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 2013e2021 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 1.7e5.0 years), 1115 patients (45.0%) had MACE(PRONOUNCE) and 344 (13.9%) had MAC(ECVM). GnRH agonist users had lower risks of MACE(PRONOUNCE) (Log-rank P < 0.001) and MACE(CVM) (Log-rank P 1/4 0.027). However, no differences were observed within 1 year of follow-up (MACE(PRONOUNCE): Log-rank P 1/4 0.308; MACE(CVM): Log-rank P 1/4 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 1/4 0.001), whereas no differences were observed in those with such risk factor(s) (MACE(PRONOUNCE): Log-rank P 1/4 0.569; MACE(CVM): Log-rank P 1/4 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.

Automated summary

This prospective cohort study aimed to compare the long-term cardiovascular risks between GnRH agonists and antagonists. The results showed that Asian patients with prostate cancer who used GnRH agonists had lower cardiovascular risks compared to those who used antagonists, especially in patients without known cardiovascular risk factors.