Aims Protein kinase inhibitors (PKI) have revolutionized the prognosis of several types of cancer, justifying the acceleration of their clinical evaluation before they obtain marketing authorization. Pharmacovigilance signals of heart failure (HF) following exposure to PKIs have been detected in recent years. Our objective was to identify the PKIs most frequently associated with the development of HF. Methods Using the French National Healthcare Database, all patients newly exposed to a PKI between January 2011 and June 2014 were followed up for 18 months. Specific hospitalisation diagnosis and long-term disease codes related to HF were used to identify HF patients. HF Incidence Rate Ratios (IRR) were measured and adjusted Hazard Ratios (aHR) were estimated using a Cox model. Results Thirteen PKIs were studied. Among the 49,714 new PKI users during the study period, the mean IRR of HF was 3.38 per 100 person-years, with a median time to onset of 155 days. We found a significant increase in the incidence of HF for 6 drugs: pazopanib (aHR= 2.42, 95% CI: 1.67-3.52), dasatinib (aHR= 2.22, 95% CI: 1.42-3.44), ruxolitinib (aHR= 2.11, 95% CI: 1.69-2.64), crizotinib (aHR= 1.71, 95% CI: 1.07-2.72), everolimus (aHR= 1.45, 95% CI: 1.26-1.67) and vemurafenib (aHR= 1.37, 95% CI: 1.01-1.86). Conclusions Our study provides knowledge on HF following exposure to a PKI. Additional studies could confirm these results for dasatinib, everolimus, pazopanib and ruxolitinib, and particularly for the two drugs with results slightly above the significance threshold, crizotinib and vemurafenib in our sensitivity analyses.

Aim: Although medicine misuse is a public health issue, it has multiple meanings in the medical literature. This study aimed to characterize, classify and identify the most appropriate definitions of medicine misuse. Methods: A systematic review was performed in Medline, ISI Web of Science, SocINDEX, PsycInfo, PsycArticles, and Psychological and Behavioral Sciences Collection, using keywords related to misuse, appropriateness, and medicine between November 1st, 2008 and November 1st, 2018. Additional searches were conducted in websites of regulatory agencies and public health institutions. Two authors independently selected studies providing both definitions and examples of misuse, while a third resolved disagreements. Definitions were used to propose a hierarchical classification based on initiator, intent, purpose, and context of medicine misuse. The study is registered on PROSPERO: CRD42018115789. Results: Of 2,901 identified records, 44 were included. A total of 63 definitions and 60 examples of misuse were retrieved. When the prescriber is initiator and according to intent, potential medicine misuse referred to “intentional or unintentional prescribing not in line with clinical evidence”. Based on context, he could prescribe medicines not clinically justified, i.e. “overprescribing”, or prescribe indicated medicines incorrectly, i.e. “misprescribing”. Among other groups of definitions, those overlapping with drug abuse or medication use errors were considered out-of-scope. Conclusion: This systematic review provides a comprehensive overview of the terms and definitions used to characterize medicine misuse and could serve as a basis for a terminology that makes clear distinctions between misuse, abuse, and errors.