ASCVD Risk Stratification Among Cancer Survivors

May 10, 2021   |  Jeffrey Kolominsky, MD; Wendy Bottinor, MD; Mahmoud Al Rifai, MD, MPH, FACC; Antonio Abbate, MD, FACC; Salim S. Virani, MD, FACC; Jaideep Patel, MD, FACC

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Quick Takes

  • 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
Immunotherapy		 CAD
Cerebrovascular attack
Prostate/testicular Anti-androgens
Platinum agents (cisplatin)		 Metabolic syndrome
CAD
Breast Chest radiotherapy
Hormone therapy		 CAD
Cerebrovascular attack
Lung Chest radiotherapy CAD
Adult leukemia/lymphoma Tyrosine kinase inhibitors CAD
Peripheral artery disease Cerebrovascular attack
Ovarian/testicular Platinum agents (cisplatin) CAD
Colorectal VEGF inhibitors (bevacizumab, sorafenib)
Antimetabolites (fluorouracil)		 Hypertension, arterial thrombosis
Vasospasm, ischemia

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

Summary
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.

References

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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, 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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