Life-threatening adverse drug reactions causing - QT prolongation
Description
- Drug-induced prolongation of ventricular repolarisation -> acquired long QT -> torsades de pointes (TdP) -> VF and sudden cardiac death
- TdP = polymorphic VT with a continuously varying axis ("twisting of the points") on a background of a long QT
- Usually pause-dependent: initiated by a short-long-short RR sequence
- Most episodes are self-terminating -> syncope; a minority degenerate to VF
- *QT prolongation is a surrogate marker, not the disease - risk is multiplicative across drug, electrolyte and patient factors*
Epidemiology
- ~2-3% of all prescriptions are for a drug with recognised TdP risk
- Drug-induced TdP incidence is low per exposure but the exposure base is enormous
- F>M (~2:1) - women have a longer baseline QTc from puberty; oestrogen effect on IKr
- Risk concentrated in inpatients: elderly, multiple QT drugs, electrolyte disturbance, renal or hepatic impairment
- A leading cause of post-marketing drug withdrawal (terfenadine, cisapride, astemizole, sertindole, droperidol high-dose)
- Congenital long QT syndrome prevalence ~1:2000 - many acquired cases carry a subclinical variant ("reduced repolarisation reserve")
Aetiopathogenesis
- Nearly all culprit drugs block IKr, the rapid delayed rectifier K+ current, encoded by hERG (KCNH2)
- hERG channel has a large, promiscuous inner cavity -> an unusually wide range of unrelated drugs bind it
- -> prolonged phase 3 repolarisation -> early afterdepolarisations (EADs) via reactivated L-type Ca2+ current
- -> triggered activity + transmural dispersion of repolarisation -> re-entry -> TdP
Drugs - by class
| Class | Highest risk |
|---|---|
| Antiarrhythmics | *Sotalol, amiodarone, quinidine, procainamide, disopyramide, flecainide, dofetilide, ibutilide** |
| Antipsychotics | Haloperidol (esp. IV), droperidol, quetiapine, olanzapine, ziprasidone, amisulpride, clozapine, pimozide |
| Antidepressants | Citalopram/escitalopram (dose-dependent), TCAs, venlafaxine |
| Antimicrobials | Macrolides (erythromycin, clarithromycin, azithromycin), fluoroquinolones (moxifloxacin > ciprofloxacin), azoles (fluconazole, voriconazole), pentamidine, hydroxychloroquine/chloroquine |
| Antiemetics | Ondansetron (esp. IV, high dose), domperidone, droperidol |
| Oncology | Arsenic trioxide, nilotinib, vandetanib, osimertinib, ribociclib, oxaliplatin |
| Other | Methadone (dose-related), sodium thiosulfate, cilostazol, donepezil |
- *Penicillins, cephalosporins, nitrofurantoin and doxycycline do NOT prolong the QT* - useful discriminator
- Amiodarone prolongs the QT markedly but causes TdP rarely - it prolongs repolarisation homogeneously; do not stop amiodarone for QT prolongation alone
Patient risk multipliers
- Hypokalaemia, hypomagnesaemia, hypocalcaemia (the commonest and most correctable)
- Bradycardia, AV block, recent conversion from AF ("pause-dependent")
- Female sex, age >65
- Structural heart disease, heart failure, recent MI
- Renal or hepatic impairment -> drug accumulation
- CYP3A4/CYP2D6 inhibition -> inc parent drug level (the interaction, not the drug, is often the cause)
- Congenital LQTS or family history of sudden death
- Anorexia nervosa, starvation, diuretics, vomiting/diarrhoea
Diagnosis
Measuring the QT properly
- Measure in lead II or V5, largest QT of 3-5 beats, from QRS onset to the end of the T wave (tangent method)
- Exclude the U wave unless it merges with the T wave
- Correct for rate: Bazett (QT/sqrt RR) over-corrects at high rates - use Fridericia or Hodges above ~100/min
- In QRS >120 ms (LBBB, paced): use JT interval, or subtract the excess QRS duration
Thresholds
| Men | Women | |
|---|---|---|
| Normal | <=440 ms | <=460 ms |
| Prolonged | >450 ms | >470 ms |
| High risk | >500 ms | >500 ms |
- QTc >500 ms, or an increase of >60 ms from baseline, is the action threshold
- Absolute QTc predicts risk better than the change, but both matter
Risk scoring
- Tisdale score (inpatient): age >=68, female, loop diuretic, K+ <=3.5, admission QTc >=450, acute MI, sepsis, heart failure, >=1 QT drug, >=2 QT drugs
- >=11 = high risk -> continuous monitoring
- CredibleMeds (crediblemeds.org) - the reference list of known/possible/conditional TdP risk
Investigations
- K+, Mg2+, Ca2+ - check and correct in everyone
- UEC, LFT, TSH, troponin if ischaemia suspected
- Continuous telemetry if QTc >500 ms or high Tisdale score
- Echocardiogram if structural disease suspected
- Family history of sudden death or congenital LQTS -> genetic evaluation after recovery
Management
A. Acute torsades de pointes
Sustained TdP is a peri-arrest rhythm.
1. Haemodynamically unstable or degenerating to VF -> immediate DC cardioversion/defibrillation
2. IV magnesium sulfate 2 g (8 mmol) over 1-2 min, repeat once, then infusion
- *Works even when serum magnesium is normal* - suppresses EADs
3. Correct K+ to the high-normal range (4.5-5.0 mmol/L), correct Ca2+
4. Stop every QT-prolonging drug
5. Increase the heart rate to ~90-110/min to abolish the pauses
- Overdrive transvenous or transcutaneous pacing, OR
- Isoprenaline infusion (contraindicated in congenital LQTS and in ischaemia)
6. Treat bradycardia and AV block; atropine as a temporising measure
- *Avoid amiodarone and all class Ia/III antiarrhythmics* - they prolong the QT further
- Lidocaine (class Ib) shortens the QT and is the antiarrhythmic of choice if one is needed
B. Asymptomatic QT prolongation on treatment
- Recheck electrolytes, correct K+ and Mg2+ aggressively
- Review every drug on the chart against CredibleMeds; stop or substitute
- Check for a new CYP inhibitor - the recent addition is usually the cause
- Repeat ECG after the change; telemetry if QTc >500 ms
- QTc >500 ms or increase >60 ms -> stop the culprit wherever clinically possible
C. Prevention - where most of the benefit lies
- Baseline ECG and electrolytes before starting a high-risk drug (sotalol, methadone, antipsychotic in an older inpatient, arsenic trioxide)
- Avoid combining two or more QT-prolonging drugs - risk is more than additive
- Substitute where a safe alternative exists:
- Macrolide -> doxycycline or a beta-lactam
- Ondansetron -> metoclopramide or prochlorperazine (if the indication permits)
- Haloperidol -> non-pharmacological delirium management first
- Dose-cap where specified: citalopram max 20 mg/day if age >65, hepatic impairment or on a CYP2C19 inhibitor
- Correct diuretic-induced hypokalaemia; avoid hypomagnesaemia with PPIs
- Methadone: ECG at baseline, at dose stabilisation, and with any dose increase above 100 mg/day
- Counsel patients on syncope, palpitations, and drugs to avoid; give a written list
- Report to the TGA (Blue Card / adverse event reporting)
Associations
- Congenital long QT syndrome - LQT1 (KCNQ1), LQT2 (KCNH2/hERG), LQT3 (SCN5A); subclinical variants in up to 10-15% of drug-induced TdP
- Electrolyte disturbance - hypokalaemia, hypomagnesaemia, hypocalcaemia
- Heart failure, LV hypertrophy, recent myocardial infarction
- Bradyarrhythmia, complete heart block, recent cardioversion of AF
- Female sex, age >65
- Renal and hepatic impairment
- Polypharmacy and CYP3A4 inhibitors - clarithromycin, azoles, protease inhibitors, grapefruit
- Anorexia nervosa, eating disorders, starvation, alcoholism
- Hypothyroidism, subarachnoid haemorrhage, hypothermia, HIV
- Opioid substitution therapy (methadone)
Natural history & complications
- Most drug-induced QT prolongation is asymptomatic and fully reversible on stopping the drug
- QT normalises within days for most drugs; weeks-months for amiodarone (long half-life)
- TdP: usually self-terminating -> presyncope, syncope, seizure-like activity
- Drug-induced TdP is repeatedly misdiagnosed as epilepsy - get an ECG in every unexplained collapse
- Degeneration to VF -> sudden cardiac death
- Recurrence risk is high until the precipitant and the electrolytes are corrected
- After recovery:
- Repeat ECG off all culprit drugs; if the QT remains long, investigate for congenital LQTS and screen first-degree relatives
- Lifelong avoidance list; MedicAlert
- Complications: syncopal injury, anoxic brain injury, sudden cardiac death, inappropriate epilepsy diagnosis and antiepileptic exposure
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