Acquired QT Prolongation and Drug-Induced Arrhythmia

Definition and Pathophysiology

Acquired long QT syndrome (LQTS) is characterised by an abnormal prolongation of the QT interval on the surface electrocardiogram (ECG), which predisposes the myocardium to a specific form of polymorphic ventricular tachycardia (VT) known as torsades de pointes (TdP). Drug-induced LQTS and TdP represent a multifactorial clinical entity that typically emerges when multiple modifiable and non-modifiable risk factors converge.

The electrophysiological mechanism underlying TdP involves prolonged ventricular repolarisation, which allows for the recovery of time-dependent inward currents. This process creates early afterdepolarisations (EADs) that generate premature ventricular contractions (PVCs) and increases transmural dispersion of repolarisation, thereby facilitating reentry. Episodes of TdP are frequently pause-dependent, initiated by either a slowing of the heart rate or a PVC-induced pause. The subsequent sinus beat typically exhibits a longer QT interval, and the T wave is interrupted by a PVC, which serves as the first beat of the polymorphic VT. Sustained episodes may eventually degenerate into ventricular fibrillation (VF).

Proarrhythmia, defined as a drug-induced or drug-exacerbated cardiac arrhythmia, constitutes a major clinical problem. It can manifest as an increase in the frequency of a pre-existing arrhythmia, the sustenance of a previously non-sustained arrhythmia, or the development of an entirely new arrhythmia. Electrophysiologic mechanisms of proarrhythmia include prolongation of repolarisation, increased transmural dispersion, EAD-mediated TdP, and alterations in reentry pathways. Proarrhythmic events occur in 5% to 10% of patients receiving antiarrhythmic agents, and this risk is amplified in the presence of heart failure.

Clinical Presentation and Symptoms

Patients with acquired QT prolongation and drug-induced TdP typically present with near-syncope, syncope, or cardiac arrest. Before the onset of sustained VT, patients frequently experience PVCs and runs of non-sustained VT. Sustained episodes of TdP will degenerate to VF, necessitating immediate defibrillation.

In the context of cancer therapy, patients may develop new cardiac symptoms such as syncope, pre-syncope, or rapid palpitations. These symptoms often accompany QTc prolongation with new-onset bradycardia or a high degree of heart block. In patients with severe mental illness (SMI) receiving antipsychotic therapy, sinus tachycardia is common, and symptoms may reflect underlying arrhythmia or sudden cardiac death (SCD).

Evaluation and Physical Examination

A comprehensive evaluation is mandatory for patients presenting with sudden cardiac arrest (SCA) if the underlying cardiac disease is unknown or if disease progression is suspected. Reversible causes may account for up to 50% of SCA cases, though determining the exact underlying cause and its reversibility is often difficult.

Physical examination and clinical evaluation should focus on identifying factors that trigger ventricular arrhythmias (VA), such as electrolyte imbalances (e.g., hypokalaemia), bradycardia, ischaemia, coronary spasm, thrombosis, fever, acute starvation, and dieting. Clinicians should maintain a high index of suspicion for drug-induced arrhythmias in patients receiving agents known to alter the electrical properties of the heart (inducing QRS or QT prolongation) or causing electrolyte abnormalities, such as thiazide and loop diuretics.

Diagnostics

Electrocardiogram (ECG)

The ECG is the primary diagnostic tool for evaluating acquired QT prolongation. The upper 99% limits of normal for corrected QT (QTc) values in the general population are 450 ms for men and 460 ms for women. While there is no absolute QTc threshold at which TdP occurs, a QTc ≥ 500 ms is associated with a two- to three-fold higher risk for TdP. Conversely, TdP rarely occurs when the QTc is < 500 ms.

Before an episode of TdP, the QTc interval is typically prolonged to 480 ms or greater. Following defibrillation, the QT interval may appear shorter in response to tachycardia and catecholamine administration, which can obfuscate the initial diagnosis.

Heart rate correction of the QT interval is optimally performed using the Fridericia formula (QTcF = QT / 3√RR). This method is preferred over the Bazett formula, which tends to overestimate the QT interval at higher heart rates. The Bazett formula demonstrates more error than Fridericia at both high and low heart rates. Measurement of the QT interval can be complicated by abnormal T-wave morphology, necessitating expert consultation for correct interpretation.

Specific ECG monitoring recommendations apply to various clinical scenarios:

• In patients receiving antipsychotic drugs, a 12-lead ECG should be recorded before and after initiation, with further ECG controls performed yearly during long-term follow-up.

• For selected cancer drugs, specific manufacturer recommendations guide ECG monitoring, dosage adjustments, or discontinuation of therapy in the event of QTc prolongation.

• In patients with cancer, a QTc > 480 ms requires closer monitoring, though changes in the QT interval of > 60 ms from baseline should not routinely affect treatment decisions if the QTc remains < 500 ms.

Electrophysiology

Intracardiac electrophysiologic studies (EPS) have a limited role in acquired LQTS. EPS is considered equivocal (Class II) for identifying the proarrhythmic effect of a drug in patients who experience sustained VT or cardiac arrest while receiving the drug. It is also equivocal for patients with equivocal QT interval abnormalities or T-U wave configurations alongside syncope or symptomatic arrhythmias, where catecholamine infusion may unmask a distinct QT abnormality. EPS is inappropriate (Class III) for patients with clinically manifest congenital QT prolongation or those with acquired prolonged QT syndrome whose symptoms are closely related to an identifiable cause.

Biomarkers and Laboratory Findings

Laboratory evaluation is critical for identifying correctable triggers of QT prolongation and TdP. Electrolyte abnormalities are prominent culprits and should be closely monitored and corrected. Specific thresholds for increased risk include:

• Hypokalaemia (≤ 3.5 mEq/L)

• Hypomagnesaemia (≤ 1.6 mEq/L)

• Hypocalcaemia (≤ 8.5 mEq/L)

Other reversible laboratory or systemic abnormalities that may contribute to QT prolongation include hypothyroidism, acute myocardial ischaemia, and impaired renal or hepatic function, which can lead to inadequate dose adjustment and accumulation of QT-prolonging drugs.

Risk Factors for Drug-Induced QT Prolongation and TdP

The risk of drug-induced QT prolongation and TdP is determined by a combination of correctable and non-correctable factors.

Females are more susceptible than males, likely due to sex-related differences in baseline QTc duration and pharmacokinetic profiles. Individual susceptibility may also be related to genetic polymorphisms or mutations that influence repolarisation. With genetic testing, some patients who experience drug-induced TdP are found to have an underlying inherited LQTS. Various combinations of single-nucleotide polymorphisms influence repolarisation and act as genetic factors in determining risk.

Drug interactions that elevate concentrations of an offending agent or its metabolite—such as the inhibition of cytochrome P450 metabolism—are also important precipitating factors. Proarrhythmia may occur when non-antiarrhythmic drugs, foods, or over-the-counter medicines are added to a patient's regimen, further interacting with the QT interval or altering antiarrhythmic drug metabolism.

Treatment and Management

Acute Management

Sustained episodes of TdP require immediate defibrillation. Following defibrillation, management focuses on suppressing recurrent episodes and correcting underlying triggers.

Intravenous magnesium sulphate is an effective therapy for TdP, even in the absence of hypomagnesaemia. The administration of 1 to 2 g of magnesium sulphate via rapid IV infusion usually suppresses recurrent episodes. If magnesium alone is ineffective, potassium supplementation should be provided, and the infusion may be repeated as needed to suppress PVCs and non-sustained VT.

Bradycardia should be corrected by increasing the underlying heart rate. This can be achieved through isoprenaline (isoproterenol) infusion or transvenous pacing. Pacing should be implemented at a rate of 100 to 120 depolarisations per minute, or as required to suppress PVCs. In patients with cancer who experience QTc prolongation associated with severe bradycardia or sinus pauses, isoprenaline infusion or temporary pacing may be beneficial despite present restrictions.

All provocative drugs should be stopped, and associated electrolyte disturbances (hypokalaemia, hypocalcaemia, and hypomagnesaemia) must be corrected. Clinicians should note that shortening of the QT interval may lag behind the excretion of the offending drug by several days. Substances known to prolong the QT interval, such as sotalol, should be strictly avoided.

Long-Term Management and Secondary Prevention

Patients who have experienced TdP should be viewed as having a distinct susceptibility to the arrhythmia. They warrant lifelong avoidance of all medications known to prolong the QT interval. An updated list of "QT-liability" or "torsadegenic" drugs is maintained at https://www.crediblemeds.org.

For survivors of SCA attributed to a reversible and correctable cause, subsequent implantable cardioverter defibrillator (ICD) implantation is associated with lower all-cause mortality, except for aborted cardiac arrest occurring in the presence of acute myocardial infarction (MI). The need for prophylactic ICD implantation should be considered based on the underlying cardiac disease and an individual evaluation of the future risk of life-threatening VA. In the context of cancer therapy, the improved prognosis for many malignancies is increasing the number of patients who are candidates for an ICD, particularly when life expectancy is > 1 year. This includes patients who experienced resuscitated sudden cardiac death or severe VA from a QTc-prolonging drug when no alternative treatment is available. Decisions on device therapy must carefully consider life expectancy, quality of life, and complication risks.

Drugs, Doses, and Practical Considerations

The list of drugs with "QT-liability" is extensive and includes both antiarrhythmic and non-cardiac medications.

Antiarrhythmic Agents

Drugs that block the repolarising potassium current IKr are the most common offenders. These include class IA agents (quinidine, procainamide, disopyramide), class IC agents (flecainide), and class III agents (dofetilide, ibutilide, sotalol, amiodarone, dronedarone).

• Class I agents: Inactivation of sodium channels by class I agents can cause QRS prolongation. In the Cardiac Arrhythmia Suppression Trial (CAST), encainide and flecainide reduced spontaneous VAs but were associated with a total mortality of 7.7% versus 3.0% in the placebo group, highlighting a late proarrhythmic risk.

• Class III agents: Dofetilide exhibits QT prolongation that is more pronounced at slower heart rates. Amiodarone prolongs the QT interval but rarely causes TdP. Sotalol has a prominent beta-blocker effect.

• Digitalis: Digitalis glycosides characteristically produce shortening of the QT interval with a "scooped" or downsloping ST-T complex. Digitalis toxicity can produce asystole or TdP. Toxicity can be identified on ECG by group beating patterns of QRS complexes with shortening of R-R intervals, consistent with nonparoxysmal junctional tachycardia with probable atrioventricular Wenckebach exit block.

• Cancer therapy-induced VA: Treatment should follow general clinical guidelines. Asymptomatic, self-terminating VA does not require drug discontinuation unless additional cardiovascular risk factors or persistent ECG abnormalities are present. Symptomatic VA requires cancer drug dose reduction or discontinuation. The administration of class IA, IC, and III antiarrhythmic drugs is limited by the risk of drug-drug interactions and QTc prolongation. Beta-blockers and class IB drugs are less likely to cause drug interactions or QTc prolongation. Beta-blockers are the preferred choice if the cancer drug is also associated with cancer therapy-related cardiac dysfunction (CTRCD). Amiodarone is the antiarrhythmic drug of choice in patients with structural heart disease and haemodynamic instability.

Psychiatric and Analgesic Medications

• Antipsychotics: Sertindole, amisulpride, ziprasidone, iloperidone, risperidone, olanzapine, and quetiapine can prolong the QTc. QT-prolonging effects are dose dependent, so the lowest effective dose should always be used. Interactions with other QT-prolonging drugs (e.g., amiodarone, sotalol, erythromycin) must be avoided.

• Antidepressants: Tricyclic antidepressants (TCAs) are associated with an increased risk of QTc prolongation compared to newer antidepressants. Citalopram and escitalopram possibly increase the risk of QTc prolongation at dosages over 20 mg compared with placebo. In patients with VA, it is preferable to switch to antidepressants with less propensity to cause ventricular arrhythmias. TCAs also possess class IA-like properties and can lead to QRS and QT(U) prolongation; a right axis shift of the terminal 40-msec frontal plane QRS axis may be a helpful marker of tricyclic antidepressant overdose.

• Opioids: Methadone carries a high risk for causing QT prolongation and ventricular arrhythmias. Tramadol, fentanyl, and oxycodone carry an intermediate risk.

Other Medications and Substances

• Antimicrobials: Erythromycin, pentamidine, and hydroxychloroquine (especially in combination with azithromycin) have been reported to cause QT prolongation.

• Other agents: Phenothiazines, haloperidol, antihistamines, and the gastrointestinal stimulant cisapride are known torsadegenic agents. Cocaine can cause a variety of ECG changes, including those mimicking STEMI and life-threatening arrhythmias. Energy drinks, primarily due to high doses of caffeine, may be associated with prolonged QT intervals and arrhythmias.

Guideline Recommendations

General Management of Acquired LQTS

• Acquired LQTS is usually defined by a QTc > 500 ms or a drug-induced change from baseline of > 60 to 70 ms.

• In patients with QTc intervals > 500 ms, suspected causal drugs should be stopped and switched to alternative medications with lower QT-prolonging properties. These patients should be evaluated by a cardiologist for underlying genetic conditions.

• In cases of intermediate QTc prolongation (e.g., ≥ 470 ms in men; ≥ 480 ms in women), dose reduction or switching to a different medication may be considered, and repeated ECGs should be documented. An individualized risk-benefit assessment is useful, considering additional risk factors, symptoms, and the QT-prolonging potential of the prescribed drug.

• In patients treated with QTc-prolonging drugs, serum electrolytes and other risk factors should be closely monitored and corrected, and concomitant QT-prolonging drugs should be avoided if possible.

• Cardiology consultation is advised for patients with an abnormal baseline QTc interval, those treated with QT-prolonging drugs, those who develop new cardiac symptoms (syncope, pre-syncope, rapid palpitations, or QTc prolongation with new-onset bradycardia/high-degree heart block), and those with known inherited arrhythmia disorders.

Cancer Therapy-Specific Recommendations

• The Fridericia correction formula (QTcF) is recommended for patients with cancer.

• Changes in the QT interval of > 60 ms from baseline should not routinely affect treatment decisions if the QTc remains < 500 ms.

• Decisions regarding the use of antiarrhythmic drugs or device therapy (ICD, catheter ablation) must consider life expectancy, quality of life, and complication risks.

Prognosis and Follow-up

The prognosis of drug-induced LQTS and TdP is highly dependent on the prompt recognition of the arrhythmia, the immediate institution of acute management (defibrillation, magnesium, and pacing), and the complete withdrawal of the offending agent. Patients who survive an episode of SCA in the context of a presumed reversible cause may still face a high mortality rate.

Long-term follow-up necessitates rigorous avoidance of all QT-prolonging medications, as patients who have experienced TdP possess a definitive susceptibility to the arrhythmia. In the context of antipsychotic therapy, yearly ECG monitoring is recommended during long-term follow-up. For patients with cancer, the ongoing challenge for cardio-oncology teams is to identify patients more susceptible to developing VA, determine whether a VA is directly due to cancer therapy-related cardiovascular toxicity (CTR-CVT), individualize the treatment strategy, and optimize clinical monitoring during treatment.