so some advise caution with other QT prolonging drugs)

Sodium stibogluconate (dose-related QT interval prolongation occurs; magnitude not stated, therefore some advise caution with other QT prolonging drugs)

Solifenacin (QTcF interval prolonged by 2 milliseconds with a 10 mg dose; however, because of post-marketing reports of QT interval prolongation, some advise caution with other QT prolonging drugs)

Spiramycin

Sulpiride (because of a few reports of QT interval prolongation, some do not recommend the use of other QT prolonging drugs)

Tacrolimus (because of a few reports of QT interval prolongation, some advise caution with other QT prolonging drugs)

Telavancin (increase in QTc of less than 5 milliseconds, but some advise caution with other QT prolonging drugs)

Telithromycin (minimal effects seen in some studies, but others suggest an effect similar to clarithromycin in small proportion of patients)

Tizanidine (small in vivo studies suggest no increase in QT or QTc intervals; however, chronic toxicity studies in dogs have resulted in QT prolongation and therefore some advise caution with other QT prolonging drugs)

Trazodone (because of post-marketing reports of QT interval prolongation, some advise caution with other QT prolonging drugs)

Vinflunine (because of a few reports of QT interval prolongation, some do not recommend the use of other QT prolonging drugs)

Zotepine (dose-related QT prolongation said to occur, magnitude not stated)

Zuclopentixol (appears to cause QT prolongation in overdose; because of the known effects of other antipsychotics, some advise caution with other QT prolonging drugs)

†  Indicates drug suspended/restricted in some countries because of this effect
*  All 5-HT -receptor antagonists have been associated with QT-interval prolongation, but the evidence is variable; see 5-HT3-receptor antagonists + Drugs that prolong the QT interval.
This list is not exhaustive

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Provenance

Record: 5011
Objective:
Clinical condition:
Target patient group:
Target professional group(s): Pharmacists
Secondary Care Doctors
Adapted from:

Evidence base

  • QT interval and drug therapy. DTB, 2016, 54: 33-36. doi: 10.1136/dtb.2016.3.0390
  • Claire L Preston (Ed) Stockley’s Drug Interactions. Updated 8/7/2016. Accessed via www.medicinescomplete.com
  • European Medicines Agency: Note for guidance on the clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs (CHMP/ICH/2/04). November 2005
  • NHS Greater Glasgow and Clyde Medicines Information Service. Drug Induced QT Prolongation. MedicinesUpdateExtra No 2. May 2015
  • Credible Meds. Accessed via www.crediblemeds.org
  • MHRA Drug Safety Updates. Accessed via www.gov.uk/drug-safety-update/
  • Medicines and Healthcare products Regulatory Agency. Domperidone: risks of cardiac side effects - indication restricted to nausea and vomiting, new contraindications, and reduced dose and duration of use. Drug Safety Update May 2014, vol 7, issue 10:A1
  • Medicines and Healthcare products Regulatory Agency. Ondansetron (Zofran): risk of QTc prolongation – important new intravenous dose restriction. Drug Safety Update Aug 2012, vol 6 issue 1:A2
  • Medicines and Healthcare products Regulatory Agency. Hydroxyzine: risk of QT interval prolongation and Torsades de Pointes. Drug Safety Update Apr 2015. Accessed via https://www.gov.uk/drug-safety-update on 06/03/17.

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Approved By

LTHT Drug and Therapeutics Group and Leeds Area Prescribing Group

Document history

LHP version 1.0

Related information

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