Curr Treat Options Cardio Med (2020) 22:69

DOI 10.1007/s11936-020-00873-3

Cardio-oncology (M Fradley, Section Editor)

Cardiovascular Complications
of Prostate Cancer Therapy
Courtney M. Campbell, MD, PhD1
Kathleen W. Zhang, MD2
Andrew Collier, MD, FRCPE3
Mark Linch, PhD, FRCP4
Adam C. Calaway, MD5
Lee Ponsky, MD5
Avirup Guha, MD6
Arjun K. Ghosh, MBBS, PhD, FRCP7,8,*
Address
1
Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio
State University Wexner Medical Center, Columbus, OH, USA
2
Division of Cardiology, Cardio-Oncology Center of Excellence, Washington Uni-
versity in St. Louis School of Medicine, St. Louis, MO, USA
3
Diabetes Day Centre, University Hospital, Ayr, UK
4
Department of Oncology, University College London Cancer Institute, London, UK
5
Department of Urology, University Hospitals Cleveland Medical Center, Case
Western Reserve University School of Medicine, Cleveland, OH, USA
6
Harrington Heart and Vascular Institute, Case Western Reserve University, Cleve-
land, OH, USA
7
Cardio-Oncology Service, Barts Heart Centre, St. Bartholomew’s Hospital West
Smithfield, London, UK
*,8
Cardio-Oncology Service, Hatter Cardiovascular Institute, University College
London Hospital, London, UK
Email: [email protected]

* Springer Science+Business Media, LLC, part of Springer Nature 2020

Avirup Guha and Arjun K. Ghosh contributed equally to this work.

This article is part of the Topical Collection on Cardio-oncology

Keywords Cardio-oncology I Prostate cancer I Gonadotropin-releasing hormone agonist I Gonado-tropin-releasing

hormone antagonist I Androgen receptor blockade I Androgen deprivation therapy I Hormone therapy I Cardiovascular
disease I Myocardial infarction I Stroke I Hypertension

Abstract
Purpose of review With treatment advances, the most common cause of death in prostate
cancer patients is cardiovascular disease. Discerning the contribution of prostate cancer
treatment on cardiovascular complications versus the natural progression of cardiovascu-
lar disease remains an ongoing area of investigation. Evaluating the research and
 69 Page 2 of 27 Curr Treat Options Cardio Med (2020) 22:69

identifying opportunities for further investigation is critical for optimal care of this
prostate cancer patient population.
Recent findings The degree that hormone therapy contributes to cardiovascular morbidity
and mortality remains uncertain with conflicting results from large meta-analyses. Under-
lying cardiovascular disease or multiple cardiovascular disease risk factors appear to
compound the risk of adverse events. Drug-specific cardiotoxicity in prostate cancer
treatment has not been fully delineated. Recent studies have suggested the potential
for wide-ranging prostate cancer cardiotoxic effects, including atherosclerosis accelera-
tion, myocardial infarction, cardiomyopathy, hypertension, arrhythmias, and stroke along
with other thromboembolic diseases.
Summary This review provides an overview of prostate cancer treatment, a comprehensive
analysis of the literature linking androgen deprivation therapy and cardiovascular disease, a
discussion of cardiovascular risk management and mitigation in prostate cancer patients,
and an exploration of research opportunities within cardio-oncology for prostate cancer.

Introduction
Prostate cancer is the most common non-cutaneous cancer multiple shared risk factors including male gender, older
in men in the USA, and the second leading cause of cancer age, smoking, dyslipidemia, and obesity [6–10]. In a
death in men after lung cancer. Approximately 12.1% of single-center cohort of men with intermediate- or high-
men in the USA will be diagnosed with prostate cancer risk localized prostate cancer, high and intermediate
during their lifetime [1] and as of 2017, over 3.1 million Framingham risk scores were found in 65% and 33%
men were living with prostate cancer in the USA. The of patients, respectively, highlighting the significance of
majority of men with prostate cancer are diagnosed with cardiovascular comorbidity in this population [11]. Ad-
localized disease (75.9% of all diagnoses). Localized pros- ditionally, certain therapies for prostate cancer, particu-
tate cancer generally has excellent outcomes following larly androgen deprivation therapy, may contribute to or
treatment with radiotherapy, surgery, or active surveillance accelerate the development of cardiovascular disease in
with a 10-year cancer-specific survival approaching 100% men with prostate cancer. Better understanding of the
[2]. In high-risk localized prostate cancer patients under- cardiovascular risks associated with prostate cancer ther-
going radical prostatectomy, the use of adjuvant hormone apy, as well as the overall cardiovascular risk profile of
therapy significantly improves overall survival outcomes men with prostate cancer, may reduce morbidity and all-
[3–5]. In men with metastatic prostate cancer, the 5-year cause mortality in this patient population (Fig. 1).
survival rate is significantly lower at 30.2% [1]. Recurrent This review provides an overview of prostate cancer
and metastatic prostate cancer is invariably fatal but recent treatment, a comprehensive analysis of the literature
improvements in lifespan have been achieved with early linking androgen deprivation therapy and cardiovascu-
intensification of treatment, but with a resulting expansion lar disease, a discussion of cardiovascular risk manage-
in the risk of toxicities in survivors. ment in prostate cancer patients, and an exploration of
Cardiovascular disease is an important contributor future directions for research aiming to improve the
to all-cause mortality in men with prostate cancer due to cardiovascular care of men with prostate cancer.

Overview of prostate cancer treatment

Treatment options for localized prostate cancer include expectant manage-
ment, surgery, and radiation with treatment selection occurring in the
Curr Treat Options Cardio Med (2020) 22:69 Page 3 of 27 69

Fig. 1. Potential cardiovascular complications of prostate cancer therapy. Recent studies have underscored the diversity of
cardiovascular toxicities associated with prostate cancer therapy.

context of life expectancy, risk of death from other causes, and patient
preference via shared decision-making [12]. Most prostate cancer patients
are of an advancing age and have many comorbidities. In patients with
high-risk localized disease treated with external beam radiation therapy,
 69 Page 4 of 27 Curr Treat Options Cardio Med (2020) 22:69

androgen deprivation therapy (ADT) is added as part of the standard of care

for either a short-term (6 months) or long-term (≥ 24 months) course. ADT
is also used to reduce prostate volume before definitive local treatment with
brachytherapy [13]. ADT is the first-line treatment for men with metastatic
prostate cancer with emerging roles for docetaxel chemotherapy and the
novel androgen receptor signaling pathway inhibitors (ARPI) enzalutamide,
apalutamide, and abiraterone [14].

Hormone therapy
Androgen deprivation therapy
Prostate cancer is predominantly a hormone-dependent tumor. The corner-
stone of advanced prostate cancer treatment is androgen deprivation therapy
(ADT), which lowers systemic androgen levels and thereby inhibits the prolif-
eration of prostate cancer cells. Lower levels of testosterone during ADT treat-
ment are associated with improved outcomes [15]. The US Food and Drug
Administration (FDA) defines castration as serum testosterone levels G 50 ng/dL
but improved clinical outcomes have been seen in patients that achieve testos-
terone levels G 20 ng/dL [15].

Mechanisms of action
Suppression of testicular androgens by castration (medical or surgical) is known
as ADT. By reducing the two main androgens in men, testosterone and dihy-
drotestosterone (DHT), their growth-promoting actions on prostate cancer cells
are diminished. Hypogonadism can be induced through the disruption of the
hypothalamic-pituitary-gonadal axis. ADT can be achieved surgically through a
bilateral orchiectomy or medically through gonadotrophin-releasing hormone
(GnRH) agonists or antagonists [16].

Physiology
In brief (Fig. 2), the hypothalamus releases gonadotropin-releasing hormone
(GnRH). GnRH acts on the anterior pituitary to release luteinizing hormone
(LH), follicle-stimulating hormone (FSH), and adrenocorticotrophic hor-
mone (ACTH). LH stimulates testosterone release by the Leydig cells within
the testes. FSH stimulates the Sertoli cells to promote spermatogenesis.
ACTH stimulates the adrenal glands to produce adrenal androgens. Testos-
terone (95%) and adrenal androgens (5%) bind androgen receptors resulting
in nuclear translocation, which then activates genes that are essential for cell
survival and prostate function. In prostate cancer, this pathway is excessively
activated, resulting in the uncontrolled growth of the prostate tumor cells.
Further, androgen receptors are also present in a variety of target tissues
including muscle and adipose tissue.

Surgical ADT
The most direct manner of achieving ADT is bilateral orchiectomy—castration.
Removal of the testes eliminates the predominant source of testosterone produc-
tion. This method has permanent and sustained suppression of testosterone.
Curr Treat Options Cardio Med (2020) 22:69 Page 5 of 27 69

Fig. 2. Androgen deprivation therapy targets within the hypothalamic-pituitary-gonadal axis in prostate cancer. GnRH,
gonadotropin-releasing hormone; FSH, follicular stimulating hormone; LH, luteinizing hormone; AE, androstenedione; DHEA,
dihydrotestosterone.

Medical ADT

GnRH agonist

The efficacy of GnRH agonists relies on the negative feedback loop of

the hypothalamic-pituitary axis to reduce androgen levels. When a
patient is given the initial dose of GnRH agonist, there is an initial surge
in FSH, LH, and testosterone before suppression. With repeat injections,
 69 Page 6 of 27 Curr Treat Options Cardio Med (2020) 22:69

there are micro-surges of LH and testosterone. Over 2–3 weeks, GnRH

agonists result in the downregulation of the GnRH receptor with a
reduction in LH and suppression of testosterone production. FSH is
suppressed, but the suppression is not maintained in the long term.
Drugs in this category include intramuscular or subcutaneous
leuprolide, intramuscular triptorelin, subcutaneous goserelin, and sub-
cutaneous histrelin. These medications are re-administered every 1 to
6 months, depending on the drug and delivery system.

GnRH antagonist

In contrast, GnRH antagonists result in immediate suppression of FSH, LH,

and testosterone with effective testosterone suppression in 2–3 days. There
is no initial hormone surge or micro-surges of hormones with repeat doses.
Prolonged suppression of FSH, LH, and testosterone occurs. Subcutaneous
degarelix is the only FDA-approved drug currently in this category. The use
of degarelix is modest due to significant local injection site reactions in
many patients and monthly dosing regimen. It is often used in the initia-
tion of ADT before transitioning to the better-tolerated GnRH agonists with
longer dosing intervals. Relugolix is an investigational oral GnRH antago-
nist that was recently shown to lead to rapid, sustained testosterone sup-
pression [17].
Androgen receptor signaling pathway inhibitors

Androgen receptor blockade

Outside of the hypothalamus-pituitary axis, androgen receptor (AR) block-
ade prevents testosterone binding to the androgen receptor. This approach
does not decrease circulating testosterone levels and is less effective as a
monotherapy compared to surgical castration or GnRH therapies. However,
these drugs do not decrease libido. The most common indications for AR
blockade in prostate cancer treatment are (1) as monotherapy in patients
that are intolerant or refuse ADT, (2) as a short course in conjunction with
GnRH agonists to reduce the impact of initial hormone surges, (3) in
conjunction with ADT in patients that have progressed on ADT alone and
most recently (4) use as an initial treatment with ADT in patients with
newly diagnosed hormone-sensitive prostate cancer. The early-generation
drugs in this category include flutamide, nilutamide, and bicalutamide.
More recently, additions to this drug category are enzalutamide,
apalutamide, and darolutamide, which have augmented mechanisms of
action with higher binding affinities and prevent nuclear translocation
[18–21].

Androgen synthesis inhibition

Testosterone synthesis can be blocked through the inhibition of the CYP17
enzyme. This mechanism prevents androgen production by testes, adrenal
glands, and prostate cancer cells. It is administered in conjunction with ongoing
Curr Treat Options Cardio Med (2020) 22:69 Page 7 of 27 69

GnRH based ADT and can bring testosterone levels to near zero. The main drug
in this category is abiraterone [22, 23].

Cardiovascular complications of hormone therapy

Several studies have reported an association between hormone therapy and the
increased risk of cardiovascular mortality. In 2010, cardiovascular complica-
tions from prostate cancer therapy were addressed by the joint science advisory
statement from the American Heart Association, American Cancer Society, and
American Urological Association [24]. Nevertheless, a clear consensus remains
elusive, and the understanding of the contribution of hormonal therapy on
cardiovascular disease is still evolving. A comprehensive, but not exhaustive,
discussion of the literature highlights the evolving and differing theories
connecting hormone therapy with cardiovascular adverse event risk.

Cardiovascular risk of hormone therapy for prostate cancer in general

Large cohort studies and meta-analyses assessed the cardiovascular risk of
hormone therapy in prostate cancer inclusive of all stages of the disease
(Table 1) and reached varied conclusions. An early case-controlled cohort study
found no increased risk of acute myocardial infarction or sudden cardiac death
on any hormone therapy [25]. In contrast, a later, larger cohort study and a
comprehensive meta-analysis found an increased risk of cardiac events [26, 28].
Underlying cardiovascular disease was also associated with increased risk with
both GnRH agonists or ARPI therapy [29]. A Markov decision analysis model
suggested that men with a history of myocardial infarction and prostate cancer
treated with ADT experienced net harm [30]. More recently, cohort studies have
assessed the risk of arrhythmias with prostate cancer therapy and found associ-
ations with long QT syndrome, torsades de pointes, and sudden cardiac death
[31, 32]. Specifically, enzalutamide was associated with more deaths than other
hormone therapies.

Cardiovascular risk of hormone therapy for advanced prostate cancer

ADT monotherapy
In advanced prostate cancer, large observational studies demonstrated associa-
tions between ADT monotherapy and cardiovascular morbidity and mortality
(Table 2). The first such study by Keating et al. used a Medicare database to
identify 73,196 men diagnosed with locoregional prostate cancer [33]. The
authors found that GnRH agonist treatment was associated with an increased
risk of diabetes (hazard ratio (HR) 1.44) and cardiovascular disease (HR 1.12)
including coronary artery disease, myocardial infarction, and sudden cardiac
death [33]. Subsequent retrospective, observational studies supported these
initial findings [34–36]. A significant limitation is that outcomes were assessed
primarily using diagnostic codes without clinical adjudication or confirmation
by chart review.
Table 1. Cardiotoxicity in hormone therapy for prostate cancer in general
69

Author, year Study type Patients Comparison Significant outcomes

Alibhai et al. 2009 Cohort (case controlled) 19,079 ADT (defined as GnRH agonists, Hormone therapy: no increased risk of
[25] nonsteroidal antiandrogens, or acute myocardial infarction or sudden
steroidal antiandrogens, alone or cardiac death; increased risk of
Page 8 of 27

in combination) versus no ADT diabetes

Van Hemelrijck Cohort 76,600 ADT (defined as anti-androgen, Hormone therapy: increased cardiac
et al. 2010 [26] estrogens, orchiectomy, GnRH events (HR 1.40) regardless of cardiac
agonist, combined GnRH plus history
anti-androgen) versus surveillance
versus curative (prostatectomy
and/or radiotherapy) versus men
without prostate cancer
Smith et al. 2010 Meta-analysis (9 RCTs) 1704 1 year prior to degarelix treatment Degarelix: baseline cardiovascular disease
[27] versus average of 22 months after strongest independent predictor of
degarelix treatment cardiac events during treatment
O’Farrell et al. 2015 Cohort 41,862 ADT (defined as GnRH agonist, GnRH agonist: increased overall cardiac
[29] orchiectomy, or anti-androgen) risk (HR 1.21) and increased risk with
compared to age matched, prostate cardiac history (HR 1.91)
cancer free cohort Orchiectomy: increased overall cardiac risk
(HR 1.16) and increased risk with cardiac
history (1.79)
ARPI: decreased overall cardiac risk (0.87)
and increased risk with cardiac history
(1.60)
Carneiro et al. 2015 Meta-analysis 137,658 ADT (GnRH agonist, antiandrogens, Hormone therapy: increased risk of acute
[28] (4 cohort studies GnRH agonist + anti-androgen or myocardial infarction (RR 2.01)
and 9 RCTs) orchiectomy) for at least 6 months
versus no ADT
Curr Treat Options Cardio Med

Gagliano-Juca et al. Cohort 71 ADT (defined as leuprolide plus ADT + ARPI: increased QT interval and
2018 [31] bicalutamide) +/− RT versus no ADT decreased QRS shortening
Salem et al. 2019 Cohort 3096 ADT (defined as abiraterone, Enzalutamide: associated with sudden
[32] (Pharmaco-vigilance leuprorelin, goserelin, triptorelin, cardiac death, acquired long QT, and
database) degarelix, enzalutamide, torsades de pointes
bicalutamide, flutamide,
finasteride, dutasteride) versus
(2020) 22:69

men not on ADT

Table 2. Cardiotoxicity in advanced prostate cancer treatment

Author, year Study type Patients Comparison Significant outcomes

Androgen deprivation therapy (ADT) monotherapy
Keating et al. 2006 [33] Cohort 73,196 GnRH agonist or bilateral orchiectomy GnRH agonist: increase aHR for diabetes
versus no ADT (1.44), coronary artery disease (1.16),
myocardial infarction (1.11), sudden
cardiac death (1.160)
Orchiectomy: increased aHR for diabetes
Curr Treat Options Cardio Med

(1.43)
Saigal et al. 2007 [34] Cohort 22,816 GnRH agonist for 12 months versus no GnRH agonist: 20% higher risk of serious
ADT cardiovascular morbidity
Nguyen et al. 2011 [37] Meta-analysis 4141 GnRH agonist versus no ADT GnRH agonist: no increased risk of
(11 RCTs) cardiovascular death (RR 0.93)
ADT+/− androgen receptor signaling
(2020) 22:69

pathway inhibitors (ARPI)

Keating et al. 2010 [35] Cohort 37,443 ADT (defined as orchiectomy, GnRH Orchiectomy: increased risk of coronary
agonists, oral antiandrogens, artery disease (HR 1.40) and
combined androgen blockade) versus myocardial infarction (2.11)
no ADT GnRH agonist: increased risk of diabetes
(HR 1.28), coronary artery disease (HR
1.19), myocardial infarction (1.28),
sudden cardiac death (HR 1.35), and
stroke (HR 1.22)
GnRH agonist + ARPI: increased risk of
coronary artery disease (HR 1.27)
ARPI: no increased cardiac risk
Zhao et al. 2014 [36] Meta-analysis 295,406 ADT (defined as orchiectomy, GnRH Orchiectomy: no increased CVD, but
(6 cohort studies) agonist, oral antiandrogens, and increased CV mortality (HR 1.69)
combination thereof) versus no ADT GnRH agonist: increased CVD (HR 1.19) and
CV mortality (HR 1.36)
GnRH agonist + ARPI: increased CVD (HR
1.46) and CV mortality (HR 1.44)
ARPI alone: no increased CVD or CV
mortality
DiNunno et al. 2019 [39] Meta-analysis (3 RCTs) 4117 ADT (defined as orchiectomy, GnRH ADT + ARPI: increased risk of cardiac
Page 9 of 27

agonist, or GnRH antagonist) plus events (RR 2.3), hypertension (RR

apalutamide, enzalutamide, or 1.4), mortality (RR 4.9)
69

darolutamide versus ADT plus placebo

 69 Page 10 of 27 Curr Treat Options Cardio Med (2020) 22:69

However, a meta-analysis that included data from 11 randomized clinical

trials including a total of 4141 patients showed that the rates of cardiovascular
death were not significantly different between men that did and did not receive
GnRH agonist monotherapy therapy [37]. Importantly, the use of ADT was
associated with a lower risk of prostate cancer-specific mortality and all-cause
mortality. Nevertheless, cancer clinical trials often underreport cardiovascular
events, potentially limiting the applicability of the meta-analysis [38]. Further,
these clinical trial populations may not be generalizable to the entire prostate
cancer population.

ADT +/− ARPI therapy

In men with advanced prostate cancer, the addition of first-generation ARPI on
cardiovascular risk was assessed with large cohort studies (Table 2) [35, 36].
Treatment with ARPI alone did not confer increased risk of cardiovascular
disease or mortality compared to no ADT. ADT plus ARPI had a different risk
profile than ADT alone, but there was no direct comparison. This risk profile of
ADT plus ARPI may be due to ADT alone or an interactive effect of ARPI with
ADT.
The second generation of ARPI is more potent androgen receptor inhibitors
and potentially have an increased cardiovascular risk profile. A meta-analysis of
three randomized control trials (RCT) using apalutamide, enzalutamide, or
darolutamide showed that there was a significantly increased risk of cardiovas-
cular events (relative risk (RR) 2.4), hypertension (RR 1.4), and death due to an
adverse event (RR 4.9) compared to advanced prostate cancer patients treated
with ADT alone [39].

Cardiovascular risk hormone therapy for localized prostate cancer

Adjuvant ADT monotherapy

The cardiovascular risk of adjuvant ADT monotherapy following prostate ra-
diotherapy was assessed in two RCTs, which found no significant differences in
cardiovascular mortality, but did not assess cardiovascular morbidity (Table 3)
[40, 41].

Adjuvant ADT +/− ARPI therapy

Overall, the addition of ARPI to ADT in adjuvant therapy had variable reported
effects (Table 3). An RCT demonstrated no significant differences in cardiovas-
cular mortality [42], but a meta-analysis of three RCTs found a significantly
increased risk of fatal myocardial infarction (HR 5.9) and shorter time to fatal
myocardial infarction [43]. Large cohort studies also found increased cardio-
vascular risk in older men or men with a history of cardiac disease. [44, 45]

Cardiac events with GnRH agonist versus GnRH antagonist use

Some studies directly compare cardiac events between the GnRH agonist and
GnRH antagonist (Table 4). The first clinical trial directly comparing treatment
with GnRH agonist (leuprolide) and GnRH antagonist (degarelix) found no
significant difference in cardiovascular disease incidence at 1 year [27]. A
subsequent meta-analysis of 6 RCTs found that the risk of a cardiac event within
Table 3. Cardiotoxicity in hormone therapy for localized prostate cancer treatment

Author, year Study type Patients Comparison Significant outcomes

Adjuvant ADT monotherapy
Efstathiou et al. 2008 [41] RCT 1554 Radiotherapy (RT) plus 4 months Long term goserelin: no significant difference in
goserelin or RT plus 28 months cardiovascular mortality (HR 1.09)
goserelin
Efstathiou et al. 2009 [40] RCT 945 RT plus goserelin or RT alone Goserelin: no significant difference in
cardiovascular mortality (HR 0.99)
Curr Treat Options Cardio Med

Adjuvant ADT +/− ARPI

Tsai et al. 2007 [44] Cohort 4892 Definitive local therapy plus ADT use ADT +/− ARPI: increased risk of
(defined as GnRH agonist and/or cardiovascular-related death (HR 2.6), 5.5%
anti-androgen therapy) versus defini- incidence of death in men 9 65 years old
tive local therapy plus no ADT
D’Amico et al. 2007 [43] Meta-analysis 1372 RT plus leuprolide or goserelin with ADT + flutamide: increased risk of fatal
(2020) 22:69

(3 RCTs) intermittent flutamide for 3–6 months myocardial infarction (HR 5.9); shorter times
versus RT plus no ADT to fatal myocardial infarction in men
9 65 years old
Roach et al. 2008 [42] RCT 456 RT plus goserelin and flutamide or RT plus Goserelin + flutamide: no significant difference
no ADT in fatal cardiac events
Nanda et al. 2009 [45] Cohort 5077 Brachytherapy with leuprolide or ADT + ARPI: no increased risk of all-cause mor-
goserelin plus bicalutamide or tality in men with no comorbidity (HR 0.97)
flutamide versus brachytherapy plus or a single cardiac risk factor (HR 1.04)
no ADT ADT + ARPI: increased risk of all-cause mortality
(HR 1.96) in men with history of ischemic car-
diomyopathy or myocardial infarction
Page 11 of 27
69
Table 4. Cardiac events with GnRH agonist versus GnRH antagonist use
69

Author, year Study type Patients Comparison Significant outcomes

Smith et al. 2010 [27] RCT 504 Leuprolide versus degarelix No significant difference in cardiovascular
disease between treatment arms
Albertsen et al. 2014 [46] Meta-analysis 2328 GnRH agonist +/− ARPI versus GnRH Degarelix: fewer cardiac events with 1 year
Page 12 of 27

(6 RCTs) antagonist (degarelix) compared to GnRH agonist-treated men (HR

0.44), but only in men with underlying car-
diovascular disease
Margel et al. 2019 [48] RCT 80 GnRH agonist +/− ARPI (physician Degarelix: decreased CV events and
discretion) versus degarelix (GnRH cerebrovascular events
antagonist)
Perrone et al. 2020 [47] Cohort 9785 GnRH agonist versus GnRH antagonist GnRH antagonist: decreased incidence of CV
events (8.8 vs 6.2, p = 0.002)
Shore et al. 2020 [17] RCT 930 Leuprolide versus relugolix (GnRH Relugolix: decreased incidence of major adverse
antagonist) cardiovascular events (HR 0.46)
Curr Treat Options Cardio Med
(2020) 22:69
Curr Treat Options Cardio Med (2020) 22:69 Page 13 of 27 69

1 year was significantly lower in men treated with GnRH antagonist compared
to GnRH agonist (6.5% versus 14.7%; HR 0.44; 95% confidence interval [CI],
0.26–0.74; p = 0.002), but only in men with underlying cardiovascular disease
[46]. A cohort study of 9785 patients demonstrated a significant decrease in the
incidence of cardiovascular events in patients treated with GnRH antagonist
versus GnRH antagonist (8.8 vs 6.2, p = 0.002); ARPI use was excluded [47].
In a small randomized control trial of prostate cancer patients with pre-
existing cardiovascular disease (n = 80), men treated with GnRH agonists expe-
rienced significantly more major cardiovascular events and cerebrovascular
events than men treated with GnRH antagonists [48]. Increased serum NT-
proBNP was strongly associated with cardiovascular and cerebrovascular events.
Limitations included the degree of underlying risk factor control and the
unequal distribution of diabetes between the two arms. A recently published
phase III randomized clinical trial compared leuprolide with investigational
oral GnRH antagonist, relugolix, for the treatment of advanced prostate cancer
[17, 49]. The study found a 54% lower risk of a major adverse cardiovascular
event in men treated with relugolix (2.9% versus 6.2%, HR 0.46; 95% CI, 0.24–
0.88). No ARPI was used to limit the initial testosterone surge in the leuprolide
treatment group.
Together, these studies suggest that GnRH antagonists have a decreased risk
of cardiac events compared to GnRH agonist: degarelix for men with underlying
cardiovascular disease and relugolix for all men. A potential mechanism of
decreased risk with GnRH antagonist is more consistent testosterone suppres-
sion with no initial testosterone surge like in GnRH agonist use. ARPI was not
used or used inconsistently in these comparison studies.

Hormone therapy and cardiovascular risk mechanisms

The primary driver of cardiovascular morbidity and mortality in ADT is thought
to be the consequence of decreased serum testosterone, but other potential
contributors have been identified. For ARPIs, the level of serum testosterone can
be increased. In addition, GnRH agonists are associated with an initial testos-
terone surge. The mechanism of probable increased cardiovascular risk is cer-
tainly multifactorial.

Metabolic derangements
ADT is associated with significant, reproducible metabolic derangements. This
correlation of metabolic changes with GnRH agonism was published first in
1990. A metabolic analysis study of 10 men treated with GnRH agonist,
buserelin, observed significant increases in body weight, cholesterol, and fat
mass after 12 months of treatment [50]. This study confirmed in humans the
observations of weight gain and increased body fat with no changes in food
intake that were made previously in animal models of GnRH agonism or
castration.
Multiple subsequent studies demonstrated increases in fat mass and de-
creases in lean mass with ADT therapy [51]. In a study of 79 men treated with
GnRH agonist or bilateral orchiectomy, the fat mass increased by 11% and lean
body mass decreased by 3.8% over 12 months [52]. In a study of 65 men treated
69 Page 14 of 27 Curr Treat Options Cardio Med (2020) 22:69

with a GnRH agonist for prostate cancer, the fat mass increased by 6.6% and
lean mass decreased by 2.0% over 12 months [53]. A study of 40 men treated
with leuprolide for 12 months demonstrated an increase in fat mass of 9.4%
that consisted primarily of abdominal fat accumulation and decrease in lean
body mass by 2.7% [54]. Within 3 months of beginning ADT, alterations to
insulin handling are apparent. A study of 16 men treated with GnRH agonists
had significantly increased fasting insulin levels after 3 months [55]. A 12-week
prospective study assessed insulin sensitivity of men treated with leuprolide and
bicalutamide [56]. Fasting plasma insulin levels increased by 25.9%, and
glycosylated hemoglobin increased by 2.9%.
Although these changes are often categorized as metabolic syndrome, there
are specific patterns seen in men treated with ADT. Metabolic syndrome in-
cludes hypertension, hyperglycemia, excess visceral abdominal fat, elevated
triglycerides, and elevated low-density lipoprotein levels. In men treated with
ADT, excess subcutaneous abdominal fat, hyperglycemia predominates with
often elevation of both low-density and high-density lipoprotein. In a study of
58 men with prostate cancer, metabolic alterations occurred in 9 50% of men
undergoing at least 12 months of ADT with a particular increase in abdominal
obesity and hyperglycemia but with a similar prevalence of hypertension and
cholesterol [57].

Atherosclerosis and plaque destabilization

Increased atherosclerosis may be induced by low serum testosterone through
the aforementioned metabolic changes. Atherosclerosis can be increased by
multiple mechanisms related to lack of testosterone signaling: increased triglyc-
eride circulation from inhibition of triglyceride synthesis, increased adipocytes,
and decreased expression of local fibrinolysis and increased cholesterol efflux
[58–60]. The latter can result in increased low-density lipoprotein (LDL),
increased fatty streaks, and ultimately intimal thickening.
Given the increase in cardiac events often within a follow-up of only a year,
additional attention has been paid to mechanisms that may induce atheroscle-
rotic plaque destabilization and promote coagulation. For example, a GnRH
agonist can increase T cell proliferation resulting in fibrotic cap disruption and
plaque instability [61]. A GnRH antagonist will result in a lack of T cell
stimulatory response. These mechanisms may underlie the disparate event rates
between GnRH agonists and antagonists. In addition, androgen signaling is
linked to increased foam cells that produce pro-inflammatory cytokines [62]. In
animal models of atherosclerosis, testosterone decreases vascular cell adhesion
molecules and increases pro-inflammatory cytokines [62, 63].

Arterial stiffness
An initial study of 22 prostate cancer patients treated with GnRH agonist,
leuprorelin, demonstrated an increase in arterial stiffness through pulse wave
velocity measurement after 3 months of therapy [64]. In a subsequent study of
16 men with prostate cancer treated with GnRH agonist and 15 control men
without cancer, arterial stiffness was assessed before and after 3 months of
treatment [55]. Systemic arterial compliance was measured by simultaneous
recording of aortic flow and carotid artery pressure. Pulse wave velocity was also
recorded. Men treated with GnRH agonists had a significant decrease in
Curr Treat Options Cardio Med (2020) 22:69 Page 15 of 27 69

systemic arterial compliance and an increase in central but not peripheral pulse
wave velocities. This correlated with increased fasting insulin levels and total
cholesterol levels.
A randomized trial compared arterial stiffness between men with prostate
cancer treated for 24 weeks with GnRH agonist (goserelin) and androgen
receptor blocker (bicalutamide) [65]. Both treatments significantly increased
pulse wave velocities at 12 weeks, but the effect was not maintained at 24 weeks
in those treated with androgen receptor blockade.
The abrupt changes in arterial stiffness that have been observed in men
treated with hormone therapy are attributed to changes in cholesterol deposi-
tion. How this observation translates to an increased clinical risk of cardiovas-
cular events is not clear, but may be linked to hypertension or myocardial
infarction risk.

Hypertension
Increases in hypertension have not been observed in GnRH agonist-treated
populations. However, a large meta-analysis of six studies that included 6735
men with prostate cancer demonstrated an increased risk of hypertension (RR
1.84) in those treated with abiraterone and enzalutamide [66]. Inhibition of
CYP17 with abiraterone leads to hypermineralocorticism which manifests as
hypertension, hypokalemia, and peripheral edema. The
hypermineralocorticism can be prevented by concurrent treatment with low-
dose corticosteroid.

Arrhythmias and heart failure

In addition to hypertension, abiraterone has been associated with increased
reporting of atrial tachyarrhythmia and heart failure in comparison to
enzalutamide, ADT, and all other drugs in a large pharmacovigilance database
[67]. This increased risk was considered consistent with the
hypermineralocorticism induced by abiraterone. In a small cohort study, over
a quarter of patients on abiraterone experienced development or worsening of
cardiovascular disease including hypertension, congestive heart failure, and
cardiac arrhythmias [68]. In the initial randomized, double-blind, placebo-
controlled trial for abiraterone, heart failure, tachycardia and atrial fibrillation
were frequently reported in abiraterone compared to placebo, but differences in
the overall incidence of cardiac events did not reach statistical significance [69].

Prolonged QT interval
Hormone therapy has been associated with a prolonged QT interval. The most
likely mechanism is through direct modulation of the potassium channels by
testosterone [70]. Alternatively, GnRH receptors are expressed in cardiac tissue
[71]. In vitro GnRH agonists can increase intracellular calcium in mouse
cardiomyocytes [72]. This may lead to a prolonged QT interval, which could
potentially underlie the increase in sudden cardiac death that is seen early after
initiation of hormone therapy [33, 43]. Enzalutamide was shown to prolong
action potentials significantly and generate triggered activity and
afterdepolarizations in induced pluripotent stem cells [32].
69 Page 16 of 27 Curr Treat Options Cardio Med (2020) 22:69

Non-hormonal prostate cancer therapies and cardiovascular risk

Docetaxel
Docetaxel is a taxane chemotherapy which causes polymerization of microtu-
bules preventing effective mitosis and cell division. Docetaxel was first shown to
improve survival in metastatic castrate-resistant prostate cancer patients when
added to ADT in 2004 [73]. More recently, docetaxel has been shown to be
effective when used much earlier in the treatment pathway, leading to a 15-
month survival benefit and a 5-year median survival [74, 75]. Arrhythmias are
the most commonly observed cardiotoxicity by taxanes, including atrial fibril-
lation and asymptomatic bradycardias [76]. In addition, taxanes have been
associated with an increased incidence of cardiomyopathy when used in con-
junction with anthracyclines [77–80]. Whether docetaxel exacerbates
cardiotoxicity associated with hormone therapy has not been evaluated.

Poly(ADP-ribose) polymerase inhibitors

Deoxyribonucleic acid (DNA) has mechanisms to ensure the fidelity of both
single-strand and double-strand DNA. Corruption of either repair pathway can
be compensated for by the other. This system has been therapeutically exploited
in cancers that have defects in double-strand DNA (both germline or somatic)
as inhibition of single-strand DNA repair using poly(ADP-ribose) polymerase
(PARP) inhibition leads to a catastrophic accumulation of DNA errors leading
to cell death, a process known as syngeneic lethality. A recent study has reported
a 3.4-month improved overall survival in metastatic castration-resistant pros-
tate cancer patients who had previously received a novel ARPI and had muta-
tions in homologous recombination (in particular BRCA1, BRCA2, and ATM)
who were randomized to receive olaparib or physicians choice of abiraterone or
enzalutamide (O vs A/E: 18.5 m vs 15.1 m, HR 0.64, p = 0.02) [81].
PARP inhibitors are potentially cardioprotective with benefits seen in preclin-
ical models of myocardial infarction, heart failure, and atherosclerosis [82]. PARP
inhibition was associated with decreased cardiotoxicity when used in conjunction
with cardiotoxic therapies, such as imatinib and doxorubicin [83, 84]. However,
PARP inhibitors cause a modest, dose-dependent increase in QT interval [85].
PARP inhibitor-induced torsades de pointes was reported in a patient with under-
lying prolonged QT interval [86]. Further research is needed to determine how
PARP inhibitors alter cardiovascular risk in prostate cancer patients.

Immunotherapy
The use of immune checkpoint inhibitors (ICI) has led to a step-change in the
management of numerous cancers [87, 88]. While prostate cancer was one of
the first cancers to have an FDA-approved immunotherapy, in the form of the
cellular therapy Sipuleucel-T [89], checkpoint inhibitors remain experimental
for this disease. What is clear is that some patients do gain a robust and durable
response to these agents, and there is considerable work focusing on the
Curr Treat Options Cardio Med (2020) 22:69 Page 17 of 27 69

identification of predictive biomarkers [90, 91]. ICIs have increasingly recog-

nized, significant cardiotoxicities including myocarditis, pericarditis, heart fail-
ure, and arrhythmias [87, 92–94]. Full discussion of these cardiac toxicities is
beyond the scope of this review.

Cardiovascular risk management

Although the relative contribution of specific hormonal therapy to cardiovascular
adverse events remains under investigation, the cardio-oncology management of
men with prostate cancer undergoing therapy is important. Men with and
without underlying cardiovascular disease can benefit from aggressive cardiac
risk factor treatment. American Society of Clinical Oncology prostate cancer
survivorship care guidelines recommend cardiovascular risk factor evaluation
and screening. The “ABCDE” algorithm for managing cardiovascular risk factors
for prostate cancer survivors provides an excellent framework [95]. This risk factor
management approach can be bolstered by the addition of prompts for cardiac
monitoring and risk mitigation, as described below (Fig. 3). Follow-up should be
considered every 3 months during treatment for aggressive risk factor surveillance,
adverse event monitoring, and potential intervention initiation.

& “A” stands for awareness and aspirin. Prostate cancer survivors should have
increased awareness of cardiovascular signs and symptoms. Also, patients
should be on low-dose aspirin, if indicated by cardiovascular guidelines,
for primary or secondary prevention of cardiovascular events.

Fig. 3. Augmented ABCDE for prostate cancer cardiovascular care, emphasizing cardiovascular disease risk factor management,
cardiac monitoring, and cardiotoxicity risk mitigation.
69 Page 18 of 27 Curr Treat Options Cardio Med (2020) 22:69

– Arrhythmias have been linked to some hormone therapies. Querying for

palpitations or syncope history is important.
& Blood pressure, “B,” should be well controlled with a goal G 140/90 mmHg.

– Biomarker screening should also be considered given the recent linkage of

elevated NT-proBNP with the risk of adverse cardiovascular events.
& “C” signifies cigarettes and cholesterol. Optimal cardiovascular care should
include aggressive lipid control based on current cardiovascular guidelines.

– CT imaging should be evaluated if available for evidence of atherosclerosis,

which may prompt the initiation of statin therapy. Additional cardiac
imaging such as an echocardiogram can also be considered as patients
with underlying cardiomyopathies have poor outcomes and guideline-
directed therapy initiation is needed.
& Diabetes and diet fall under the “D.” ADT is associated with the develop-
ment of diabetes, an independent risk factor for cardiovascular disease.
Good diabetes management of pre-existing disease and surveillance for the
development of diabetes is important. A heart-healthy diet can further
improve control of cardiac risk factors.

– Drug choice for hormone therapy is important as some may have dispro-
portionate CV risk, particularly for patients with an underlying CV risk.
Joint decision-making between patient, oncologist, and cardiologist
should aim to minimize this risk.
& “E” stands for exercise. Exercise remains critical in decreasing the risk of
cardiovascular events.

– EKG and exposure length should be considered. Given the more recently
appreciated contribution of hormone therapy to abnormal heart rhythm,
EKGs to monitor for prolonged QT is important. In addition, depending
on the length of hormone therapy exposure, there may be a differing
cardiovascular risk that should be considered.

Future directions
The degree that hormone therapy contributes to cardiovascular morbidity and
mortality remains uncertain. GnRH agonists may increase cardiac risk com-
pared to GnRH antagonists. The addition of androgen receptor blockade in
analyses appears to worsen cardiovascular event risk. Specific drug
cardiotoxicity profiles remain to be determined (Fig. 1). The presence of under-
lying cardiovascular disease or multiple risk factors seems to compound the risk
of adverse events.
Current recommendations for cardiovascular risk reduction during prostate
cancer hormone therapy remain broad. This lack of precision reflects the
ambiguity of the current data and analysis. Within prostate cancer, the cardio-
oncology field is in its infancy. The potential cardiovascular complications of
Curr Treat Options Cardio Med (2020) 22:69 Page 19 of 27 69

hormone therapy are far ranging and many research questions remain (Figs. 1
and 4). With further research, personalized recommendations may be achiev-
able for cardiovascular risk reduction via optimal prostate cancer treatment
choice, ideal cardiac surveillance, and aggressive cardiovascular risk modifica-
tion (Fig. 5).

Fig. 4. Research opportunities for the intersection of cardio-oncology and prostate cancer care to improve patient outcomes.
 69 Page 20 of 27 Curr Treat Options Cardio Med (2020) 22:69

Cardiotoxicity of specific hormonal therapies

Granular data of cardiotoxicity risk is not yet available for most prostate cancer
therapies. Research has been focused on the cardiotoxicity of androgen depri-
vation therapy as a whole with very little direct comparison between different
classes, which include orchiectomy, GnRH agonist, GnRH antagonist, or addi-
tion of ARPIs. Even less data is available comparing different agents within these
classes—such as whether there is a difference in cardiotoxicity between
leuprolide and goserelin. Recent studies have started to explore these compar-
isons [66, 96]. Further, a single case report associated abiraterone use with
cardiomyopathy that recovered after drug cessation [97]. The nuances of these
individual therapies are important to elucidate for optimal cardiotoxicity risk
reduction.
Currently, androgen deprivation therapy choice is guided primarily by
oncologist recommendation-based cancer characteristics and patient prefer-
ence. Increased understanding of specific therapy cardiotoxicity and patient’s
underlying cardiovascular risk could also be part of the treatment decision
pathway to minimize adverse events. Identifying the vulnerable patient popu-
lations and matching with less cardiotoxic medications will likely improve
overall clinical outcomes. Randomized control trials will be important to
determine the optimal treatment choices.

Fig. 5. Algorithm for cardiovascular risk mitigation for patients undergoing prostate cancer treatment.
Curr Treat Options Cardio Med (2020) 22:69 Page 21 of 27 69

Radiation therapy risks

The vascular risk conferred by radiation therapy in prostate cancer is
unknown. Chest radiation is associated with accelerated coronary artery
disease in a dose-dependent manner in patients with breast cancer and
Hodgkin’s lymphoma [98–100]. The potential effect of pelvic radiation
therapy on accelerated arterial atherosclerosis has not been explored. In
clinical practice, vascular calcification has been noted in men with prior
prostate cancer radiation therapy, but whether this observation translates
into increased cardiovascular risk is not known. Future research should
investigate the vascular effects of radiation therapy in men with prostate
cancer, along with potential vascular benefits to newer modes of radiation
delivery and potential utility for vasculoprotective therapies (such as
statins). In the interim, cardio-oncologists should consider incorporating
routine assessment for peripheral arterial disease in patients with a history
of prostate cancer—particularly if the patient has evidence of disease on CT
imaging or has undergone radiation therapy for their prostate cancer.

Cardiovascular monitoring: biomarkers, arrhythmias, and cardiomyopathy

In breast cancer treatment, recent studies have evaluated the use of serial
cardiovascular biomarkers for early detection of adverse cardiac responses to
therapy [101, 102]. Similar studies in the prostate cancer population are limit-
ed. In a randomized trial of 43 men with prostate cancer treated with either
GnRH agonist (goserelin) or androgen receptor blocker (bicalutamide) for
24 weeks, NT-proBNP was significantly increased in the androgen receptor
blocker-treated group with no significant change in the GnRH agonist-treated
group [103]. In this study, the significance of this NT-proBNP increase was not
clear. There was no significant difference in left ventricular function, blood
pressure, or body mass index. Yet in a randomized control trial comparing
GnRH agonist versus GnRH antagonist, increasing serum NT-proBNP was
strongly associated with cardiovascular and cerebrovascular events [48]. These
data suggest a role for monitoring cardiac biomarkers in patients receiving
hormone therapy.
Recent studies have revealed previously unrecognized cardiotoxicity of ac-
quired long QT and potential arrhythmia risk. A baseline EKG may be prudent
and a low threshold for event monitoring can be considered. Cardiomyopathy
is also a new association linked to anti-androgen use. No studies have looked
systematically for new heart failure, and monitoring for this potential adverse
event is important. The role of active cardiovascular monitoring for early signs
of adverse events should be further explored in the research setting for the
prostate cancer population.

Cardiac interventions
Determining interventions to reduce the cardiotoxicity of prostate cancer
therapies is critical. Aggressive cardiovascular risk factor control is likely
beneficial, but the benefit has not been established. Large cohort and
clinical trial studies often contain data about the presence or absence of
a cardiovascular risk factor. Yet the degree of diabetes or cholesterol
control is not available.
 69 Page 22 of 27 Curr Treat Options Cardio Med (2020) 22:69

Given the high incidence of cardiovascular and cerebrovascular events on

hormone therapy, pre-treatment with cardiac medications should be
researched. Depending on planned therapy type and patient risk factors, the
addition of anti-arrhythmic, beta-blocker, or angiotensin-converting enzyme
inhibitors may be beneficial. Low-dose rivaroxaban may have a mortality
benefit in patients with CAD or PAD [104], particularly given adverse CV effects
associated with hormone therapy.
Increased cardiac monitoring may identify patients at risk of adverse events
related to prostate cancer therapy. Research can establish ideal responses and
interventions for these patients. These interventions can encompass the alter-
ation of therapy including cessation, therapy delay, dose reduction, alternative
hormone therapy, or initiation of cardiac medications.

Ongoing trials
The multi-center PRONOUNCE trial is designed to help answer some of these
questions [105]. A target of 900 men with prostate cancer and pre-existing
cardiovascular disease will be randomized to GnRH agonist leuprolide or
GnRH antagonist degarelix for 12 months. In addition to major adverse car-
diovascular event assessment, serial labs will be obtained, including cardiovas-
cular, inflammatory, and immune biomarkers. A total of 544 patients have
been randomized, but after a feasibility analysis, recruitment for this trial has
been halted [49].

Conclusions
Prostate cancer patients are a high cardiovascular risk population and cardiac
morbidity will only increase in light of recent treatment intensification leading
to increased toxicity and improved cancer-specific survival. Consequently,
cardio-oncology should be inextricably intertwined with prostate oncology.
However, the link between prostate cancer therapy and cardiovascular adverse
events remains ill-defined. There is a clear need to integrate careful cardiovas-
cular toxicity data and translational cardiovascular biomarkers into randomized
clinical trials of prostate cancer to enable risk stratification, personalized cardiac
surveillance, and improved patient outcomes.

Compliance with Ethical Standards

Conflict of Interest
Courtney M. Campbell declares that she has no conflict of interest. Kathleen W. Zhang declares that she has no
conflict of interest. Andrew Collier declares that he has no conflict of interest. Mark Linch declares that he has no
conflict of interest. Adam Christopher Calaway declares that he has no conflict of interest. Lee Ponsky declares that
he has no conflict of interest. Avirup Guha declares that he has no conflict of interest. Arjun K. Ghosh declares that he
has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.
Curr Treat Options Cardio Med (2020) 22:69 Page 23 of 27 69

References and Recommended Reading

1. Howlader N, Noone AM, Krapcho M, Miller D, Brest A, 13. Wang H, Wallner K, Sutlief S, Blasko J, Russell K, Ellis
Yu M, et al., editors. SEER cancer statistics review, W. Transperineal brachytherapy in patients with large
1975–2017. Bethesda: National Cancer Institute. prostate glands. Int J Cancer. 2000;90:199–205.
https://seer.cancer.gov/csr/1975_2017/. Based on No- 14. Sartor O, de Bono JS. Metastatic prostate cancer. N Engl
vember 2019 SEER data submission, posted to the J Med. 2018;378:645–57.
SEER web site, April 2020. 15. Klotz L, O’Callaghan C, Ding K, Toren P, Dearnaley D,
2. Hamdy FC, Donovan JL, Lane JA, Mason M, Metcalfe Higano CS, et al. Nadir testosterone within first year of
C, Holding P, et al. 10-year outcomes after monitoring, androgen-deprivation therapy (ADT) predicts for time
surgery, or radiotherapy for localized prostate cancer. N to castration-resistant progression: a secondary analysis
Engl J Med. 2016;375:1415–24. of the PR-7 trial of intermittent versus continuous ADT.
3. Bolla M, Van Tienhoven G, Warde P, Dubois JB, J Clin Oncol. 2015;33:1151–6.
Mirimanoff RO, Storme G, et al. External irradiation 16. Crawford ED, Heidenreich A, Lawrentschuk N, Tombal
with or without long-term androgen suppression for B, Pompeo ACL, Mendoza-Valdes A, et al. Androgen-
prostate cancer with high metastatic risk: 10-year re- targeted therapy in men with prostate cancer: evolving
sults of an EORTC randomised study. Lancet Oncol. practice and future considerations. Prostate Cancer
2010;11:1066–73. Prostatic Dis. 2019;22:24–38.
4. Denham JW, Steigler A, Lamb DS, Joseph D, Turner S, 17. Shore ND, Saad F, Cookson MS, George DJ, Saltzstein
Matthews J, et al. Short-term neoadjuvant androgen DR, Tutrone R, et al. Oral relugolix for androgen-
deprivation and radiotherapy for locally advanced deprivation therapy in advanced prostate cancer. N
prostate cancer: 10-year data from the TROG 96.01 Engl J Med. 2020;382:2187–96.
randomised trial. Lancet Oncol. 2011;12:451–9. 18. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Stern-
5. Horwitz EM, Bae K, Hanks GE, Porter A, Grignon DJ, berg CN, Higano CS, et al. Enzalutamide in metastatic
Brereton HD, et al. Ten-year follow-up of radiation prostate cancer before chemotherapy. N Engl J Med.
therapy oncology group protocol 92-02: a phase III 2014;371:424–33.
trial of the duration of elective androgen deprivation in 19. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN,
locally advanced prostate cancer. J Clin Oncol. Miller K, et al. Increased survival with enzalutamide in
2008;26:2497–504. prostate cancer after chemotherapy. N Engl J Med.
6. Platz EA, Till C, Goodman PJ, Parnes HL, Figg WD, 2012;367:1187–97.
Albanes D, et al. Men with low serum cholesterol have
20. Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik
a lower risk of high-grade prostate cancer in the place-
BA, Graff JN, et al. Apalutamide treatment and
bo arm of the prostate cancer prevention trial. Cancer
metastasis-free survival in prostate Cancer. N Engl J
Epidemiol Biomark Prev. 2009;18:2807–13.
Med. 2018;378:1408–18.
7. Platz EA, Clinton SK, Giovannucci E. Association be-
21. Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E,
tween plasma cholesterol and prostate cancer in the
Polyakov S, et al. Darolutamide in nonmetastatic,
PSA era. Int J Cancer. 2008;123:1693–8.
castration-resistant prostate cancer. N Engl J Med.
8. Cao Y, Ma J. Body mass index, prostate cancer-specific
2019;380:1235–46.
mortality, and biochemical recurrence: a systematic
review and meta-analysis. Cancer Prev Res (Phila). 22. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S,
2011;4:486–501. Chu L, et al. Abiraterone and increased survival in
metastatic prostate cancer. N Engl J Med.
9. Discacciati A, Orsini N, Wolk A. Body mass index and
2011;364:1995–2005.
incidence of localized and advanced prostate cancer–a
dose-response meta-analysis of prospective studies. 23. Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis
Ann Oncol. 2012;23:1665–71. CJ, de Souza P, et al. Abiraterone in metastatic prostate
10. Huncharek M, Haddock KS, Reid R, Kupelnick B. cancer without previous chemotherapy. N Engl J Med.
Smoking as a risk factor for prostate cancer: a meta- 2013;368:138–48.
analysis of 24 prospective cohort studies. Am J Public 24. Levine GN, D’Amico AV, Berger P, Clark PE, Eckel RH,
Health. 2010;100:693–701. Keating NL, et al. Androgen-deprivation therapy in
11. Davis MK, Rajala JL, Tyldesley S, Pickles T, Virani SA. prostate cancer and cardiovascular risk: a science advi-
The prevalence of cardiac risk factors in men with sory from the American Heart Association, American
localized prostate cancer undergoing androgen depri- Cancer Society, and American Urological Association:
vation therapy in British Columbia, Canada. J Oncol. endorsed by the American Society for Radiation On-
2015;2015:820403. cology. Circulation. 2010;121:833–40.
12. Litwin MS, Tan HJ. The diagnosis and treatment of 25. Alibhai SM, Duong-Hua M, Sutradhar R, Fleshner NE,
prostate cancer: a review. Jama. 2017;317:2532–42. Warde P, Cheung AM, et al. Impact of androgen
 69 Page 24 of 27 Curr Treat Options Cardio Med (2020) 22:69

deprivation therapy on cardiovascular disease and di- 38. Bonsu JM, Guha A, Charles L, Yildiz VO, Wei L, Baker
abetes. J Clin Oncol. 2009;27:3452–8. B, et al. Reporting of cardiovascular events in clinical
26. Van Hemelrijck M, Garmo H, Holmberg L, Ingelsson E, trials supporting FDA approval of contemporary cancer
Bratt O, Bill-Axelson A, et al. Absolute and relative risk therapies. J Am Coll Cardiol. 2020;75:620–8.
of cardiovascular disease in men with prostate cancer: 39. Di Nunno V, Mollica V, Santoni M, Gatto L, Schiavina
results from the population-based PCBaSe Sweden. J R, Fiorentino M, et al. New hormonal agents in patients
Clin Oncol. 2010;28:3448–56. with nonmetastatic castration-resistant prostate cancer:
27. Smith MR, Klotz L, Persson BE, Olesen TK, Wilde AA. meta-analysis of efficacy and safety outcomes. Clin
Cardiovascular safety of degarelix: results from a 12- Genitourin Cancer. 2019;17:e871–7.
month, comparative, randomized, open label, parallel 40. Efstathiou JA, Bae K, Shipley WU, Hanks GE, Pilepich
group phase III trial in patients with prostate cancer. J MV, Sandler HM, et al. Cardiovascular mortality after
Urol. 2010;184:2313–9. androgen deprivation therapy for locally advanced
28. Carneiro A, Sasse AD, Wagner AA, Peixoto G, Kataguiri prostate cancer: RTOG 85-31. J Clin Oncol.
A, Neto AS, et al. Cardiovascular events associated with 2009;27:92–9.
androgen deprivation therapy in patients with prostate 41. Efstathiou JA, Bae K, Shipley WU, Hanks GE, Pilepich
cancer: a systematic review and meta-analysis. World J MV, Sandler HM, et al. Cardiovascular mortality and
Urol. 2015;33:1281–9. duration of androgen deprivation for locally advanced
29. O'Farrell S, Garmo H, Holmberg L, Adolfsson J, Stattin prostate cancer: analysis of RTOG 92-02. Eur Urol.
P, Van Hemelrijck M. Risk and timing of cardiovascular 2008;54:816–23.
disease after androgen-deprivation therapy in men 42. Roach M 3rd, Bae K, Speight J, Wolkov HB, Rubin P,
with prostate cancer. J Clin Oncol. 2015;33:1243–51. Lee RJ, et al. Short-term neoadjuvant androgen depri-
30. Lester-Coll NH, Goldhaber SZ, Sher DJ, D'Amico AV. vation therapy and external-beam radiotherapy for lo-
Death from high-risk prostate cancer versus cardiovas- cally advanced prostate cancer: long-term results of
cular mortality with hormonal therapy: a decision RTOG 8610. J Clin Oncol. 2008;26:585–91.
analysis. Cancer. 2013;119:1808–15. 43. D’Amico AV, Denham JW, Crook J, Chen MH,
31. Gagliano-Juca T, Travison TG, Kantoff PW, Nguyen PL, Goldhaber SZ, Lamb DS, et al. Influence of androgen
Taplin ME, Kibel AS, et al. Androgen deprivation ther- suppression therapy for prostate cancer on the fre-
apy is associated with prolongation of QTc interval in quency and timing of fatal myocardial infarctions. J
men with prostate cancer. J Endocr Soc. 2018;2:485– Clin Oncol. 2007;25:2420–5.
96. 44. Tsai HK, D'Amico AV, Sadetsky N, Chen MH, Carroll
32. Salem JE, Yang T, Moslehi JJ, Waintraub X, PR. Androgen deprivation therapy for localized pros-
Gandjbakhch E, Bachelot A, et al. Androgenic effects on tate cancer and the risk of cardiovascular mortality. J
ventricular repolarization: a translational study from Natl Cancer Inst. 2007;99:1516–24.
the International Pharmacovigilance Database to iPSC- 45. Nanda A, Chen MH, Braccioforte MH, Moran BJ,
Cardiomyocytes. Circulation. 2019;140:1070–80. D'Amico AV. Hormonal therapy use for prostate cancer
33. Keating NL, O'Malley AJ, Smith MR. Diabetes and and mortality in men with coronary artery disease-
cardiovascular disease during androgen deprivation induced congestive heart failure or myocardial infarc-
therapy for prostate cancer. J Clin Oncol. tion. Jama. 2009;302:866–73.
2006;24:4448–56. 46. Albertsen PC, Klotz L, Tombal B, Grady J, Olesen TK,
34. Saigal CS, Gore JL, Krupski TL, Hanley J, Schonlau M, Nilsson J. Cardiovascular morbidity associated with
Litwin MS. Androgen deprivation therapy increases gonadotropin releasing hormone agonists and an an-
cardiovascular morbidity in men with prostate cancer. tagonist. Eur Urol. 2014;65:565–73.
Cancer. 2007;110:1493–500. 47. Perrone V, Degli Esposti L, Giacomini E, Veronesi C,
35. Keating NL, O’Malley AJ, Freedland SJ, Smith MR. Blini V, Oderda M. Cardiovascular risk profile in pros-
Diabetes and cardiovascular disease during androgen tate cancer patients treated with GnRH agonists versus
deprivation therapy: observational study of veterans antagonists: an Italian real-world analysis. Ther Clin
with prostate cancer. J Natl Cancer Inst. 2010;102:39– Risk Manag. 2020;16:393–401.
46. 48. Margel D, Peer A, Ber Y, Shavit-Grievink L, Tabachnik T,
36. Zhao J, Zhu S, Sun L, Meng F, Zhao L, Zhao Y, et al. Sela S, et al. Cardiovascular morbidity in a randomized
Androgen deprivation therapy for prostate cancer is trial comparing GnRH agonist and GnRH antagonist
associated with cardiovascular morbidity and mortali- among patients with advanced prostate cancer and
ty: a meta-analysis of population-based observational preexisting cardiovascular disease. J Urol.
studies. PLoS One. 2014;9:e107516. 2019;202:1199–208.
37. Nguyen PL, Je Y, Schutz FA, Hoffman KE, Hu JC, 49. Higano CS. Cardiovascular disease and androgen axis–
Parekh A, et al. Association of androgen deprivation targeted drugs for prostate cancer. N Engl J Med.
therapy with cardiovascular death in patients with 2020;382:2257–9.
prostate cancer: a meta-analysis of randomized trials. 50. Tayek JA, Heber D, Byerley LO, Steiner B, Rajfer J,
JAMA. 2011;306:2359–66. Swerdloff RS. Nutritional and metabolic effects of
Curr Treat Options Cardio Med (2020) 22:69 Page 25 of 27 69

gonadotropin-releasing hormone agonist treatment for 63. Hatakeyama H, Nishizawa M, Nakagawa A, Nakano S,
prostate cancer. Metabolism. 1990;39:1314–9. Kigoshi T, Uchida K. Testosterone inhibits tumor ne-
51. Berruti A, Dogliotti L, Terrone C, Cerutti S, Isaia G, crosis factor-alpha-induced vascular cell adhesion
Tarabuzzi R, et al. Changes in bone mineral density, molecule-1 expression in human aortic endothelial
lean body mass and fat content as measured by dual cells. FEBS Lett. 2002;530:129–32.
energy x-ray absorptiometry in patients with prostate 64. Smith JC, Bennett S, Evans LM, Kynaston HG, Parmar
cancer without apparent bone metastases given an- M, Mason MD, et al. The effects of induced
drogen deprivation therapy. J Urol. 2002;167:2361–7 hypogonadism on arterial stiffness, body composition,
discussion 2367. and metabolic parameters in males with prostate can-
52. Smith MR. Changes in fat and lean body mass during cer. J Clin Endocrinol Metab. 2001;86:4261–7.
androgen-deprivation therapy for prostate cancer. 65. Dockery F, Bulpitt CJ, Agarwal S, Vernon C, Rajkumar
Urology. 2004;63:742–5. C. Effect of androgen suppression compared with an-
53. Lee H, McGovern K, Finkelstein JS, Smith MR. Changes drogen receptor blockade on arterial stiffness in men
in bone mineral density and body composition during with prostate cancer. J Androl. 2009;30:410–5.
initial and long-term gonadotropin-releasing hormone 66. Iacovelli R, Verri E, Cossu Rocca M, Aurilio G, Cullurà
agonist treatment for prostate carcinoma. Cancer. D, De Cobelli O, et al. The incidence and relative risk of
2005;104:1633–7. cardiovascular toxicity in patients treated with new
54. Smith MR, Finkelstein JS, McGovern FJ, Zietman AL, hormonal agents for castration-resistant prostate can-
Fallon MA, Schoenfeld DA, et al. Changes in body cer. Eur J Cancer. 2015;51:1970–7.
composition during androgen deprivation therapy for 67. Bretagne M, Lebrun-Vignes B, Pariente A, Shaffer CM,
prostate cancer. J Clin Endocrinol Metab. Malouf GG, Dureau P, et al. Heart failure and atrial
2002;87:599–603. tachyarrhythmia on abiraterone: a pharmacovigilance
55. Dockery F, Bulpitt CJ, Agarwal S, Donaldson M, study. Arch Cardiovasc Dis. 2020;113:9–21.
Rajkumar C. Testosterone suppression in men with 68. Tsao PA, Estes JP, Griggs JJ, Smith DC, Caram MEV.
prostate cancer leads to an increase in arterial stiffness Cardiovascular and metabolic toxicity of abiraterone in
and hyperinsulinaemia. Clin Sci (Lond). castration-resistant prostate cancer: post-marketing ex-
2003;104:195–201. perience. Clin Genitourin Cancer. 2019;17:e592–601.
56. Smith MR, Lee H, Nathan DM. Insulin sensitivity dur- 69. Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN,
ing combined androgen blockade for prostate cancer. J Jones RJ, et al. Abiraterone acetate for treatment of
Clin Endocrinol Metab. 2006;91:1305–8. metastatic castration-resistant prostate cancer: final
57. Braga-Basaria M, Dobs AS, Muller DC, Carducci MA, overall survival analysis of the COU-AA-301
John M, Egan J, et al. Metabolic syndrome in men with randomised, double-blind, placebo-controlled phase 3
prostate cancer undergoing long-term androgen-depri- study. Lancet Oncol. 2012;13:983–92.
vation therapy. J Clin Oncol. 2006;24:3979–83. 70. Ridley JM, Shuba YM, James AF, Hancox JC. Modula-
58. Langer C, Gansz B, Goepfert C, Engel T, Uehara Y, von tion by testosterone of an endogenous hERG potassi-
Dehn G, et al. Testosterone up-regulates scavenger re- um channel current. J Physiol Pharmacol.
ceptor BI and stimulates cholesterol efflux from mac- 2008;59:395–407.
rophages. Biochem Biophys Res Commun. 71. Kakar SS, Jennes L. Expression of gonadotropin-
2002;296:1051–7. releasing hormone and gonadotropin-releasing hor-
59. Qiu Y, Yanase T, Hu H, Tanaka T, Nishi Y, Liu M, et al. mone receptor mRNAs in various non-reproductive
Dihydrotestosterone suppresses foam cell formation human tissues. Cancer Lett. 1995;98:57–62.
and attenuates atherosclerosis development. Endocri- 72. Dong F, Skinner DC, Wu TJ, Ren J. The heart: a novel
nology. 2010;151:3307–16. gonadotrophin-releasing hormone target. J
60. Nettleship JE, Jones TH, Channer KS, Jones RD. Phys- Neuroendocrinol. 2011;23:456–63.
iological testosterone replacement therapy attenuates 73. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A,
fatty streak formation and improves high-density li- Chi KN, et al. Docetaxel plus prednisone or
poprotein cholesterol in the Tfm mouse: an effect that mitoxantrone plus prednisone for advanced prostate
is independent of the classic androgen receptor. Circu- cancer. N Engl J Med. 2004;351:1502–12.
lation. 2007;116:2427–34. 74. Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF,
61. Sung N, Salazar García MD, Dambaeva S, Beaman KD, Eisenberger M, et al. Chemohormonal therapy in met-
Gilman-Sachs A, Kwak-Kim J. Gonadotropin-releasing astatic hormone-sensitive prostate cancer. N Engl J
hormone analogues lead to pro-inflammatory changes Med. 2015;373:737–46.
in T lymphocytes. Am J Reprod Immunol. 2016;76:50– 75. Vale CL, Burdett S, Rydzewska LHM, Albiges L, Clarke
8. NW, Fisher D, et al. Addition of docetaxel or
62. Corcoran MP, Meydani M, Lichtenstein AH, Schaefer bisphosphonates to standard of care in men with
EJ, Dillard A, Lamon-Fava S. Sex hormone modulation localised or metastatic, hormone-sensitive prostate
of proinflammatory cytokine and C-reactive protein cancer: a systematic review and meta-analyses of ag-
expression in macrophages from older men and post- gregate data. Lancet Oncol. 2016;17:243–56.
menopausal women. J Endocrinol. 2010;206:217–24.
 69 Page 26 of 27 Curr Treat Options Cardio Med (2020) 22:69

76. Rowinsky EK, Eisenhauer EA, Chaudhry V, Arbuck SG, 89. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ,
Donehower RC. Clinical toxicities encountered with Penson DF, et al. Sipuleucel-T immunotherapy for
paclitaxel (Taxol). Semin Oncol. 1993;20:1–15. castration-resistant prostate cancer. N Engl J Med.
77. Biganzoli L, Cufer T, Bruning P, Coleman RE, 2010;363:411–22.
Duchateau L, Rapoport B, et al. Doxorubicin-paclitaxel: 90. Sharma P, Pachynski RK, Narayan V, Flechon A, Gravis
a safe regimen in terms of cardiac toxicity in metastatic G, Galsky MD, et al. Initial results from a phase II study
breast carcinoma patients. Results from a European of nivolumab (NIVO) plus ipilimumab (IPI) for the
Organization for Research and Treatment of Cancer treatment of metastatic castration-resistant prostate
multicenter trial. Cancer. 2003;97:40–5. cancer (mCRPC; CheckMate 650). J Clin Oncol.
78. Giordano SH, Booser DJ, Murray JL, Ibrahim NK, 2019;37(suppl 7S):abstr 142.
Rahman ZU, Valero V, et al. A detailed evaluation of 91. Antonarakis ES, Piulats JM, Gross-Goupil M, Goh J,
cardiac toxicity: a phase II study of doxorubicin and Ojamaa K, Hoimes CJ, et al. Pembrolizumab for
one- or three-hour-infusion paclitaxel in patients with treatment-refractory metastatic castration-resistant
metastatic breast cancer. Clin Cancer Res. prostate cancer: multicohort, open-label phase II
2002;8:3360–8. KEYNOTE-199 study. J Clin Oncol. 2020;38:395–405.
79. Rahman Z, Champlin R, Rondon G, Frye D, Valero V, 92. Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B,
Mehra R, et al. Phase I/II study of dose-intense doxo- Johnson DB. Increased reporting of fatal immune
rubicin/paclitaxel/cyclophosphamide with peripheral checkpoint inhibitor-associated myocarditis. Lancet.
blood progenitor cells and cytokine support in patients 2018;391:933.
with metastatic breast cancer. Semin Oncol. 93. Zhang L, Jones-O'Connor M, Awadalla M, Zlotoff DA,
1997;24:S17-77–s17-80. Thavendiranathan P, Groarke JD, et al. Cardiotoxicity
80. Lenneman CG, Sawyer DB. Cardio-oncology: an up- of immune checkpoint inhibitors. Curr Treat Options
date on cardiotoxicity of cancer-related treatment. Circ Cardiovasc Med. 2019;21:32.
Res. 2016;118:1008–20. 94. Zhang L, Zlotoff DA, Awadalla M, Mahmood SS,
81. de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Nohria A, MZO H, et al. Major adverse cardiovascular
et al. Olaparib for metastatic castration-resistant pros- events and the timing and dose of corticosteroids in
tate cancer. N Engl J Med. 2020;382:2091–102. immune checkpoint inhibitor-associated myocarditis.
82. Henning RJ, Bourgeois M, Harbison RD. Poly(ADP- Circulation. 2020;141:2031–4.
ribose) polymerase (PARP) and PARP inhibitors: 95. Bhatia N, Santos M, Jones LW, Beckman JA, Penson DF,
mechanisms of action and role in cardiovascular dis- Morgans AK, et al. Cardiovascular effects of androgen
orders. Cardiovasc Toxicol. 2018;18:493–506. deprivation therapy for the treatment of prostate can-
83. Sarszegi Z, Bognar E, Gaszner B, Kónyi A, Gallyas F, cer: ABCDE steps to reduce cardiovascular disease in
Sumegi B, et al. BGP-15, a PARP-inhibitor, prevents patients with prostate cancer. Circulation.
imatinib-induced cardiotoxicity by activating Akt and 2016;133:537–41.
suppressing JNK and p38 MAP kinases. Mol Cell 96. Barber M, Nguyen LS, Wassermann J, Spano JP, Funck-
Biochem. 2012;365:129–37. Brentano C, Salem JE. Cardiac arrhythmia consider-
84. Ali M, Kamjoo M, Thomas HD, Kyle S, Pavlovska I, ations of hormone cancer therapies. Cardiovasc Res.
Babur M, et al. The clinically active PARP inhibitor 2019;115:878–94.
AG014699 ameliorates cardiotoxicity but does not 97. Tsugu T, Nagatomo Y, Nakajima Y, Kageyama T, Akise
enhance the efficacy of doxorubicin, despite improving Y, Endo J, et al. Cancer therapeutics-related cardiac
tumor perfusion and radiation response in mice. Mol dysfunction in a patient treated with abiraterone for
Cancer Ther. 2011;10:2320–9. castration-resistant prostate cancer. J Med Ultrason
85. Center for Drug Evaluation and Research. Multidisci- (2001). 2019;46:239–43.
plinary Review and Evaluation: Rubraca (rucaparib). 98. Armenian SH, Lacchetti C, Barac A, Carver J, Constine
Food and Drug Administration (FDA); 2016 . https:// LS, Denduluri N, et al. Prevention and monitoring of
www.accessdata.fda.gov/drugsatfda_docs/nda/2016/ cardiac dysfunction in survivors of adult cancers:
209115Orig1s000MultiDisciplineR.pdf (26 American Society of Clinical Oncology Clinical Practice
June 2020). Guideline. J Clin Oncol. 2017;35:893–911.
86. Segan L, Beekman A, Parfrey S, Perrin M. PARP 99. Darby SC, Ewertz M, McGale P, Bennet AM, Blom-
inhibitor-induced torsades de pointes in long QT syn- Goldman U, Bronnum D, et al. Risk of ischemic heart
drome: a case report. Eur Heart J Case Rep. disease in women after radiotherapy for breast cancer.
2019;4(1):1–5. N Engl J Med. 2013;368:987–98.
87. Lyon AR, Yousaf N, Battisti NML, Moslehi J, Larkin J. 100. van Nimwegen FA, Schaapveld M, Cutter DJ, Janus
Immune checkpoint inhibitors and cardiovascular CP, Krol AD, Hauptmann M, et al. Radiation dose-
toxicity. Lancet Oncol. 2018;19:e447–58. response relationship for risk of coronary heart dis-
88. Flynn MJ, Larkin JMG. Novel combination strategies ease in survivors of Hodgkin lymphoma. J Clin
for enhancing efficacy of immune checkpoint inhibi- Oncol. 2016;34:235–43.
tors in the treatment of metastatic solid malignancies. 101. Demissei BG, Freedman G, Feigenberg SJ, Plastaras JP,
Expert Opin Pharmacother. 2017;18:1477–90. Maity A, Smith AM, et al. Early changes in
Curr Treat Options Cardio Med (2020) 22:69 Page 27 of 27 69

cardiovascular biomarkers with contemporary tho- aspirin in relation to vascular risk in the COMPASS
racic radiation therapy for breast cancer, lung cancer, trial. J Am Coll Cardiol. 2019;73:3271–80.
and lymphoma. Int J Radiat Oncol Biol Phys. 105. Melloni C, Slovin SF, Blemings A, Goodman SG,
2019;103:851–60. Evans CP, Nilsson J, et al. Cardiovascular safety of
102. Demissei BG, Hubbard RA, Zhang L, Smith AM, degarelix versus leuprolide for advanced prostate
Sheline K, McDonald C, et al. Changes in cardiovas- cancer. JACC Cardio Oncol. 2020;2:70.
cular biomarkers with breast cancer therapy and as-
sociations with cardiac dysfunction. J Am Heart Assoc.
2020;9:e014708.
103. Dockery F, Bulpitt CJ, Agarwal S, Vernon C, Publisher’s Note
Nihoyannopoulos P, Kemp M, et al. Anti-androgens
increase N-terminal pro-BNP levels in men with Springer Nature remains neutral with regard to jurisdic-
prostate cancer. Clin Endocrinol. 2008;68:59–65. tional claims in published maps and institutional
104. Anand SS, Eikelboom JW, Dyal L, Bosch J, Neumann affiliations.
C, Widimsky P, et al. Rivaroxaban plus aspirin versus