ASCVD Risk Stratification Among Cancer Survivors
- Adult cancer survivors are at elevated risk for atherosclerotic cardiovascular disease (ASCVD), which is driven by traditional risk factors and treatment of the malignancy itself.
- Standard practices may not adequately estimate ASCVD risk in adult cancer survivors due primarily to a paucity of evidence-based guidelines for appropriate screening and management in this unique group.
- Future studies are needed to validate the use of multi-modality imaging and primary prevention therapies in this patient population.
As of 2019, there were approximately 16.9 million cancer survivors living in the United States, with a projected increase to 22.1 million by 2030.1 In this unique population, cardiovascular disease ranks second only to malignancy itself as the cause of death.1 The high prevalence of ASCVD in adult cancer survivors is due to their shared risk factors including obesity, diabetes, hypertension, hyperlipidemia, tobacco use, poor diet, physical inactivity, and older age. Estimates of the prevalence of pre-existing coronary artery disease (CAD) in oncology patients range from 5.7% (breast) to 20.8% (lung) in the United States.2 Treatment- and malignancy-related factors contribute to this relationship.4 For example, there is a doubling of CAD risk in patients with clonal hematopoiesis of indeterminate potential.3 When compared with their siblings, childhood cancer survivors have a two- to twelvefold risk of developing a myocardial infarction, depending on malignancy subtype.4 In spite of this, evidence suggests under-recognition and treatment of ASCVD among cancer survivors.1
ASCVD Risk Associated With Cancer Therapy
The cardiotoxic effects of chemotherapeutics and radiation therapy contribute to ASCVD risk (Table 1). Chest irradiation and chemotherapeutic agents such as platinum, anti-metabolites, vascular endothelial growth factor (VEGF) inhibitors, and tyrosine kinase inhibitors (nilotinib) have been linked to acceleration of atherosclerosis and CAD.5 VEGF inhibitors can lead to hypertension, increasing the risk of ASCVD.5,6 Platinum therapy (cisplatin) induces procoagulant and endothelial toxicity such that there is an 8% absolute risk of CAD over 20 years.7 Immune checkpoint inhibitors are associated with a threefold increased risk of ASCVD events via accelerated atherosclerosis.8 Despite techniques to limit total radiation dose, these patients remain at elevated risk of future CAD via endothelial injury, thrombosis, and plaque rupture.7,9-11 Antimetabolites (fluorouracil, capecitabine) induce vasospasm as well as endothelial injury, leading to ischemia.7,12 Androgen deprivation therapy causes dyslipidemia and insulin resistance, which are established risk factors for ASCVD.13
Table 1: Association of Oncologic Treatment With Development of Adverse Cardiac Events4,7,12,14
|Survivor Group||Associated Therapies||ASCVD Morbidity/Mortality|
|Childhood cancer (leukemia, Hodgkin's lymphoma)||Chest radiotherapy
Platinum agents (cisplatin)
|Adult leukemia/lymphoma||Tyrosine kinase inhibitors||CAD
Peripheral artery disease Cerebrovascular attack
|Ovarian/testicular||Platinum agents (cisplatin)||CAD|
|Colorectal||VEGF inhibitors (bevacizumab, sorafenib)
|Hypertension, arterial thrombosis
ASCVD Risk Stratification
Traditional risk stratification tools fail to capture the heightened risk of ASCVD events among cancer survivors.15-19 The role of primary prevention of ASCVD among cancer survivors is also not well-characterized, although some guidance has been proposed.7,20,21,26 The Canadian Society of Cardiology emphasizes the need to adhere to standard risk-stratification guidelines prior to and after initiation of targeted cancer therapy.20 The American Society of Oncology highlights Hodgkin's disease and testicular cancers as being high-risk malignancies for CAD, but data are nonexistent for primary prevention in these patients.21 A consensus panel from the European Society of Cardiology recommends evaluation of traditional risk factors prior to initiation of cancer therapy, screening select populations (e.g., those on fluoropyrimidines) with electrocardiography, and testing for presence of CAD when indicated.7 The Childhood Cancer Survivor Study Cardiovascular Risk Calculator can also be applied to patients ≤50 years of age following treatment of a childhood cancer.22 Jurado et al. recommend mediastinal radiation be included as a risk-enhancing factor alongside smoking when calculating 10-year risk for ASCVD for a patient with cancer.23
In the absence of robust, high-quality evidence regarding prevention of CAD in patients treated for cancer, the American Heart Association (AHA) Life's Simple 7 offers a simple yet proven framework for patient counseling.24 Abstinence from smoking, maintenance of regular exercise, and prevention of the metabolic syndrome are all key components of reducing cardiovascular risk.
Other Risk Stratification Tools and Screening Recommendations
Although there are no guidelines directed toward risk stratification of patients with cancer for ASCVD prevention, there are consensus statements offered by several societies about when and how to screen for CAD.7,12,25 The Society for Cardiovascular Angiography and Intervention recommends yearly assessment of risk factors coupled with a history and clinical exam to ascertain the need for structural or functional imaging. This includes careful assessment for symptoms of CAD and a physical exam. In patients who received chemotherapy that poses continued vasotoxic risk (e.g., nilotinib, ponatinib, and cisplatin), screening with coronary computed tomography angiography (CCTA) or noninvasive stress testing every 5 years is suggested.12 Similar recommendations are offered for patients who received chest radiotherapy due to the risk of silent ischemia.12,26
The American College of Cardiology (ACC), American Society of Echocardiography (ASE), and European Association of Cardiovascular Imaging (EACVI) have released expert panels on monitoring for radiation-associated heart disease.25,27 For example, the ACC/ASE/EACVI recommend screening echocardiography 10 years after treatment and then at 5-year intervals thereafter. In patients deemed high risk for radiation-induced heart disease, they advocate for screening at 5 years post-treatment and noninvasive stress testing every 5 years. Recommended screening modalities are stress echocardiography and cardiac magnetic resonance imaging due to their higher specificity; however, if these studies are equivocal, then cardiac computed tomography can be considered.
Observational studies suggest that screening for CAD with CCTA may be of utility; however, timing of imaging remains unclear.28 Similarly, available evidence suggests coronary artery calcium (CAC) scoring may help risk stratify patients who have received radiation or chemotherapy.29 Patient deaths in the CAC consortium were more often attributed to malignancy when CAC = 0. When CAC scoring was >300, ASCVD was the primary cause of death.30 Other imaging modalities such as cardiac magnetic resonance imaging, fluorodeoxyglucose positron emission tomography, and single-photon emission computed tomography can be applied to the oncology patient as is standard practice for ischemic evaluations.31
Management of ASCVD Risk in Cancer Survivors
Data on the use of statins as primary prevention in adult cancer survivors are not available. Current recommendations are to follow available society guidelines, such that oncologic patients with elevated 10-year risk for ASCVD events should be initiated on statin therapy.32 Non-statin therapies including ezetimibe or PCSK9 inhibitors can be used in patients with particularly high-risk profiles and insufficient low-density lipoprotein cholesterol lowering; diet, lifestyle, and physical activity counseling, along with managing comorbidities such as hypertension, obesity, and diabetes, should occur in tandem.32
Effective strategies are needed to mitigate ASCVD risk among cancer survivors. There have been no prospective studies that validate standard ASCVD screening tools in this population or the consequences of instituting primary prevention therapy. A growing body of evidence supports the inclusion of cancer as a risk-enhancing factor. Multi-modality imaging is recommended by several societies, but the integration of CAC and CCTA into risk stratifying the oncologic patient requires further research. In lieu of these data, the AHA's Life's Simple 7 is a highly applicable clinical tool for attenuating ASCVD risk. Providing care to patients with cancer is challenging considering the underlying traditional cardiac risk factors in the setting of evolving cancer therapies. As such, a multidisciplinary survivorship team is likely necessary to provide comprehensive cardiac care.
- Miller KD, Nogueira L, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin 2019;69:363-85.
- Al-Kindi SG, Oliveira GH. Prevalence of Preexisting Cardiovascular Disease in Patients With Different Types of Cancer: The Unmet Need for Onco-Cardiology. Mayo Clin Proc 2016;91:81-3.
- Jaiswal S, Natarajan P, Silver AJ, et al. Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med 2017;377:111-21.
- Mulrooney DA, Yeazel MW, Kawashima T, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ 2009;339:b4606.
- Curigliano G, Cardinale D, Dent S, et al. Cardiotoxicity of anticancer treatments: Epidemiology, detection, and management. CA Cancer J Clin 2016;66:309-25.
- Kim TD, Rea D, Schwarz M, et al. Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib. Leukemia 2013;27:1316-21.
- Zamorano JL, Lancellotti P, Rodriguez Muñoz D, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016;37:2768-801.
- Drobni ZD, Alvi RM, Taron J, et al. Association Between Immune Checkpoint Inhibitors With Cardiovascular Events and Atherosclerotic Plaque. Circulation 2020:142:2299-311.
- Mertens AC, Liu Q, Neglia JP, et al. Cause-specific late mortality among 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 2008;100:1368-79.
- Armstrong GT, Chen Y, Yasui Y, et al. Reduction in Late Mortality among 5-Year Survivors of Childhood Cancer. N Engl J Med 2016;374:833-42.
- Mulrooney DA, Armstrong GT, Huang S, et al. Cardiac Outcomes in Adult Survivors of Childhood Cancer Exposed to Cardiotoxic Therapy: A Cross-sectional Study. Ann Intern Med 2016;164:93-101.
- Iliescu CA, Grines CL, Herrmann J, et al. SCAI Expert consensus statement: Evaluation, management, and special considerations of cardio-oncology patients in the cardiac catheterization laboratory (endorsed by the cardiological society of india, and sociedad Latino Americana de Cardiologıa intervencionista). Catheter Cardiovasc Interv 2016;87:E202-E223.
- Kintzel PE, Chase SL, Schultz LM, O'Rourke TJ. Increased risk of metabolic syndrome, diabetes mellitus, and cardiovascular disease in men receiving androgen deprivation therapy for prostate cancer. Pharmacotherapy 2008;28:1511-22.
- Strongman H, Gadd S, Matthews A, et al. Medium and long-term risks of specific cardiovascular diseases in survivors of 20 adult cancers: a population-based cohort study using multiple linked UK electronic health records databases. Lancet 2019;394:1041-54.
- Hess CN, Roe MT, Clare RM, et al. Relationship Between Cancer and Cardiovascular Outcomes Following Percutaneous Coronary Intervention. J Am Heart Assoc 2015;4.e001779
- Landes U, Kornowski R, Bental T, et al. Long-term outcomes after percutaneous coronary interventions in cancer survivors. Coron Artery Dis 2017;28:5-10.
- Reed GW, Masri A, Griffin BP, Kapadia SR, Ellis SG, Desai MY. Long-Term Mortality in Patients With Radiation-Associated Coronary Artery Disease Treated With Percutaneous Coronary Intervention. Circ Cardiovasc Interv 2016;9:e003483.
- D'Agostino RB Sr, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation 2008;117:743-53.
- Karmali KN, Goff DC Jr, Ning H, Lloyd-Jones DM. A systematic examination of the 2013 ACC/AHA pooled cohort risk assessment tool for atherosclerotic cardiovascular disease. J Am Coll Cardiol 2014;64:959-68.
- Virani SA, Dent S, Brezden-Masley C, et al. Canadian Cardiovascular Society Guidelines for Evaluation and Management of Cardiovascular Complications of Cancer Therapy. Can J Cardiol 2016;32:831-41.
- Carver JR, Shapiro CL, Ng A, et al. American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J Clin Oncol 2007;25:3991-4008.
- Chow EJ, Chen Y, Hudson MM, et al. Prediction of Ischemic Heart Disease and Stroke in Survivors of Childhood Cancer. J Clin Oncol 2018;36:44-52.
- Jurado J, Thompson PD. Prevention of coronary artery disease in cancer patients. Pediatr Blood Cancer 2005;44:620-4.
- Lloyd-Jones DM, Hong Y, Labarthe D, et al. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association's strategic Impact Goal through 2020 and beyond. Circulation 2010;121:586-613.
- Desai MY, Windecker S, Lancellotti P, et al. Prevention, Diagnosis, and Management of Radiation-Associated Cardiac Disease: JACC Scientific Expert Panel. J Am Coll Cardiol 2019;74:905-27.
- Heidenreich PA, Hancock SL, Lee BK, Mariscal CS, Schnittger I. Asymptomatic cardiac disease following mediastinal irradiation. J Am Coll Cardiol 2003;42:743-9.
- Lancellotti P, Nkomo VT, Badano LP, et al. Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. J Am Soc Echocardiogr 2013;26:1013-32.
- Andersen R, Wethal T, Günther A, et al. Relation of coronary artery calcium score to premature coronary artery disease in survivors >15 years of Hodgkin's lymphoma. Am J Cardiol 2010;105:149-52.
- Roos CTG, van den Bogaard VAB, Greuter MJW, et al. Is the coronary artery calcium score associated with acute coronary events in breast cancer patients treated with radiotherapy? Radiother Oncol 2018;126:170-6.
- Whelton SP, Al Rifai M, Dardari Z, et al. Coronary artery calcium and the competing long-term risk of cardiovascular vs. cancer mortality: the CAC Consortium. Eur Heart J Cardiovasc Imaging 2019;20:389-95.
- Biersmith MA, Tong MS, Guha A, Simonetti OP, Addison D. Multimodality Cardiac Imaging in the Era of Emerging Cancer Therapies. J Am Heart Assoc 2020;9.
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:e285-e350.
Clinical Topics: Cardio-Oncology, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Computed Tomography, Echocardiography/Ultrasound, Magnetic Resonance Imaging, Nuclear Imaging, Diet, Exercise, Hypertension
Keywords: Cardio-oncology, Cardiotoxicity, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Survivors, Vascular Endothelial Growth Factor A, Cardiovascular Diseases, Cisplatin, Cholesterol, LDL, PCSK9 protein, human, Proprotein Convertase 9, Androgen Antagonists, Androgens, Coronary Artery Disease, American Heart Association, Metabolic Syndrome X, Antimetabolites, Echocardiography, Stress, Insulin Resistance, Hyperlipidemias, Testicular Neoplasms, Cause of Death, Risk Factors, Early Detection of Cancer, Prostatic Neoplasms, Exercise, Atherosclerosis, Myocardial Infarction, Diabetes Mellitus, Primary Prevention, Electrocardiography, Magnetic Resonance Imaging, Thrombosis, Hypertension, Angiography, Positron-Emission Tomography, Obesity, Ischemia, Tobacco Use, Acceleration, Risk Assessment, Diet, Protein Kinase Inhibitors, Radiation Dosage, Reference Standards, Breast Neoplasms
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