Cardiovascular Morbidity in a Randomized Trial Comparing GnRH Agonist and GnRH Antagonist among Patients with Advanced Prostate Cancer and Preexisting Cardiovascular Disease

No AccessJournal of UrologyAdult Urology1 Dec 2019Cardiovascular Morbidity in a Randomized Trial Comparing GnRH Agonist and GnRH Antagonist among Patients with Advanced Prostate Cancer and Preexisting Cardiovascular DiseaseThis article is commented on by the following:Editorial Comment David Margel, Avivit Peer, Yaara Ber, Liat Shavit-Grievink, Tzlil Tabachnik, Sivan Sela, Guy Witberg, Jack Baniel, Daniel Kedar, Wilhelmina C. M. Duivenvoorden, Eli Rosenbaum, and Jehonathan H. Pinthus David MargelDavid Margel *Correspondence: Division of Urology, Rabin Medical Center, 39 Jabotinsky Rd., Petah Tikva4941492, Israel telephone: 972-50-7890053; FAX: 972-3-9376569; E-mail Address: [email protected] Division of Urology, Rabin Medical Center, Petach Tikva, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Financial interest and/or other relationship with Ferring. More articles by this author , Avivit PeerAvivit Peer Department of Oncology, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel More articles by this author , Yaara BerYaara Ber Division of Urology, Rabin Medical Center, Petach Tikva, Israel More articles by this author , Liat Shavit-GrievinkLiat Shavit-Grievink Division of Urology, Rabin Medical Center, Petach Tikva, Israel Davidoff Cancer Centre, Rabin Medical Center, Petach Tikva, Israel More articles by this author , Tzlil TabachnikTzlil Tabachnik Division of Urology, Rabin Medical Center, Petach Tikva, Israel More articles by this author , Sivan SelaSivan Sela Division of Urology, Rabin Medical Center, Petach Tikva, Israel More articles by this author , Guy WitbergGuy Witberg Department of Cardiology, Rabin Medical Center, Petach Tikva, Israel More articles by this author , Jack BanielJack Baniel Division of Urology, Rabin Medical Center, Petach Tikva, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel More articles by this author , Daniel KedarDaniel Kedar Division of Urology, Rabin Medical Center, Petach Tikva, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel More articles by this author , Wilhelmina C. M. DuivenvoordenWilhelmina C. M. Duivenvoorden Division of Urology, Department of Surgery, McMaster University, Hamilton, Ontario, Canada More articles by this author , Eli RosenbaumEli Rosenbaum Davidoff Cancer Centre, Rabin Medical Center, Petach Tikva, Israel Equal study contribution. More articles by this author , and Jehonathan H. PinthusJehonathan H. Pinthus Division of Urology, Department of Surgery, McMaster University, Hamilton, Ontario, Canada Financial interest and/or other relationship with Ferring. Equal study contribution. More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000384AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: Androgen deprivation therapy may increase the risk of cardiovascular disease. Limited data suggest that GnRH (gonadotropin-releasing hormone) antagonist may be associated with a lower risk of cardiovascular disease than GnRH agonist. Materials and Methods: We performed a phase II, randomized, open label study in men with prostate cancer and preexisting cardiovascular disease who were randomized to receive GnRH agonists or antagonists for 1 year. The primary outcome was endothelial function measured by the EndoPAT 2000 device (Itamar Medical, Caesarea, Israel). The predefined secondary outcome was a new cardiovascular event. Patients were followed for the development of cardiovascular disease, defined as death, myocardial infarction, a cerebrovascular event, percutaneous angioplasty with coronary stent insertion or hospitalizations due to cardiac events. Results: A total of 80 patients were enrolled in study, including 41 and 39 who received GnRH antagonist and agonist, respectively. Patients in each arm had similar baseline characteristics. We did not detect a difference in the primary end point (endothelial function) between the groups (mean ± SD reactive hyperemia index 2.07 ± 0.15 vs 1.92 ± 0.11, p=0.42). However, during the trial period a new cardiovascular event (the secondary end point) developed in 15 patients. Of cases new major cardiovascular and cerebrovascular events developed in 9, including death in 2, myocardial infarction in 1, a cerebrovascular event in 2 and percutaneous angioplasty with coronary stent insertion in 4. Of the patients 20% randomized to GnRH agonist experienced a major cardiovascular and cerebrovascular event compared to 3% of those on GnRH antagonist (p=0.013). The absolute risk reduction in major cardiovascular and cerebrovascular events at 12 months using GnRH antagonist was 18.1% (95% CI 4.6–31.2, p=0.032). Conclusions: To our knowledge this is the first prospective study to test cardiovascular outcomes among patients with prostate cancer who received androgen deprivation therapy. No differences in the primary end point were noted between the study arms. However, the secondary end point revealed that patients treated with GnRH agonist experienced significantly more major cardiovascular and cerebrovascular events than those treated with GnRH antagonist. These phase II results suggest that in patients with prostate cancer who have preexisting cardiovascular disease selecting the androgen deprivation therapy modality may differentially affect cardiac outcomes. References 1. : Reimbursement policy and androgen-deprivation therapy for prostate cancer. N Engl J Med 2010; 363: 1822. Google Scholar 2. : Androgen-deprivation therapy for nonmetastatic prostate cancer is associated with an increased risk of peripheral arterial disease and venous thromboembolism. Eur Urol 2012; 61: 1119. Google Scholar 3. : Androgen-deprivation therapy in treatment of prostate cancer and risk of myocardial infarction and stroke: a nationwide Danish population-based cohort study. Eur Urol 2014; 65: 704. Google Scholar 4. FDA Drug Safety Communication: Update to Ongoing Safety Review of GnRH Agonists and Notification to Manufacturers of GnRH Agonists to Add New Safety Information to Labeling Regarding Increased Risk of Diabetes and Certain Cardiovascular Diseases. 2010. Available at https://www.fda.gov/Drugs/DrugSafety/ucm229986.htm. Accessed July 17, 2018. Google Scholar 5. : Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA 2011; 306: 2359. Google Scholar 6. : The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int 2008; 102: 1531. Google Scholar 7. : Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. Eur Urol 2014; 65: 565. Google Scholar 8. : Androgen deprivation therapy and cardiovascular risk: no meaningful difference between GnRH antagonist and agonists—a nationwide population-based cohort study based on 2010-2013 French Health Insurance data. Eur J Cancer 2017; 77: 99. Google Scholar 9. : Endothelial function in health and disease: new insights into the genesis of cardiovascular disease. Am J Med, suppl., 1998; 105: 32S. Google Scholar 10. : Test-retest reliability of pulse amplitude tonometry measures of vascular endothelial function: implications for clinical trial design. Vasc Med 2012; 17: 29. Google Scholar 11. : Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol 2004; 44: 2137. Google Scholar 12. : Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J 2010; 31: 1142. Google Scholar 13. U.S. Food and Drug Administration: Guidance for Industry. Diabetes Mellitus Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 2008. Available at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. Accessed September 12, 2018. Google Scholar 14. : Biomarkers in atrial fibrillation: a clinical review. Euro Heart J 2013; 34: 1475. Google Scholar 15. : Peripheral endothelial function and cardiovascular events in high-risk patients. J Am Heart Assoc 2013; 2: e000426. Google Scholar 16. : Minim: Allocation by Minimisation in Clinical Trials, version 1.5. Available at http://www-users.york.ac.uk/∼mb55/guide/minim.htm. Accessed September 27, 2018. Google Scholar 17. : Interpreting the results of secondary end points and subgroup analyses in clinical trials: should we lock the crazy aunt in the attic?BMJ 2001; 322: 989. Google Scholar 18. : Gonadotropin releasing hormone blockers and cardiovascular disease risk: analysis of prospective clinical trials of degarelix. J Urol 2011; 186: 1835. Link, Google Scholar 19. : Androgen deprivation therapy and cardiovascular disease: what is the linking mechanism?Ther Adv Urol 2016; 8: 118. Google Scholar 20. : Endothelial dysfunction and cardiovascular disease. Pathophysiol Haemost Thromb 2002; 32: 274. Google Scholar 21. : Endothelial function in a cardiovascular risk population with borderline ankle-brachial index. Vasc Health Risk Manag 2011; 7: 97. Google Scholar 22. : Testosterone, sex hormone-binding globulin and the metabolic syndrome: a systematic review and meta-analysis of observational studies. Int J Epidemiol 2011; 40: 189. Google Scholar 23. : Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 1685. Google Scholar 24. : Pathologic assessment of the vulnerable human coronary plaque. Heart 2004; 90: 1385. Google Scholar 25. : The immune system in atherosclerosis. Nat Immunol 2011; 12: 204. Google Scholar 26. : GnRH-I and GnRH-II have differential modulatory effects on human peripheral blood mononuclear cell proliferation and interleukin-2 receptor gamma-chain mRNA expression in healthy males. Clin Exp Immunol 2005; 142: 103. Google Scholar 27. : The potential role of follicle-stimulating hormone in the cardiovascular, metabolic, skeletal, and cognitive effects associated with androgen deprivation therapy. Urol Oncol 2017; 35: 183. Google Scholar 28. : Plasma N-terminal pro-B-type natriuretic peptide as a predictor of perioperative and long-term outcome after vascular surgery. J Vasc Surg 2009; 49: 435. Google Scholar 29. : Cardiovascular disease characteristics of newly diagnosed prostate cancer patients: findings from the pilot phase of RADICAL PC: a prospective study of cardiovascular disease in men with prostate cancer (abstract MP14-04). J Urol, suppl., 2017; 197: e163. Link, Google Scholar The corresponding author certifies that, when applicable, a statement(s) has been included in the manuscript documenting institutional review board, ethics committee or ethical review board study approval; principles of Helsinki Declaration were followed in lieu of formal ethics committee approval; institutional animal care and use committee approval; all human subjects provided written informed consent with guarantees of confidentiality; IRB approved protocol number; animal approved project number. No direct or indirect commercial, personal, academic, political, religious or ethical incentive is associated with publishing this article. Editor’s Note: This article is the third of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 1277 and 1278. © 2019 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited byLifshitz K, Ber Y, Shenhar C, Nillson J, Peer A, Rosenbaum E, Baniel J, Kedar D, Ben Zadok O and Margel D (2021) Cardiovascular Proteomics: A Post Hoc Analysis from a Phase II Randomized Clinical Trial Comparing GnRH Antagonist vs GnRH Agonist among Men with Advanced Prostate CancerJournal of Urology, VOL. 206, NO. 4, (952-959), Online publication date: 1-Oct-2021.Zhang K, Reimers M, Calaway A, Fradley M, Ponsky L, Garcia J, Cullen J, Baumann B, Addison D, Campbell C, Ghosh A, Lenihan D, Desai N, Weintraub N and Guha A (2021) Cardiovascular Events in Men with Prostate Cancer Receiving Hormone Therapy: An Analysis of the FDA Adverse Event Reporting System (FAERS)Journal of Urology, VOL. 206, NO. 3, (613-622), Online publication date: 1-Sep-2021.Smith J (2019) This Month in Adult UrologyJournal of Urology, VOL. 202, NO. 6, (1069-1070), Online publication date: 1-Dec-2019.Related articlesJournal of Urology5 Sep 2019Editorial Comment Volume 202Issue 6December 2019Page: 1199-1208Supplementary Materials Advertisement Copyright & Permissions© 2019 by American Urological Association Education and Research, Inc.Keywordsandrogen antagoniststreatment outcomeprostatic neoplasmsgonadotrophin-releasing hormonecardiovascular diseasesMetricsAuthor Information David Margel Division of Urology, Rabin Medical Center, Petach Tikva, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel *Correspondence: Division of Urology, Rabin Medical Center, 39 Jabotinsky Rd., Petah Tikva4941492, Israel telephone: 972-50-7890053; FAX: 972-3-9376569; E-mail Address: [email protected] Financial interest and/or other relationship with Ferring. More articles by this author Avivit Peer Department of Oncology, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel More articles by this author Yaara Ber Division of Urology, Rabin Medical Center, Petach Tikva, Israel More articles by this author Liat Shavit-Grievink Division of Urology, Rabin Medical Center, Petach Tikva, Israel Davidoff Cancer Centre, Rabin Medical Center, Petach Tikva, Israel More articles by this author Tzlil Tabachnik Division of Urology, Rabin Medical Center, Petach Tikva, Israel More articles by this author Sivan Sela Division of Urology, Rabin Medical Center, Petach Tikva, Israel More articles by this author Guy Witberg Department of Cardiology, Rabin Medical Center, Petach Tikva, Israel More articles by this author Jack Baniel Division of Urology, Rabin Medical Center, Petach Tikva, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel More articles by this author Daniel Kedar Division of Urology, Rabin Medical Center, Petach Tikva, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel More articles by this author Wilhelmina C. M. Duivenvoorden Division of Urology, Department of Surgery, McMaster University, Hamilton, Ontario, Canada More articles by this author Eli Rosenbaum Davidoff Cancer Centre, Rabin Medical Center, Petach Tikva, Israel Equal study contribution. More articles by this author Jehonathan H. Pinthus Division of Urology, Department of Surgery, McMaster University, Hamilton, Ontario, Canada Financial interest and/or other relationship with Ferring. Equal study contribution. More articles by this author Expand All The corresponding author certifies that, when applicable, a statement(s) has been included in the manuscript documenting institutional review board, ethics committee or ethical review board study approval; principles of Helsinki Declaration were followed in lieu of formal ethics committee approval; institutional animal care and use committee approval; all human subjects provided written informed consent with guarantees of confidentiality; IRB approved protocol number; animal approved project number. No direct or indirect commercial, personal, academic, political, religious or ethical incentive is associated with publishing this article. Editor’s Note: This article is the third of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 1277 and 1278. Advertisement PDF downloadLoading ...