Prostate cancer is the most common type of cancer among men in the United States, accounting for an estimated 174,000 cases in 2019. The average age of diagnosis is 66 years.¹ The vast majority of men diagnosed with prostate cancer are treated with curative intent, and among those who are not cured, it is often an indolent disease course with a long natural history. Overall, 5-year survival is excellent at 98%, with death typically occurring among those with stage IV disease.¹ Mortality in these patients is commonly due to non-cancer-related causes like cardiovascular disease.

A mainstay of treatment for prostate cancer is androgen deprivation therapy (ADT). Some drugs in this class work by reducing the levels of luteinizing hormone or follicle-stimulating hormone and thus decreasing testosterone levels. For instance, both gonadotropin receptor hormone (GnRH) agonists (i.e., leuprolide, goserelin, and triptorelin) and GnRH antagonists (i.e., degarelix) decrease luteinizing hormone and follicle-stimulating hormone levels, leading to lower testosterone levels. Other medications in this class, such as adrenal androgen receptor inhibitors (i.e., abiraterone) and direct androgen receptor inhibitors (i.e., enzalutamide), work downstream to lower testosterone activity. GnRH agonists and antagonists are quite effective for the treatment of prostate cancer and are used with curative intent in men with high-risk non-metastatic disease and for standard therapy in those with metastatic disease. Increasingly, abiraterone is being used in combination with GnRH agonists with the goal of improving survival among those with stage IV prostate cancer. Understanding the impact of ADT therapy on cardiovascular risk is important because many of the risk factors that lead to prostate cancer also lead to cardiovascular disease (i.e., age, smoking, diet, and obesity), and the direct effects of ADT on cardiovascular risk remains unclear.

Since 2006, concern was raised that ADT leads to increased cardiovascular risk. In a study of over 73,000 Medicare enrollees with localized prostate cancer, Keating and colleagues described an increase in diabetes mellitus (adjusted hazard ratio [HR] 1.44; 95% confidence interval [CI], 1.34-1.55), coronary heart disease (adjusted HR 1.16; 95% CI, 1.1-1.21), myocardial infarction (adjusted HR 1.11; 95% CI, 1.01-1.21), and sudden cardiac death (adjusted HR 1.16; 95% CI, 1.05-1.27) among the 36% of men on GnRH agonists.² Similar findings were described in smaller studies.^3-5 These studies were concerning, but over the next few years, these findings were reproducible only in individuals with cardiovascular risk factors or prior heart disease and not the total population.^6-8

What was clear was that ADT leads to changes in metabolic states including hyperinsulinemia, hypercholesterolemia, and changes in body composition with increased fat and decreased lean mass, all of which can lead to cardiovascular disease.⁹ The findings led to a 2010 joint statement by the American Heart Association, American Cancer Society, and American Urologic Association recommending risk factor modification with lipid-lowering therapy, antihypertensive therapy, glucose-lowering therapy, and antiplatelet therapy, acknowledging the potential cardiovascular risk from ADT.¹⁰

Since 2010, additional studies have sought to clarify the effects of ADT on the cardiovascular system. One large meta-analysis in 2015 described an increased risk of myocardial infarction (adjusted HR 1.57; 95% CI, 1.26-1.4), nonfatal cardiovascular disease (adjusted HR 1.38; 95% CI, 1.29-1.48), and stroke (adjusted HR 1.51; 95% CI, 1.24-1.84) when given GnRH. Similar findings were seen in a smaller observational study.^11,12 Unsurprisingly, other studies demonstrated increased risk of cardiovascular mortality and ADT among only those with cardiovascular risk factors or prior heart disease and not the entire population.^13-15 Additionally, a recent small study concluded that ADT may prolong the QTc interval, a potential mechanism for sudden cardiac death.¹⁶ The risk goes beyond GnRH agonists, with the newer agents (abiraterone and enzalutamide) also affecting the cardiovascular system. Both significantly increase the rate of hypertension after initiation, and abiraterone also appears to increase the risk of cardiac toxicity.^17,18

Although data are still inconclusive, it appears that ADT does increase cardiovascular risk, particularly among individuals with prior cardiovascular disease or cardiac risk factors. Additionally, with the known unfavorable effects on cardiovascular risk factors such as increasing lipids, blood pressure, and blood glucose and changing body composition, risk factor optimization is important for individuals on ADT. Referral to a primary care physician or cardio-oncologist who can evaluate the patient and optimize all the risk factors is important to decrease cardiovascular events in these individuals. We propose using the ABCDE method to evaluate each person on ADT.¹⁹ The initial visit should focus on awareness of aspirin use, blood pressure measurements, cholesterol levels, cigarette use, diet, diabetes, and exercise habits along with electrocardiogram monitoring of QTc. Individuals should be followed every 6 months to ensure their risk factors are well controlled. Additionally, for individuals on abiraterone or enzalutamide, it is recommended that blood pressure be monitored every month after the initiation of ADT. Through early risk factor modification, the goal is to decrease the risk of cardiovascular morbidity and mortality in patients undergoing ADT.

References

1. Cancer Stat Facts: Kidney and Renal Pelvis Cancer (National Cancer Institute website). 2019. Available at: https://seer.cancer.gov/statfacts/html/kidrp.html. Accessed June 24, 2019.
2. Keating NL, O'Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 2006;24:4448-56.
3. Tsai HK, D'Amico AV, Sadetsky N, Chen MH, Carroll PR. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst 2007;99:1516-24.
4. D'Amico AV, Denham JW, Crook J, et al. Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions. J Clin Oncol 2007;25:2420-5.
5. D'Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Causes of death in men undergoing androgen suppression therapy for newly diagnosed localized or recurrent prostate cancer. Cancer 2008;113:3290-7.
6. Efstathiou JA, Bae K, Shipley WU, et al. Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85-31. J Clin Oncol 2009;27:92-9.
7. Alibhai SM, Duong-Hua M, Sutradhar R, et al. Impact of androgen deprivation therapy on cardiovascular disease and diabetes. J Clin Oncol 2009;27:3452-8.
8. Nanda A, Chen MH, Braccioforte MH, Moran BJ, D'Amico AV. Hormonal therapy use for prostate cancer and mortality in men with coronary artery disease-induced congestive heart failure or myocardial infarction. JAMA 2009;302:866-73.
9. Gupta D, Lee Chuy K, Yang JC, Bates M, Lombardo M, Steingart RM. Cardiovascular and Metabolic Effects of Androgen-Deprivation Therapy for Prostate Cancer. J Oncol Pract 2018;14:580-7.
10. Levine GN, D'Amico AV, Berger P, et al. 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. Circulation 2010;121:833-40.
11. Bosco C, Bosnyak Z, Malmberg A, Adolfsson J, Keating NL, Van Hemelrijck M. Quantifying observational evidence for risk of fatal and nonfatal cardiovascular disease following androgen deprivation therapy for prostate cancer: a meta-analysis. Eur Urol 2015;68:386-96.
12. O'Farrell S, Garmo H, Holmberg L, Adolfsson J, Stattin P, Van Hemelrijck M. Risk and timing of cardiovascular disease after androgen-deprivation therapy in men with prostate cancer. J Clin Oncol 2015;33:1243-51.
13. Nguyen PL, Je Y, Schutz FA, et al. Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA 2011;306:2359-66.
14. Wilcox C, Kautto A, Steigler A, Denham JW. Androgen deprivation therapy for prostate cancer does not increase cardiovascular mortality in the long term. Oncology 2012;82:56-8.
15. D'Amico AV, Chen MH, Renshaw A, Loffredo M, Kantoff PW. Long-term Follow-up of a Randomized Trial of Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer. JAMA 2015;314:1291-3.
16. Gagliano-Jucá T, Travison TG, Kantoff PW, et al. Androgen Deprivation Therapy Is Associated With Prolongation of QTc Interval in Men With Prostate Cancer. J Endocr Soc 2018;2:485-96.
17. Iacovelli R, Ciccarese C, Bria E, et al. The Cardiovascular Toxicity of Abiraterone and Enzalutamide in Prostate Cancer. Clin Genitourin Cancer 2018;16:e645-e53.
18. Moreira RB, Debiasi M, Francini E, et al. Differential side effects profile in patients with mCRPC treated with abiraterone or enzalutamide: a meta-analysis of randomized controlled trials. Oncotarget 2017;8:84572-8.
19. Bhatia N, Santos M, Jones LW, et al. Cardiovascular Effects of Androgen Deprivation Therapy for the Treatment of Prostate Cancer: ABCDE Steps to Reduce Cardiovascular Disease in Patients With Prostate Cancer. Circulation 2016;133:537-41.

Clinical Topics: Arrhythmias and Clinical EP, Cardio-Oncology, Dyslipidemia, Prevention, SCD/Ventricular Arrhythmias, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Diet, Hypertension, Smoking

Keywords: Gonadotropin-Releasing Hormone, Leuprolide, Goserelin, Triptorelin Pamoate, Risk Factors, Antihypertensive Agents, Luteinizing Hormone, Follicle Stimulating Hormone, Blood Glucose, Receptors, Androgen, Cardiovascular Diseases, American Cancer Society, Blood Pressure, Testosterone, American Heart Association, Aspirin, Hypercholesterolemia, Cardiotoxicity, Cardiotoxins, Glucose, Physicians, Primary Care, Confidence Intervals, Lipids, Androstenes, Phenylthiohydantoin, Prostatic Neoplasms, Myocardial Infarction, Stroke, Hypertension, Diabetes Mellitus, Obesity, Medicare, Coronary Disease, Diet, Hyperinsulinism, Heart Diseases, Death, Sudden, Cardiac, Body Composition, Smoking, Electrocardiography, Referral and Consultation, Receptors, Gonadotropin, Cholesterol

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