Background: Androgen deprivation therapy (ADT) is used to delay tumour development and improve survival in patients with prostate cancer. However, several randomized controlled trials and observational studies have suggested that ADT may increase the risk of cardiovascular events.
Objective: The aim of the study was to evaluate the risk of coronary heart disease (CHD) and heart failure (HF) in patients with prostate cancer receiving ADT in UK primary care, and to evaluate the risks associated with individual ADT and combination ADT.
Methods: The UK General Practice Research Database was used to identify a cohort of patients with a first prostate cancer diagnosis during 1999–2005. These patients were followed up to assess the occurrence of acute myocardial infarction (AMI), death from CHD, incident HF and hospitalization due to acute decompensated HF. Nested case-control analyses were performed to assess the risk of these outcomes associated with anti-androgen therapy, as well as different types of ADT and combinations of ADT.
Results: Current anti-androgen use was associated with a significant increase in the risk of hospitalization due to HF (odds ratio [OR] 2.15; 95% CI 1.08, 4.29), but not of incident HF, CHD or AMI. When assessed individually, there was no significant association of bicalutamide or cyproterone use with the risk of AMI or CHD. Current use of bicalutamide 50 mg/day was associated with a significant increase in the risk of HF (OR 3.28; 95% CI 1.31, 8.18); however, this increased risk of HF was only found in patients taking bicalutamide 50 mg/day in combination with luteinizing hormone-releasing hormone (LHRH) receptor agonists. There were no cases of hospitalized HF in patients taking bicalutamide 50 mg/day as monotherapy and there was no significant association between current use of bicalutamide 150 mg/day and the risk of hospitalized HF. Combination therapy with LHRH agonists and anti-androgens was associated with a significant increase in the risk of CHD (OR 4.35; 95% CI 1.94,9.75), AMI (OR 3.57; 95% CI 1.44, 8.86), incident HF (OR 3.19; 95% CI 1.10, 9.27) and hospitalized HF (OR 3.39; 95% CI 1.07, 10.70) compared with non-use of these drugs.
Conclusions: In men with prostate cancer, combination therapy with LHRH agonists and anti-androgens is associated with significant increases in the risk of CHD, AMI, incident HF and hospitalized HF. Individual therapies do not appear to increase the risk of these outcomes.
Office for National Statistics. Cancer statistics registrations: registrations of cancer diagnosed in 2006. Newport: The Office for National Statistics, 2008Google Scholar
Rachet B, Maringe C, Nur U, et al. Population-based cancer survival trends in England and Wales up to 2007: an assessment of the NHS cancer plan for England. Lancet Oncol 2009 Apr; 10(4): 351–69PubMedCrossRefGoogle Scholar
Yannucci J, Manola J, Garnick MB, et al. The effect of androgen deprivation therapy on fasting serum lipid and glucose parameters. J Urol 2006 Aug; 176(2): 520–5PubMedCrossRefGoogle Scholar
Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab 2006 Apr; 91(4): 1305–8PubMedCrossRefGoogle Scholar
Basaria S, Muller DC, Carducci MA, et al. Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy. Cancer 2006 Feb 1; 106(3): 581–8PubMedCrossRefGoogle Scholar
Braga-Basaria M, Muller DC, Carducci MA, et al. Lipoprotein profile in men with prostate cancer undergoing androgen deprivation therapy. Int J Impot Res 2006 Sep–Oct; 18(5): 494–8PubMedCrossRefGoogle Scholar
Bolla M, Van Tienhoven G, Warde P, et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol 2010 Nov; 11(11): 1066–73PubMedCrossRefGoogle Scholar
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 Jan 1; 27(1): 92–9PubMedCrossRefGoogle Scholar
Wirth MP, See WA, McLeod DG, et al. Bicalutamide 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer: results from the second analysis of the early prostate cancer program at median follow up of 5.4 years. J Urol 2004 Nov; 172 (5 Pt 1): 1865–70PubMedCrossRefGoogle Scholar
McLeod DG, Iversen P, See WA, et al. Bicalutamide 150mg plus standard care vs standard care alone for early prostate cancer. BJU Int 2006 Feb; 97(2): 247–54PubMedCrossRefGoogle Scholar
Keating NL, O’Malley AJ, Freedland SJ, et al. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst 2010 Jan 6; 102(1): 39–46PubMedCrossRefGoogle Scholar
Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 2006 Sep 20; 24(27): 4448–56PubMedCrossRefGoogle Scholar
Saigal CS, Gore JL, Krupski TL, et al. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer 2007 Oct 1; 110(7): 1493–500PubMedCrossRefGoogle Scholar
D’Amico AV, Chen MH, Renshaw AA, et al. Causes of death in men undergoing androgen suppression therapy for newly diagnosed localized or recurrent prostate cancer. Cancer 2008 Dec 15; 113(12): 3290–7PubMedCrossRefGoogle Scholar
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 Jun 10; 25(17): 2420–5PubMedCrossRefGoogle Scholar
Tsai HK, D’Amico AV, Sadetsky N, et al. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst 2007 Oct 17; 99(20): 1516–24PubMedCrossRefGoogle Scholar
Van Hemelrijck M, Garmo H, Holmberg L, et al. Absolute and relative risk of cardiovascular disease in men with prostate cancer: results from the Population-Based PCBaSe Sweden. J Clin Oncol 2010 Jul 20; 28(21): 3448–56PubMedCrossRefGoogle Scholar
Robinson D, Garmo H, Lindahl B, et al. Ischemic heart disease and stroke before and during endocrine treatment for prostate cancer in PCBaSe Sweden. Int J Cancer. Epub 2011 Mar 8Google Scholar
Alibhai SM, Duong-Hua M, Sutradhar R, et al. Impact of androgen deprivation therapy on cardiovascular disease and diabetes. J Clin Oncol 2009 Jul 20; 27(21): 3452–8PubMedCrossRefGoogle Scholar
Lawson DH, Sherman V, Hollowell J. The general practice research database. Scientific and Ethical Advisory Group. Q J Med 1998 Jun; 91(6): 445–52CrossRefGoogle Scholar
Herrett E, Thomas SL, Schoonen WM, et al. Validation and validity of diagnoses in the General Practice Research Database: a systematic review. Br J Clin Pharmacol 2010 Jan; 69(1): 4–14PubMedCrossRefGoogle Scholar
Ronquist G, Rodriguez LA, Ruigomez A, et al. Association between captopril, other antihypertensive drugs and risk of prostate cancer. Prostate 2004 Jan 1; 58(1): 50–6PubMedCrossRefGoogle Scholar
García Rodríguez LA, Gonzalez-Perez A. Inverse association between nonsteroidal anti-inflammatory drugs and prostate cancer. Cancer Epidemiol Biomarkers Prev 2004 Apr; 13(4): 649–53PubMedGoogle Scholar
García Rodríguez LA, Varas-Lorenzo C, Maguire A, et al. Nonsteroidal antiinflammatory drugs and the risk of myocardial infarction in the general population. Circulation 2004 Jun 22; 109(24): 3000–6PubMedCrossRefGoogle Scholar
García Rodríguez LA, Varas C, Patrono C. Differential effects of aspirin and non-aspirin nonsteroidal antiinflammatory drugs in the primary prevention of myocardial infarction in postmenopausal women. Epidemiology 2000 Jul; 11(4): 382–7PubMedCrossRefGoogle Scholar
Jones TH. Testosterone deficiency: a risk factor for cardiovascular disease? Trends Endocrinol Metab 2010 Aug; 21(8): 496–503PubMedCrossRefGoogle Scholar
Rahman F, Christian HC. Non-classical actions of testosterone: an update. Trends Endocrinol Metab 2007 Dec; 18(10): 371–8PubMedCrossRefGoogle Scholar
Tsang S, Liu J, Wong TM. Testosterone and cardioprotection against myocardial ischemia. Cardiovasc Hematol Disord Drug Targets 2007 Jun; 7(2): 119–25PubMedCrossRefGoogle Scholar
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. Circulation 2010 Feb 16; 121(6): 833–40PubMedCrossRefGoogle Scholar
Alberti KG, Zimmet P, Shaw J. The metabolic syndrome: a new worldwide definition. Lancet 2005 Sep 24–30; 366(9491): 1059–62PubMedCrossRefGoogle Scholar
Rothman KJ, Greenland S, Lash TL. Modern epidemiology. 3rd ed. Philadelphia (PA): Wolters Kluwer Health/ Lippincott Williams & Wilkins, 2008Google Scholar