Long-term Cardiovascular Risks of Gonadotropin-releasing Hormone Agonists and Antagonists: A Population-based Cohort Study

Aims: Gonadotropin-releasing hormone (GnRH) agonists and antagonists, critical medications for prostate cancer (PCa) treatment, may differ in cardiovascular safety. This prospective cohort study aimed to compare the long-term cardiovascular risks between GnRH agonists and antagonists. Materials and methods: Patients with PCa receiving GnRH agonists or antagonists during 2013–2021 in Hong Kong were identified. Patients with <6 months' prescriptions, who were switching between drugs, had missing baseline prostate-specific antigen level or had a prior stroke or myocardial infarction were excluded. Patients were followed up until September 2021. The primary outcome was major adverse cardiovascular events (MACE) as in the PRONOUNCE trial (MACE_PRONOUNCE), i.e. a composite of all-cause mortality, stroke and myocardial infarction. The secondary outcome was MACE_CVM, i.e. a composite of cardiovascular mortality, stroke and myocardial infarction. Inverse probability treatment weighting was used to balance covariates between groups. The Log-rank test was used to compare the cumulative freedom from the primary outcome between groups. Results: In total, 2479 patients were analysed (162 GnRH antagonist users and 2317 agonist users; median age 75.0 years, interquartile range 68.0–81.6 years). Inverse probability treatment weighting achieved good covariate balance between groups. Over a median follow-up duration of 3.0 years (interquartile range 1.7–5.0 years), 1115 patients (45.0%) had MACE_PRONOUNCE and 344 (13.9%) had MACE_CVM. GnRH agonist users had lower risks of MACE_PRONOUNCE (Log-rank P < 0.001) and MACE_CVM (Log-rank P = 0.027). However, no differences were observed within 1 year of follow-up (MACE_PRONOUNCE: Log-rank P = 0.308; MACE_CVM: Log-rank P = 0.357). Among patients without cardiovascular risk factors at baseline, GnRH agonist users had lower risks of MACE_PRONOUNCE (Log-rank P < 0.001) and MACE_CVM (Log-rank P = 0.001), whereas no differences were observed in those with such risk factor(s) (MACE_PRONOUNCE: Log-rank P = 0.569; MACE_CVM: Log-rank P = 0.615). Conclusions: GnRH antagonists may be associated with higher long-term, but not short-term, cardiovascular risks than agonists in Asian patients with PCa, particularly in those without known cardiovascular risk factors.