Cardiotoxicity Associated with Gemcitabine: Literature Review and a Pharmacovigilance Study.

Marc Hilmi,Bénédicte Lebrun-Vignes,Xavier Waintraub,Aurore Vozy,Lee S Nguyen,Stéphane Ederhy,Javid Moslehi,Joe-Elie Salem,Christian Funck-Brentano,Ariel Cohen

doi:10.3390/ph13100325

Abstract

Background: Gemcitabine is a nucleoside analog, widely used either alone or in combination, for the treatment of multiple cancers. However, gemcitabine may also be associated with cardiovascular adverse-drug-reactions (CV-ADR). Methods: First, we searched for all cases of cardiotoxicity associated with gemcitabine, published in MEDLINE on 30 May 2019. Then, we used VigiBase, the World Health Organization’s global database of individual case safety reports, to compare CV-ADR reporting associated with gemcitabine against the full database between inception and 1 April 2019. We used the information component (IC), an indicator value for disproportionate Bayesian reporting. A positive lower end of the 95% credibility interval for the IC (IC025) ≥ 0, is deemed significant. Results: In VigiBase, 46,898 reports were associated with gemcitabine on a total of 18,908,940 in the full database. Gemcitabine was associated with higher reporting for myocardial ischemia (MI, n: 119), pericardial diseases (n: 164), supraventricular arrhythmias (SVA, n: 308) and heart failure (HF, n: 484) versus full database with IC025 ranging between 0.40 and 2.81. CV-ADR were associated with cardiovascular death in up to 17% of cases. Conclusion: Treatment with gemcitabine is associated with potentially lethal CV-ADRs, including MI, pericardial diseases, SVA and HF. These events should be considered in patient care and clinical trial design.

Highlights

Gemcitabine is a cytidine analog that incorporates into DNA and terminates chain elongation by inhibiting ribonucleotide reductase and DNA repair [1]
We present three news cases of cardiotoxicity associated with gemcitabine (Table 1) and their management (i), we perform a literature review focusing on the description of cardiovascular adverse-drug-reactions (CV-adverse drug reaction (ADR)) reported on gemcitabine in MEDLINE (ii) and (iii) we use VigiBase, the WHO’s international pharmacovigilance database of individual case safety reports to describe the reported CV-ADR cases associated with gemcitabine
Twenty-three cases reporting gemcitabine-associated CV-ADR were retrieved from literature review including myocardial ischaemia (MI, n: 4), heart failure (HF, n: 10), supraventricular arrhythmias (SVA, n: 6), and pericardial disorders (n: 8), 2 of which were in a context of capillary leak syndrome (CLS)

Summary

Introduction

Gemcitabine is a cytidine analog that incorporates into DNA and terminates chain elongation by inhibiting ribonucleotide reductase and DNA repair [1]. It is still widely used, either alone or in combination to treat various cancers including lung, pancreas, bladder, breast, ovary and bile duct carcinomas, lymphomas and uterine sarcomas [2]. Conclusion: Treatment with gemcitabine is associated with potentially lethal CV-ADRs, including MI, pericardial diseases, SVA and HF. These events should be considered in patient care and clinical trial design

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