Mechanism: How ADT accelerates CVD ? Professor Bertrand Tombal, MD, - - PowerPoint PPT Presentation

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Mechanism: How ADT accelerates CVD ?

Professor Bertrand Tombal, MD, PhD Cliniques universitaires Saint-Luc Université catholique de Louvain Brussels, Belgium

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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

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Observational Studies Consistently Show an Increased Risk

• f CVD in Patients Treated LHRH Agonists

3

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

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Relative Risk of CVD with LHRH Agonists: in Randomized Controlled Trials (RCTs)

4

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

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• Short-term increased risk of CVD (in

men with pre-existing disease)

• Long-term metabolic changes in

everybody

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D’Amico et al. J Clin Oncol,2007, 25:2420-2425.

Early CV events and ADT

• 1,372 men who were enrolled
• nto 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.

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Nanda et al. JAMA 2009; 302:866-73

Risk factors of CVD Pre-existing cardiovascular morbidity

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Lipid core Fibrous cap Lumen Lumen Fibrous cap Lipid core Vulnerab rable e plaque

Plaque instability is at the heart of cardiovascular disease

Stable e plaque

Libby P. Circulation. 1995;91:2844-2850

Thick Cap Thin Rich in SMC and matrix Composition Rich in inflammatory cells: proteolytic activity Poor Lipid Rich Low Inflammatory state High

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Most acute CVD events are caused by rupture of a vulnerable atherosclerotic plaque

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Plaque instability → clinical event

Simon and Zidar Circ Res 2012

ADT causes instability

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• Short-term increased risk of CVD (in

men with pre-existing disease)

• Long-term metabolic changes in

everybody

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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

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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

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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

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Dyslipidaemia and ADT

Smith et al. J Clin Endocrinol Metab, 91(4):1305–1308, 2006

• Prospective 12-wk study, 25 men with locally advanced or recurrent prostate

cancer, LHRH agonists.

9.4 9.7 8.7 23

5 10 15 20 25 Total cholesterol HDL cholesterol LDL cholesterol TG % change at 12-weeks

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0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 Diabetes CHD HR compared to no ADT GnRHa Orchiectomy MAB

• 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. 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.

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0.5 1 1.5 2 2.5 Myocardial Infarction Cardiac death HR compared to no ADT GnRHa Orchiectomy MAB

• 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. 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.

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• Proven impact on standard CV risk factor
• Proven impact on CV events
• Disputable effect of CV 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; [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.