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\begin{document}

\title{Incidence of heart failure following exposure to a Protein Kinase
Inhibitor (PKI), a French population-based study.}



\author[1]{Yoann Zelmat}%
\author[1]{Cécile Conte}%
\author[2]{Pernelle Noize}%
\author[1]{Clémentine Vabre}%
\author[1]{Pajiep Marie-Christelle}%
\author[1]{Margaux Lafaurie}%
\author[1]{Maryse Lapeyre-Mestre}%
\author[1]{Fabien Despas}%
\affil[1]{Medical and Clinical Pharmacology Unit, University Hospital Centre Toulouse, 37, allées Jules-Guesde, 31000 Toulouse, France; Clinical Investigation Center (CIC) 1436, University Hospital Centre Toulouse, 31059 Toulouse cedex 9, France; Equipe Pharmacologie en Population, cohorteS, biobanqueS, PEPPS, Toulouse University}%
\affil[2]{Bordeaux University, INSERM, BPH, U1219}%


\vspace{-1em}



  
  \date{May 21, 2024}


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\begin{abstract}
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.%
\end{abstract}%



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