Verdaguer Joaquim, Chouchana Laurent, Robert Marion, Bergeron Sandrine, Montastruc François, Barus Romain
Department of Medical and Clinical Pharmacology, Faculty of Medicine, Centre of PharmacoVigilance and Pharmacoepidemiology, Toulouse University Hospital, 31000 Toulouse, France.
Department of Perinatal, Pediatric and Adult Pharmacology, Centre of Pharmacovigilance, Cochin Hospital, AP-HP.centre-université Paris Cité, 75000 Paris, France.
Therapie. 2025 May-Jun;80(3):305-309. doi: 10.1016/j.therap.2024.09.001. Epub 2024 Oct 5.
Fluoropyrimidine-based therapies, 5-fluorouracil (5-FU) and its oral prodrugs, capecitabine and tegafur/oteracil/gimeracil (S-1), are pivotal drugs to treat gastric cancer. Fluoropyrimidines are associated with cardiotoxicity including ischemic cardiopathy. The mechanisms of ischemic cardiopathy are considered to be multifactorial, potentially involving metabolites of 5-FU generated by the dihydropyrimidine dehydrogenase (DPD). By using Vigibase®, the World Health Organization pharmacovigilance database, we aimed to investigate the implication of the 5-FU metabolites induced by DPD in the occurrence of ischemic cardiopathy in patients with gastric cancer using capecitabine.
In Vigibase®, we included serious reports of ischemic cardiopathy with capecitabine and S-1 from January 1st, 2013, to September 16th, 2023. Among patients with gastric cancer, we calculated the reporting odds ratio (ROR) of ischemic cardiopathy to compare capecitabine (a prodrug without DPD antagonist) with S-1 (a prodrug associated with a DPD antagonist). The ROR was also calculated regardless of the drug indication. An ancillary analysis based on the French pharmacovigilance database was also performed. We evaluated the ROR of serious cardiac disorders induced by 5-FU intravenous infusion according to the DPD status (no deficiency versus complete or partial deficiency).
In gastric cancer, 1843 reports (including 23 ischemic cardiopathy) for capecitabine and 2225 reports (including 17 ischemic cardiopathy) for S-1 were included. Median time-to-onset was 7 (3-26) days for capecitabine and 22 (13.25-30) days for S-1. Capecitabine was associated with an increased ROR of ischemic cardiopathy compared with S-1 in gastric cancer (ROR=1.6; [95% CI=1.5-1.8]) and regardless of the indication (7.3; [95% CI=6.6-8.0]). In the ancillary analysis, among 5-FU users, the lack of DPD deficiency increased the ROR for cardiac disorders (2.1; [95% CI=1.9-2.3]) compared to the DPD deficiency.
This work supports the role of toxic 5-FU metabolites generated by dihydropyrimidine dehydrogenase in the occurrence of ischemic cardiopathy among patients with gastric cancer using capecitabine.
基于氟嘧啶的疗法，即5-氟尿嘧啶（5-FU）及其口服前体药物卡培他滨和替吉奥（S-1），是治疗胃癌的关键药物。氟嘧啶与包括缺血性心脏病在内的心脏毒性有关。缺血性心脏病的机制被认为是多因素的，可能涉及二氢嘧啶脱氢酶（DPD）产生的5-FU代谢产物。通过使用世界卫生组织药物警戒数据库Vigibase®，我们旨在研究DPD诱导的5-FU代谢产物在使用卡培他滨的胃癌患者缺血性心脏病发生中的作用。
在Vigibase®中，我们纳入了2013年1月1日至2023年9月16日期间使用卡培他滨和S-1后出现缺血性心脏病的严重报告。在胃癌患者中，我们计算缺血性心脏病的报告比值比（ROR），以比较卡培他滨（一种不含DPD拮抗剂的前体药物）和S-1（一种与DPD拮抗剂相关的前体药物）。无论药物适应症如何，均计算ROR。还基于法国药物警戒数据库进行了辅助分析。我们根据DPD状态（无缺陷与完全或部分缺陷）评估了5-FU静脉输注引起的严重心脏疾病的ROR。
在胃癌患者中，纳入了1843份卡培他滨报告（包括23例缺血性心脏病）和2225份S-1报告（包括17例缺血性心脏病）。卡培他滨的中位发病时间为7（3-26）天，S-1为22（13.25-30）天。与S-1相比，卡培他滨在胃癌患者中与缺血性心脏病的ROR增加相关（ROR=1.6；[95%CI=1.5-1.8]），且无论适应症如何（7.3；[95%CI=6.6-8.0]）。在辅助分析中，在使用5-FU的患者中，与DPD缺陷相比，缺乏DPD缺陷会增加心脏疾病的ROR（2.1；[95%CI=1.9-2.3]）。
这项研究支持二氢嘧啶脱氢酶产生的有毒5-FU代谢产物在使用卡培他滨的胃癌患者缺血性心脏病发生中的作用。
