Abstract
Purpose
We investigated whether ADT use was associated with the risk of ischemic cardiovascular diseases (CVD) and cerebrovascular diseases (CrVD) in a nationwide population-based cohort.
Methods
Claims data of the Health Insurance and Review Assessment system in South Korea were used. In total, 195,308 men with newly diagnosed prostate cancer between January 1, 2008 and December 31, 2017 were identified. After applying the exclusion criteria, 131,189 men were enrolled. The study cohort was divided into ADT and non-ADT groups. Study outcomes were newly developed CVD, cardiovascular intervention (CVI), and CrVD. To control for potential confounders, various cardiovascular risk factors were balanced between groups. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of events.
Results
Univariable analysis revealed that ADT was significantly associated with an increased risk of CVD and CrVD. Multivariable analysis did not reveal this association. In the propensity score matched cohort (n = 61,722), multivariable analysis demonstrated that ADT independently reduced the risk of CVD (HR 0.890; 95% CI 0.846–0.936; p < 0.0001), CVI (HR 0.873; 95% CI 0.770–0.991; p = 0.0352), and CrVD (HR 0.869; 95% CI 0.824–0.917; p < 0.0001). CVD risk was significantly decreased in patients using ADT for over 2 years. CVI and CrVD risks were significantly lower in men using ADT for over 3 years.
Conclusion
This study demonstrated that ADT may reduce the risk of CVD, CVI, and CrVD, and ADT duration is associated with this risk reduction.
This is a preview of subscription content, access via your institution.


Data availability
The data are not publicly available due to privacy or ethical restrictions.
References
Abdollah F et al (2015) Medical androgen deprivation therapy and increased non-cancer mortality in non-metastatic prostate cancer patients aged ≥ 66 years. Eur J Surg Oncol 41:1529–1539. https://doi.org/10.1016/j.ejso.2015.06.011
Alibhai SM, Duong-Hua M, Sutradhar R, Fleshner NE, Warde P, Cheung AM, Paszat LF (2009) Impact of androgen deprivation therapy on cardiovascular disease and diabetes. J Clin Oncol 27:3452–3458. https://doi.org/10.1200/jco.2008.20.0923
Anderson JR, Cain KC, Gelber RD (1983) Analysis of survival by tumor response. J Clin Oncol 1:710–719. https://doi.org/10.1200/jco.1983.1.11.710
Bolla M et al (2010) 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 11:1066–1073. https://doi.org/10.1016/s1470-2045(10)70223-0
Bosco C, Bosnyak Z, Malmberg A, Adolfsson J, Keating NL, Van Hemelrijck M (2015) Quantifying observational evidence for risk of fatal and nonfatal cardiovascular disease following androgen deprivation therapy for prostate cancer: a meta-analysis. Euro Urol 68:386–396. https://doi.org/10.1016/j.eururo.2014.11.039
Carneiro A et al (2015) Cardiovascular events associated with androgen deprivation therapy in patients with prostate cancer: a systematic review and meta-analysis. World J Urol 33:1281–1289. https://doi.org/10.1007/s00345-014-1439-6
Cho IS, Chae YR, Kim JH, Yoo HR, Jang SY, Kim GR, Nam CM (2017) Statistical methods for elimination of guarantee-time bias in cohort studies: a simulation study. BMC Med Res Methodol 17:126. https://doi.org/10.1186/s12874-017-0405-6
Corona G et al (2011) Testosterone and metabolic syndrome: a meta-analysis study. J Sex Med 8:272–283. https://doi.org/10.1111/j.1743-6109.2010.01991.x
Corona G, Rastrelli G, Di Pasquale G, Sforza A, Mannucci E, Maggi M (2018) Endogenous Testosterone Levels and Cardiovascular Risk: Meta-Analysis of Observational Studies. J Sex Med 15:1260–1271. https://doi.org/10.1016/j.jsxm.2018.06.012
D'Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW (2008) Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA 299:289–295. https://doi.org/10.1001/jama.299.3.289
Efstathiou JA, Bae K, Shipley WU, Hanks GE, Pilepich MV, Sandler HM, Smith MR (2009) Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85–31. J Clin Oncol 27:92–99. https://doi.org/10.1200/jco.2007.12.3752
Elagizi A, Köhler TS, Lavie CJ (2018) Testosterone and Cardiovascular Health. Mayo Clin Proc 93:83–100. https://doi.org/10.1016/j.mayocp.2017.11.006
Gagliano-Jucá T, Basaria S (2019) Testosterone replacement therapy and cardiovascular risk. Nat Rev Cardiol 16:555–574. https://doi.org/10.1038/s41569-019-0211-4
Gandaglia G et al (2014) The impact of androgen-deprivation therapy (ADT) on the risk of cardiovascular (CV) events in patients with non-metastatic prostate cancer: a population-based study. BJU Int 114:E82–E89. https://doi.org/10.1111/bju.12732
Jepsen P, Johnsen SP, Gillman MW, Sorensen HT (2004) Interpretation of observational studies Heart 90:956–960. https://doi.org/10.1136/hrt.2003.017269
Jespersen CG, Norgaard M, Borre M (2014) Androgen-deprivation therapy in treatment of prostate cancer and risk of myocardial infarction and stroke: a nationwide Danish population-based cohort study. Eur Urol 65:704–709. https://doi.org/10.1016/j.eururo.2013.02.002
Keating NL, O'Malley A, Freedland SJ, Smith MR (2012) Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst 104:1518–1523. https://doi.org/10.1093/jnci/djs376
Keating NL, O'Malley AJ, Smith MR (2006) Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 24:4448–4456. https://doi.org/10.1200/jco.2006.06.2497
Kim JA, Yoon S, Kim LY, Kim DS (2017) Towards Actualizing the Value Potential of Korea Health Insurance Review and Assessment (HIRA) Data as a Resource for Health Research: Strengths, Limitations, Applications, and Strategies for Optimal Use of HIRA Data. J Korean Med Sci 32:718–728. https://doi.org/10.3346/jkms.2017.32.5.718
Kim TJ et al (2019) Impact of cerebrovascular disease on survival benefits from local treatment in patients with de novo metastatic hormone-sensitive prostate cancer. Yonsei Med J 60:1129–1137. https://doi.org/10.3349/ymj.2019.60.12.1129
Martín-Merino E, Johansson S, Morris T, García Rodríguez LA (2011) Androgen deprivation therapy and the risk of coronary heart disease and heart failure in patients with prostate cancer: a nested case-control study in UK primary care. Drug Saf 34:1061–1077. https://doi.org/10.2165/11594540-000000000-00000
Melloni C, Roe MT (2019) Androgen deprivation therapy and cardiovascular disease. Urol Oncol. https://doi.org/10.1016/j.urolonc.2019.02.010
Messing EM et al (2006) Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 7:472–479. https://doi.org/10.1016/s1470-2045(06)70700-8
Mi X, Hammill BG, Curtis LH, Lai EC, Setoguchi S (2016) Use of the landmark method to address immortal person-time bias in comparative effectiveness research: a simulation study. Stat Med 35:4824–4836. https://doi.org/10.1002/sim.7019
Nguyen PL et al (2011) Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA 306:2359–2366. https://doi.org/10.1001/jama.2011.1745
Roberts CB, Albertsen PC, Shao YH, Moore DF, Mehta AR, Stein MN, Lu-Yao GL (2011) Patterns and correlates of prostate cancer treatment in older men. Am J Med 124:235–243. https://doi.org/10.1016/j.amjmed.2010.10.016
Ruige JB, Mahmoud AM, De Bacquer D, Kaufman JM (2011) Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis. Heart 97:870–875. https://doi.org/10.1136/hrt.2010.210757
Shores MM, Matsumoto AM (2014) Testosterone, aging and survival: biomarker or deficiency. Curr Opin Endocrinol Diabetes Obes 21:209–216. https://doi.org/10.1097/med.0000000000000057
Tivesten A, Pinthus JH, Clarke N, Duivenvoorden W, Nilsson J (2015) Cardiovascular risk with androgen deprivation therapy for prostate cancer: potential mechanisms. Urol Oncol 33:464–475. https://doi.org/10.1016/j.urolonc.2015.05.030
Van Hemelrijck M et al (2010) Absolute and relative risk of cardiovascular disease in men with prostate cancer: results from the Population-Based PCBaSe Sweden. J Clin Oncol 28:3448–3456. https://doi.org/10.1200/jco.2010.29.1567
Wang LH, Liu CK, Chen CH, Kao LT, Lin HC, Huang CY (2016) No increased risk of coronary heart disease for patients receiving androgen deprivation therapy for prostate cancer in Chinese/Taiwanese men. Andrology 4:128–132. https://doi.org/10.1111/andr.12141
Zhao J et al (2014) Androgen deprivation therapy for prostate cancer is associated with cardiovascular morbidity and mortality: a meta-analysis of population-based observational studies. PLoS ONE 9:e107516. https://doi.org/10.1371/journal.pone.0107516
Acknowledgements
This study was supported by Korean Urological Oncology Society research grant 2018
Funding
Not applicable.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors report no conflicts of interest in relation to this work.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Kim, D., Lee, H.S., Park, JY. et al. Does androgen-deprivation therapy increase the risk of ischemic cardiovascular and cerebrovascular diseases in patients with prostate cancer? A nationwide population-based cohort study. J Cancer Res Clin Oncol 147, 1217–1226 (2021). https://doi.org/10.1007/s00432-020-03412-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-020-03412-6