Elsevier

European Urology

Volume 65, Issue 3, March 2014, Pages 565-573
European Urology

Platinum Priority – Prostate Cancer
Editorial by Derek J. Rosario, Liam Bourke and Nancy L. Keating on pp. 574–576 of this issue
Cardiovascular Morbidity Associated with Gonadotropin Releasing Hormone Agonists and an Antagonist

https://doi.org/10.1016/j.eururo.2013.10.032Get rights and content

Abstract

Background

Androgen deprivation therapy (ADT) is associated with increased cardiovascular morbidity.

Objective

To determine whether cardiovascular morbidity differs following initiation of gonadotropin-releasing hormone (GnRH) agonists compared with an antagonist.

Design, setting, and participants

Pooled data from six phase 3 prospective randomized trials that recruited 2328 men between 2005 and 2012 to compare the efficacy of GnRH agonists against an antagonist. Men recruited had pathologically confirmed prostate cancer, an Eastern Cooperative Oncology Group score <2, a minimum life expectancy of 12 mo, and were naïve to ADT. Men were excluded if they had a prolonged baseline QT/corrected QT interval, other risk factors for heart failure, hypokalemia or a family history of long QT syndrome, or had another cancer diagnosed within 5 yr.

Intervention

Men were randomized to receive a GnRH agonist or an antagonist for either 3–7 mo (n = 642) or 12 mo (n = 1686). Treatment groups were balanced for common baseline characteristics.

Outcome measurements and statistical analysis

Event analysis was based on death from any cause or cardiac events. Data documenting adverse experiences were classified based on the Medical Dictionary for Regulatory Activities. The following conditions defined a cardiac event: arterial embolic or thrombotic events, hemorrhagic or ischemic cerebrovascular conditions, myocardial infarction, and other ischemic heart disease. Kaplan-Meier curves and log-rank tests were used to compare time to a cardiovascular event or death.

Results and limitations

Among men with preexisting cardiovascular disease, the risk of cardiac events within 1 yr of initiating therapy was significantly lower among men treated with a GnRH antagonist compared with GnRH agonists (hazard ratio: 0.44; 95% confidence interval, 0.26–0.74; p = 0.002). Since our analysis is post hoc, our findings should only be interpreted as hypothesis generating.

Conclusions

GnRH antagonists appear to halve the number of cardiac events experienced by men with preexisting cardiovascular disease during the first year of ADT when compared to GnRH agonists.

Introduction

Ever since Huggins and Hodges published their landmark study, clinicians have relied on androgen deprivation therapy (ADT) to treat men with prostate cancer (PCa). In 1959, the Veterans Administration Cooperative Urological Research Group was established to facilitate large-scale, prospective, randomized trials to define safe and effective treatments for PCa. They noted significantly increased rates of cardiovascular (CV) morbidity among men receiving higher doses of diethylstilbestrol as compared with men undergoing orchiectomy.

Gonadotropin-releasing hormone (GnRH) agonists were introduced in the 1990s to lower the risks of cardiac events associated with estrogens. A growing body of literature, however, has described several side effects associated with GnRH agonist therapy that include a 10–50% increased risk of bone fractures, peripheral insulin sensitivity, coronary heart disease, myocardial infarction, and sudden cardiac death, in addition to adverse effects on body mass, cholesterol, and quality of life [1], [2]. In a recent mini-review, Bourke et al. commented that “a cause and effect relationship between ADT and increased risk of CV disease remains a plausible hypothesis that is yet to be falsified” [3]. Concerns regarding increased CV risks prompted the US Food and Drug Administration (FDA) to mandate in 2010 that manufacturers of GnRH agonists include additional safety information to the warnings and precautions section of drug labels.

Still, the relationship between ADT and CV disease remains controversial [4]. One theory suggests that ADT exacerbates preexisting cardiac risk factors, making them more evident during treatment [5], [6]. CV mortality among PCa patients receiving radiation therapy was higher among men receiving concomitant ADT when compared to those who did not, and was observed primarily among men with moderate to severe preexisting CV disease [5], [7].

We explored this hypothesis using data previously collected for phase 3 and 3B randomized trials of an FDA-approved GnRH antagonist. Specifically, we investigated whether these two drug classes had a similar impact on the short-term risk of CV events among men initiating GnRH therapy.

Section snippets

Data sources

Six prospective, phase 3, randomized controlled trials (n = 2328) were conducted by Ferring Pharmaceuticals to test the efficacy of a new GnRH antagonist compared to GnRH agonists. These trials included two 12-mo trials (CS21, n = 610; and CS35, n = 848), one 7-mo trial (CS37, n = 403), and three 3-mo trials (CS28, n = 40; CS30, n = 245; and CS31, n = 182). These six trials include all of the phase 3 trial data collected by Ferring Pharmaceuticals concerning the performance of the GnRH antagonist, degarelix.

Results

The study cohort consisted of 2328 patients who received either GnRH agonists (n = 837) or an antagonist (n = 1491). The two treatment groups were balanced for CV history and baseline characteristics such as a history of diabetes, elevated blood pressure, elevated cholesterol levels, and the use of statin medications (Table 2). The baseline incidence of CV disease was approximately 30% in both treatment groups (Table 3). The most frequent preexisting event was myocardial ischemia (11%), followed by

Discussion

Our analysis suggests that ADT may be an independent risk factor for CV events. Patients with preexisting CV disease who were treated with a GnRH antagonist appear to have had a significantly lower risk of experiencing a CV event or death when compared to patients receiving a GnRH agonist within 1 yr of initiating ADT. The relative risk reduction appears to be as high as 56%, while the absolute risk reduction is about 8.2%. We did not see a similar reduction among men without preexisting CV

Conclusions

GnRH antagonists appear to halve the risk of CV events among men with preexisting CV disease when compared to GnRH agonists. One possible explanation could be the activation of T cells to the Th1 phenotype, resulting in atherosclerotic plaque destabilization. Animal models, as well randomized clinical trials, will be needed to validate this observation and define the mechanism.

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