Abigail Coughtrie, Elijah Behr, Deborah Layton and Saad Shakir
Several drugs have been withdrawn due to QT prolongation (QTp) or Torsade de Pointes (TdP). The DARE study aimed to improve knowledge of the epidemiology of proarrhythmia [documented TdP, ventricular fibrillation (VF) or polymorphic/non-polymorphic VT (non-QTp); exacerbation of preexisting proarrhythmia, newly documented proarrhythmia or conversion of unsustained proarrhythmia to sustained; severe (>500ms) or moderate (450ms male/470ms female) QTp with past medical history (PMH) of presyncope or syncope] by identifying a cohort of cases.
Characterise cases and estimate contribution of individual drugs to risk of proarrhyth.
Self-reported data on demography, symptoms, PMH and drug history (DH) were gained for proarrythmia cases referred by cardiologists in England 2003-2011. PMH/DH were verified from hospital notes. Implicated drugs were adjudicated by 2 cardiologists and classified (ATC system). Proarrythmia risk and cytochrome (CYP) P450 activity were categorised using CredibleMeds; potential drug-drug interactions were identified using Medscape Drug Interaction Checker. Analysis comprised descriptive statistics and radar plots.
Of 124 cases, 95 (77%) were QTp-related and 29 (23%) non QTp-related; mean age 62 yrs [SD 15]; 63% female; PMH: 66 (53%) high blood pressure, 90 (73%) heart rhythm problems, 34 (27%) heart valve problems; 33 (27%) hypokalaemia at presentation. Of 166 implicated drugs, 70 (42%) were antiarrhythmics (C01B) [40 amiodarone; 23 flecainide]. A single drug was implicated in 90 (73%) pts and multiple drug combinations in 32 (26%) pts [27 >1 CYP inhibitor]. Potential drug-drug interactions were QTp (19), cardiotoxic (5), conditional (6), other (1). Drugs with known/possible/conditional QTp risk were implicated individually in 88 (71%) pts or in combination in 24 (19%) pts.
Antiarrhythmics, non-cardiac drugs and drug combinations were implicated in the 124 clinically-validated proarrhythmia cases. Underlying cardiovascular disease was present in most cases. Selection bias is possible due to referral and adjudication by cardiologists only.