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

O’Farrell, Sean; Garmo, Hans; Holmberg, Lars; Adolfsson, Jan; Stattin, Pär; Hemelrijck, Mieke Van

doi:10.1200/jco.2014.59.1792

Cited by 224 publications

(174 citation statements)

References 37 publications

(9 reference statements)

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“…Recent studies, however, have suggested that the number of CVD events in PCa patients differs between different types of ADT, indicating that other mechanisms than the mere lack of testosterone is involved. In observational studies and a post hoc analysis of randomized controlled trials, a higher rate of CVD events was found in patients treated with GnRH receptor agonists compared with bilateral orchiectomy or GnRH antagonists 4, 5, 9. These studies are hypothesis‐generating and the findings await confirmation in randomized trials with CVD as a prespecified end point, but the idea of a divergent effect of orchiectomy, GnRH agonists and antagonists on atherosclerosis‐related disease is supported by experimental studies.…”

Section: Introductionmentioning

confidence: 99%

Differences in Hypercholesterolemia and Atherogenesis Induced by Common Androgen Deprivation Therapies in Male Mice

Poulsen

Mortensen

Koechling

et al. 2016

JAHA

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BackgroundTreatment of prostate cancer often involves androgen deprivation therapy (ADT) by gonadotropin‐releasing hormone (GnRH) receptor agonists, GnRH receptor antagonists, or orchiectomy. ADT may increase the rate of cardiovascular disease events, but recent clinical studies suggested that not all means of ADT carry the same risk, raising the possibility of non–testosterone‐mediated effects of different forms of ADT on atherosclerosis. Here we compared effects of ADT on atherosclerosis in intact and orchiectomized Apoe‐deficient mice.Methods and ResultsChow‐fed Apoe‐deficient mice were allocated to orchiectomy and/or monthly injections with the GnRH receptor agonist leuprolide or the GnRH receptor antagonist degarelix. Atherosclerosis was quantified at 26 weeks of age in the aortic arch by en face examination and in the aortic root by histology. In intact Apoe‐deficient mice, all types of ADT reduced testosterone production to castration levels. Although hypercholesterolemia was accentuated in leuprolide‐treated mice, the amount and composition of atherosclerosis was not different between the different types of ADT. In orchiectomized Apoe‐deficient mice, leuprolide, but not degarelix, augmented hypercholesterolemia, changed body, thymus, and spleen weights, and increased atherosclerosis in the aortic root. No direct effects of the drugs were detectable on cytokine secretion from murine bone marrow–derived macrophages or on splenocyte proliferation.ConclusionsNo differences in the development of atherosclerosis were detected among groups of intact Apoe‐deficient mice treated with different types of ADT. A pro‐atherogenic, possibly cholesterol‐mediated, effect of leuprolide was seen in orchiectomized mice that might be relevant for understanding the potential cardiovascular risk associated with GnRH agonist‐based ADT.

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Section: Introductionmentioning

confidence: 99%

Differences in Hypercholesterolemia and Atherogenesis Induced by Common Androgen Deprivation Therapies in Male Mice

Poulsen

Mortensen

Koechling

et al. 2016

JAHA

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“…PCa cases and their matched comparison cohort of PCa-free men were subsequently linked to a series of national healthcare registers and demographic databases to obtain data on discharge diagnoses, surgical procedures, socio-economic status and cause of death. Based on information from the National Patient Register, comorbidities were measured using the Charlson comorbidity index (CCI), which assigns weights to a number of medical conditions, including diabetes, hypertension and cardiovascular diseases, allowing a final comorbidity score to be calculated for each individual [13,15]. Each condition is assigned a score of 1, 2, 3 or 6, and the final CCI is given as the sum of these scores [13].…”

Section: Study Population and Data Collectionmentioning

confidence: 99%

“…The aim of the present study was to investigate the risk of TED in men with PCa on ADT by considerably expanding our previous analyses using data from PCBaSe Sweden 3.0. We accounted for known TED risk factors, such as changes in medication, TURP, palliative radiotherapy and nephrostomy, as well as surgical cancer treatments to distil the impact of different types and duration of ADT on the risk of TED [1,2,12,13].…”

Section: Introductionmentioning

confidence: 99%

Risk of thromboembolic disease in men with prostate cancer undergoing androgen deprivation therapy

et al. 2015

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ObjectivesTo investigate the risk of thromboembolic disease (TED) in men with prostate cancer (PCa) on androgen deprivation therapy (ADT), while accounting for known TED risk factors. Materials and MethodsWe assessed TED risk for 42 263 men with PCa who were receiving ADT compared with a matched cohort of 190 930 without PCa. The associations between ADT and deep vein thrombosis (DVT) or pulmonary embolism (PE) were analysed using multivariate Cox proportional hazard regression models, while accounting for previous PCa-related surgeries and the following proxies for disease progression: transurethral resection of the prostate, palliative radiotherapy and nephrostomy. ResultsBetween 1997 and 2013, 11 242 men with PCa received antiandrogen monotherapy, 26 959 men received gonadotropinreleasing hormone (GnRH) agonists, 1 091 men received combined androgen blockade and 3 789 men underwent orchiectomy. When accounting for previous surgeries and proxies of disease progression, GnRH agonist users and surgically castrated men had a higher risk of TED than the comparison cohort: hazard ratios (HRs) 1.67 (95% confidence interval [CI] 1.40-1.98) and 1.61 (95% CI 1.15-2.28), respectively. Men on anti-androgen monotherapy had a lower risk: HR for DVT 0.49 (95% CI 0.33-0.74). TED risk was highest among those who switched from anti-androgen to GnRH agonists: HR for PE 2.55 (95% CI 1.76-3.70). This increased from 2.52 (95% CI 1.54-4.12) in year 1, to 4.05 (95% CI 2.51-6.55) in year 2. ConclusionThe incidence of TED among men on ADT increased with the duration of therapy and the risk was highest for those who switched regimen, suggesting that disease progression as well as ADT contribute to the propagation of TED risk. Nonetheless, these findings support the hypothesis that only men with a relevant indication should receive systemic ADT.

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“…While increased risk of CVD in patients receiving ADT has been demonstrated in a number of observational studies, 9 these findings have been…”

Section: Controversies In Adt-associated Cvdmentioning

confidence: 88%

“…9 Furthermore, there is evidence for the increased incidence of CV events in PC patients receiving GnRH agonist-based ADT, which is not seen with antagonist-based ADT. 10 Given the patient demographics of PC, as many as 30% of men with advanced PC are likely to be at high risk of a CV event -making CV risk a key factor in assessing patients for the optimal ADT modality.…”

Section: Discussionmentioning

confidence: 99%

Managing cardiovascular risk in high‐risk prostate cancer

Plummer¹,

Collins²,

Rosario³

et al. 2017

Trends Urol & Men's Health

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Men living with prostate cancer have a high rate of cardiovascular events, and many of them have risk factors that would be an indication for primary prevention under current guidance. These risks may be increased by certain androgen deprivation therapies. This article reports the outcome of a consensus meeting at which the authors discussed these issues. They suggest a simple assessment tool for use with prostate cancer patients to rapidly assess cardiovascular risk and allow appropriate risk‐management strategies to be implemented.

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

Abstract: 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.

Cited by 224 publications

References 37 publications

Differences in Hypercholesterolemia and Atherogenesis Induced by Common Androgen Deprivation Therapies in Male Mice

Differences in Hypercholesterolemia and Atherogenesis Induced by Common Androgen Deprivation Therapies in Male Mice

Risk of thromboembolic disease in men with prostate cancer undergoing androgen deprivation therapy

Managing cardiovascular risk in high‐risk prostate cancer

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