2.1 Study selection
Is Androgen Deprivation Therapy for Prostate Cancer Associated with Cardiovascular
disease ? A Meta-Analysis and systematic review.
Zhen Liang MS
1, Longlong Chen MS
2. Yawei Xu MS
1, Yongjiao Yang MS
2, Rui Hu MS
1, Wei Zhang MS
1, Yuxuan Song MS
1, Yi Lu MS
1, Ningjing Ou MS
1, Xiaoqiang Liu Phd
1
Tianjin Medical University General Hospital Urology Department Tianjin People’s Republic of China
Second Hospital Tianjin Medical University Urology Department Tianjin People’s Republic of China
Prof.
Xiaoqiang Liu , MD, PhD
Department of Urolody, Tianjin Institute of Andrology, Tianjin Medical University
General Hospital Tianjin People’s Republic of China
Background: Whether androgen deprivation therapy (ADT) is associated with an increased risk
of developing cardiovascular related disease is poorly defined. The aim of the present
meta‐analysis is to explore the relationship between ADT and the risk of cardiovascular
disease (CVD).
Method: For this systematic review and meta-analysis, we searched databases until April
2019 for randomized controlled trial (RCT) or observational studies that reported
data on ADT administration and cardiovascular disease (CVD) incidence. The relationship
was evaluated through estimate relative risk ratio (RR) and 95% confidence intervals
(CIs)
Result: A statistically significant difference was detected for acute myocardial infarction
(AMI) (RR = 1.13; 95% CI, 1.10–1.15; P< 0.05) including a total of 142,186 cases and
174,404 controls. Significant difference between coronary heart disease (CHD) and
ADT was also observed, with summary (RR=1.11; 95% confidence interval CI: 1.10-1.13),
from 157,339 ADT users and 349,636 non-ADT users of 7 eligible studies.
Conclusions: Pooled result demonstrated that ADT could significantly increase the risk of CHD,
AMI and sudden cardiac death (SCD). Various ADT modalities have different impact on
cardiovascular disease risk in different level. Our meta-analysis also suggests that
the application of ADT in prostate cancer patients for over 5 years resulted in a
significant increase in cardiovascular morbidity. Moreover, subgroup analyses for
different types of ADT indicated that compared with the individual administration
of ADT, GnRH plus AA (oral anti-androgens) is more likely significantly lead to AMI.
Recognized as the most commonly diagnosed disease in male, the incidence and mortality
of prostate cancer have been increasing in recent years [1, 2]. This situation can
be attributed to population aging, improvement of diagnostic tools and the national
surveillance programs for early prostate cancer detection [3].
Nearly half of the patients who were diagnosed prostate cancer (PCa) receive androgen
deprivation therapy (ADT) [4] and commonly suffer from adverse side effects which
would lead to the decline in quality of life (QOL)[5]. Owing to improvements in diagnosis
and treatment of cancer, the quantity of prostate cancer survivors is increasing [6].
However, most of survivors are burdened with continuous adverse effects of ADT including
cardiovascular complications.[7, 8] Keating et al[9] first reported an excess risk
of acute myocardial infarction (AMI), sudden cardiac death (SCD) in a large group
of patients for men 66 years or older. Since then several observational studies and
randomized controlled trials have also assessed the association between risk of cardiovascular
events and ADT, yet have demonstrated equivocal findings [10-12].
Nonetheless, there are considerable disagreements on the association between ADT and
cardiovascular disease. Nanda et al. [13] indicated that all-cause mortality and coronary
heart disease (CHD) specifically only happened in patients with preexisting CVD. Martı´n-Merino[14]
demonstrated individual ADT therapy does not appear to increase the risk of CVD outcomes,
only the combination of oral anti-androgens(AA) and Luteinizing Hormone Releasing
Hormone (LHRH) is associated with significant increase in risk of cardiovascular disease[14].
Therefore, it is necessary to perform a meta-analysis of long duration of follow-up,
large-scale studies with high quality of implementation and design.
Several meta-analysis have focused on ADT related cardiovascular mortality and morbility
through processing data from trials with different primary end points [15, 16]. However,
investigators were not able to stratify the outcome by different kinds of ADT. Besides,
the former meta-analysis did not detect a statistically significant difference between
AMI and CHD, classification bias and insuffificient data on such safety secondary
outcomes prevent an explicit conclusion.
In light of uncertainties about this clinical issue and the limitations exist in former
meta-analysis of for adverse-effect research, we performed a systematic review of
existing literatures in bibliographic databases to further explore the relationship
between the application of ADT for AMI, CVD, and SCD respectively.
The systematic literature review (SLR) was reported and conducted according to the
recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis
(PRISMA) Statement and the Cochrane Collaboration[17]. The systematic review includes
electronic search in the Ovid versions of Pubmed, Embase, and Web of Science. A literature
search was performed for studies published up to March 28th 2019 by two researchers
independently. Any uncertainty about inclusion was checked by a third researcher. The
search was not limited by geographic region or country; however, it was limited to
English publications. The main key words used for search were: prostate cancer or
prostate tumor or prostate carcinoma, androgen and deprivation or androgen suppression
or endocrine treatment; and cardiovascular or myocardial infarction or coronary heart
disease or cardiac death or heart disease. All identified publications went through
a three-step parallel review of title, abstract, and full text, based on predefined
exclusion criteria and inclusion criteria. Reviews of included studies were searched
manually to find out additional eligible studies. The author was contacted when the
clinical trial method or results were unclear or sufficient data was not reported.
2.1 Study selection
Studies were included in our meta-analysis if (1) the type of study should be population-based
cohort observation study or case control study with no subject selection bias; (2)
both the experimental group and randomized controlled trials (RCT) were clearly prespecified,
SCD, CHD and AMI were assessed as outcomes; (3) included studies had to provide sufficient
data for the calculation of risk estimates with 95% confidence intervals (CIs); (4)
ADT type for included patients should be specified in article; (5) baseline cardiac
comorbidity should be separated from newly emerging cardiovascular disease.
2.2 Quality Assessment and Data extraction
Quality assessment of the included studies was evaluated through the Newcastle-Ottawa
quality assessment scale (NOS) for observational study, a 9-item measure designed
for observational studies with a focus on data quality, sample representativeness,
and appropriateness of analysis with scores of<7 indicated low-quality studies and≥7
indicated high-quality[18]. As for the included RCT studies, Cochrane Collaboration’s
tool for risk of bias was performed[19]. We evaluated the quality of each study by
assessing the risk of bias in 7 domains: study participation and attrition, prognostic
factor measurement, outcome measurement, confounding measurement, and statistical
analysis and reporting. For each study, the criteria listed on the checklist was rated
as a low, unclear, or high risk of bias. The evaluation was performed by two authors
independently, and disagreements were resolved by discussion. The risk of bias summary
and risk of bias graph were generated through Review Manager (RevMan), version 5.3
(The Nordic Cochrane Centre, The Cochrane Collaboration, 2009, Copenhagen, Denmark)
Data was extracted from the included studies independently by two censors in this
study. The following data will be extracted: details of study (year, design, total
number of participants, number of ADT users, number of control group, follow-up duration)
details of participants (median age, country/region outcomes measure of AMI, CHD and
SCD).
Statistics analyses were conducted using the pooled data unless otherwise stated.
To assess the heterogeneity of the included studies, Cochran's Q and I
2 tests were used. An I
2 >50% or P<0.05 were defined as statistical significance. When more than one type
of ADT were respectively compared with the same control group in one study, the random-effects
model was then used for data analysis to combine different types of ADT groups. The
effect of ADT compared with no ADT on the risk of CHD amongst men with PCa was quantified
by computing the pooled risk ratio (RR) with 95% confidence interval (CI) through
a random-effects model. Forest plots were generated to display the RR estimates for
each study. Meta-analysis was subgrouped according to type of ADT. ADT was assigned
into different types of treatment: orchiectomy, GnRH agonists, anti-androgens, and
anti-androgens plus GnRH agonists. The data analyses were performed using STATA version
14.0 and Review Manager (version5.2; The Cochrane Collaboration, Oxford).
To analyze the source of heterogeneity and potential factors, the random-effects model
was also applied in the subgroups analysis. P<0.01 was defined as statistically significant
for subgroup analysis. We performed the subgroup meta-analysis on the various types
of ADT (e.g. GnRH, AA, GnRH +AA and Orchiectomy) vs non-ADT to minimize existing heterogeneity.
3.1 Literature Search and Characteristics
Figure1 represents a flowchart demonstrated the selection process that met our criteria
aforementioned, a total of 1541 potential records were initially identified from Embase,
Pubmed and Web of Science through the search terms listed above. A total of 1541 articles
were screened, out of which 531 duplicate studies were excluded. 50 were considered
closely correlated to the concept of this study and underwent full text review. 14
studies were removed because they did not mention AMI, CHD or SCD as outcomes. 2 were
excluded due to lack of data, 7 studies were excluded because ADT duration was shorter
than 6 months, 6 did not specifically report the type of ADT. Additionally, we remove
9 retrospective researches from our study, 2 were excluded for using the same databases
as studies that were already included. In the end, 8 articles were included in our
meta-analysis of AMI[9, 14, 20-25], representing a total population of 316,590 patients.7[9,
14, 21-23, 26, 27] studies were included in the CHD analysis, representing a total
of 529,357 patients. 5 studies [12, 20, 21, 28, 29] were included in the SCD analysis,
representing a total of 182,403 patients. All included studies were of observational
design and published between 2008 and 2017. In the references of the primarily selected
articles，no additional articles were eligible with potential data for the meta-analysis.
Details of the included studies are summarized in
Tables 1
, which lists the basic characteristics of the included studies for SCD AMI and CHM.
Quality assessment of observational studies was conducted via NOS and included studies
were demonstrated to be of high quality. Information on RCT study quality is presented
in Figure2. The overall methodological quality of the included studies was high and
no research was excluded for low quality.
3.2 Association between ADT and AMI
The subgroup analysis result indicated that the source of heterogeneity was due to
the variation of ADT. 8 studies were identified to explore the relationship between
ADT and AMI. The result indicated that the appication of ADT for prostate cancer was
associated with the risk of AMI. (RR = 1.13; 95% CI, 1.10–1.15; P< 0.05) (Figure3)
Data from 4 studies were eligible for AA[9, 14, 23, 24] subgroup-analyses; 3[9, 14,
23] were available for GnRH plus AA, 4 [9, 14, 21, 23]for GnRH and 5[9, 14, 21, 23,
25] for orchiectomy. Among 142,186 ADT users, 13,270 (9.3%) developed AMI compared
with 15,598 events (8.9%) among 174,404 non-ADT users. Subgroup analysis by different
type of ADT for meta-analysis showed the following results. A significant association
was observed between AMI and AA (RR = 1.41; 95% CI, 1.24–1.59; P< 0.05); Gnrh(RR =
1.20; 95% CI, 1.17–1,22; P< 0.05); GnRH plus AA (RR = 2.47; 95% CI 2.34–2.61;P<0.05);
orchiectomy (RR = 1.43; 95% CI 1.33–1.54;P<0.05). (Figure 4) The I
2 statistic indicated heterogeneity (I
2 = 95%), even though every individual estimate suggested a positive association.
3.3 Association between ADT and CHD
A total of 506,975 from 7 studies [9, 14, 21-23, 26, 27] were participated in study
investigating the relationship between ADT and CHD. A significantly increased CHD
risk was found in the prostate cancer patients treated with ADT. (RR=1.11; 95% confidence
interval CI: 1.10-1.13); (Figure5) data from 5 studies [9, 14, 23, 26, 27] were eligible
for AA subgroup-analyses. 4 [9, 14, 23, 27] reported data about GnRH plus AA; 5 [9,
14, 21, 23, 27] for GnRH and 5 [9, 14, 21, 23, 26] for orchiectomy. Among 157,339
ADT users, 22,382 (14.2%) developed CHD compared with 32,863 events (9.3%) among 349,636
non-ADT users. Significant association was found in every type of ADT, except for
AA (RR = 0.94; 95% CI, 0.89–1.00; P< 0.05); Gnrh (RR = 1.16; 95% CI, 1.14–1.18; P<
0.05) GnRH plus AA (RR = 1.77; 95% CI 1.66–1.88; P< 0.05); orchiectomy (RR = 1.37;
95% CI, 1.30–1.45; P< 0.05) respectively. (Figure 6)
3.4 Association between ADT and SCD
The relationship between ADT and SCD was also investigated in our study. A total of
822,403 events were identified, including 11,096 from 79,881 ADT users and 12,263
from 102,522 WW/AS (watchful waiting/ active surveillance) groups. The RRs for each
study for different kinds of ADT are shown in Figure 7. We identified that ADT are
related to increased incidence of SCD, the sum of included studies are quite limited
so that it is difficult to perform a subgroup analysis based on different type of
ADT(RR=1.23; 95% CI 1.20–1.26; P< 0.05) (Figure 7).
3.5 Subgroup by duration of ADT
In order to reduce the impact of inconsistent endpoints on our conclusion, whether
the duration of ADT application was associated with a significant effect on the risk
of CVD events was also explored in our study. The included studies were separated
into different groups based on the duration of ADT application, and we define the
5 year as the cut-off value. 3 studies[20, 21, 24] with 53,115 ADT users and 53,124
controls were assigned into the group with ADT application longer than 5 years, and
others were distributed to the group with ADT application shorter than 5 years. For
results of a subgroup meta-analysis of prospective cohort studies revealed a significant positive
association between duration of ADT application and the incident for AMI.
Pooled data suggested the incidence of AMI in >5 year group was 17.6% higher than
that from <5 year group.
(RR = 1.87, 95%CI: 1.81–1.92, P<0.05, for >5 year group) (RR = 1.32, 95%CI: 1.24–1.40,
P<0.05 for≤5 year group). As for the CHD group, the amount of included studies is
quite limited so the subgroup analysis was not performed.
Controversies still exist with potential risk of the concomitant use of ADT which
remains to be solved in this new era. To the best of our knowledge, this is the first
comprehensive assessment of the association between ADT and cardiovascular risk performed
by meta-analysis based on different types of ADT and makes a distinction among SCD,
AMI and CHD. Similar to the results of this present analysis, another meta-analysis[15]
exploring the relationship between cardiovascular disease and ADT, 6 trials with a
total number of 8282 patients showed that ADT is associated with both cardiovascular
mortality (CVM) and CVD, especially GnRH alone and GnRH plus AA can significantly
increase the incidence of cardiovascular events in PCa patients. O’Farrell et al.[26]indicated
an invariable increase in risk of CVD in men with PCa treated with a GnRH agonist
in a large observational study when compared with a matched PCa-free group. Similarly,
Bosco et al. [30] revealed an increased risk of non-fatal CVD events (MI and stroke)
in patients treated with ADT, particularly GnRH agonists, compared with those who
do not receiving ADT (relative risk [RR] 1.38, 95% CI 1.29−1.48).
Our results suggest that the application of all kinds of ADT for prostate cancer was
associated with AMI; long-term use of GnRH plus AA can significantly increase the
risk of major adverse cardiac events such as AMI compared with the others. AA alone
can only significantly increase the incident of AMI, but have little impact on CHD.
The pooled results for the duration of the ADT application investigation revealed
that taking ADT more than 5 years leads to an increase in the risk of AMI. Both the
individual use of GnRH agonists and orchiectomy could increase the risk of cardiac
adverse effect significantly, and the risk of CHD was similar for men treated with
GnRH agonists and men treated with orchiectomy. Three prior studies [20, 31, 32] are
distinctly discordant with our result, demonstrating that AA use is not associated
with an excess risk of AMI. The discordance was likely due to their small number of
end points. In addition, several other studies reported that although the combination
treatment with GnRH agonists and orchiectomy is positively associated with an increased
risk of CHD, AMI, and SCD, orchiectomy alone was not associated with CHD events [33,
34]. This may owe to men treated with orchiectomy were older, presented with more
advanced stage of prostate cancer and had more comorbidities, which in turn influenced
the risk of endpoint [35]. The variation in inclusion criteria of patients and duration
of ADT application may also contribute to the inconsistency, as suggested by Keating
et al.[9]. Furthermore, three studies [36-38] did not report an association between
ADT and cardiovascular related death, for the previous or later ADT users were not
ruled out of consideration in control group.
The application of GnRH remains to be the cornerstone of management for patients with
prostate cancer. However, there are many consequences of androgen deprivation including
decreasing in physical function; reducing quality of life[39]; bone mineral density
(BMD) loss [40, 41]; and increasing risk of metabolic [42]. Metabolic syndrome (MS)
is known as a risk factor for cardiovascular disease[43]. Most data, predominantly
derived from GnRH agonists was found to have an association between ADT and increase
of triglyceride and LDL levels. Previous researches [44, 45] showed that deficiency
of testosterone was thought to decrease lean body mass and increase fat, decrease
glucose tolerance and increase insulin resistance, all of which could generate a state
similar to the metabolic syndrome. The occurrence of metabolic syndrome would lead
to the development of atherosclerosis which would accelerate the progress of cardiovascular
events[46]. Besides, GnRH agonists is thought to have an indirectly impact on development
of CHD by increasing the risk of metabolic changes such as dyslipidemia hyperglycemia,
and obesity which are also well-established causal risk factors for the development
of atherosclerosis [47]. Furthermore, it has been proved that human heart tissue express
the GnRH receptor, and a basic study on rat heart tissue demonstrated that stimulation
of the cells with GnRH agonists causes progression in the contractility of the cardiomyocyte
[48].
Orchiectomy can lead to a low level of testosterone and it remains unclear how low
testosterone levels trigger major cardiovascular events. Callou de Sá et al.[49]
indicated that men with CHD have higher oestradiol and FEI levels. As a matter of
fact, elevated level estrogen can increase heart attack risk by accelerating coagulation
and platelet aggregation in coronary arteries[50]. The direct evidence provided by
Thomsen et al. [33], comparing the impact of GnRH and orchiectomy on cardiovascular
disease revealed that GnRH agonists do not increase the risk of CHD in comparison
to orchiectomy. Although further studies are needed to determine whether interventions
like orchiectomy that raise estrogen levels might have an impact on CHD disease risk
in men, causions are warranted for caregivers that they should consider the serious
risk of CHD complications when deciding the type of androgen deprivation therapy for
patient with prostate cancer.
From our subgroup analysis for the duration of ADT indicated that increasing duration of
ADT was associated with an excess risk of AMI. In an observational study, Efstathiou
et al.[28] found no evidence to prove that longer-term ADT with a GnRH increased cardiovascular
mortality compared with short-term in men with locally advanced prostate cancer. Bolla
et al. [51] performed a random control study, one to receive short-term androgen suppression,
and the other to receive 2·5 years of further treatment, the result revealed that
overall mortality was higher with short-term than with long-term deprivation. As their
endpoint was prostate cancer specific mortality and other efficacy endpoints, they
draw a conclusion that overall quality of life did not differ significantly between
the two groups. Evidence indicated that short-term ADT (3–6 months) results in the
development of insulin resistance without causing hyperglycemia [52]. However, long-term
ADT over 12 months is associated with hyperglycemia, frank diabetes, and metabolic
syndrome all of which are risk factors for cardiovascular disease[53].The optimum
duration of ADT application should be adapted to comorbid conditions and risk factors
of individual patients.
In our analysis, we found the application of ADT was also associated with excess cardiovascular
mortality. Nguyen et al. [40] indicated the application of ADT is connected with a
significantly increased risk of CAD, AMI, and, particularly, SCD in patients with
non-metastatic PCa. This finding is corroborated by our study. However, multiple previous
studies fail to demonstrate a correlation between ADT and the risk of CVD mortality.
One of an important reason is most of these aforementioned studies are designed retrospectively,
which means population included in these studies are relied on historical cohorts.
In addition Nanda et al. [54] suggested that the excess SCD with ADT seemed to happen
in only the first 6 to 24 months after. A significant improvement in prostate cancer–specific
survival and overall survival was also detected for the administration of ADT. Therefore,
periodic cardiovascular evaluation is required for patients before underwent ADT treatment.
Some intrinsic limitations in this meta-analysis should be taken into account in
this study. First, unnegligible limitation of our study is that the CHD definitions
of some included studies were not explicit so we had to hypothesize they were comparable
amongst the different studies. Second, current meta-analysis included very few studies
in every subgroup analysis which means publication bias could not be excluded as funnel
plots included only 4 or 5 studies, besides, they suffered from substantial heterogeneity
which could be related to methodological parameters and population characteristics.
Third, our analysis pooled together both RCTs and observational studies, and subgroup
analyses based on study design were not also performed in the AMI and CHD subgroup,
because all the included studies are designed observationally for the AMI and CHD
subgroup. Fourth, data in some included studies are not provided completely, so we
have to calculate the RRs by ourselves, this may affect the overall result of our
study to some extent.
Pooled result demonstrated that ADT could significantly increase the risk of CHD,
AMI, and SCD. In addition, our results support the hypothesis that the various ADT
modalities have different impact on CVD risk in different level. Our meta-analysis
also suggested that the application of ADT in prostate cancer patients for over 5
years resulted in a significant increase in cardiovascular morbidity. Moreover, subgroup
analysis for different types of ADT indicated that compared with the individual administration
of ADT, GnRH plus AA is more likely significantly lead to AMI.Therefore, ADT is associated
with a significant negative impact on quality of life. Special attention and periodic
cardiovascular assessment are required for these patients. More epidemiological and
experimental studies are needed to differentiate the CVD effects on different types
of ADT.
6.Conflict of interests: The authors declare that there are no conflicts of interest.
7. Acknowledgments: This work was supported by the Zhao Yi-Cheng Medical Science Foundation of China (Tianjin
ICP prepared No.15000470)
8. Tables and figures legends
T
able 1. Characteristics of randomized included studies
Figure 1. Article selection
Figure 2. Risk of bias for the included RCT studies
Figure 3. Acute myocardial infarction risk associated with ADT
Figure 4. RRs of acute myocardial infarction Related to different type of ADT.
Figure 5. Coronary heart disease risk associated with ADT
Figure 6. RRs of coronary heart disease Related to different type of ADT.
Figure 7. Sudden cardiac death risk associated with ADT
Figure 8. RRs of acute myocardial infarction Related to different duration of ADT
application.
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