Risk and Timing of Cardiovascular Disease After Androgen-Deprivation Therapy in Men With Prostate Cancer

Purpose Findings on the association between risk of cardiovascular disease (CVD) and the duration and type of androgen-deprivation therapy (ADT) in men with prostate cancer (PCa) are inconsistent. Methods By using data on filled drug prescriptions in Swedish national health care registers, we investigated the risk of CVD in a cohort of 41,362 men with PCa on ADT compared with an age-matched, PCa-free comparison cohort (n = 187,785) by use of multivariable Cox proportional hazards regression models. Results From 2006 to 2012, 10,656 men were on antiandrogens (AA), 26,959 were on gonadotropin-releasing hormone (GnRH) agonists, and 3,747 underwent surgical orchiectomy. CVD risk was increased in men on GnRH agonists compared with the comparison cohort (hazard ratio [HR] of incident CVD, 1.21; 95% CI, 1.18 to 1.25; and orchiectomy: HR, 1.16; 95% CI, 1.08 to 1.25). Men with PCa on AA were at decreased risk (HR of incident CVD, 0.87; 95% CI, 0.82 to 0.91). CVD risk was highest during the first 6 months of ADT in men who experienced two or more cardiovascular events before therapy, with an HR of CVD during the first 6 months of GnRH agonist therapy of 1.91 (95% CI, 1.66 to 2.20), an HR of CVD with AA of 1.60 (95% CI, 1.24 to 2.06), and an HR of CVD with orchiectomy of 1.79 (95% CI, 1.16 to 2.76) versus the comparison cohort. Conclusion Our results support that there should be a solid indication for ADT in men with PCa so that benefit outweighs potential harm; this is of particular importance among men with a recent history of CVD.

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The Association between the Risk of Cardiovascular Disease and Androgen Deprivation Therapy in Patients with Prostate Cancer. A Meta-Analysis and systematic review.

10.21203/rs.2.10884/v3 ◽

2019 ◽

Author(s):

Zhen Liang ◽

Jun Zhu ◽

Xiaoxin Duo ◽

Shangheng Shi ◽

Yawei Xu ◽

...

Keyword(s):

Prostate Cancer ◽

Heart Failure ◽

Cardiovascular Disease ◽

Androgen Deprivation Therapy ◽

Meta Analysis ◽

Androgen Deprivation ◽

Relative Risk Ratio ◽

Control Group ◽

Gnrh Agonists ◽

Increased Risk

Abstract Background : Androgen deprivation therapy (ADT) is widely being applied in men who suffered from prostate cancer, our aim is to evaluate whether ADT is associated with an excess risk of cardiovascular disease (CVD). Method : Studies comparing the the incidence of CVD between ADT group and control group were identified through literature search in electronic databases (Pubmed, Embase, Web of Science) until July 2019 and only observational studies and randomized controlled trials (RCT) were included. The estimating relative risk ratio (RR) and 95% confidence intervals (CI) were calculated through random effects meta-analyses. Result : A statistically significant association was detected for acute myocardial infarction (AMI) with RR = 1.22; 95% confidence interval CI, 1.05–1.43; P< 0.05. Significant relationship between coronary heart disease (CHD) and ADT was also observed, with summary RR=1.19; 95%CI, 1.03-1.38; P<0.05. ADT was associated with a risk increasement for heart failure (HF) with RR=1.15; 95% CI 1.01–1.33; P< 0.05. On the contrary, ADT was not associated with an increased risk of sudden cardiac death (SCD). Conclusions : From this study, ADT is associated with increased risk of AMI, CHD, and heart failure (HF); in contrast, this association is not detected in SCD; various modalities of ADT could significantly increase the risk of CHD, AMI, except for oral anti-androgen (AA). Our meta-analysis also suggests that the long-term application of ADT in prostate cancer patients would not result in a significant increase in AMI incidence compared with short-term. Moreover, the combined application of AA and GnRH agonists would lead to a similar risk of AMI compared with orchiectomy or GnRH agonists monotherapy whereas higher risk of CHD was detected when compared GnRH agonists plus AA with orchiectomy.

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Outcomes of men with recurrent M0 prostate cancer who defer androgen deprivation therapy until metastasis.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.5016 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 5016-5016

Author(s):

Catherine Handy Marshall ◽

Wei Fu ◽

Hao Wang ◽

Bruce J. Trock ◽

Mario A. Eisenberger

Keyword(s):

Prostate Cancer ◽

Androgen Deprivation Therapy ◽

Proportional Hazards ◽

Local Treatment ◽

Drug Approval ◽

Cox Proportional Hazards ◽

Androgen Deprivation ◽

Clinical State ◽

Optimal Timing ◽

Kaplan Meier

5016 Background: Optimal timing and criteria for implementation of androgen deprivation therapy (ADT) in men with relapsed M0 prostate cancer (PCa) remains undefined. Early ADT induces the non-metastatic castration resistant PCa (nmCRPC) clinical state. FDA approved apalutamide (SPARTAN) and enzalutamide (PROSPER) for nmCRPC based on prolongation of metastasis free survival (MFS) which is now considered a valid endpoint for drug approval. Because overall survival (OS) in PCa is usually long and long-term ADT is associated with irreversible adverse events and high costs, we sought to evaluate OS and other outcomes of men with relapsed PCa and ADT deferred until metastasis. Methods: Retrospective review of 2,636 men who had radical prostatectomy (RP) between 1981-2017 and developed biochemically recurrent PCa from a single-institution. Patients who received ADT prior to metastasis were excluded. Kaplan-Meier survival estimates of MFS and OS were defined from RP to event or censor. Multivariable Cox proportional hazards regression was used to identify prognostic factors. Results: 1,686 men treated with deferred ADT until metastasis or censored metastasis-free were eligible. Medians: follow up 10 years (IQR5-16), age 60 years, PSADT 33 months, Gleason < 7 (24%), Gleason 7 (55%), Gleason > 7 (21%). 688 (41%) received salvage radiotherapy. Median MFS and OS were 21 and 22 years, respectively (Table). In multivariable models, age (HR 1.06, 95% CI 1.04-1.1), Gleason < 8 vs ≥8 (HR 0.4; 0.3-0.5) , RP stage (organ confined vs not 0.6; 0.5-0.8), PSADT (0.995, 0.993-0.997) and salvage RT (0.88; 0.81, 0.96) were associated with OS. Conclusions: Deferred ADT in relapsing M0 patients is associated with long OS measured from time of local treatment, comparable to OS with salvage ADT in contemporary experience. Drug approval trials in nmCRPC should focus on patients at high risk for metastasis and death prior to ADT, and determine standardized criteria for initiation of ADT. Prolongation of MFS in nmCRPC requires further validation and may not necessarily reflect a net OS benefit. [Table: see text]

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Associations between Peripheral Thromboembolic Vascular Disease and Androgen Deprivation Therapy in Asian Prostate Cancer Patients

Scientific Reports ◽

10.1038/s41598-019-50522-4 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Yu-Chuan Lu ◽

Chao-Yuan Huang ◽

Huei-Ming Yeh ◽

Jian-Hua Hong ◽

Chao-Hsiang Chang ◽

...

Keyword(s):

Prostate Cancer ◽

Vascular Disease ◽

Androgen Deprivation Therapy ◽

Proportional Hazards ◽

Day Treatment ◽

Arterial Occlusion ◽

Incidence Rates ◽

Cox Proportional Hazards ◽

Androgen Deprivation ◽

Chemical Castration

Abstract This study aimed to investigate the risks of thromboembolic vascular disease following androgen deprivation therapy (ADT) administered to prostate cancer (PCa) patients. A total of 24,464 men with newly diagnosed PCa during 2000–2008 were recruited through a longitudinal health insurance database in Taiwan. All PCa patients were stratified into two: ADT and non-ADT groups. Patients with ADT treatment were grouped into three: surgical castration, chemical castration, and anti-androgen alone. The risks of pulmonary embolism (PE), peripheral arterial occlusion disease (PAOD), and deep vein thrombosis (DVT) were assessed in multiple Cox proportional-hazards regression with time-dependent covariates. During the 12-year follow-up period, incidence rates per 1000 person-years in ADT and non-ADT groups were 2.87 and 1.62 for DVT, 1.00 and 0.52 for PE, and 1.03 and 0.70 for PAOD, respectively. The DVT and PE risks were significantly increased in patients receiving combined androgen blockade (CAB) compared with the counterpart ADT non-recipients. After adjusting for potential risk factors, PCa patients receiving CAB had the highest PE risk (HR = 3.11), followed by DVT risk (HR = 2.53). The DVT risk remained elevated throughout the entire duration of chemical castration. However, high PE risk was observed in patients with ≤720-day treatment duration. No association was found between ADT and PAOD risks. Overall, the risks of PE and DVT were considerably heightened in Asian men subjected to CAB for PCa, whereas PAOD risk was unrelated to such treatments.

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Association of Androgen Deprivation Therapy With Depression in Localized Prostate Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2015.64.1969 ◽

2016 ◽

Vol 34 (16) ◽

pp. 1905-1912 ◽

Cited By ~ 77

Author(s):

Kathryn T. Dinh ◽

Gally Reznor ◽

Vinayak Muralidhar ◽

Brandon A. Mahal ◽

Michelle D. Nezolosky ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Deprivation Therapy ◽

Proportional Hazards ◽

Psychiatric Treatment ◽

Secondary Analysis ◽

Cox Proportional Hazards ◽

Androgen Deprivation ◽

Primary Analysis ◽

Increased Risk ◽

Inpatient Psychiatric Treatment

Purpose Androgen deprivation therapy (ADT) may contribute to depression, yet several studies have not demonstrated a link. We aimed to determine whether receipt of any ADT or longer duration of ADT for prostate cancer (PCa) is associated with an increased risk of depression. Methods We identified 78,552 men older than age 65 years with stage I to III PCa using the SEER-Medicare–linked database from 1992 to 2006, excluding patients with psychiatric diagnoses within the prior year. Our primary analysis was the association between pharmacologic ADT and the diagnosis of depression or receipt of inpatient or outpatient psychiatric treatment using Cox proportional hazards regression. Drug data for treatment of depression were not available. Our secondary analysis investigated the association between duration of ADT and each end point. Results Overall, 43% of patients (n = 33,882) who received ADT, compared with patients who did not receive ADT, had higher 3-year cumulative incidences of depression (7.1% v 5.2%, respectively), inpatient psychiatric treatment (2.8% v 1.9%, respectively), and outpatient psychiatric treatment (3.4% v 2.5%, respectively; all P < .001). Adjusted Cox analyses demonstrated that patients with ADT had a 23% increased risk of depression (adjusted hazard ratio [AHR], 1.23; 95% CI, 1.15 to 1.31), 29% increased risk of inpatient psychiatric treatment (AHR, 1.29; 95% CI, 1.17 to 1.41), and a nonsignificant 7% increased risk of outpatient psychiatric treatment (AHR, 1.07; 95% CI, 0.97 to 1.17) compared with patients without ADT. The risk of depression increased with duration of ADT, from 12% with ≤ 6 months of treatment, 26% with 7 to 11 months of treatment, to 37% with ≥ 12 months of treatment (P trend < .001). A similar duration effect was seen for inpatient (P trend < .001) and outpatient psychiatric treatment (P trend < .001). Conclusion Pharmacologic ADT increased the risk of depression and inpatient psychiatric treatment in this large study of elderly men with localized PCa. This risk increased with longer duration of ADT. The possible psychiatric effects of ADT should be recognized by physicians and discussed with patients before initiating treatment.

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A nomogram for testosterone recovery following combined androgen deprivation therapy and radiation therapy for prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.67 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 67-67

Author(s):

Daphna Spiegel ◽

Julian C. Hong ◽

W. Robert Lee ◽

Joseph Kamel Salama

Keyword(s):

Prostate Cancer ◽

Radiation Therapy ◽

Androgen Deprivation Therapy ◽

Median Duration ◽

Proportional Hazards ◽

Medical Center ◽

Cox Proportional Hazards ◽

Androgen Deprivation ◽

Cox Proportional Hazards Models ◽

Pre Treatment

67 Background: Combined androgen deprivation therapy (ADT) and radiation therapy (RT) is a frequently used localized prostate cancer (PC) treatment. Testosterone recovery (TR) after combined ADT-RT is not well-characterized. We studied TR in men who received RT and either short-term (ST) ADT or long-term (LT) ADT with LHRH agonists. Methods: We identified consecutive localized PC patients treated with ADT-RT at the Durham VA Medical Center (DVAMC) from 1/2011-10/2016. All patients had a documented baseline testosterone (T) level. Individual patient records were reviewed. TR was defined as time from last ADT injection to T normalization ( > 240 ng/dL). The Kaplan-Meier method was used to estimate time to TR. Cox proportional hazards models were generated to identify TR predictors with a nomogram built based on a parsimonious multivariate model. Results: 252 patients were identified. Median follow-up was 26.7 months. Median age was 65. Prior to treatment, 69% had a normal baseline T. 67% were treated with STADT, median duration 6 months. 33% were treated with LTADT, median duration 18 months. Median time for TR was 22.6 months for all patients (19.5 months for STADT and 25.6 months for LTADT). At 1 and 2 years post ADT, estimated TR was 13% and 53% (17% and 57% for STADT and 3% and 42% for LTADT). 2-year biochemical control was 99.2% and 97.6% for STADT and LTADT, respectively; 98.9% and 98.6% for those with and without TR, respectively. On multivariate analysis, higher pre-treatment T (HR = 1.004 95% CI 1.003-1.006, p < 0.001), use of STADT (HR = 2.48 95% CI 1.45-4.25, p = 0.001), and lower BMI (HR = 0.95 95% CI 0.91-0.98, p = 0.001) were associated with shorter time to TR. White race was a negative TR predictor (HR = 0.65 95% CI 0.43-0.9992, p = 0.049). Age, smoking, and Charlson Comorbidity Index were not significant independent TR predictors. A nomogram was generated to predict probability of TR at 1, 2, and 3 years. Conclusions: In this VA population of localized PC patients treated from 2011-2016, TR following the use of ADT-RT was variable. Using pre-treatment T levels, ADT duration, BMI, and race, a predictive nomogram can estimate the likelihood of TR.

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The Association between the Risk of Cardiovascular Disease and Androgen Deprivation Therapy in Patients with Prostate Cancer. A Meta-Analysis and systematic review.

10.21203/rs.2.10884/v2 ◽

2019 ◽

Author(s):

Zhen Liang ◽

Jun Zhu ◽

Xiaoxin Duo ◽

Shangheng Shi ◽

Yawei Xu ◽

...

Keyword(s):

Prostate Cancer ◽

Cardiovascular Disease ◽

Androgen Deprivation Therapy ◽

Meta Analysis ◽

Androgen Deprivation ◽

Relative Risk Ratio ◽

Gnrh Agonists ◽

Combined Application ◽

Increased Risk

Abstract Background : Androgen deprivation therapy (ADT) is widely being applied in men who suffered from prostate cancer, our aim is to evaluate whether ADT is associated with an excess risk of cardiovascular disease (CVD). Method : Literature search in electronic databases was conducted until July 2019 for observational studies and randomized controlled trials (RCT) to select eligible studies. The relationship was evaluated through estimating relative risk ratio (RR) and 95% confidence intervals (CI). Result : A statistically significant association was detected for acute myocardial infarction (AMI) with RR = 1.22; 95% confidence interval CI, 1.05–1.43; P< 0.05 including a total of 142,012 cases and 174,099 controls. Significant relationship between coronary heart disease (CHD) and ADT was also observed, with summary RR=1.19; 95%CI, 1.03-1.38, from 157,165 ADT users and 375,754 non-ADT users. Conclusions : From this study, ADT is associated with increased risk of AMI, CHD, and heart failure (HF); in contrast, this association is not detected in sudden cardiac death (SCD); various modalities of ADT could significantly increase the risk of CHD, AMI, except for oral anti-androgen (AA). Our meta-analysis also suggests that the long-term application of ADT in prostate cancer patients would not result in a significant increase in AMI incidence compared with short-term. Moreover, the combined application of AA and GnRH agonists would lead to a similar risk of AMI compared with orchiectomy or GnRH agonists monotherapy whereas higher risk of CHD was detected when compared GnRH agonists plus AA with orchiectomy.

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The prevalence of cardiovascular disease and its risk factors among prostate cancer patients treated with and without androgen deprivation.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.364 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 364-364

Author(s):

Jehonathan H. Pinthus ◽

Bobby Shayegan ◽

Laurence Klotz ◽

D. Robert Siemens ◽

Patrick P. Luke ◽

...

Keyword(s):

Prostate Cancer ◽

Risk Factors ◽

Cardiovascular Disease ◽

Risk Factor ◽

Cardiovascular Risk ◽

Androgen Deprivation Therapy ◽

Androgen Deprivation ◽

Risk Scores ◽

Cvd Risk ◽

Framingham Risk

364 Background: Cardiovascular disease (CVD) is the second most common cause of death in prostate cancer (PC) patients, yet the prevalence of CVD and its risk factors have been incompletely described in this population. Androgen deprivation therapy (ADT) is a risk factor for CVD. The objective of this study were to describe the CVD characteristics and risk factors in PC patients and the relationship between CVD risk and how ADT is used in real-world practice. Methods: RADICAL-PC (Role of Androgen Deprivation Therapy in CArdiovascular Disease – A Longitudinal Prostate Cancer Study) is an ongoing prospective cohort study. We recruited 2395 consecutive men (mean age 68 years) with newly diagnosed PC or with a plan to prescribe ADT for the first time. Cardiovascular risk was estimated by calculating Framingham risk scores. A Framingham score >17 (corresponding with a predicted 10-year CVD risk of >30%) was considered high-risk. Multivariable logistic regression was performed with ADT use as the outcome variable and CVD risk factors as the exposures of interest. Results: The prevalence of known CVD for the entire cohort was 22% and 35% had a Framingham risk score >17. Most participants (58%) were current or former smokers; 16% had diabetes; 45% had hypertension and 23% had high blood pressure but had not received a diagnosis of hypertension; 31% were obese (BMI ≥30kg/m2); 24% had low levels of physical activity. There was a positive relationship between each major cardiovascular risk factor and the use of ADT. However, after adjustment for age, education, alcohol use, BMI and time from PC diagnosis to eligibility assessment, these associations were significantly attenuated. Participants in whom ADT was planned had higher Framingham risk scores than those not intending to receive ADT. This risk was abolished after adjustment for confounders. Conclusions: One in three men with PC is at high cardiovascular risk. Men receiving ADT are a priori at higher CVD risk than PC patients whose treatment strategy does not include ADT. These differences are explained by confounding factors. Clinical trial information: NCT03127631.

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Added value of cardiovascular calcifications for prediction of recurrent cardiovascular events and cardiovascular interventions in patients with established cardiovascular disease

The International Journal of Cardiovascular Imaging ◽

10.1007/s10554-021-02164-9 ◽

2021 ◽

Author(s):

Cilie C. van ’t Klooster ◽

◽

Yolanda van der Graaf ◽

Hendrik M. Nathoe ◽

Michiel L. Bots ◽

...

Keyword(s):

Cardiovascular Disease ◽

Heart Valve ◽

Cardiovascular Events ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Added Value ◽

Cvd Risk ◽

Major Cardiovascular Events ◽

Cox Proportional Hazards Models ◽

Cardiovascular Interventions

AbstractThe purpose is to investigate the added prognostic value of coronary artery calcium (CAC), thoracic aortic calcium (TAC), and heart valve calcium scores for prediction of a combined endpoint of recurrent major cardiovascular events and cardiovascular interventions (MACE +) in patients with established cardiovascular disease (CVD). In total, 567 patients with established CVD enrolled in a substudy of the UCC-SMART cohort, entailing cardiovascular CT imaging and calcium scoring, were studied. Five Cox proportional hazards models for prediction of 4-year risk of MACE + were developed; traditional CVD risk predictors only (model I), with addition of CAC (model II), TAC (model III), heart valve calcium (model IV), and all calcium scores (model V). Bootstrapping was performed to account for optimism. During a median follow-up of 3.43 years (IQR 2.28–4.74) 77 events occurred (MACE+). Calibration of predicted versus observed 4-year risk for model I without calcium scores was good, and the c-statistic was 0.65 (95%CI 0.59–0.72). Calibration for models II–V was similar to model I, and c-statistics were 0.67, 0.65, 0.65, and 0.68 for model II, III, IV, and V, respectively. NRIs showed improvement in risk classification by model II (NRI 15.24% (95%CI 0.59–29.39)) and model V (NRI 20.00% (95%CI 5.59–34.92)), but no improvement for models III and IV. In patients with established CVD, addition of the CAC score improved performance of a risk prediction model with classical risk factors for the prediction of the combined endpoint MACE+ . Addition of the TAC or heart valve score did not improve risk predictions.

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