Albertsen et al. Eur Urol 2014[25] | Pooled, retrospective study of 6 prospective trials | N = 2328 Number of deaths from any cause and the number of cardiac events among all men receiving any form of ADT. Cardiac events included; arterial embolic and thrombotic events, hemorrhagic or ischemic cerebrovascular conditions, myocardial infarction or other ischemic heart disease. | In patients with pre-existing CV disease at baseline there was a 56% relative risk reduction of a CV event or death in patients treated with degarelix compared with patients treated with a GnRH agonist (HR: 0.44; 95% CI, 0.26–0.74; p = 0.002). Absolute risk reduction of a CV event or death was 8.2%, NNT = 12. |
Scailteux et al. Eur J Cancer 2017[33] | Retrospective population-based cohort study (RWE) | N = 35,118 Occurrence of ‘ischaemic events’ | No significant association between GnRH antagonists and CV risk, although combined androgen blockade was associated with an increased risk and anti-androgen therapy was associated with a decreased risk of ischaemic events compared with GnRH agonist therapy. |
Abufaraj et al. Eur Urol 2020[26] | Meta-analyses | N = 2,632 CV events; arterial embolic and throm- botic events, ischemic cerebrovascular events, myocardial infarction, and other ischemic heart disease. | GnRH antagonist was associated with fewer cardiovascular events (RR: 0.52, 95% CI: 0.34–0.80) |
Sciarra et al. Medicine 2016[27] | Meta-analyses | N = 1719 Treatment related severe cardiovascular side effects; QT interval increase, angina pectoris, atrial fibrillation, cardiac failure, and myocardial ischemia | Treatment-related severe cardiovascular side effects were reported in 1.6% and 3.6% of patients in the degarelix and GnRH agonists group, respectively (OR = 0.55, 95% CI: 0.26–1.14, P > 0.1) |
Ma et al. Minerva Urologica e Nefrologica 2020[28] | Meta-analyses | N = 32,887 CVD outcomes | The results of meta-analysis showed that compared with GnRH agonist, the incidents of CVD was equal to GnRH antagonist therapy for patient with PCa (RR 0.98, 95% CI 0.94—1.02). |
Cardwell et al. Epidemiology 2019[35] | Retrospective population-based cohort study (RWE) | N = 20,216 Cardiovascular events consisting of either death from cardiovascular disease or hospitalization for cardiovascular disease. CV disease type included acute myocardial infarction, stroke, venous thromboembolism, heart failure, arrhythmia, and other cardiovascular diseases. | 30% increase in CV risk with ADT compared with untreated patients; they report a 30% increase in risk with GnRH agonists and a 50% increase in risk with degarelix |
Hupe et al. Front Oncol 2018[34] | Retrospective population-based cohort study (RWE) using a German health insurance database | N = 2,382 To analyse real world information on healthcare characteristics and treatment patterns in patients with locally advanced or metastatic PCa dependent on the prescribed GnRH agonist/antagonist agents (GnRHa) in the first 3 years after initiation. | No significant differences in the incidence of CVD or diabetes between GnRH agonists or antagonists overall, although there was a significant increase in hypertension in patients receiving a GnRH agonist (16.4%) compared with those receiving a GnRH antagonist (6.9%, p = 0.022) |
Margel et al. J Urol 2020[21] | Prospective, randomised controlled trial of 80 patients | N = 80 The study primary end point was to compare endothelial function between the 2 arms. Cardiovascular events were a pre-defined secondary outcome including; death, MI, CVA, a transient ischemic attack, heart catheterization with or without intervention and cardiac related hospitalization. MACCEs were defined as death, MI, CVA and heart catheterization with stent insertion | After 12 months, 8 (20%) patients randomised to GnRH agonist had a MACCE compared to 1 (3%) treated with the antagonist. Absolute risk reduction of a CV event or death was 18.1% (95% CI 4.6–31.2), NNT = 6. |
Davey et al. J Urol 2020[64] | Retrospective population-based cohort study (RWE) from UK primary care database | N = 9.081 The incidence of cardiac events following initiation of GnRH antagonist (degarelix) or GnRH agonist (leuprorelin, goserelin or triptorelin) as therapy in patients with prostate cancer. CV events included; heart failure; myocardial infarction (MI); arrhythmia; ischaemic heart disease. | The relative risk of experiencing any CV event was lower with degarelix than all GnRH agonists (6.9% vs 17.7%) (ARR = 10.8, NNT = 9) |
Perrone et al. Therapeutics and Clinical Risk Management 2020[31] | Retrospective population-based cohort study (RWE) | N = 9,785 The incidence rate of CV events (acute myocardial infarction, ischemic heart diseases, cerebrovascular diseases, cardiac dysrhythmias, heart failure, atherosclerosis, aneurism, other CV-related conditions) was calculated among patients not switching to androgen deprivation therapy (ADT) in the overall cohort and in a sub-cohort of patients without previous CV events | 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), with mean time to CV event beyond 1 year. |
Cone et al. BJU Int. 2020[32] | Retrospective Pharmacovigilance database (Vigibase) | Cardiovascular reactions related to GnRH antagonist (degarelix) or agonist (leuprolide, goserelin, triptorelin, histrelin) therapy for prostate cancer. CV events included; myocardial infarction (MI), heart failure (HF), carditis (cardiomyopathies, pericarditis, and myocarditis), new valvular dysfunction, and new arrythmias. | Pharmacovigilance data showed increased odds of cardiac events, driven by MI and HF, for GnRH agonists but not for GnRH antagonists. 805 (7.7%) cardiac related events were found for agonists and 102 (6.4%) for antagonists. |
Shore et al. NEJM 2020[23] | Prospective, Randomised controlled trial 934 patients | N = 930 The primary end point was the sustained castration rate, defined as the cumulative probability of testosterone suppression to less than 50 ng per deciliter during receipt of trial treatment from day 29 through 48 weeks. Cardiovascular or cerebrovascular risk factors included prespecified event terms in the MACE query and a manual search of known risk factors, including hypertension; dyslipidemia; diabetes; a history of myocardial infarction or cardiovascular disease; a history of stroke, transient ischemic attack, or cerebral haemorrhage; peripheral arterial disease; atrial fibrillation and other arrhythmias; heart-valve disease; chronic obstructive pulmonary disease; chronic kidney disease; chronic liver disease; carotid-artery stenosis or occlusion; venous thromboembolic events; and heart failure. | In a prespecified analysis, in men with a history of MACE, the incidence of major adverse cardiovascular events (MACE) was lower in the relugolix group than in the leuprolide group (3.6% vs. 17.8%, respectively). ARR = 14.2, NNT = 7 |
George et al. International Journal of Cancer 2020[36] | Retrospective population-based cohort study (RWE) using data from 5 countries | N = 50,909 To combine real-world data from 5 countries to compare risk of CVD between agonists and antagonists. CVD included; ischaemic heart disease (IHD), acute myocardial infarction (AMI), arrhythmia, heart failure (HF) and stroke. | There was no difference in risk of any CVD for men on GnRH antagonists and agonists (HR: 1.25; 95% CI: 0.96–1.61; I2: 64%). Men on GnRH antagonists showed increased risk of acute myocardial infarction (HR: 1.62; 95% CI: 1.11–2.35; I2: 0%) and arrhythmia (HR: 1.55; 95% CI: 1.11–2.15, I2: 17%) compared to GnRH agonists. |