Articles

Platinum Priority – Prostate Cancer
Editorial by Paul L. Nguyen on pp. 710–712 of this issue

Androgen-deprivation Therapy in Treatment of Prostate Cancer and Risk of Myocardial Infarction and Stroke: A Nationwide Danish Population-based Cohort Study

By: Christina G. Jespersen a b lowast , Mette Nørgaard c and Michael Borre a

European Urology, Volume 65 Issue 1, April 2014, Pages 704-709

Published online: 01 April 2014

Keywords: Castration, Gonadotropin-releasing hormone, Myocardial infarction, Orchiectomy, Prostatic neoplasms, Stroke

Abstract Full Text Full Text PDF (369 KB)

Abstract

Background

Androgen-deprivation therapy (ADT) has been suggested to increase the risk for cardiovascular diseases, including myocardial infarction (MI) and stroke, but data are inconsistent.

Objectives

To investigate the association between ADT and risk for MI and stroke in Danish men with prostate cancer.

Design, setting, and participants

A national cohort study of all patients with incident prostate cancer registered in the Danish Cancer Registry from January 1, 2002, through 2010 was conducted.

Outcome measurements and statistical analysis

We used Cox regression analysis to estimate hazard ratios (HR) of MI and stroke for ADT users versus nonusers, adjusting for age, prostate cancer stage, comorbidity, and calendar period. Additionally, we stratified the analysis on preexisting MI/stroke status.

Results and limitations

Of 31 571 prostate cancer patients, 9204 (29%) received medical endocrine therapy and 2060 (7%) were orchidectomized. Patients treated with medical endocrine therapy had an increased risk for MI and stroke with adjusted HRs of 1.31 (95% confidence interval [CI], 1.16–1.49) and 1.19 (95% CI, 1.06–1.35), respectively, compared with nonusers of ADT. We found no increased risk for MI (HR: 0.90; 95% CI, 0.83–1.29) or stroke (HR: 1.11; 95% CI, 0.90–1.36) after orchiectomy. One limitation of the study is that information on prognostic lifestyle factors was not included and might have further informed our estimates.

Conclusions

In this nationwide cohort study of >30 000 prostate cancer patients, we found that endocrine hormonal therapy was associated with increased risk for MI and stroke. In contrast, we did not find this association after orchiectomy.

Take Home Message

Based on data from >30 000 Danish prostate cancer patients, we have confirmed an association between endocrine hormonal therapy and excess risk of myocardial infarction and stroke. In contrast, we did not find a similar association after orchiectomy.

Keywords: Castration, Gonadotropin-releasing hormone, Myocardial infarction, Orchiectomy, Prostatic neoplasms, Stroke.

1. Introduction

The indication for androgen-deprivation therapy (ADT) in prostate cancer (PCa) treatment has been symptomatic, locally advanced, and metastatic prostate cancer [1] . In recent years, however, the use of ADT in the form of gonadotropin-releasing hormone (GnRH) agonists has also included neoadjuvant, temporary GnRH agonists in multimodal treatment of localized PCa [2] . Use of ADT, both GnRH agonists, and orchiectomy results in hypogonadism, which is associated with profound adverse effects including development of metabolic syndrome and, thereby, increased risk for diabetes and cardiovascular diseases [3], [4], [5], and [6].

Some studies have reported nearly 30% excess risk for MI and stroke in patients using GnRH agonists compared with nonusers [7], [8], [9], [10], [11], and [12], while others found no association [13] and [14]. An association between ADT and cardiovascular mortality has been investigated in several clinical trials and no increase in mortality has been found [15], [16], and [17] except in one recent US study where use of neoadjuvant hormone therapy was associated with increased all-cause mortality in patients with low-risk PCa and at least one risk factor for cardiovascular disease [18] . Thus, data relating to an association between ADT and cardiovascular morbidity and mortality are conflicting.

MI and stroke are serious complications with 1-yr mortality rates of 24% [19] and 21% [20] , respectively. An association between ADT and MI and stroke may thus be of clinical importance. Therefore, we conducted this population-based study to investigate the association between ADT (including treatment with GnRH agonists, oral antiandrogens, or orchiectomy) and MI and stroke in Danish men with PCa.

2. Patients and methods

Denmark has 5.5 million inhabitants who are provided with free, tax-supported health care by the National Health Service. Since 1968, a unique 10-digit civil registration number has been assigned to all Danish residents by the central office of civil registration, and this number allows unambiguous linkage among all Danish registries [21] . We linked data from the Danish Civil Registration System, the Danish Cancer Registry, the Danish National Patient Registry (DNPR), and the Danish Cause of Death Registry.

2.1. Identifying patients with prostate cancer

We identified all men with PCa through the Danish Cancer Registry in the period 2002–2010. This is a population-based, nationwide registry with data on incident cancer in Denmark since 1943 [22] . Data include civil registration number and stage at diagnosis. We used the International Classification of Diseases (ICD)-10 code DC61.9 to identify patients with PCa [23] . Until 2003, tumor stage was recorded as localized, regional, or distant. Thereafter, stage was recorded using the TNM system. We classified stage as localized if TNM categories were designated T1–2, N0/x, M0/x; regional if T3–4 or N1–3, M0; and distant if T1-4, N0-3, M1.

2.2. Treatment

Information on treatment was obtained through the DNPR [24] . This registry contains data on all somatic hospital admissions since 1977 and on outpatient and emergency room visits since 1995. It includes dates of admission and discharge, medical treatments, surgical procedures, and up to 20 diagnoses coded by physicians at discharge. We used the ICD-10 code BWHCx to identify patients treated with GnRH agonists or antiandrogens (ie, medical endocrine therapy) between January 1, 2002, and February 16, 2012. We used the codes KKFC10, KKFC13, and KKFC15 to identify orchidectomized patients. Patients treated with both GnRH agonists and orchiectomy were excluded.

2.3. Ascertainment of myocardial infarction and stroke

From the DNPR, we identified all diagnoses of MI (ICD-8 codes 410.09/410.99 and IDC-10 codes DI21.x), and ischemic strokes or transient ischemic attacks (ICD-8 codes 433.09/99, 434.09/99, 436.01/436.90, and ICD-10 codes DI63.x and DI64.x) after initiation of ADT [23] and [25]. Through the Danish National Registry of Causes of Death [26] , we identified fatal MIs (IDC-10 codes DI21.x and DI46.x) and strokes (ICD-10 codes DI63.x and DI64.x).

Preexisting MI or stroke was defined if a diagnosis of these diseases was recorded ≤10 yr before PCa diagnosis.

2.4. Comorbidities at diagnosis

Through the DNPR, we identified comorbidities included in the Charlson comorbidity index. This index comprises 19 conditions, each weighted according to its potential to influence mortality [27] . We calculated the index score for each patient based on diagnoses recorded ≤10 yr before PCa diagnosis. For the stratified analysis, we excluded MI and stroke when computing the index. We categorized the index score into four comorbidity levels: 0, none; 1, low; 2, moderate; and ≥3, high.

2.5. Statistics

We used Cox regression analysis with time-varying treatment variables (ie, patients contributed risk time in the nontreatment group until initiation of treatment) to estimate hazard ratios (HRs) assessing the effect of ADT on time to first nonfatal or fatal MI or stroke, while controlling for age, PCa stage, comorbidities, and study year. Patients were followed from date of PCa diagnosis until death, February 16, 2012, or occurrence of MI or stroke (after initiation of ADT), whichever came first. Once medical endocrine therapy was initiated, the patient was considered exposed for the remaining follow-up time. Patients not receiving ADT served as the reference in all analyses.

We excluded patients on medical endocrine therapy when analyzing the effects of orchiectomy, and excluded orchidectomized patients when analyzing the effects of medical endocrine therapy. In an additional analysis, we stratified data by preexisting MI/stroke status. We also stratified data by fatal and nonfatal cardiovascular events. Furthermore, we repeated the analyses, treating death as a competing risk. The models were tested for interactions of all covariates and none were found. The assumptions for the Cox model were assessed graphically and analytically and were found appropriate.

We repeated analyses using multiple imputation for missing data on tumor stage, which did not alter results, and therefore we abstained from using the multiple imputation. Estimates are presented with 95% confidence intervals (CIs). Statistical analyses were performed using Stata software v.11 S/E (StataCorp LP, College Station, TX, USA). The study was approved by the Danish Data Protection Agency (journal no. 2009-41-3793).

3. Results

We included 31 571 men with a primary diagnosis of PCa in Denmark between 2002 and 2010 and followed them for a median of 3.3 yr (interquartile range [IQR]: 1.8–5.2). The median age at PCa diagnosis was 71 yr (IQR: 65–78 yr). Overall, 11 264 of the 31 571 PCa patients (36%) received ADT, 9204 (29%) received medical endocrine therapy, and 2060 (7%) were orchidectomized. The annual number of patients diagnosed with PCa increased during the entire study period ( Fig. 1 ). Cardiovascular events were evenly distributed throughout the study period ( Fig. 2 ).

gr1

Fig. 1 Number of patients treated with endocrine medical therapy, orchiectomy, or no androgen deprivation therapy between 2002 and 2010.

gr2

Fig. 2 Distribution of cardiovascular events (993 myocardial infarctions and 243 strokes) following orchiectomy or endocrine medical therapy between 2002 and 2012.

3.1. Medical endocrine therapy and risk of myocardial infarction or stroke

Overall rates of MI and stroke among patients treated with endocrine medical therapy were 14 and 15 per 1000 person-years at risk, respectively ( Table 1 ). Use of medical endocrine therapy was associated with an increased risk for MI compared with nonusers. The crude HR was 1.42 (95% CI, 1.26–1.60) and the adjusted HR was 1.31 (95% CI, 1.16–1.49) ( Table 2 ). The risk of stroke was also increased with a crude HR of 1.30 (95% CI, 1.16–1.47) and an adjusted HR of 1.19 (95% CI, 1.06–1.35).

Table 1 Characteristics of 31 571 prostate cancer patients diagnosed between 2002 and 2010

Medical endocrine therapy, no. (%) Orchiectomy, no. (%) No ADT, no. (%) Entire cohort, no. (%)
Patients 9204 (29) 2060 (7) 20 307 (64) 31 571
Age, yr, median (IQR) 72 (66–79) 78 (72–83) 70 (64–77) 71 (65–78)
Age at PCa diagnosis, yr
 30–59 672 (7) 65 (3) 2281 (11) 3018 (10)
 60–69 2892 (32) 326 (16) 7845 (39) 11 063 (35)
 70–79 3879 (42) 814 (40) 7080 (35) 11 773 (37)
 80+ 1761 (19) 855 (41) 3101 (15) 5717 (18)
Comorbidity index score
 None (0) 5516 (60) 1073 (52) 12 685 (63) 19 274 (61)
 Low (1) 1599 (17) 413 (20) 3341 (16) 5353 (17)
 Moderate (2) 1213 (13) 308 (15) 2506 (12) 4027 (13)
 High (>2) 876 (10) 266 (13) 1775 (9) 2917 (9)
Tumor stage
 Localized 3161 (35) 473 (23) 11 228 (55) 14 862 (47)
 Regional 1858 (20) 142 (7) 2052 (10) 4052 (13)
 Distant 1951 (21) 819 (40) 1669 (8) 4439 (14)
 Unknown 2234 (24) 626 (30) 5358 (27) 8218 (26)
Period of PCa diagnosis
 2002–2004 2351 (31) 960 (13) 4294 (56) 7605
 2005–2007 3587 (33) 728 (7) 6642 (60) 10 957
 2008–2010 3266 (25) 372 (3) 9371 (72) 13 009
Patients with MI 471 (5.1) 102 (5.0) 824 (4.1) 1397 (4.4)
MI per 1000 yr at risk 14 17 11 12
Patients with strokes 522 (5.7) 141 (6.8) 922 (4.5) 1585 (5.0)
Strokes per 1000 yr at risk 15 24 12 14

ADT = androgen deprivation therapy; IQR = interquartile range; PCa = prostate cancer; MI = myocardial infarction.

Table 2 Crude and adjusted hazard ratios of fatal and nonfatal myocardial infarction or stroke in 31 571 prostate cancer patients by androgen deprivation therapy status

Variables Patients, no. (%) HR (95% CI) fatal and nonfatal MI HR (95% CI) fatal and nonfatal stroke
Crude Adjusted Crude Adjusted
Overall * 31 571
 No ADT 20 307 (64) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference)
 Medical endocrine therapy 9204 (29) 1.42 (1.26–1.60) 1.31 (1.16–1.49) 1.30 (1.16–1.47) 1.19 (1.06–1.35)
 Orchiectomy 2060 (7) 1.74 (1.40–2.17) 0.90 (0.71–1.14) 2.08 (1.71–2.51) 1.11 (0.90–1.36)
Patients without preexisting MI or stroke ** 28 231 (89)
 No ADT 18 283 (65) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference)
 Medical endocrine therapy 8175 (29) 1.45 (1.27–1.66) 1.33 (1.15–1.53) 1.34 (1.17–1.53) 1.21 (1.05–1.39)
 Orchiectomy 1773 (6) 1.68 (1.30–2.16) 0.84 (0.64–1.10) 2.11 (1.69–2.64) 1.14 (0.89–1.45)
Patients with preexisting MI or stroke ** 3340 (11)
 No ADT 2024 (61) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference)
 Medical endocrine therapy 1029 (31) 1.21 (0.92–1.60) 1.20 (0.90–1.60) 1.11 (0.87–1.41) 1.08 (0.84–1.39)
 Orchiectomy 287 (8) 1.61 (1.04–2.49) 1.15 (0.72–1.84) 1.56 (1.07–2.27) 1.04 (0.70–1.56)

* Adjusted for age, stage, study year, and all comorbidities except prostate cancer.

** Adjusted for age, stage, study year, and all comorbidities except prostate cancer, MI, and stroke.

HR = hazard ratio; CI = confidence interval; MI = myocardial infarction; ADT = androgen deprivation therapy.

For patients without preexisting MI or stroke, adjusted HRs of a new MI or stroke after initiation of medical endocrine therapy were 1.33 (95% CI, 0.115–1.53) and 1.21 (95% CI, 1.05–1.39), respectively, compared with nonusers of ADT; adjusted HRs were lower for patients with preexisting MI or stroke: 1.20 (95% CI, 0.90–1.60) and 1.08 (95% CI, 0.84–1.39), respectively ( Table 2 ).

3.2. Orchiectomy and risk of myocardial infarction or stroke

Overall rates of MI and stroke among orchidectomized patients were 17 and 24 per 1000 years at risk, respectively ( Table 1 ).

Orchidectomized patients had a crude HR of MI of 1.74 (95% CI, 1.40–2.17) ( Table 2 ) compared with patients with no ADT, but after adjustment, the HR decreased to 0.90 (95% CI, 0.71–1.14). Likewise, the crude HR of stroke of 2.08 (95% CI, 1.71–2.51) decreased to 1.11 (95% CI, 0.90–1.36) after adjustment. Adjustment for age explained most of this decrease.

For patients without preexisting MI or stroke, adjusted HRs of a new MI or stroke after orchiectomy were 0.84 (95% CI, 0.64–1.10) and 1.14 (95% CI, 0.89–1.45), respectively, compared with patients with no ADT. For patients with preexisting MI or stroke, the adjusted HR of a new MI was 1.15 (95% CI, 0.72–1.84) and for stroke, 1.04 (95% CI, 0.70–1.56) ( Table 2 ).

HRs for fatal and nonfatal events were similar. When we conducted the analysis treating death as a competing risk, our results did not change (data not shown).

4. Discussion

In this nationwide cohort study of >30 000 PCa patients, we found that endocrine hormonal therapy was associated with increased risk for MI and stroke. In contrast, we did not find a similar association after orchiectomy.

These findings are in line with the results of other recent studies [7], [8], [9], [10], [11], and [12], and the association appears biologically plausible due to development of metabolic syndrome, which predisposes to development of thrombosis [3], [4], [5], and [6]. Only two previous studies [13] and [14] found no association between endocrine hormonal therapy and MI or stroke. In a nested case-control study of 5103 patients diagnosed with PCa between 1999 and 2005, Martin-Merino et al. found an adjusted odds ratio of MI of 1.13 (95% CI, 0.66–1.94) among GnRH agonist users [13] . Although not significant, this HR is still compatible with a 30% increased risk for MI, as found in the present study. In a Canadian, matched-cohort study by Alibhai et al. of 38 158 patients with a mean observation time of 6.5 yr, respective, adjusted HRs of MI and stroke were 0.92 (95% CI, 0.84–1.00) and 0.88 (95% CI, 0.81–0.95) for ADT users compared with never users [14] . This result may be biased, however, since patients had to receive ADT treatment for 6 mo before being classified as ADT users. In this 6-mo immortal-time period, events could occur in the unexposed group but not in the exposed group, and this might explain the conflicting results.

Our finding of no association between orchiectomy and MI or stroke is consistent with the results of three of the five previous studies on the topic [7], [8], and [28]. In one of the two studies that found an association between orchiectomy and MI or stroke, Van Hemelrijk et al., using the Swedish background population as reference for PCa patients treated with various forms of ADT, found the postorchiectomy, age-standardized incidences of MI and stroke were 1.20 (95% CI, 1.02–1.41) and 1.19 (95% CI, 1.02–1.37), respectively [9] . The authors were unable, though, to determine whether the observed increased risk for MI and stroke was a result of orchiectomy or the cancer itself. It is also possible that the stress of being diagnosed with PCa results in an increased risk for cardiovascular disease [29] . The other study showing an association between orchiectomy and stroke was a nested case-control study using the General Practice Research Database, a primary-care database in the United Kingdom [10] . They found an adjusted rate ratio of stroke of 1.77 (95% CI, 1.25–2.51) based on 47 orchidectomized patients with stroke and 248 without stroke from a study cohort of 22 310 PCa patients diagnosed from 1988 to 2008. Our study was larger, more contemporary, and included all Danish PCa patients diagnosed in the study period, which may explain the discrepant findings.

Orchiectomy and medical endocrine therapy cause comparable castration levels, and the two treatments share numerous adverse effects. Yet, we did not find an association between orchiectomy and cardiovascular adverse effects. Recent research has shown a direct role of GnRH agonists on the cardiac receptors regulating cardiac contractile function; treatment with GnRH agonists could lead to a dysfunction of this system and thereby play an important role in the cardiac pathology in men treated with GnRH agonists, which could explain our findings [30] .

In our study, PCa patients with preexisting MI or stroke tended to have a lower risk for MI or stroke after PCa diagnosis compared with patients without preexisting MI or stroke. This may be due to the beneficial effect of potential lifestyle changes after cardiovascular disease diagnosis (eg, smoking cessation, increased exercise, weight loss) and the use of secondary medical prophylaxis. Our finding supports the Science Advisory from 2010 by the American Heart Association, American Cancer Society, and American Urological Association, which concluded that “given the metabolic effects of ADT, it is advisable that patients in whom ADT is initiated be referred to their primary care physician for periodic cardiac follow-up evaluation. This evaluation should include assessment of blood pressure, lipid profile, and glucose level” [31] .

The major strengths of our study were its large size based on national data and the virtually complete follow-up. The registration of PCas is thought to be virtually complete because free health care is available to all residents in Denmark [22] . The positive and negative predictive values of medical endocrine therapy in the DNPR has previously been estimated to be 93% (95% CI, 86.1–97.1) and 94% (95% CI, 87.4–97.8), respectively, and both the positive and negative predictive values of orchiectomy have been found to be 100% (97.5% CI, 92.9–100) [32] . One limitation of the study is that the ICD-10 code BWHC covers treatment with GnRH agonists and antiandrogens, and therefore the isolated effect of GnRH agonists was not assessed. Moreover, since we did not have access to data on injections administered by the general practitioners, we could not determine the exact number of injections per patient. Therefore, we were unable to categorize ADT exposure according to duration. ADT is, however, a continuous treatment in most cases. Even if a few patients would stop treatment (and still be counted as a GnRH-agonist user in our follow-up), this would bias our estimate towards the null and thereby underestimate the observed risk. Also the increased risk for cardiovascular events in ADT users in our study persisted throughout the entire follow-up. Of interest, we found that orchidectomized patients, who have a continuous/irreversible treatment, had a lower risk for cardiovascular events than the patients treated with GnRH agonists.

We used PCa patients without ADT to make our reference as comparable as possible with the patients in the ADT group with regard to cancer type and distribution of risk factors for PCa, being well aware that they compose a heterogeneous group regarding PCa treatment. It is possible that patients in the ADT group received chemotherapy (ie, added toxicity) more often than the reference group, but chemotherapy was first introduced in Denmark in 2005 and we do not expect significant confounding from chemotherapy, since the number of treated patients is relatively small.

Unfortunately, our study did not include information on prognostic lifestyle factors such as smoking or obesity, or clinical data such as Gleason score, prostate-specific antigen level, cardiovascular risk factors, treatments for cardiovascular diseases, and other treatments for PCa, which might have further informed our estimates.

5. Conclusions

In conclusion, we found that endocrine medical therapy was associated with increased risk for MI and stroke, but we did not find a similar association after orchiectomy. Possibly, orchiectomy serves as an alternative treatment without the increased cardiac risk for patients with advanced disease. Decisions about ADT should weigh improvements in cancer-specific outcomes against potential increased risks for cardiovascular diseases.


Author contributions: Christina G. Jespersen had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the analysis.

Study concept and design: Jespersen, Nørgaard, Borre.

Acquisition of data: Jespersen, Nørgaard.

Analysis and interpretation of data: Jespersen, Nørgaard, Borre.

Drafting of the manuscript: Jespersen.

Critical revision of the manuscript for important intellectual content: Nørgaard, Borre.

Statistical analysis: Jespersen, Nørgaard.

Obtaining funding: Borre.

Administrative, technical, or material support: None.

Supervision: Nørgaard, Borre.

Other (specify): None.

Financial disclosures: Christina G. Jespersen certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: This work has been supported by funding from the Aarhus University Research Foundation, The Danish Cancer Society, The Foundation for Scientific Research in Central Jutland, Agnes Niebuhr Anderssons Foundation, Frimodt Heineke Foundation, and Kong Christian Den Tiendes Foundation. The sponsors had no role in the analysis, interpretation of the results, or drafting of the manuscript.

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Footnotes

a Department of Urology, Aarhus University Hospital, Aarhus, Denmark

b Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark

c Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark

lowast Corresponding author. Department of Urology, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus N, Denmark.

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