Drug Induced QTc Prolongation

• Introduction
• Basic Considerations
• Practical Approach
• Monitoring
• Measuring the QT Interval

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)

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