Gonadotropin-releasing hormone blockers and cardiovascular disease risk: analysis of prospective clinical trials of degarelix

Abstract

Purpose: We investigated associations of baseline cardiovascular disease risk profile, dosing regimen and treatment duration with incident cardiovascular disease events during androgen deprivation therapy with degarelix in patients with prostate cancer.

Materials and methods: Data on 1,704 men who participated in a total of 9 clinical trials were pooled for analysis. Patients received treatment with 1-month (20 to 240 mg) or 3-month (240 to 480 mg) doses of degarelix for an average of 22 months. End points were ischemic heart disease, cerebrovascular disorders, arterial thrombotic/embolic events and intermittent claudication.

Results: First time cardiovascular disease events were reported in 92 men in the year before study entry and in 168 after degarelix treatment. Event rates were similar before and after degarelix treatment in the total population (5.5 vs 6.1/100 person-years, p = 0.45) and in men without cardiovascular disease (5.6 vs 4.3/100 person-years, p = 0.11). In contrast, event rates appeared higher after degarelix treatment in men with cardiovascular disease at baseline (5.3 to 10.5 events per 100 person-years, p = 0.0013). On multivariate analysis cardiovascular disease at baseline was the strongest independent predictor of events, followed by older age, alcohol abstinence and obesity (each p <0.05). Degarelix dose and schedule were not independently associated with cardiovascular disease events.

Conclusions: In men with prostate cancer observed rates of cardiovascular disease events were similar before and after degarelix treatment. Events were largely confined to men with preexisting cardiovascular disease and further modulated by age and modifiable risk factors. Randomized, controlled trials and longer followup are key to fully clarify the comparative safety of gonadotropin-releasing hormone antagonists vs agonists.

Figure 1

Summary of degarelix studies in the safety database. “A” after the number of the trial denotes safety extension trial of the original trial.

Figure 2

Long-term testosterone suppression in studies with regular degarelix dosing as per protocol (n=1462). Results shown are medians ± inter-quartile range.

Figure 3

1-Kaplan-Meier plots of time to first new CVD event in the total population (upper panel), in subjects with no CVD (middle panel) and in subjects with established CVD (lower panel) starting 1 year prior degarelix treatment. Dotted lines indicate 95% confidence intervals. Event rates were comparable before and after degarelix treatment in the total population, decreased in subjects without CVD, but virtually increased in patients with established CVD. However, the acceleration in event rate started 6 month prior treatment initiation with no significant further increase captured after treatment initiation. Numbers indicate new CVD events in the respective time-intervals.

Figure 4

1-Kaplan-Meier plots of time to first new CVD event during degarelix treatment in subjects stratified according to baseline CVD risk profile.