Assessing drugs for risk of arrhythmia
Concern has been expressed about drugs that prolong the QT interval of the electrocardiogram, precipitating torsade de pointes (Tdp), a potentially fatal arrhythmia. However, a growing body of evidence is showing that an increase in the QT interval does not necessarily lead to TdP, casting doubt on clinical and regulatory decisions that have been made. The 'Arrhythmogenic potential of drugs' (ARITMO) project was designed to examine the relationship between medications and arrhythmia. To date, it has assessed three classes of drugs: antipsychotics, antihistamines, and anti-infective agents. Literature reviews, databases with pharmacokinetic parameters, and databases with a cardiac safety profile were used to study the drugs. In addition, researchers examined the relationship between these drugs and ventricular arrhythmia (VA) and sudden cardiac death (SCD). They also looked at patient profiles to see if they could find new parameters that would predict TdP. Finally, the investigators conducted genetic analyses. Out of 450 drugs under study, a comparison between literature review and database analysis could be provided for 205 drugs: 26 antihistamines, 36 antipsychotics, and 143 anti-infective agents. ARITMO provided new information for 16 antihistamines and 20 antipsychotics and confirmed that anti-infective agents were generally in the low-risk category. These and similar results have numerous implications. They can be used to help regulators make decisions about the risk associated with these drugs. They also can be used to prioritise drugs that should be evaluated. Finally, the findings can be used to quantify risk and validate preclinical predictive models. The integrated evidence that has emerged from the ARITMO project will allow for better regulatory and clinical decision making. Furthermore, an infrastructure has been established that can be used for other drugs. This effort represents a collaborative network for doing research and delivering state-of-the-art results.
Keywords
arrhythmia, Arrhythmogenic potential, QT interval, antihistamines, antipsychotics, anti-infective agents, regulatory decisions, clinical decisions
