- Email: [email protected]
Cardiovascular risk profile of veteran men beginning androgen deprivation therapy
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Cardiovascular risk profile of veteran men beginning androgen deprivation therapy Lindsay Williams, RN, BSN, PHN, Elisabeth Hicks, MA, Lorna Kwan, MPH, Mark Litwin, MD, MPH, and Sally Maliski, RN, PhD, FAAN
We sought to describe the cardiovascular profile of veteran men before beginning androgen deprivation therapy (ADT), with the eventual benefit of targeting treatments to manage harmful cardiovascular side effects. We performed a secondary analysis with chi-square and Fisher’s exact tests for associations between demographics and cardiovascular comorbidities on 375 veteran men diagnosed with prostate cancer. Those who were overweight and current smokers were more likely to be younger, whereas men with a systolic blood pressure >120 mmHg were more likely to be older (all P < 0.05). Men with total cholesterol 180 mg/dL were more likely to be identified in the Hispanic/other/unknown ethnicity category. Interventions to manage cardiovascular risk should focus on preventive lifestyle changes for younger men, and chronic disease management for older men. Men in the smaller Hispanic/other/unknown category are at risk for marginalization within the Veteran Administration system owing to their low numbers and should be closely monitored for cholesterol levels when receiving ADT. (J Vasc Nurs 2014;32:99-104)
In the past decade, use of androgen deprivation therapy (ADT) to treat prostate cancer has risen seven-fold, from 9.8% of patients in 1989 to 1992 to 74.6% in 1999 to 2001.3 However, along with demonstrated survival benefits, ADT is associated with multiple side effects, and a poorer health-related quality of life.4–12 ADT, accomplished through orchiectomy (removal of the testicles), or the administration of luteinizing hormonereleasing hormones, can lead to loss of libido, erectile dysfunction, hot flashes, gynecomastia, depression, and bone density loss. Specifically, side effects of ADT can trigger metabolic, coronary, and vascular changes that can hasten cardiovascular disease (CVD).4–12 These include gains in weight, body fat, and losses in lean muscle mass. Furthermore, total cholesterol, high-density lipoprotein cholesterol (HDL), and low-density lipoprotein cholesterol tend to rise, coupled with increasing insulin resistance and central arterial pressure, suggesting decreased arterial compliance.4–12 Subsequently, these ADT-related changes can cause atherosclerotic plaque instability, plaque proFrom the UCLA School of Nursing; Department of Urology, UCLA David Geffen School of Medicine, Los Angeles, California. Corresponding author: Lindsay Williams, RN, BSN, PHN, UCLA School of Nursing, 700 Tiverton Avenue, Los Angeles, CA 90095 (E-mail: [email protected]). This study has been presented as a poster at the UCLA/Charles Drew University (CDU) Resource Centers for Minority Aging Research (RCMAR) Center for Health Improvement for Minority Elders (CHIME) Scientific Retreat, Los Angeles, California, October 21, 2013. 1062-0303/$36.00 Published by Elsevier Inc. on behalf of the Society for Vascular Nursing, Inc. http://dx.doi.org/10.1016/j.jvn.2014.01.004
gression, and increase the risk of coronary artery disease, peripheral arterial disease, and venous thromboembolism.23 The literature suggests that ADT treatment is significantly associated with a shorter time to death from cardiovascular causes, even when controlling for CVD risk, as well as a 1.2 times increased risk of cardiovascular events.24 A retrospective review of 2,378 prostate cancer cases suggested that overall survival is shortened for men with prostate cancer who receive ADT versus those who do not (44% and 20%, respectively).25 As of September 2011, there were a projected 22 million living veterans whose overall characteristics differ significantly from the civilian population.13 Male veterans are generally older than civilian men, with a median age of 64 and 41, respectively. Nationwide, 80.9% of males are classified White non-Hispanic, 13.2% non-White Non-Hispanic (Black, American Indian/Alaska Native, Native Hawaiian and Other Pacific Islander, some other race, and multiracial), and 5.9% as Hispanic. Furthermore, male veterans are on average more likely to have a combination of public and private health insurance than their civilian counterparts.13 California has the highest living veteran population of any state, with numbers reaching almost two million. Vietnam-era Veterans are reaching their mid-60s, where prostate cancer is most commonly diagnosed and wartime exposures place them at higher risk for aggressive prostate cancers.1,2 One kind of wartime exposure is Agent Orange, a carcinogenic defoliant used during the Vietnam war. It is associated with a 75% increase in aggressive prostate cancer with a Gleason sum of $7 and a 110% increase in prostate cancers with a Gleason sum of $8.2 Because Gleason sums are systems of grading prostate cancer tumors, with a higher number indicating a higher likelihood of metastasis, Agent Orange exposure can hasten the course of prostate cancer and the likelihood of a negative outcome for Vietnamera Veterans.22 Collier et al call for a consideration of baseline cardiovascular risk factors when determining treatment options for prostate cancer. One such method of measurement is the Framingham Risk
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Score (FRS), a tool to measure individual risk for CVD.15–17 Balancing the risks and benefits of ADT is crucial for identifying men at greater risk for negative outcomes is fundamental in risk management. The male veteran population, with an increased risk of prostate cancer and cohesive data from health care services, can serve as an example for understanding the health status of men starting ADT and a starting point for crafting health promotion interventions for men using ADT. Therefore, the purpose of this study was to describe the cardiovascular risk factors of veteran men with prostate cancer before beginning ADT therapy. Identifying a general starting profile of veteran men receiving ADT can inform health care providers of the potential harm and benefit to individuals throughout the duration of treatment.
MATERIALS AND METHODS
Data sources and participants This cross-sectional, correlational study is a secondary analysis of a dataset utilized by Daskivich et al, which received institutional review board (IRB) approval (VA IRB #0003- Creation of a Prostate Cancer Specific Comorbidity Index).14 The primary analysis used the California Cancer Registry to identify all men newly diagnosed with prostate cancer at the Greater Los Angeles and Long Beach Veterans Affairs Medical Centers between 1997 and 2004. Medical records were reviewed to ascertain age, race, height and weight, smoking status, hemoglobin (Hg) 1Ac, total cholesterol, HDL, FRS, blood pressure, prostate-specific antigen (PSA) at time of diagnosis, clinical T stage, Gleason score, primary prostate cancer treatment, and comorbidities at diagnosis as well as date and cause of death. The primary analysis only included men with nonmetastatic, low-risk prostate cancer, whereas our analysis focused on men receiving ADT, regardless of disease progression. Agent Orange exposure is not known in this sample, because it was not in the original registry data. Unfortunately there are no current estimates on the percentage of men exposed to Agent Orange in the Vietnam War.2 The primary analysis and this study excluded men with no prostate cancer diagnosis (n = 40), histology other than adenocarcinoma (n = 46), had prostate cancer diagnosed incidentally at the time of cystoprostatectomy (n = 25), and individuals with insufficient data to determine cardiovascular risk factors and treatment type (n = 206). Of the primary sample of 1,482 participants, our secondary analysis selected 375 subjects who underwent immediate ADT or delayed ADT/watchful waiting. The men designated as delayed ADT/watchful waiting delayed their ADT therapy between 6 and 12 months as the tumor was monitored for growth and prognosis. In these cases, the benefits of monitoring the tumor without invasive treatment outweighed the risks of premature treatment. Of the 375 subjects, 176 passed away by the end of the follow-up period, 18 from cardiovascular causes and 48 from cancer-related causes.
Cardiovascular comorbidities We selected the following seven measures to represent cardiovascular risk and/or comorbidity: Body mass index (BMI), HgA1c, total cholesterol, HDL, FRS, systolic BP (SBP), and smoking status. In the original study, HgA1c data were only
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collected for participants with a diabetes mellitus diagnosis and was therefore not available for all subjects in our analysis. Cardiovascular measures were categorized into risk groups by clinical guidelines and clinical significance.15 For example, cut points for HgA1c, total cholesterol, HDL, FRS and SBP were based on widely accepted clinical practice-based guidelines.16 We hypothesized that older veterans ($65) would be significantly more likely to have risk factors that indicate chronic disease, namely, higher HgA1c, total cholesterol, HDL, FRS, and more likely to smoke.8,17–21 The FRS was created by the Framingham Heart Study to predict 10-year CVD risk in the general population living in the United States.17 The FRS score is used in a variety of different clinical settings and is recommended by the US Preventive Services Task Force as a tool to assess cardiovascular risk.16 Risk factors for CVD are weighted and compiled into an overall score. This score has been used to test the predictability of CVD onset within 10 years, and mortality from CVD, with high reliability.17,18 The CVD outcomes measured by the FRS include coronary death, myocardial infarction, coronary insufficiency, angina, ischemic stroke, hemorrhagic stroke, transient ischemic attack, peripheral artery disease, and heart failure.17 Scores are assigned based on the cardiovascular predictors of age, diabetes, smoking history, SBP, total cholesterol, HDL, and BMI. These scores are added together for a composite score, with a higher score indicating a higher 10 year CVD risk. Scores from 0 to 12 indicate low risk, or a <10% chance of developing heart disease; 13 to 14 indicate intermediate risk (10%-20% chance); and >14 indicate a >20% chance, or high risk.17,18,26
Statistical analysis Distributions of age, race, PSA, clinical T stage, and Gleason score were reported for the entire sample. These variables were also compared across each of the cardiovascular risk categories using a chi-square or Fisher’s exact test as appropriate. All tests were two-sided and all analyses were conducted by a health sciences biostatistician in SAS 9.3 (SAS Institute, Cary, NC).
RESULTS Clinical and demographic characteristics of our sample are shown in Table 1. Of the 375 participants in the sample, 147 (39%) were ages 66 to 75 at diagnosis, 109 (29%) were ages 76 to 85, and 84 (22%) were ages 56 to 65. Thirty-five men, approximately 9% of the sample, were either <56 (n = 25) or >85 (n = 10) at diagnosis. Men outside of the 60s age range were included in this analysis to give a comprehensive view of the cardiovascular risks of men with prostate cancer. The majority of men were identified as either White (43%) or Black (36%). Consistent with an advanced prostate cancer diagnosis, almost 40% of men had a PSA score of >20, and another 27% with a PSA between 10 and 20. At the time of diagnosis, the predominant clinical T stage was T1, comprising 51% of the sample, with approximately 26% of the sample at clinical T stage T0. Finally, 25% participants had a Gleason score of <7, 43% with a score of 7, and the remaining 32% with a score of >7. Although there are missing data with regard to cardiovascular risk factors, we were able to obtain a comprehensive profile of this sample before initiating ADT (Table 1). The missing data
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TABLE 1
TABLE 1
DEMOGRAPHIC DATA AND CARDIOVASCULAR COMORBIDITY DISTRIBUTIONS (N = 375)
CONTINUED
Demographic data Age at diagnosis (y) #55 56-65 66-75 76-85 >85 Race/ethnicity White, non-Hispanic Black Hispanic/other/unknown PSA at diagnosis #10 10-20 >20 Clinical T stage cT0 cT1 cT2 cT3 Gleason score <7 7 >7 Cardiovascular comorbidities BMI (n = 328) Normal Overweight Obese Smoking status (n = 375) Never/past Current HgA1c at diagnosis (n = 83) >6 #6 Total cholesterol (n = 325) >180 #180 Framingham score (n = 234) 0-12 13-14
n
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Demographic data
n
%
>14 HDL (n = 314) $60 <60 Systolic BP (n = 370) >120 #120
106
45.3
48 266
15.3 84.7
312 58
84.3 15.7
%
25 84 147 109 10
6.7 22.4 39.2 29.1 2.7
160 137 78
42.7 36.5 20.8
126 100 147
33.6 26.7 39.2
97 192 53 33
25.9 51.2 14.1 8.8
92 160 118
24.5 42.7 31.5
89 129 110
27.1 39.3 33.5
286 89
76.3 23.7
69 14
83.1 16.9
188 137
57.8 42.2
36 92
15.4 39.3 (Continued )
BMI = body mass index; BP = blood pressure; HDL = high-density lipoprotein cholesterol; PSA = prostate-specific antigen.
correspond with lacking information from the registry database and medical records. BMI information was collected on 328 of the total 375 participants, and of those, 72% were overweight or obese. All 375 men had data available for their current smoking status, and 76% of men were never or past smokers. HgA1c at diagnosis data was only collected for men with a documented diabetes diagnosis, yielding 83 men. Sixty-nine (83%) had a value of >6. For the remaining comorbidities, total cholesterol, FRS, HDL, and SBP, there were 325, 234, 314, and 370 participants with available data, respectively. In reference to total cholesterol, 188 men (58%) had a value of >180, and 137 men (42%), had a value of #180. The majority of men (84%) had a FRS of $13, an HDL score of <60, and a SBP of >120. Tables 2 and 3, 4 show only the significant associations between subject demographics and cardiovascular risk factors. Age was the subject characteristic with the most significant associations with the cardiovascular comorbidities. Older men ($56) tended to have comorbidities that are more chronic, as they were more likely to have a higher FRS (>12), and a higher SBP, albeit SBP is one component of the Framingham score. Men who identified outside of White and Black race, namely in the Hispanic/other/unknown category, were more likely to have a total cholesterol of >180 mg/dL. Finally, men with a PSA score of >20 were more likely to have a SBP of >120 mmHg.
DISCUSSION Our results indicate that men receiving ADT are at an increased risk of CVD before treatment begins, which may be exacerbated by the detrimental side effects of ADT. The literature suggests that men receiving ADT are at higher risk for dyslipidemia, particularly an increase in harmful low-density lipoprotein and decreased arterial compliance.4,8 In addition, men are susceptible to hypertension, which can be exacerbated by smoking and increased BMI.7,8,9 Younger men (<56 years), seem to have lifestyles that place them at risk for CVD, because they are significantly more likely to be overweight and current smokers. This is especially problematic, because ADT may exacerbate visceral fat deposition
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TABLE 2 SIGNIFICANT ASSOCIATIONS BETWEEN SUBJECT DEMOGRAPHICS AND CARDIOVASCULAR COMORBIDITIES Framingham risk score (N = 234) 0-12 n
13-14 %
Age at diagnosis (y) #55 10 28 56-65 17 47 66-75 8 22 76-85 1 3 >85 0 0 PSA #10 10-20 >20
Systolic BP (N = 370) #120
>14
>120
n
%
n
%
P
n
%
n
%
P
4 27 40 20 1
4 29 43 22 1
4 14 48 34 6
4 13 45 32 6
<0.0001*
8 14 13 22 1
14 24 22 38 2
16 69 133 85 9
5 22 43 27 3
0.0113
28 9 20
49 16 35
97 91 123
31 29 40
0.0181
BP = blood pressure; PSA = prostate-specific antigen. *Fisher’s exact test.
TABLE 3 SIGNIFICANT ASSOCIATION BETWEEN SUBJECT DEMOGRAPHICS AND METABOLIC COMORBIDITIES Total cholesterol (N = 325) #180
Race White, nonHispanic Black Hispanic/other/ unknown
>180
n
%
n
%
P
63
46
80
43
0.0415
55 19
40 14
61 47
32 25
and weight gain.4,8 Therefore, health interventions with a focus on healthy lifestyle changes, such as smoking cessation, dietary changes, and exercise can be used to counteract these potentially detrimental side effects. Although the Hispanic/other/unknown group is relatively small in the study sample and make up only 4% to 6% of the total veteran population, this group includes a heterogeneous group of American Indian/Alaskan natives, Asian, Pacific
Islander, and other designations.19 This group, owing to its small number, is at risk for marginalization considering its significantly higher total cholesterol levels at baseline. These levels can be heightened by ADT, increasing the risk of CVD for this group of men. Therefore, men outside of the Caucasian and African-American ethnic categories should be closely monitored for total cholesterol when receiving ADT, because they potentially may have higher total cholesterol than their counterparts. Although the justification for this positive association between increased PSA and SBP is unknown, the connection could lie at the intersection of physical activity, blood pressure, and PSA. Loprinzi and Kohli20 report that participants were 16% more likely to have an elevated PSA concentration for every 1hour increase in sedentary behavior. Furthermore, participants were 18% less likely to have an elevated PSA with every 1hour increase in light physical activity. Considering the connection between SBP and physical activity, perhaps lesser amounts of physical activity correspond with higher SBPs, and therefore a higher PSA. However, there is some controversy on the feasibility and benefit of the PSA screening examination. The PSA screening exam has been subject to scrutiny and criticism, as The US Preventive Service Task Force21 currently recommends against PSA-based screening in the general US population. Therefore, a potential association between these two factors is clouded by disputes over when and who should receive a PSA examination. Further research is needed to first establish an alternative means of testing and subsequently the presumed connection between heightened SBP and PSA.21
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TABLE 4 SIGNIFICANT ASSOCIATIONS BETWEEN SUBJECT DEMOGRAPHICS AND MODIFIABLE LIFESTYLE BEHAVIORS Body mass index (n = 328) Normal n
Overweight
Smoking (n = 375) Obese
Current
Never/past
%
n
%
n
%
P
n
%
n
%
P
Age at diagnosis (y) #55 6 7 56-65 13 15 66-75 36 40 76-85 27 30 >85 7 8
9 30 56 33 1
7 23 43 26 1
5 32 37 36 0
5 29 34 33 0
0.0039
11 28 36 14 0
12 31 40 16 0
14 56 111 95 10
5 20 39 33 4
0.0004
This study has some limitations. This study population may not be generalizable to the general male population, because the sample consisted of veteran men who are also Veterans Affairs Health Services users. Furthermore, the study sample is not reflective of the overall veteran male population, although the California is among the most diverse states in the United States. Owing to database restrictions, it was not possible to continue tracking ADT cases for possible outcomes past 2004, to collect missing data for cardiovascular risk factors, or to survey for Agent Orange exposure. Despite these limitations, our study provides valuable information about the cardiovascular risk of a diverse cohort of veteran men before beginning ADT therapy that can guide practitioners on treatment decision making for prostate cancer. Vascular nurses and advanced practice nurses can benefit from these results as they can provide education for selfmanagement and monitor cardiovascular status when caring for men with prostate cancer. Vascular nurses can consider the potentially harmful cardiovascular effects of ADT and design treatment options that minimize the future risk of CVD.
CONCLUSION By analyzing the cardiovascular comorbidities of veteran men beginning ADT therapy, the evidence suggests men face an elevated risk of developing CVD as a result of ADT on two fronts: Age and ethnicity. Older (>56) tended to have chronic comorbidities, whereas younger men had comorbidities that were easier to modify. Men who identify as Hispanic/other/unknown tended to have higher total cholesterol, whereas men with a high PSA tended to have a SBP of >120 mmHg. Lifestyle changes coupled with chronic disease management can prevent the development of CVD as a result of ADT. Health care practitioners and men receiving ADT would benefit from targeted treatment guidelines based on the comorbidities established in this veteran population. Knowledge gaps remain about the relationship between pre-ADT cardiovascular comorbidities and post-ADT outcomes, in veterans and the general population.
This study brings attention to this dearth of knowledge and creates a background for future studies.
ACKNOWLEDGMENTS The authors thank the UCLA School of Nursing; UCLA David Geffen School of Medicine, Department of Urology; and Timothy Daskivich, MD-UCLA David Geffen School of Medicine, Department of Urology. REFERENCES 1. Cooperberg MR, Grossfeld MD, Carroll PR. National practice patterns and time trends in androgen ablation for localized prostate cancer. J Natl Cancer Inst 2003;95(13):981-9. 2. Higano C. Side effects of androgen deprivation therapy: monitoring and minimizing toxicity. Urology 2003;61(suppl 1):32-8. 3. Johansson E, Bill-Axelson A, Holmberg L, et al. Time, symptom burden, androgen deprivation, and self-assessed quality of life after radical prostatectomy or watchful waiting: the Randomized Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) clinical trial. Eur Urol 2009; 55(2):422-30. 4. Kattan MW. Measuring hot flashes in men treated with hormone ablation therapy: an unmet need. Urol Nurs 2006; 26(1):13-8. 5. Labrie F, Cusan L, Gomez J, et al. Long-term combined androgen blockade along for localized prostate cancer. Mol Urol 1999;3:217-26. 6. Levine G, D’Amico A, Berger P, et al. Androgen-deprivation therapy in prostate cancer and cardiovascular risk. CA Cancer J Clin 2010;60(3):294-301. 7. Kabir S, Mancuso P, Rashid P. Androgen deprivation therapy–managing side effects. Aust Fam Physician 2008; 37(8):641-6. 8. Nishiyama T, Ishizaki F, Anraku T, et al. The influence of androgen deprivation therapy on metabolism in patients with prostate cancer. J Clin Endocrinol Metab 2005;90:657-66.
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9. Saylor PJ, Smith MR. Metabolic complications of androgen deprivation therapy for prostate cancer. J Urol 2013; 189(suppl 1):S34-42. 10. Tsai H, D’Amico A, Sadetsky N, et al. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst 2007;99(20):1515-24. 11. Hu JC, Williams SB, O’Malley AJ, et al. Androgen-deprivation therapy for nonmetastatic prostate cancer is associated with an increased risk of peripheral arterial disease and venous thromboembolism. Eur Assoc Urol 2012;61: 1119-28. 12. Collier AC, Ghosh S, McGlynn B, et al. Prostate cancer, androgen deprivation therapy, obesity, the metabolic syndrome, type 2 diabetes, and cardiovascular disease: a review. Am J Clin Oncol 2012;35:504-9. 13. Beyer DC, McKeough T, Thomas T. Impact of short course hormonal therapy on overall and cancer specific survival after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2005;61:1299-305. 14. National Center for Veterans Analysis and Statistics. The Veteran population model. 2011; http://www.va.gov/ vetdata/veteran_population.asp. 15. Howlader N, Noone AM, Krapcho M, et al editors. SEER cancer statistics review, 1975-2010. Bethesda (MD): National Cancer Institute. April 2013; http://seer.cancer.gov/ csr/1975_2010/, Accessed November 2012. 16. Ansbaugh N, Shannon J, Mori M, et al. Agent Orange as a risk factor for high-grade prostate cancer. Cancer 2013; 119(13):2399-404. 17. NCI Dictionary of Cancer Terms. Gleason score. 2012; http://www.cancer.gov/dictionary?cdrid=45696.
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18. Salinas JJ, Abdelbary B, Wilson J, et al. Using the Framingham Risk Score to evaluate immigrant effect on cardiovascular disease risk in Mexican Americans. J Health Care Poor Underserved 2012;23:666-7. 19. Agency for Healthcare Research and Quality. National Guidelines Clearinghouse: Guidelines by Topic. 2012; http://www.guideline.gov/browse/by-topic.aspx. 20. Framingham Heart Study. General cardiovascular disease: 10-year risk. 2011; http://www.framinghamheartstudy.org/ risk/gencardio.html. 21. Daskivich TJ, Chamie K, Kwan L, et al. Overtreatment of men with low-risk prostate cancer and significant comorbidity. Cancer 2011;117:2058-66. 22. D’Agostino RB, Grundy S, Sullivan LM, et al. Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic group’s investigation. JAMA 2001; 286(2):180-7. 23. Office of the Actuary. Veteran population projections model. 2011; http://www.va.gov/vetdata/docs/QuickFacts/ Population_quickfacts.pdf. 24. Loprinzi PD, Kohli M. Effect of physical activity and sedentary behavior on serum prostate-specific antigen concentrations: results from the National Health and Nutrition Examination Survey (NHANES), 2003-2006. Mayo Clin Proc 2013;88(1):11-21. 25. U.S. Preventive Services Task Force. Screening for prostate cancer, topic page. 2012; http://www.uspreventiveservicestask force.org/prostatecancerscreening.htm. 26. The Heart Institute of Doylestown Hospital. Framingham risk scoring sheet. http://www.cbfymca.org/docs/ Framingham%20Risk%20Scoring%20Sheet.pdf.
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Cardiovascular risk profile of veteran men beginning androgen deprivation therapy Lindsay Williams, RN, BSN, PHN, Elisabeth Hicks, MA, Lorna Kwan, MPH, Mark Litwin, MD, MPH, and Sally Maliski, RN, PhD, FAAN
We sought to describe the cardiovascular profile of veteran men before beginning androgen deprivation therapy (ADT), with the eventual benefit of targeting treatments to manage harmful cardiovascular side effects. We performed a secondary analysis with chi-square and Fisher’s exact tests for associations between demographics and cardiovascular comorbidities on 375 veteran men diagnosed with prostate cancer. Those who were overweight and current smokers were more likely to be younger, whereas men with a systolic blood pressure >120 mmHg were more likely to be older (all P < 0.05). Men with total cholesterol 180 mg/dL were more likely to be identified in the Hispanic/other/unknown ethnicity category. Interventions to manage cardiovascular risk should focus on preventive lifestyle changes for younger men, and chronic disease management for older men. Men in the smaller Hispanic/other/unknown category are at risk for marginalization within the Veteran Administration system owing to their low numbers and should be closely monitored for cholesterol levels when receiving ADT. (J Vasc Nurs 2014;32:99-104)
In the past decade, use of androgen deprivation therapy (ADT) to treat prostate cancer has risen seven-fold, from 9.8% of patients in 1989 to 1992 to 74.6% in 1999 to 2001.3 However, along with demonstrated survival benefits, ADT is associated with multiple side effects, and a poorer health-related quality of life.4–12 ADT, accomplished through orchiectomy (removal of the testicles), or the administration of luteinizing hormonereleasing hormones, can lead to loss of libido, erectile dysfunction, hot flashes, gynecomastia, depression, and bone density loss. Specifically, side effects of ADT can trigger metabolic, coronary, and vascular changes that can hasten cardiovascular disease (CVD).4–12 These include gains in weight, body fat, and losses in lean muscle mass. Furthermore, total cholesterol, high-density lipoprotein cholesterol (HDL), and low-density lipoprotein cholesterol tend to rise, coupled with increasing insulin resistance and central arterial pressure, suggesting decreased arterial compliance.4–12 Subsequently, these ADT-related changes can cause atherosclerotic plaque instability, plaque proFrom the UCLA School of Nursing; Department of Urology, UCLA David Geffen School of Medicine, Los Angeles, California. Corresponding author: Lindsay Williams, RN, BSN, PHN, UCLA School of Nursing, 700 Tiverton Avenue, Los Angeles, CA 90095 (E-mail: [email protected]). This study has been presented as a poster at the UCLA/Charles Drew University (CDU) Resource Centers for Minority Aging Research (RCMAR) Center for Health Improvement for Minority Elders (CHIME) Scientific Retreat, Los Angeles, California, October 21, 2013. 1062-0303/$36.00 Published by Elsevier Inc. on behalf of the Society for Vascular Nursing, Inc. http://dx.doi.org/10.1016/j.jvn.2014.01.004
gression, and increase the risk of coronary artery disease, peripheral arterial disease, and venous thromboembolism.23 The literature suggests that ADT treatment is significantly associated with a shorter time to death from cardiovascular causes, even when controlling for CVD risk, as well as a 1.2 times increased risk of cardiovascular events.24 A retrospective review of 2,378 prostate cancer cases suggested that overall survival is shortened for men with prostate cancer who receive ADT versus those who do not (44% and 20%, respectively).25 As of September 2011, there were a projected 22 million living veterans whose overall characteristics differ significantly from the civilian population.13 Male veterans are generally older than civilian men, with a median age of 64 and 41, respectively. Nationwide, 80.9% of males are classified White non-Hispanic, 13.2% non-White Non-Hispanic (Black, American Indian/Alaska Native, Native Hawaiian and Other Pacific Islander, some other race, and multiracial), and 5.9% as Hispanic. Furthermore, male veterans are on average more likely to have a combination of public and private health insurance than their civilian counterparts.13 California has the highest living veteran population of any state, with numbers reaching almost two million. Vietnam-era Veterans are reaching their mid-60s, where prostate cancer is most commonly diagnosed and wartime exposures place them at higher risk for aggressive prostate cancers.1,2 One kind of wartime exposure is Agent Orange, a carcinogenic defoliant used during the Vietnam war. It is associated with a 75% increase in aggressive prostate cancer with a Gleason sum of $7 and a 110% increase in prostate cancers with a Gleason sum of $8.2 Because Gleason sums are systems of grading prostate cancer tumors, with a higher number indicating a higher likelihood of metastasis, Agent Orange exposure can hasten the course of prostate cancer and the likelihood of a negative outcome for Vietnamera Veterans.22 Collier et al call for a consideration of baseline cardiovascular risk factors when determining treatment options for prostate cancer. One such method of measurement is the Framingham Risk
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Score (FRS), a tool to measure individual risk for CVD.15–17 Balancing the risks and benefits of ADT is crucial for identifying men at greater risk for negative outcomes is fundamental in risk management. The male veteran population, with an increased risk of prostate cancer and cohesive data from health care services, can serve as an example for understanding the health status of men starting ADT and a starting point for crafting health promotion interventions for men using ADT. Therefore, the purpose of this study was to describe the cardiovascular risk factors of veteran men with prostate cancer before beginning ADT therapy. Identifying a general starting profile of veteran men receiving ADT can inform health care providers of the potential harm and benefit to individuals throughout the duration of treatment.
MATERIALS AND METHODS
Data sources and participants This cross-sectional, correlational study is a secondary analysis of a dataset utilized by Daskivich et al, which received institutional review board (IRB) approval (VA IRB #0003- Creation of a Prostate Cancer Specific Comorbidity Index).14 The primary analysis used the California Cancer Registry to identify all men newly diagnosed with prostate cancer at the Greater Los Angeles and Long Beach Veterans Affairs Medical Centers between 1997 and 2004. Medical records were reviewed to ascertain age, race, height and weight, smoking status, hemoglobin (Hg) 1Ac, total cholesterol, HDL, FRS, blood pressure, prostate-specific antigen (PSA) at time of diagnosis, clinical T stage, Gleason score, primary prostate cancer treatment, and comorbidities at diagnosis as well as date and cause of death. The primary analysis only included men with nonmetastatic, low-risk prostate cancer, whereas our analysis focused on men receiving ADT, regardless of disease progression. Agent Orange exposure is not known in this sample, because it was not in the original registry data. Unfortunately there are no current estimates on the percentage of men exposed to Agent Orange in the Vietnam War.2 The primary analysis and this study excluded men with no prostate cancer diagnosis (n = 40), histology other than adenocarcinoma (n = 46), had prostate cancer diagnosed incidentally at the time of cystoprostatectomy (n = 25), and individuals with insufficient data to determine cardiovascular risk factors and treatment type (n = 206). Of the primary sample of 1,482 participants, our secondary analysis selected 375 subjects who underwent immediate ADT or delayed ADT/watchful waiting. The men designated as delayed ADT/watchful waiting delayed their ADT therapy between 6 and 12 months as the tumor was monitored for growth and prognosis. In these cases, the benefits of monitoring the tumor without invasive treatment outweighed the risks of premature treatment. Of the 375 subjects, 176 passed away by the end of the follow-up period, 18 from cardiovascular causes and 48 from cancer-related causes.
Cardiovascular comorbidities We selected the following seven measures to represent cardiovascular risk and/or comorbidity: Body mass index (BMI), HgA1c, total cholesterol, HDL, FRS, systolic BP (SBP), and smoking status. In the original study, HgA1c data were only
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collected for participants with a diabetes mellitus diagnosis and was therefore not available for all subjects in our analysis. Cardiovascular measures were categorized into risk groups by clinical guidelines and clinical significance.15 For example, cut points for HgA1c, total cholesterol, HDL, FRS and SBP were based on widely accepted clinical practice-based guidelines.16 We hypothesized that older veterans ($65) would be significantly more likely to have risk factors that indicate chronic disease, namely, higher HgA1c, total cholesterol, HDL, FRS, and more likely to smoke.8,17–21 The FRS was created by the Framingham Heart Study to predict 10-year CVD risk in the general population living in the United States.17 The FRS score is used in a variety of different clinical settings and is recommended by the US Preventive Services Task Force as a tool to assess cardiovascular risk.16 Risk factors for CVD are weighted and compiled into an overall score. This score has been used to test the predictability of CVD onset within 10 years, and mortality from CVD, with high reliability.17,18 The CVD outcomes measured by the FRS include coronary death, myocardial infarction, coronary insufficiency, angina, ischemic stroke, hemorrhagic stroke, transient ischemic attack, peripheral artery disease, and heart failure.17 Scores are assigned based on the cardiovascular predictors of age, diabetes, smoking history, SBP, total cholesterol, HDL, and BMI. These scores are added together for a composite score, with a higher score indicating a higher 10 year CVD risk. Scores from 0 to 12 indicate low risk, or a <10% chance of developing heart disease; 13 to 14 indicate intermediate risk (10%-20% chance); and >14 indicate a >20% chance, or high risk.17,18,26
Statistical analysis Distributions of age, race, PSA, clinical T stage, and Gleason score were reported for the entire sample. These variables were also compared across each of the cardiovascular risk categories using a chi-square or Fisher’s exact test as appropriate. All tests were two-sided and all analyses were conducted by a health sciences biostatistician in SAS 9.3 (SAS Institute, Cary, NC).
RESULTS Clinical and demographic characteristics of our sample are shown in Table 1. Of the 375 participants in the sample, 147 (39%) were ages 66 to 75 at diagnosis, 109 (29%) were ages 76 to 85, and 84 (22%) were ages 56 to 65. Thirty-five men, approximately 9% of the sample, were either <56 (n = 25) or >85 (n = 10) at diagnosis. Men outside of the 60s age range were included in this analysis to give a comprehensive view of the cardiovascular risks of men with prostate cancer. The majority of men were identified as either White (43%) or Black (36%). Consistent with an advanced prostate cancer diagnosis, almost 40% of men had a PSA score of >20, and another 27% with a PSA between 10 and 20. At the time of diagnosis, the predominant clinical T stage was T1, comprising 51% of the sample, with approximately 26% of the sample at clinical T stage T0. Finally, 25% participants had a Gleason score of <7, 43% with a score of 7, and the remaining 32% with a score of >7. Although there are missing data with regard to cardiovascular risk factors, we were able to obtain a comprehensive profile of this sample before initiating ADT (Table 1). The missing data
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TABLE 1
TABLE 1
DEMOGRAPHIC DATA AND CARDIOVASCULAR COMORBIDITY DISTRIBUTIONS (N = 375)
CONTINUED
Demographic data Age at diagnosis (y) #55 56-65 66-75 76-85 >85 Race/ethnicity White, non-Hispanic Black Hispanic/other/unknown PSA at diagnosis #10 10-20 >20 Clinical T stage cT0 cT1 cT2 cT3 Gleason score <7 7 >7 Cardiovascular comorbidities BMI (n = 328) Normal Overweight Obese Smoking status (n = 375) Never/past Current HgA1c at diagnosis (n = 83) >6 #6 Total cholesterol (n = 325) >180 #180 Framingham score (n = 234) 0-12 13-14
n
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Demographic data
n
%
>14 HDL (n = 314) $60 <60 Systolic BP (n = 370) >120 #120
106
45.3
48 266
15.3 84.7
312 58
84.3 15.7
%
25 84 147 109 10
6.7 22.4 39.2 29.1 2.7
160 137 78
42.7 36.5 20.8
126 100 147
33.6 26.7 39.2
97 192 53 33
25.9 51.2 14.1 8.8
92 160 118
24.5 42.7 31.5
89 129 110
27.1 39.3 33.5
286 89
76.3 23.7
69 14
83.1 16.9
188 137
57.8 42.2
36 92
15.4 39.3 (Continued )
BMI = body mass index; BP = blood pressure; HDL = high-density lipoprotein cholesterol; PSA = prostate-specific antigen.
correspond with lacking information from the registry database and medical records. BMI information was collected on 328 of the total 375 participants, and of those, 72% were overweight or obese. All 375 men had data available for their current smoking status, and 76% of men were never or past smokers. HgA1c at diagnosis data was only collected for men with a documented diabetes diagnosis, yielding 83 men. Sixty-nine (83%) had a value of >6. For the remaining comorbidities, total cholesterol, FRS, HDL, and SBP, there were 325, 234, 314, and 370 participants with available data, respectively. In reference to total cholesterol, 188 men (58%) had a value of >180, and 137 men (42%), had a value of #180. The majority of men (84%) had a FRS of $13, an HDL score of <60, and a SBP of >120. Tables 2 and 3, 4 show only the significant associations between subject demographics and cardiovascular risk factors. Age was the subject characteristic with the most significant associations with the cardiovascular comorbidities. Older men ($56) tended to have comorbidities that are more chronic, as they were more likely to have a higher FRS (>12), and a higher SBP, albeit SBP is one component of the Framingham score. Men who identified outside of White and Black race, namely in the Hispanic/other/unknown category, were more likely to have a total cholesterol of >180 mg/dL. Finally, men with a PSA score of >20 were more likely to have a SBP of >120 mmHg.
DISCUSSION Our results indicate that men receiving ADT are at an increased risk of CVD before treatment begins, which may be exacerbated by the detrimental side effects of ADT. The literature suggests that men receiving ADT are at higher risk for dyslipidemia, particularly an increase in harmful low-density lipoprotein and decreased arterial compliance.4,8 In addition, men are susceptible to hypertension, which can be exacerbated by smoking and increased BMI.7,8,9 Younger men (<56 years), seem to have lifestyles that place them at risk for CVD, because they are significantly more likely to be overweight and current smokers. This is especially problematic, because ADT may exacerbate visceral fat deposition
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TABLE 2 SIGNIFICANT ASSOCIATIONS BETWEEN SUBJECT DEMOGRAPHICS AND CARDIOVASCULAR COMORBIDITIES Framingham risk score (N = 234) 0-12 n
13-14 %
Age at diagnosis (y) #55 10 28 56-65 17 47 66-75 8 22 76-85 1 3 >85 0 0 PSA #10 10-20 >20
Systolic BP (N = 370) #120
>14
>120
n
%
n
%
P
n
%
n
%
P
4 27 40 20 1
4 29 43 22 1
4 14 48 34 6
4 13 45 32 6
<0.0001*
8 14 13 22 1
14 24 22 38 2
16 69 133 85 9
5 22 43 27 3
0.0113
28 9 20
49 16 35
97 91 123
31 29 40
0.0181
BP = blood pressure; PSA = prostate-specific antigen. *Fisher’s exact test.
TABLE 3 SIGNIFICANT ASSOCIATION BETWEEN SUBJECT DEMOGRAPHICS AND METABOLIC COMORBIDITIES Total cholesterol (N = 325) #180
Race White, nonHispanic Black Hispanic/other/ unknown
>180
n
%
n
%
P
63
46
80
43
0.0415
55 19
40 14
61 47
32 25
and weight gain.4,8 Therefore, health interventions with a focus on healthy lifestyle changes, such as smoking cessation, dietary changes, and exercise can be used to counteract these potentially detrimental side effects. Although the Hispanic/other/unknown group is relatively small in the study sample and make up only 4% to 6% of the total veteran population, this group includes a heterogeneous group of American Indian/Alaskan natives, Asian, Pacific
Islander, and other designations.19 This group, owing to its small number, is at risk for marginalization considering its significantly higher total cholesterol levels at baseline. These levels can be heightened by ADT, increasing the risk of CVD for this group of men. Therefore, men outside of the Caucasian and African-American ethnic categories should be closely monitored for total cholesterol when receiving ADT, because they potentially may have higher total cholesterol than their counterparts. Although the justification for this positive association between increased PSA and SBP is unknown, the connection could lie at the intersection of physical activity, blood pressure, and PSA. Loprinzi and Kohli20 report that participants were 16% more likely to have an elevated PSA concentration for every 1hour increase in sedentary behavior. Furthermore, participants were 18% less likely to have an elevated PSA with every 1hour increase in light physical activity. Considering the connection between SBP and physical activity, perhaps lesser amounts of physical activity correspond with higher SBPs, and therefore a higher PSA. However, there is some controversy on the feasibility and benefit of the PSA screening examination. The PSA screening exam has been subject to scrutiny and criticism, as The US Preventive Service Task Force21 currently recommends against PSA-based screening in the general US population. Therefore, a potential association between these two factors is clouded by disputes over when and who should receive a PSA examination. Further research is needed to first establish an alternative means of testing and subsequently the presumed connection between heightened SBP and PSA.21
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TABLE 4 SIGNIFICANT ASSOCIATIONS BETWEEN SUBJECT DEMOGRAPHICS AND MODIFIABLE LIFESTYLE BEHAVIORS Body mass index (n = 328) Normal n
Overweight
Smoking (n = 375) Obese
Current
Never/past
%
n
%
n
%
P
n
%
n
%
P
Age at diagnosis (y) #55 6 7 56-65 13 15 66-75 36 40 76-85 27 30 >85 7 8
9 30 56 33 1
7 23 43 26 1
5 32 37 36 0
5 29 34 33 0
0.0039
11 28 36 14 0
12 31 40 16 0
14 56 111 95 10
5 20 39 33 4
0.0004
This study has some limitations. This study population may not be generalizable to the general male population, because the sample consisted of veteran men who are also Veterans Affairs Health Services users. Furthermore, the study sample is not reflective of the overall veteran male population, although the California is among the most diverse states in the United States. Owing to database restrictions, it was not possible to continue tracking ADT cases for possible outcomes past 2004, to collect missing data for cardiovascular risk factors, or to survey for Agent Orange exposure. Despite these limitations, our study provides valuable information about the cardiovascular risk of a diverse cohort of veteran men before beginning ADT therapy that can guide practitioners on treatment decision making for prostate cancer. Vascular nurses and advanced practice nurses can benefit from these results as they can provide education for selfmanagement and monitor cardiovascular status when caring for men with prostate cancer. Vascular nurses can consider the potentially harmful cardiovascular effects of ADT and design treatment options that minimize the future risk of CVD.
CONCLUSION By analyzing the cardiovascular comorbidities of veteran men beginning ADT therapy, the evidence suggests men face an elevated risk of developing CVD as a result of ADT on two fronts: Age and ethnicity. Older (>56) tended to have chronic comorbidities, whereas younger men had comorbidities that were easier to modify. Men who identify as Hispanic/other/unknown tended to have higher total cholesterol, whereas men with a high PSA tended to have a SBP of >120 mmHg. Lifestyle changes coupled with chronic disease management can prevent the development of CVD as a result of ADT. Health care practitioners and men receiving ADT would benefit from targeted treatment guidelines based on the comorbidities established in this veteran population. Knowledge gaps remain about the relationship between pre-ADT cardiovascular comorbidities and post-ADT outcomes, in veterans and the general population.
This study brings attention to this dearth of knowledge and creates a background for future studies.
ACKNOWLEDGMENTS The authors thank the UCLA School of Nursing; UCLA David Geffen School of Medicine, Department of Urology; and Timothy Daskivich, MD-UCLA David Geffen School of Medicine, Department of Urology. REFERENCES 1. Cooperberg MR, Grossfeld MD, Carroll PR. National practice patterns and time trends in androgen ablation for localized prostate cancer. J Natl Cancer Inst 2003;95(13):981-9. 2. Higano C. Side effects of androgen deprivation therapy: monitoring and minimizing toxicity. Urology 2003;61(suppl 1):32-8. 3. Johansson E, Bill-Axelson A, Holmberg L, et al. Time, symptom burden, androgen deprivation, and self-assessed quality of life after radical prostatectomy or watchful waiting: the Randomized Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) clinical trial. Eur Urol 2009; 55(2):422-30. 4. Kattan MW. Measuring hot flashes in men treated with hormone ablation therapy: an unmet need. Urol Nurs 2006; 26(1):13-8. 5. Labrie F, Cusan L, Gomez J, et al. Long-term combined androgen blockade along for localized prostate cancer. Mol Urol 1999;3:217-26. 6. Levine G, D’Amico A, Berger P, et al. Androgen-deprivation therapy in prostate cancer and cardiovascular risk. CA Cancer J Clin 2010;60(3):294-301. 7. Kabir S, Mancuso P, Rashid P. Androgen deprivation therapy–managing side effects. Aust Fam Physician 2008; 37(8):641-6. 8. Nishiyama T, Ishizaki F, Anraku T, et al. The influence of androgen deprivation therapy on metabolism in patients with prostate cancer. J Clin Endocrinol Metab 2005;90:657-66.
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9. Saylor PJ, Smith MR. Metabolic complications of androgen deprivation therapy for prostate cancer. J Urol 2013; 189(suppl 1):S34-42. 10. Tsai H, D’Amico A, Sadetsky N, et al. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst 2007;99(20):1515-24. 11. Hu JC, Williams SB, O’Malley AJ, et al. Androgen-deprivation therapy for nonmetastatic prostate cancer is associated with an increased risk of peripheral arterial disease and venous thromboembolism. Eur Assoc Urol 2012;61: 1119-28. 12. Collier AC, Ghosh S, McGlynn B, et al. Prostate cancer, androgen deprivation therapy, obesity, the metabolic syndrome, type 2 diabetes, and cardiovascular disease: a review. Am J Clin Oncol 2012;35:504-9. 13. Beyer DC, McKeough T, Thomas T. Impact of short course hormonal therapy on overall and cancer specific survival after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2005;61:1299-305. 14. National Center for Veterans Analysis and Statistics. The Veteran population model. 2011; http://www.va.gov/ vetdata/veteran_population.asp. 15. Howlader N, Noone AM, Krapcho M, et al editors. SEER cancer statistics review, 1975-2010. Bethesda (MD): National Cancer Institute. April 2013; http://seer.cancer.gov/ csr/1975_2010/, Accessed November 2012. 16. Ansbaugh N, Shannon J, Mori M, et al. Agent Orange as a risk factor for high-grade prostate cancer. Cancer 2013; 119(13):2399-404. 17. NCI Dictionary of Cancer Terms. Gleason score. 2012; http://www.cancer.gov/dictionary?cdrid=45696.
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18. Salinas JJ, Abdelbary B, Wilson J, et al. Using the Framingham Risk Score to evaluate immigrant effect on cardiovascular disease risk in Mexican Americans. J Health Care Poor Underserved 2012;23:666-7. 19. Agency for Healthcare Research and Quality. National Guidelines Clearinghouse: Guidelines by Topic. 2012; http://www.guideline.gov/browse/by-topic.aspx. 20. Framingham Heart Study. General cardiovascular disease: 10-year risk. 2011; http://www.framinghamheartstudy.org/ risk/gencardio.html. 21. Daskivich TJ, Chamie K, Kwan L, et al. Overtreatment of men with low-risk prostate cancer and significant comorbidity. Cancer 2011;117:2058-66. 22. D’Agostino RB, Grundy S, Sullivan LM, et al. Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic group’s investigation. JAMA 2001; 286(2):180-7. 23. Office of the Actuary. Veteran population projections model. 2011; http://www.va.gov/vetdata/docs/QuickFacts/ Population_quickfacts.pdf. 24. Loprinzi PD, Kohli M. Effect of physical activity and sedentary behavior on serum prostate-specific antigen concentrations: results from the National Health and Nutrition Examination Survey (NHANES), 2003-2006. Mayo Clin Proc 2013;88(1):11-21. 25. U.S. Preventive Services Task Force. Screening for prostate cancer, topic page. 2012; http://www.uspreventiveservicestask force.org/prostatecancerscreening.htm. 26. The Heart Institute of Doylestown Hospital. Framingham risk scoring sheet. http://www.cbfymca.org/docs/ Framingham%20Risk%20Scoring%20Sheet.pdf.