Mechanism: How ADT accelerates CVD? Professor Bertrand Tombal, MD, PhD Cliniques universitaires Saint-Luc Université catholique de Louvain Brussels, Belgium
Credentials and conflict of interests Professor and Chairman, Division of Urology, Cliniques universitaires Saint Luc, Brussels, BE President of of European Organization Of Research and Treatment of Cancer (EORTC) Investigator and paid advisor for Amgen, Astellas, Bayer Medivation, Ferring, Janssen, Sanofi Aventis This presentation reflects the personal view of Bertrand TOMBAL
Observational Studies Consistently Show an Increased Risk of CVD in Patients Treated LHRH Agonists CI, confidence interval; CVD, cardiovascular disease LHRH, luteinizing hormone-releasing hormone RCT, randomized control trial SEER, surveillance, epidemiology, and end results 3 O Farrell S, et al. J Clin Oncol 2015;33:1243 51
Relative Risk of CVD with LHRH Agonists: in Randomized Controlled Trials (RCTs) CI, confidence interval; CVD, cardiovascular disease LHRH, luteinizing hormone-releasing hormone RCT, randomized control trial SEER, surveillance, epidemiology, and end results O Farrell S, et al. J Clin Oncol 2015;33:1243 51 4
Short-term increased risk of CVD (in men with pre-existing disease) Long-term metabolic changes in everybody
Early CV events and ADT 1,372 men who were enrolled onto 3 RCTs between February 1995 and June 2001. Randomly assigned to receive EBRT with no vs. 3 vs. 6, 3 vs. 8, or 0 vs. 6 months of ADT. D Amico et al. J Clin Oncol,2007, 25:2420-2425.
Risk factors of CVD Pre-existing cardiovascular morbidity Nanda et al. JAMA 2009; 302:866-73
Plaque instability is at the heart of cardiovascular disease Stable plaque Vulnerable plaque Lumen Fibrous cap Lipid core Lumen Fibrous cap Lipid core Thick Cap Thin Rich in SMC and matrix Composition Rich in inflammatory cells: proteolytic activity Poor Lipid Rich Low Inflammatory state High Libby P. Circulation. 1995;91:2844-2850
Most acute CVD events are caused by rupture of a vulnerable atherosclerotic plaque
Plaque instability clinical event ADT causes instability Simon and Zidar Circ Res 2012
Short-term increased risk of CVD (in men with pre-existing disease) Long-term metabolic changes in everybody
Sarcopenia During Androgen-Deprivation Therapy for Prostate Cancer Smith MR. et al., J Clin Oncol. 2012 May 29. [Epub ahead of print] 252 patients from the denosumab osteoporotic fracture prevention trial (132, denosumab; 120, placebo), followed by whole lean body mass assessment
Sarcopenic obesity and ADT Prospective 12-wk study, 25 men with locally advanced or recurrent prostate cancer, LHRH agonists. Smith et al. J Clin Endocrinol Metab, 91(4):1305 1308, 2006
Sarcopenic obesity and ADT Prospective 12-wk study, 25 men with locally advanced or recurrent prostate cancer, LHRH agonists. Smith et al. J Clin Endocrinol Metab, 91(4):1305 1308, 2006
Dyslipidaemia and ADT Prospective 12-wk study, 25 men with locally advanced or recurrent prostate cancer, LHRH agonists. TG 23 LDL cholesterol 8.7 HDL cholesterol 9.7 Total cholesterol 9.4 0 0 5 10 15 20 25 % change at 12-weeks Smith et al. J Clin Endocrinol Metab, 91(4):1305 1308, 2006
HR compared to no ADT Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. Keating NL et al. JNCI 2010 102(1):39-46. Association between ADT and diabetes, coronary heart disease, myocardial infarction, sudden death, and stroke in a observational study of 37443 men from 01/2001 to 12/2005, including 39% treated with ADT. 1.6 1.4 1.2 1 0.8 0.6 0.4 GnRHa Orchiectomy MAB 0.2 0 Diabetes CHD
HR compared to no ADT Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. Keating NL et al. JNCI 2010 102(1):39-46. Association between ADT and diabetes, coronary heart disease, myocardial infarction, sudden death, and stroke in a observational study of 37443 men from 01/2001 to 12/2005, including 39% treated with ADT. 2.5 2 1.5 1 GnRHa Orchiectomy MAB 0.5 0 Myocardial Infarction Cardiac death
Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. Levine et al. Circulation 2010;121;833-840; Proven impact on standard CV risk factor Proven impact on CV events Disputable effect of CV death [10-20-2010] The U.S. Food and Drug Administration (FDA) has notified the manufacturers of the Gonadotropin-Releasing Hormone (GnRH) agonists of the need to add new safety information to the Warnings and Precautions section of the drug labels. This new information warns about increased risk of diabetes and certain cardiovascular diseases (heart attack, sudden cardiac death, stroke) in men receiving these medications for the treatment of prostate cancer.