Cardiovascular Risk Profiles of GnRH Agonists and Antagonists: Real-World Analysis from UK General Practice - Beyond the Abstract

Cardiovascular (CV) mortality is now the most common cause of death in men with prostate cancer, even exceeding prostate cancer mortality.1 Several studies have shown androgen deprivation therapy, which is still the cornerstone of treatment for men with hormone-dependent prostate cancer, is associated with an increased risk of cardiovascular disease (CVD).2,3 However, recent evidence suggests it is now time to consider which androgen deprivation therapy (ADT) modality is most suitable for patients with cardiovascular risk factors.4

The aim of this study was to use real-world data from a UK primary care database (Optimum patient care database) to clarify whether CV risk in prostate cancer patients was lower in those treated with GnRH antagonists vs. LHRH agonists. A total of 9,081 patients were identified from the database as patents with a diagnosis for prostate cancer and new users of degarelix, leuprorelin, triptorelin, or goserelin. We found patients receiving degarelix had a higher baseline prostate-specific antigen (PSA), indicating more advanced prostate cancer than those initiating therapy with a GnRH agonist. Further, more patients receiving degarelix had pre-existing CVD compared with patients receiving GnRH agonists. Despite this, the relative risk of experiencing any cardiac event was lower with degarelix than all GnRH agonists (Table 1; risk ratio [RR] 6.9% vs. 17.7%; 0.39 [95% confidence interval [CI] 0.191, 0.799]; p = 0.01).

Our data support findings from previously published studies showing GnRH antagonists are associated with a lower cardiac risk than LHRH agonists. In a retrospective pooled analysis of six prospective clinical trials in men with pre-existing CVD (2328), initiating degarelix compared with GnRH agonist therapy resulted in an absolute risk reduction of 8.2% (NNT=12).5 Further, in a prospective randomized controlled trial of 80 patients with pre-existing CV disease, 20% on the agonist developed a major adverse cardiovascular event (MACE) compared to 3% on the antagonist.6 Recent publications of similar real-world studies also reflect our findings. An analysis of Italian health records showed the incidence rate of CV events was significantly higher in patients treated with GnRH agonists rather than degarelix (8.80 vs. 6.24 per 100 person-year, p-value 0.002).7 Further, pharmacovigilance data (VigiBase) showed increased odds of cardiac events (driven by myocardial infarction [MI] and heart failure [HF]), for GnRH agonists but not for GnRH antagonists.8 Finally, a Phase III randomized controlled trial of an oral antagonist (relugolix) showed in pre-specified safety analysis, the incidence of major adverse cardiovascular events (MACE) was lower in the relugolix group than in the leuprolide group (2.9% vs. 6.2%, respectively).9

Our study, along with this recently published data highlights the importance of raising awareness of the CV risks for prostate cancer patients. A careful CV assessment should be considered in all patients undergoing hormonal therapy to identify those patients at high, intermediate, and low risk (Figure 1) and the optimal ADT identified to reduce the risk of future CV events. Further, is there a possibility that patients on long-term ADT initially considered intermediate risk may progress to high risk? This may be particularly important in patients with metastatic prostate cancer on a combination of ADT plus novel hormonal therapies such as enzalutamide and abiraterone, which have also been associated with increased cardiovascular mortality.10 Those at high risk should receive appropriate lifestyle advice, regarding smoking cessation, healthy diet, weight control, and daily exercise and should be managed appropriately with European Association of Urology (EAU) guidelines recommending a cardiology consultation in men with a history of cardiovascular disease and men older than 65 prior to staring ADT1. American Urological Association (AUA) guidelines recommend patients on ADT are referred to their primary care physician for a periodic follow-up evaluation with appropriate secondary preventative measures in place for those patients with cardiac disease such as lipid-lowering therapy, antihypertensive therapy, glucose-lowering therapy, and antiplatelet therapy.11 It is therefore important to consider personalized treatment for prostate cancer patients on hormonal therapies to optimize treatment options and reduce CV events.

cardiovascular risk assessment
Figure 1. Cardiovascular risk assessment

baseline and cardio characteristics in prostate cancer
Table 1. Baseline characteristics and cardiovascular events in patients with prostate cancer treated with degarelix, leuprorelin, goserelin, or triptorelin

Written by: Patrick Davey, MD, PhD, Consultant Cardiologist, Northampton General Hospital, Northampton, UK; and Michael Kirby, MBBS, LRCP, MRCS, FRCP, Professor, University of Hertfordshire, Hatfield, England, United Kingdom


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