Risk of cardiovascular events in men on abiraterone or enzalutamide combined with GnRH agonists: nation-wide, population-based cohort study in Sweden

Men with prostate cancer (PCa) on gonadotropin-releasing hormone agonists (GnRH) have an increased risk of cardiovascular disease (CVD) compared to men with PCa not on GnRH as well as compared with PCa-free men. Whether the addition of androgen receptor targeted (ART) drugs to GnRH further increases CVD risk, remains to be fully elucidated. We investigated risk of CVD for men with castration resistant PCa (CRPC) on GnRH plus ART; abiraterone or enzalutamide vs 5,127 and 12,079 respective matched comparator men on GnRH in Prostate Cancer data Base Sweden (PCBaSe^Traject) 4.1 between 1 June 2015 and 31 December 2018. PCBaSe^Traject links National Prostate Cancer Register of Sweden to other healthcare registries and demographic databases. We conducted multivariable Cox proportional hazard models adjusting for PCa risk category, Charlson comorbidity index (CCI), insulin or statin use, civil status, level of education, history of CVD events and number of CVD drugs, with any incident or fatal CVD as the outcome. 1,310 men were treated with abiraterone and 3,579 with enzalutamide. In multivariable analysis, CVD risk was increased in men on abiraterone (hazard ratio (HR): 1.19; 95% confidence interval (CI): 1.03–1.38) and in men on enzalutamide (HR: 1.10; 95% CI: 1.01–1.20). Men with a recent CVD (<12 months) including both men on ART as well as comparators had a much higher probability of a new CVD vs men with no prior CVD. CVD risk was mildly increased in men with PCa on GnRH plus abiraterone or enzalutamide vs comparator men on GnRH. Residual confounding and detection bias may at least partly explain this association.

与未接受促性腺激素释放激素激动剂（gonadotropin-releasing hormone agonists，GnRH）治疗的前列腺癌（prostate cancer，PCa）患者，以及无前列腺癌的男性相比，接受GnRH治疗的前列腺癌患者罹患心血管疾病（cardiovascular disease，CVD）的风险更高。目前尚不明确在GnRH治疗基础上加用雄激素受体靶向（androgen receptor targeted，ART）药物是否会进一步升高心血管疾病风险，相关机制仍有待全面阐明。本研究基于瑞典前列腺癌数据库（Prostate Cancer data Base Sweden，PCBaSe^Traject）4.1版，纳入2015年6月1日至2018年12月31日期间的患者，对比接受GnRH联合ART药物（阿比特龙或恩扎卢胺）治疗的去势抵抗性前列腺癌（castration resistant PCa，CRPC）患者，分别与5127例、12079例仅接受GnRH治疗的匹配对照男性的心血管疾病发病风险。PCBaSe^Traject将瑞典国家前列腺癌注册库与其他医疗登记系统及人口统计数据库进行关联整合。本研究采用多变量Cox比例风险模型，校正前列腺癌风险分层、查尔森合并症指数（Charlson comorbidity index，CCI）、胰岛素或他汀类药物使用情况、婚姻状况、受教育水平、既往心血管疾病事件史及心血管药物使用数量等混杂因素，以新发或致死性心血管疾病为主要结局指标。本队列中，1310例患者接受阿比特龙治疗，3579例患者接受恩扎卢胺治疗。多变量分析结果显示，接受阿比特龙治疗的患者心血管疾病风险升高（风险比（hazard ratio，HR）=1.19；95%置信区间（confidence interval，CI）：1.03~1.38），接受恩扎卢胺治疗的患者心血管疾病风险亦有所升高（HR=1.10；95%CI：1.01~1.20）。无论是否接受ART药物治疗，近期（<12个月）有心血管疾病史的男性，其新发心血管疾病的概率均显著高于无既往心血管疾病史的男性。与仅接受GnRH治疗的对照男性相比，接受GnRH联合阿比特龙或恩扎卢胺治疗的前列腺癌患者心血管疾病风险仅轻度升高。该关联可能至少部分由残余混杂偏倚及检测偏倚所解释。