Drugs and life-threatening ventricular arrhythmia risk: results from the DARE study cohort

Abstract

ObjectivesTo establish a unique sample of proarrhythmia cases, determine the characteristics of cases and estimate the contribution of individual drugs to the incidence of proarrhythmia within these cases.SettingSuspected proarrhythmia cases were referred by cardiologists across England between 2003 and 2011. Information on demography, symptoms, prior medical and drug histories and data from hospital notes were collected.ParticipantsTwo expert cardiologists reviewed data for 293 referred cases: 130 were included. Inclusion criteria were new onset or exacerbation of pre-existing ventricular arrhythmias, QTc >500 ms, QTc >450 ms (men) or >470 ms (women) with cardiac syncope, all secondary to drug administration. Exclusion criteria were acute ischaemia and ischaemic polymorphic ventricular tachycardia at presentation, structural heart disease, consent withdrawn or deceased prior to study.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, n=124) and culpable drug exposures was performed.ResultsOf the 124 Caucasian cases, 95 (77%) were QTc interval prolongation-related; mean age was 62 years (SD 15), and 63% were female. Cardiovascular comorbidities included hypertension (53%) and patient-reported ‘heart rhythm problems’ (73%). Family history of sudden death (36%) and hypokalaemia at presentation (27%) were common. 165 culpable drug exposures were reported, including antiarrhythmics (42%), of which amiodarone and flecainide were the most common. Sotalol, a beta-blocking agent with antiarrhythmic activity, was also common (15%). 26% reported multiple drugs, of which 84% reported at least one cytochrome (CYP) P450 inhibitor. Potential pharmacodynamics interactions identified were mainly QT prolongation (59%).ConclusionsAntiarrhythmics, non-cardiac drugs and drug combinations were found to be culpable in a large cohort of 124 clinically validated proarrhythmia cases. Potential clinical factors that may warn the prescriber of potential proarrhythmia include older women, underlying cardiovascular comorbidity, family history of sudden death and hypokalaemia.

Use of Patient Health Records to Quantify Drug-Related Pro-arrhythmic Risk

“…This has been advocated previously by other reporters; for example, Mason 56 recently proposed a need for formal validation with patient outcomes to move away from the current “surrogate” (e.g., hERG inhibition or QTc prolongation) model of cardiac risk. However, studies tackling the epidemiology of drug-induced arrhythmia are limited in the number of patients and cases studied; the Berlin Pharmacovigilance Center (PVZ-FAKOS) 57 and the Drug-induced Arrhythmia Risk Evaluation (DARE) 58 studies are recent examples. Despite their small size (130 cases in DARE and 58 in the PVZ-FAKOS study), there is useful understanding resulting from these studies, notably identification of drugs with no previous classification risk of QTc prolongation or TdP, such as propafenone.…”

“…Finally, the data from post-market sources offer an opportunity to attribute drug risk to many of the drugs uncategorized by CiPA, CredibleMeds, or Redfern. As an example, propafenone (indicated in Figure 4 ) has recently been described as causing 3 proarrhythmia cases; 58 this was subsequently added (March 1, 2018) to the CredibleMeds listing as having a conditional risk for TdP. The disproportionality index calculated on FAERS data shows a value of more than 2.0, and using the incidence data from MarketScan data in Figure 4 also indicates that the drug resides on the upper portion of the scatterplot, consistent with the signal from FAERS.…”

“…Being able to definitively state that an arrhythmic event is the sole result of a prescribed drug is hard, and we typically use surrogates such as prolonged QTc. 2 recent studies, PVZ-FAKOS 57 and DARE, 58 have successfully addressed this issue but are limited in size of patient population. In our study, we looked at a fixed time period with patient health records following commencement of a new drug prescription to minimize the risk of confounders.…”

Electrocardiographic abnormalities in elderly patients interned in the Medical Clinic Service of the Hospital Nacional in 2018

“…Muchas de las alteraciones del ECG están también relacionadas a algunos fármacos, de uso frecuente en este grupo etario: inhibidores de la enzima conversora de la angiotensina, betabloqueantes, calcioantagonistas, digital, etc Los antiarrítmicos pueden generar QTc prolongado adquirido, responsable de arritmias ventriculares y muerte súbita (4,14) .…”

Normal range of serum potassium, prevalence of dyskalaemia and associated factors in Chinese older adults: a cross-sectional study

“…Dyskalaemia, either hyperkalaemia or hypokalaemia, may lead to muscular weakness and cardiac arrhythmias and is associated with increased hospitalisation and mortality. [1][2][3] Besides its life-threatening influences, patients with dyskalaemia might unduly discontinue administration of certain medications that bear benefits on clinical outcomes, such as ACE inhibitors (ACEI) and diuretics. 4 5 It is clinically important to characterise the epidemiology of dyskalaemia in the general population.…”