Rhythm and Blues Drugs and QT Prolongation Dr Martin Quinn St Vincents University Hospital Irish Medication Safety Network conference Farmleigh 18 Oct 2013
Drugs and QT Prolongation Anti-psychotic, antidepressant, anti-histamine, antiarrhythmic and antibiotics are the commonest The risk of arrhythmia is increased x 3-8 fold Up to 3% of prescription are for medication with the potential to prolong the QT interval
QT prolongation with medication Na channel blockade
QT prolonging medications
Cardiac Ion Channels Action potential
Torsadede Pointes
Measuring QT interval-ecg Effected by heart rate and sex Normal for males <440ms Females <460 ms
Relationship of QT to heart rate
Congenital Long QT Syndrome 5-20% of patients with drug induced prolongation have previously unrecognized long QT Usually diagnosed in patients with aborted SCD or family member with SCD Examination normal, occasional deafness or skeletal and cardiac abnormalities
Long QT syndrome 100 of mutations in 10 genes have been identified Mutations in 3 genes encoding a cardiac ion channel account for the majority. Some have multiple mutations which increases the risk of SCD Syncope/SCD usually due to torsades de pointes Sometimes associated with bradycardias
Long QT syndrome Romano-Ward the autosomal dominant form Often variable penetrance Usually a disease of young and syncope and SCD rare in those over 40 years Post mortem usually normal Jervell-Lange-Neilsonautosomalrecessive with deafness
LQT-3 Na channel
Common forms of LQTS
Uncommon forms of LQTS Disease gene Functional effect Other features LQT4 ANK2 Altered intracellular calcium control and subcellular targeting of calcium control proteins Atrial fibrillation, sinus node dysfunction LQT5 KCNE1 Decreased IKs Similar to LQT1 LQT6 KCNE2 Decreased IKr LQT7 LQT8 KCNJ2 CACNA1C Decreased inward rectifier potassium current (IK1) Increased L-type calcium current No formal linkage in a family to date; isolated mutations in drugassociated QT prolongation Anderson-Tawil syndrome, including neurological symptoms and unusual facies Timothy syndrome: syndactyly, unusual facies, neurological defects LQT9 CAV3 Increased plateau INa Similar to LQT3 LQT10 SCN4B Increased plateau INa Similar to LQT3 AKAP9 SNTA1 Decreased IKs Increased plateau INa Preliminary report only Jervell-Lange- Nielsen KCNQ1 Congenital deafness,
Risk of long QT Most powerful predictor of risk is length of QTc The incidence of syncope or SCD over 10 years in 647 patients with LQT1-3 was <20% with QTc<446 and 70% with QTc>498
Factors to watch out for History of syncope Family history SCD Drowning SIDS Death while driving
Ray et al NEJM 2009 Anti-psycotics and QT prolongation Adjusted Incidence-Rate for Sudden Cardiac Death
Effect is dose related
Adjusted Rate of Sudden Cardiac Death among Current Users of Antipsychotic Drugs, According to Dose
QT prolongation with newer antipsychotics 478 events per 166,324 patient years of use (Ray et al 2009) or 2.9/1000 With higher doses the rate is 3.3/1000 3% of patients with schizophrenia (mean age 40 years) who were treated with risperidoneor quetiapine had prolongation of the QT interval The risk was doubled in older patients with dementia (6%)
QT Prolongation with Azithromycin HR for cardiovascular death 2.8 during 5 days of therapy 47 extra deaths per million prescriptions 1 for every 21,000 Increasing to 245 per million in patients with highest risk Ray et al 2012
Important drug interactions Isozyme QT prolonging drugs Inhibitor CYP3A4 Haloperidol Pimozide Erythromycin Clarithromycin Ketoconazole Itraconazole Diltiazem CYP1A2 Imipramine Ciprofloxacin CYP2D6 Thioridazine Imipramine Amitryptyline Fluoxetine Amiodarone
Prevention History Other medications Check pulse/bp ECG at baseline and within a few days of increase in dose
Conclusion QT prolongation with medications is common (3-6%) QT interval prolongation is dose related The risk of ventricular tachycardia/scd is related to the degree of prolongation of the QT interval With up to a 3 to 4 fold increase in the risk of SCD Drug interactions are particularly important in increasing the risk