Cardiovascular Effects of GnRH Antagonists Compared With Agonists in Prostate Cancer: A Systematic Review

BACKGROUND: Androgen deprivation therapy is the cornerstone of treatment for patients with advanced prostate cancer. Meta-analysis of small, oncology-focused trials suggest gonadotropin-releasing hormone (GnRH) antagonists may be associated with fewer adverse cardiovascular outcomes compared with GnRH agonists. OBJECTIVES: This study sought to determine whether GnRH antagonists were associated with fewer major adverse cardiovascular events compared with GnRH agonists. METHODS: Electronic databases were searched for all prospective, randomized trials comparing GnRH antagonists with agonists. The primary outcome was a major adverse cardiovascular event as defined by the following standardized Medical Dictionary for Regulatory Activities terms: “myocardial infarction,” “central nervous system hemorrhages and cerebrovascular conditions,” and all-cause mortality. Bayesian meta-analysis models with random effects were fitted. RESULTS: A total of 11 eligible studies of a maximum duration of 3 to 36 months (median = 12 months) enrolling 4,248 participants were included. Only 1 trial used a blinded, adjudicated event process, whereas potential bias persisted in all trials given their open-label design. A total of 152 patients with primary outcome events were observed, 76 of 2,655 (2.9%) in GnRH antagonist-treated participants and 76 of 1,593 (4.8%) in agonist-treated individuals. Compared with GnRH agonists, the pooled OR of GnRH antagonists for the primary endpoint was 0.57 (95% credible interval: 0.37-0.86) and 0.58 (95% credible interval: 0.32-1.08) for all-cause death. CONCLUSIONS: Despite the addition of the largest, dedicated cardiovascular outcome trial, the volume and quality of available data to definitively answer this question remain suboptimal. Notwithstanding these limitations, the available data suggest that GnRH antagonists are associated with fewer cardiovascular events, and possibly mortality, compared with GnRH agonists.