Addressing Cardiovascular Complications of Cancer Therapy.

Approximately 20 million individuals in the United States are now considered cancer survivors.1 The notable improvement in cancer survival over the past several decades has been attributed in large part to a surge in effective novel anticancer therapies. Of note, cardiovascular disease (CVD) has emerged as a leading cause of nonmalignant morbidity and mortality risk in patients with cancer.2 As highlighted in a recent scientific statement from the American Heart Association (AHA), the specialty of cardio-oncology is now dedicated to increasing awareness and management of cardiovascular sequelae associated with anticancer therapies.3 Many chemotherapy drugs and radiation therapies used to treat oncological conditions are associated with cardiovascular toxicities. The major chemotherapy drug classifications that can lead to cardiovascular toxicities include some alkylating agents (eg, cyclophosphamide), anthracyclines (eg, daunorubicin), monoclonal antibodies (eg, trastuzumab), tyrosine kinase inhibitors, vascular endothelial growth factor signaling pathway inhibitors (eg, bevacizumab), checkpoint inhibitors, hormonal therapies, and corticosteroids. Radiation therapy to the mediastinum or left chest may result in myocardial damage.4 There is a gap in understanding of the mechanisms of the adverse effects, and much research is being conducted to prevent, identify, and treat these cardiovascular complications.5 Unfortunately, evidence suggests that the risk of cardiotoxicity with selected anticancer therapies may be increased among women and underrepresented populations.3 This growing body of evidence prompted the AHA statement with emphasis on promoting equity in cardio-oncology care as well as research.3 Inequity in Cardio-oncology The AHA has offered a general definition of health disparities and inequities with health disparities defined as differences among groups of people closely linked with social, economic, and environmental disadvantages.6 Healthcare inequity in cardio-oncology includes and encompasses medical, genetic, and societal issues and intrinsic cultural barriers that ultimately lead to disparate outcomes. As highlighted in the AHA statement, CVD toxicities associated with anticancer therapies (myocarditis, pericarditis, hypertension, dysrhythmias, heart failure) have been observed to differ by biological sex, race, ethnicity, socioeconomic status, and related social determinants of health (SDOH).3 Population-Specific Considerations: Sex Differences in Cardiotoxicity Risk Emerging data suggest differences in the toxicity profile of several immune and targeted anticancer therapies. For example, in phase 2 and 3 clinical trials, women demonstrated a 34% increased risk of severe, adverse events with anticancer therapy including a 60% higher risk of immune checkpoint inhibitor–associated toxicities.7 The mechanisms of these observed sex differences merit additional investigation at the preclinical and patient levels to determine the biological differences in cardiotoxicity outcomes. Differences in cardiovascular risk factors have also been documented among women treated with more traditional chemotherapies (eg, anthracyclines), commonly used in the treatment of breast cancer.3 Relatedly, a recent report from the Women's Health Initiative estimated the incidence of heart failure subtypes in racially diverse postmenopausal breast cancer survivors and examined associations between lifestyle factors and the subtypes (heart failure with preserved ejection fraction [HFpEF] and heart failure with reduced ejection fraction [HFrEF]).8 The cumulative incidences of hospitalized HFpEF and HFrEF were 6.68% and 3.96%, respectively, over a median of 7.2 years. For HFpEF, previous myocardial infarction, greater waist circumference, and smoking history were the strongest risk factors. Similar patterns with the exception of waist circumference were observed for HFrEF; however, none was significant in multivariate models. Of note, the risk of overall mortality in breast cancer survivors with hospitalized HFpEF was 5.65 (95% confidence interval, 4.11–7.76), and that in those with HFrEF was 3.77 (95% confidence interval, 2.51–5.66). In exploratory analysis, a significant difference in anthracycline-associated risk between the 2 heart failure subtypes was observed with an increased risk observed only for HFrEF. As emphasized in this report, the need to monitor for clinical heart failure overall and going beyond assessment of left ventricular ejection fraction in survivors of breast cancer is warranted, as is need for additional research linking central adiposity and subsequent HFpEF in breast cancer survivors.8 Population-Specific Considerations: Race and Ethnic Differences Documented in clinical and population level data, African American/Black patients have a substantially higher risk for severe cardiotoxicity. Of note, most of the available research has focused on women with breast cancer, with reports indicating a 3-fold increased risk of cardiotoxicity after anthracycline therapies.7,9 One study of patients treated with immune checkpoint inhibitor therapy observed in Black women a 3- to 4-fold increased risk of cardiotoxic events compared with non-Hispanic White counterparts.10 Although the reasons for these observed differences remain to be fully explicated, Black women present with later stages of cancer requiring greater intensity of anticancer therapies. Other research suggests that Black patients experience increased CVD and mortality post cancer diagnosis, even accounting for cancer stage, and socioeconomic and treatment-related factors.11 Cardiovascular risk factor burden has been identified to contribute to global cancer therapy–related CVD risk in all populations. Black men and women in the National Health and Nutrition Examination Survey community cohort had up to a 40% prevalence of hypertension compared with less than 30% among White counterparts.12 Data from cancer survivor studies indicate disproportionately higher rates of hypertension in Black populations, which may increase the risk of cancer therapy–related CVD, especially related to heart failure.3 Taken together, available data and anecdotal observations indicate knowledge gaps in cardiotoxic risks and outcomes among Black survivors of cancer and point to the need for research focused on factors and mechanistic drivers behind these differences. In the United States, Hispanic individuals are diverse in origin, heritage, sociodemographic characteristics, patterns of immigration, and degree of acculturation. Cardiovascular disease and cancer are the major causes of morbidity and mortality. Hispanic patients are less likely to be given a diagnosis of cancer early compared with non-Hispanic White counterparts.3 As such, they have a more complex CVD cancer diagnosis at later stages and restrictions to more cardiotoxic regimens attributable, in part, to lack of eligibility for novel treatments.3 Taken together, this contributes to a higher incidence of treatment complications, cardiac dysfunction, and adverse patient outcomes and suggests the need for additional research focused on the constellation of modifiable and nonmodifiable factors that contribute to inequities in diagnosis and treatment of cancer in Hispanic/Latino populations.3 As underscored in the AHA statement, there are similarities between Hispanic and Asian and Pacific Islander populations; cancer and CVD are the major causes of morbidity and mortality.3 Available data are in the aggregate and do not capture the similarities and differences in exposures and outcomes between and among the diverse Asian and Pacific Islander populations. Noted in a recent study documenting age-adjusted mortality rates in cardio-oncology patients were higher in countries with greater social vulnerability; the role of social factors in contributing to cancer therapy–related CVDs is a critically important consideration in comprehensive treatment for patients presenting with a diagnosis of cancer.13 Over the last 2 decades, survival rates for an array of pediatric cancers, particularly acute lymphocytic leukemia, have increased substantially. Global studies have indicated improved survival outcomes after a primary cancer diagnosis, but more adverse long-term outcomes compared with general populations of children and youth.3 Of note, long-term survivors have a 7-to-9 times higher risk of death from cardiac-related events compared with the general population.14,15 Such events included heart failure, valvular disease, and coronary artery disease. Survivors of pediatric cancers have also demonstrated increased rates of hypertension, dyslipidemias, and vascular diseases compared with the general population.14,15 From the perspective of primordial and primary prevention, available data support the need for monitoring and periodic assessment of CVD risk factors in children and youth presenting with a diagnosis of cancer and beg the need for additional research focused on the determinants of risk and health outcomes for this special population of cancer survivors. Social Determinants of Health: Important Considerations Social determinants of health, the circumstances in which individuals are born, grow, school, live, work, and age, are recognized as foundational contexts for promoting optimal health across the life course.16 Substantial clinical and epidemiologic data link adverse SDOH reflecting individuals' economic stability, education access and quality, healthcare access and quality, neighborhood and built environment, and social and community context to health disparities and suboptimal health across the life course.3,16 Studies have demonstrated the adverse impact of healthcare disparities on outcomes of individuals with CVD. The AHA issued a statement addressing SDOH in CVD and suggested interventions to address economic profile, healthcare coverage, health literacy, and ethnic and racial disparities.17 Similar to CVD, the role of SDOH in the risks, rates, and survival of multiple cancers is increasingly emphasized; the American Cancer Society recently released a framework of practice, research, and policy to better recognize and address the SDOH in cancer.18 Emerging evidence suggests that SDOH play a vital role in the health of cardio-oncology patients.19 Taken together, available and emerging evidence supports the need to assess SDOH in the practice of caring for cardio-oncology patients as well as attention to the strategies designed to improve equity (discussed below). Strategies Designed to Improve Equity in Cardio-oncology Care and Research On the basis of the collective evidence and observations, the AHA's statement on improving equity in cardio-oncology care and research highlights several strategies (not in rank order)3: Investigating biological mechanisms including potential biological pathways and factors (eg, gene variation) with the aim of enabling tailoring of care in an era of increasing focus on precision medicine. Intentionally diversifying clinical trials including promoting enrollment of women and individuals from underrepresented groups in cardio-oncology clinical trials as well as in leadership of such trials. Integrating SDOH into clinical care delivery with aims of raising awareness of the social and financial inequities in cardio-oncology and increasing local and public advocacy for treatment pathways that provide fiscally conscious optimal care that can help address inequities and improve patient outcomes. Improving access to care with the aim of exploring the effectiveness of including equitable telehealth/remote access in cardio-oncology care. Cardiovascular nurses functioning in clinical and community-based settings have critically important roles in providing evidence-based care for cardio-oncology patients. As members of multidisciplinary teams in cardio-oncology programs, cardiovascular nurses have opportunities to identify, assess, and manage cardiovascular risk factors including lifestyle behaviors central to optimal health as well as SDOH that impact preventive and ongoing care for cardio-oncology patients.20–22 Patients should have a thorough baseline cardiovascular risk assessment before undergoing cancer therapy.4,22 For those with preexisting CVD or risk factors, guidelines-directed management is recommended. Choosing chemotherapy drugs with lower cardiovascular toxicities may be considered if possible. Consultation between oncology and cardiology providers is strongly recommended.22 Preventive adjuvant therapies are emerging based on the cancer treatment regimen.4 Patients who have had a previous cancer diagnosis and treatment should be followed across the life span to identify cardiovascular complications that may develop in the future. Aware of the potential short- and long-term adverse effects of selected cancer therapies, particularly for women and underrepresented groups, cardiovascular nurses have opportunities across healthcare and community settings to provide evidence-based holistic care that includes and encompasses primordial, primary, and secondary prevention. As highlighted in the AHA statement3 and in this Prevention Column, substantial knowledge gaps exist in promoting equity in cardio-oncology with opportunities for nurse scientists and nursing.