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
• drug safety
• EU regulation
• QT interval
• QT shortening

Transparency

Declaration of funding

This paper was not funded.

Declaration of financial/other relationships

Amy Tanti declares that she is a former employee of the Medicines Authority who is currently a freelance pharmaceutical consultant and EU-QPPV. The other authors declare no financial conflict of interest and no competing interest. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

AT contributed to the literature research, study design, data collection and data analysis. BM contributed to data analysis. JJB contributed to the study design, project administration, supervision, formal analysis and data interpterion. JVS and ASI contributed to the supervision of the project. All authors contributed to the writing of this manuscript.

Acknowledgements

None.

Notes

i The total number of individual medicinal products in EudraVigilance as of 12 January 2017 regardless of their current authorisation status (e.g. valid, withdrawn, etc.)