QT shortening: a proarrhythmic safety surrogate measure or an inappropriate indicator of it?

Abstract

Objective: To examine whether QT interval shortening is an overlooked adverse event as compared to QT prolongation through a review of preclinical, clinical and post-marketing adverse event data available to the regulator for centrally and nationally authorized medicinal products.

Methods: Potential safety signals of QT shortening related to authorized medicinal products were detected from Eudravigilance using proportional reporting ratios. Active substances identified as having unexpected signals of QT shortening were assessed in depth using the Bradford-Hill criteria for causation. Preclinical, clinical and adverse event data related to each active substance was used in the assessments. Post marketing adverse event cases were reviewed for imputability using the French method.

Results: 80 adverse event cases of electrocardiogram QT shortening were detected from 13 different active substances which included antipsychotics and antiepileptics (Clozapine, Ziprasidone, Quetiapine, Olanzapine, Carbamazepine), cardiovascular drugs (Atenolol, Digoxin, Ramipril, Simvastatin), anti-inflammatories and analgesics (Ibuprofen, Paracetamol) and other substances Calcium Carbonate (Mineral Supplement/Antacid) and Fingolimod (Immunosuppressant). By comparison 404 active substances were found have a potential safety signal of Electrocardiogram QT prolongation. Following in depth review none of the 13 active substances identified were found to be clearly associated with QT shortening using the minimum level of evidence for regulatory action. In the preclinical data reviewed we observed cases of morphological changes to the action potential (AP) where the Action Potential Duration at 90% (APD₉₀) was not affected.

Conclusions: From a regulatory perspective one cannot refute the possibility of a clinically relevant risk from QT shortening through the current testing requirements. Lack of further investigations into any potential morphological changes to the AP, or APD₉₀ shortening beyond a specified threshold in our opinion does not fully exclude the possibility of proarrhythmic effects of active substances.

Keywords: Drug induced arrhythmia; EU regulation; QT interval; QT shortening; drug safety.