Open Access Research BMJ Open: first published as 10.1136/bmjopen-2017-016627 on 16 October 2017. Downloaded from Drugs and life-threatening ventricular arrhythmia risk: results from the DARE study cohort Abigail L Coughtrie,1,2 Elijah R Behr,3,4 Deborah Layton,1,2 Vanessa Marshall,1 A John Camm,3,4,5 Saad A W Shakir1,2 To cite: Coughtrie AL, Behr ER, ABSTRACT Strengths and limitations of this study Layton D, et al. Drugs and Objectives To establish a unique sample of proarrhythmia life-threatening ventricular cases, determine the characteristics of cases and estimate ► The Drug-induced Arrhythmia Risk Evaluation study arrhythmia risk: results from the the contribution of individual drugs to the incidence of DARE study cohort. BMJ Open has allowed the development of a cohort of cases of proarrhythmia within these cases. 2017;7:e016627. doi:10.1136/ proarrhythmia. Setting Suspected proarrhythmia cases were referred bmjopen-2017-016627 ► These cases have provided crucial safety by cardiologists across England between 2003 and 2011. information, as well as underlying clinical and ► Prepublication history for Information on demography, symptoms, prior medical and genetic data. this paper is available online. drug histories and data from hospital notes were collected. ► Only patients who did not die as a result of the To view these files please visit Participants Two expert cardiologists reviewed data the journal online (http:// dx. doi. proarrhythmia could be included. for 293 referred cases: 130 were included. Inclusion org/ 10. 1136/ bmjopen- 2017- ► Referral of cases by cardiologists alone may have criteria were new onset or exacerbation of pre-existing 016627). led to the underestimation of the prevalence of drug- ventricular arrhythmias, QTc >500 ms, QTc >450 ms induced arrhythmia from non-cardiac drugs. Received 20 March 2017 (men) or >470 ms (women) with cardiac syncope, all ► The analysis of ethnicity and differences in risk of QT Revised 5 July 2017 secondary to drug administration. Exclusion criteria were prolongation could not be investigated. Accepted 10 August 2017 acute ischaemia and ischaemic polymorphic ventricular tachycardia at presentation, structural heart disease, consent withdrawn or deceased prior to study. Descriptive analysis of Caucasian cases (95% of included cases, arrhythmic events relate to marked prolon- n=124) and culpable drug exposures was performed. gation of the QT interval of the ECG, which Results Of the 124 Caucasian cases, 95 (77%) were QTc http://bmjopen.bmj.com/ can lead to the distinctive polymorphic interval prolongation-related; mean age was 62 years (SD 15), and 63% were female. Cardiovascular comorbidities ventricular tachycardia (VT) and ‘Torsades included hypertension (53%) and patient-reported ‘heart de Pointes’ (TdP), which in turn may lead rhythm problems’ (73%). Family history of sudden death to ventricular fibrillation (VF) and sudden 1 (36%) and hypokalaemia at presentation (27%) were death. This is also known as the acquired common. 165 culpable drug exposures were reported, long QT syndrome (aLQTS). Occasionally including antiarrhythmics (42%), of which amiodarone and polymorphic and monomorphic VT without flecainide were the most common. Sotalol, a beta-blocking QT prolongation can occur.2 3 In addition to agent with antiarrhythmic activity, was also common drugs, other causes of aLQTS include endo- on September 28, 2021 by guest. Protected copyright. (15%). 26% reported multiple drugs, of which 84% crine disorders,4 cirrhosis,5 HIV and AIDS,6 reported at least one cytochrome (CYP) P450 inhibitor. 7 1Research Department, inflammation and immunity, autoimmune Potential pharmacodynamics interactions identified were Drug Safety Research Unit, disease,8 structural heart disease,9 electrolyte mainly QT prolongation (59%). Southampton, UK imbalances10 and eating disorders.11 2 Conclusions Antiarrhythmics, non-cardiac drugs and School of Pharmacy and Drug-induced arrhythmia is associated Biomedical Science, University drug combinations were found to be culpable in a large of Portsmouth, Portsmouth, UK cohort of 124 clinically validated proarrhythmia cases. with the use of cardiovascular agents (partic- 3Cardiology Clinical Academic Potential clinical factors that may warn the prescriber of ularly class III antiarrhythmic drugs) and Group, St George's University of potential proarrhythmia include older women, underlying also with many non-cardiovascular indicated London, London, UK 4 cardiovascular comorbidity, family history of sudden death drugs within different therapeutic cate- Cardiology Clinical Academic and hypokalaemia. gories, including antihistamines, antipsy- Group, St George’s University Hospitals NHS Foundation Trust, chotics and antimicrobials; an up-to-date list London, UK is maintained on the CredibleMeds register 5Faculty of Medicine, Imperial INTRODUCTION (Azcert, https:// crediblemeds. org/). College London, London, UK Drug-induced arrhythmia, or proarrhythmia, Currently, there is substantial evidence to Correspondence to is the induction or exacerbation of cardiac support a clear association between over Dr Abigail L Coughtrie; arrhythmia associated with administration 50 different drugs and risk of TdP, even abigail. coughtrie@ dsru. org of a drug. The majority of drug-induced when taken according to the terms of the Coughtrie AL, et al. BMJ Open 2017;7:e016627. doi:10.1136/bmjopen-2017-016627 1 Open Access BMJ Open: first published as 10.1136/bmjopen-2017-016627 on 16 October 2017. Downloaded from marketing authorisation, with a number of these being to sustained; severe prolongation of the QTc interval withdrawn from the market.12–14 Mechanistic proposals corrected using Bazett’s formula (>500 ms) without symp- for clinical features such as electrolyte imbalance include toms; or moderate prolongation of the QTc interval block of the rapid form of the delayed rectifier potas- (≥450 ms in men or ≥470 ms in women) with a clinical 15–17 sium current (IKr) in cardiomyocytes. Genetic factors history of cardiac syncope. have also been identified. These include single nucleo- All cases were reviewed by at least two experienced tide polymorphisms in the NOS1AP gene encoding the cardiologists, using hospital notes and interview ques- nitric oxide synthase 1 adaptor protein18; and mutations tionnaire information, to ensure appropriate inclusion of in potassium channel genes KCNH2, KCNQ1, KCNE1 and cases. Patients with acute ischaemia, ischaemic polymor- KCNE2 and/or the sodium channel gene SCN5A.19 20 phic VT and structural heart disease (using symptoms, Such mutations are also recognised to cause congenital history of ischaemia and associated therapy, risk factors or long QT syndrome (cLQTS).21 Other notable risk factors ECG, stress test and coronary angiography results) were include female sex, bradycardia, recent cardioversion, excluded. Case presentation (asymptomatic, syncope, VT, pre-existing electrolyte disturbance, elevated plasma VF and/or TdP) and aetiology (QT prolongation-asso- concentrations and/or rapid infusion of QT-prolonging ciated and non-QT prolongation-associated) were ascer- drugs and digitalis toxicity.22–24 tained. Drugs received by the patient were adjudicated for Following the removal of several QT-prolonging drugs culpability in contributing to proarrhythmia according to because of associated sudden deaths,25–28 risk minimisa- the clinical data, timing of medication and the presenting tion strategies were introduced to mitigate the arrhythmic event that prompted referral. Prior reports of associa- risk posed by drugs, including clinical studies to assess the tion with proarrhythmia were also taken into account, proarrhythmic potential for a new drug within the premar- although drugs thought to contribute to causation but keting development programme.29 However it has been without such data were not excluded. recognised that there remain limitations in the conduct No sample size calculation could be performed for the of clinical studies designed to evaluate a drug’s potential study as, at the time of study initiation, the natural history, for QT prolongation and applicability of results to vulner- relative risk and potential risk factors of proarrhythmia able patients.30 Because of the unpredictable nature of were largely unknown. the condition, the Drug-induced Arrhythmia Risk Evalua- tion (DARE) study aimed to improve the understanding Variables of the epidemiology of proarrhythmia by establishing a A proforma questionnaire obtained patients’ self-re- cohort of cases of drug-induced arrhythmia reported ported information on age, gender, ethnicity, weight, throughout England, to characterise typical patients with height, smoking status, alcohol consumption, symptoms proarrhythmia and to describe the drugs found to be before, during and after the event (including ‘blackout’, culpable in these cases of proarrhythmia. This manuscript ‘near blackout’, ‘dizziness/light-headedness’ and ‘palpi- http://bmjopen.bmj.com/ is a per-protocol descriptive analysis of risk factors for the tations’), medication taken before, during and after the condition and the contribution of individual drugs to the event (including prescription, over-the-counter/herbal risk of drug-induced arrhythmic events. and recreational), any medical and cardiovascular history (including angina, myocardial infarction, ‘heart failure’, ‘heart valve problem’, ‘heart rhythm problem’, ‘high METHODS blood pressure’, hypokalaemia, hypothyroidism, diabetes Study design and setting