Updates in the management of cancer therapy-related hypertension.

PURPOSE OF REVIEW: To provide a comprehensive review of hypertension among patients with cancer. Several cancer therapies cause hypertension which has resulted in a growing and vulnerable population of patients with difficult to control hypertension which has significant downstream effects. RECENT FINDINGS: Hypertension affects up to 50% of cancer patients and higher comorbidity when compared to the general population. Many anticancer therapies can cause hypertension through their treatment effect. Antihypertensive treatment is crucial given cardiovascular mortality is a leading cause of death among cancer patients. It is already known that hypertension is poorly controlled in the general population, and there are additional challenges in management among patients with cancer. Patients with cancer suffer from multimorbidity, are on multiple medications creating concern for drug interactions, and often have blood pressure lability, which can worsen clinical inertia among patients and their providers. It is crucial to effectively treat hypertension in cancer patients to mitigate downstream adverse cardiovascular events. SUMMARY: In recent years, there have been significant changes in management guidelines of hypertension and simultaneously as influx of new cancer therapeutics. We provide an update on hypertension treatment among patients with cancer on different chemotherapeutic agents.

Update on Immunotherapy Cardiotoxicity: Checkpoint Inhibitors, CAR T, and Beyond.

OPINION STATEMENT: Immunotherapy is an innovative approach to cancer treatment that involves using the body's immune system to fight cancer. The landscape of immunotherapy is constantly evolving, as new therapies are developed and refined. Some of the most promising approaches in immunotherapy include immune checkpoint inhibitors (ICIs): these drugs target proteins on the surface of T-cells that inhibit their ability to attack cancer cells. By blocking these proteins, checkpoint inhibitors allow T-cells to recognize and destroy cancer cells more effectively. CAR T-cell therapy: this therapy involves genetically modifying a patient's own T-cells to recognize and attack cancer cells. CAR T-cell therapy exhibits favorable response in many patients with refractory hematological cancers with growing clinical trials in solid tumors. Immune system modulators: these drugs enhance the immune system's ability to fight cancer by stimulating the production of immune cells or inhibiting the activity of immune-suppressing cells. While immunotherapy has shown great promise in the treatment of cancer, it can also pose significant cardiac side effects. Some immunotherapy drugs like ICIs can cause myocarditis, which can lead to chest pain, shortness of breath, and heart failure. Other cardiac side effects of ICIs include arrhythmias, pericarditis, vasculitis, and accelerated atherosclerosis. It is important for patients receiving immunotherapy to be monitored closely for these side effects, as prompt treatment can help prevent serious complications. Patients should also report any symptoms to their healthcare providers right away, so that appropriate action can be taken. CAR T-cell therapy can also illicit an exaggerated immune response creating cytokine release syndrome (CRS) that may precipitate cardiovascular events: arrhythmias, myocardial infarction, and heart failure. Overall, while immune modulating therapy is a promising and expanding approach to cancer treatment, it is important to weigh the potential benefits against the risks and side effects, especially in patients with high risk for cardiovascular complications.

Future Perspectives of Cardiovascular Biomarker Utilization in Cancer Survivors: A Scientific Statement From the American Heart Association.

Improving cancer survival represents the most significant effect of precision medicine and personalized molecular and immunologic therapeutics. Cardiovascular health becomes henceforth a key determinant for the direction of overall outcomes after cancer. Comprehensive tissue diagnostic studies undoubtedly have been and continue to be at the core of the fight against cancer. Will a systemic approach integrating circulating blood-derived biomarkers, multimodality imaging technologies, strategic panomics, and real-time streams of digitized physiological data overcome the elusive cardiovascular tissue diagnosis in cardio-oncology? How can such a systemic approach be personalized for application in day-to-day clinical work, with diverse patient populations, cancer diagnoses, and therapies? To address such questions, this scientific statement approaches a broad definition of the biomarker concept. It summarizes the current literature on the utilization of a multitude of established cardiovascular biomarkers at the intersection with cancer. It identifies limitations and gaps of knowledge in the application of biomarkers to stratify the cardiovascular risk before cancer treatment, monitor cardiovascular health during cancer therapy, and detect latent cardiovascular damage in cancer survivors. Last, it highlights areas in biomarker discovery, validation, and clinical application for concerted efforts from funding agencies, scientists, and clinicians at the cardio-oncology nexus.

Evaluating anthracycline + taxane versus taxane-based chemotherapy in older women with node-negative triple-negative breast cancer: a SEER-Medicare study.

PURPOSE: Adjuvant chemotherapy reduces recurrence in early-stage triple-negative breast cancer (TNBC). However, data are lacking evaluating anthracycline + taxane (ATAX) versus taxane-based (TAX) chemotherapy in older women with node-negative TNBC, as they are often excluded from trials. The purpose of this study was to evaluate the effect of adjuvant ATAX versus TAX on cancer-specific (CSS) and overall survival (OS) in older patients with node-negative TNBC. PATIENTS AND METHODS: Using the SEER-Medicare database, we selected patients aged ≥ 66 years diagnosed with Stage T1-4N0M0 TNBC between 2010 and 2015 (N = 3348). Kaplan-Meier survival curves and adjusted Cox proportional hazards models were used to estimate 3-year OS and CSS. Multivariant Cox regression analysis was used to identify independent factors associated with use of ATAX compared to TAX. RESULTS: Approximately half (N = 1679) of patients identified received chemotherapy and of these, 58.6% (N = 984) received TAX, 25.0% (N = 420) received ATAX, and 16.4% (N = 275) received another regimen. Three-year CSS and OS was improved with any adjuvant chemotherapy from 88.9 to 92.2% (p = 0.0018) for CSS and 77.2% to 88.6% for OS (p < 0.0001). In contrast, treatment with ATAX compared to TAX was associated with inferior 3-year CSS and OS. Three-year CSS was 93.7% with TAX compared to 89.8% (p = 0.048) for ATAX and OS was 91.0% for TAX and 86.4% for ATAX (p = 0.032). CONCLUSION: While adjuvant chemotherapy was associated with improved clinical outcomes, the administration of ATAX compared to TAX was associated with inferior 3-year OS and CSS in older women with node-negative TNBC. The use of adjuvant ATAX should be considered carefully in this patient population.

Current Practice in Carcinoid Heart Disease and Burgeoning Opportunities.

OPINION STATEMENT: Cardiac surgery with tricuspid valve and potentially pulmonic valve replacement at an experienced center is currently the most effective strategy available for the treatment of carcinoid heart disease. Cardiac surgery for carcinoid heart disease requires a multidisciplinary team including cardiology, medical oncology, cardiothoracic anesthesia, and cardiac surgery. Without cardiac surgery, morbidity and mortality from carcinoid heart disease is high. Aggressive management of carcinoid before and after cardiac surgery is critical. Over time, though, circulating carcinoid hormones can lead to destruction of prosthetic valves as well, resulting in recurrent right heart failure. Percutaneous options for valve repair may be on the horizon for management of carcinoid heart disease.

Innovations in Cardio-oncology Resulting from the COVID-19 Pandemic.

OPINION STATEMENT: The COVID pandemic has transformed our approach to patient care, research, and training in cardio-oncology. While the early phases of the COVID pandemic were exceptionally frightening, we now can reflect on the innovative changes that brought more effective and patient-centered care to our doorsteps: expansion of telemedicine, integration of digital health, wider adoption of cardiac biomarkers, consolidation, and coordination of cardio-oncology testing. Normally, it takes years for health care systems to adopt new technology or modify patient care pathways; however, COVID pushed healthcare providers and the health systems to change at warp speed. All of these innovations have improved our efficacy and provided a more "patient-centered" approach for our cardio-oncology patients. The changes we have made in cardio-oncology will likely remain well beyond the pandemic and continue to grow improving the cardiovascular care of oncology patients.

Collaborative cardiovascular management of patients with chronic myeloid leukemia on tyrosine kinase inhibitors.

Tyrosine kinase inhibitors (TKIs) of the BCR-ABL fusion protein have dramatically changed the mortality of chronic myeloid leukemia (CML) but they carry a risk of serious vascular morbidity. While TKIs do not cure CML, daily oral administration of a TKI can control CML and TKIs are chronic medications. Interestingly, vascular complications can occur at any time a patient is on a TKI. Therefore, it is imperative that all care team members and patients are aware of and watching for possible vascular complications. In the following review, a case of arterial thrombosis secondary to the TKI ponatinib is presented as well as a discussion of thrombotic and vascular adverse events reported with TKIs. TKIs are metabolized through the cytochrome P450 system and important drug interactions to consider are reviewed. Finally, we present a multidisciplinary approach to the management of patients with CML on TKIs.

Strategies to Prevent Cardiotoxicity.

OPINION STATEMENT: Cardiovascular disease is a leading cause of death among cancer survivors. While the field of cardiology as a whole is driven by evidence generated through robust clinical trials, data in cardio-oncology is limited to a relatively small number of prospective clinical trials with heterogeneous groups of cancer patients. In addition, many pharmaceutical trials in oncology are flawed from a cardiovascular perspective because they exclude patients with significant cardiovascular (CV) history and have wide variation in the definitions of CV events and cardiotoxicity. Ultimately, oncology trials often underrepresent the possibility of cardiovascular events in a "real world" population. Thus, the signal for CV toxicity from a cancer treatment is often not manifested until phase IV studies; where we are often caught trying to mitigate the CV effects rather than preventing them. Most of the data about cardiotoxicity from cancer therapy and cardioprotective strategies has been developed from our experience in using anthracyclines for over 50 years with dramatic improvement in cancer survivorship. However, as we are in an era where cancer drug discovery is moving at lightning pace with increasing survival rates, it is imperative to move beyond anthracyclines and commit to research on the cardiovascular side effects of all aspects of cancer therapy with a focus on prevention. We emphasize the role of pre-cancer treatment CV assessment to anticipate cardiac issues and ultimately optimizing CV risk prior to cancer therapy as an opportunity to mitigate cardiovascular risk from cancer therapy.

Cardiovascular Disease and Breast Cancer: Where These Entities Intersect: A Scientific Statement From the American Heart Association.

Cardiovascular disease (CVD) remains the leading cause of mortality in women, yet many people perceive breast cancer to be the number one threat to women's health. CVD and breast cancer have several overlapping risk factors, such as obesity and smoking. Additionally, current breast cancer treatments can have a negative impact on cardiovascular health (eg, left ventricular dysfunction, accelerated CVD), and for women with pre-existing CVD, this might influence cancer treatment decisions by both the patient and the provider. Improvements in early detection and treatment of breast cancer have led to an increasing number of breast cancer survivors who are at risk of long-term cardiac complications from cancer treatments. For older women, CVD poses a greater mortality threat than breast cancer itself. This is the first scientific statement from the American Heart Association on CVD and breast cancer. This document will provide a comprehensive overview of the prevalence of these diseases, shared risk factors, the cardiotoxic effects of therapy, and the prevention and treatment of CVD in breast cancer patients.

Nano-transfersomal formulations for transdermal delivery of asenapine maleate: in vitro and in vivo performance evaluations.

CONTEXT: Asenapine maleate (ASPM) is an antipsychotic drug for the treatment of schizophrenia and bipolar disorder. Extensive metabolism makes the oral route inconvenient for ASPM. OBJECTIVE: The objective of this study is to increase ASPM bioavailability via transdermal route by improving the skin permeation using combined strategy of chemical and nano-carrier (transfersomal) based approaches. MATERIALS AND METHODS: Transfersomes were prepared by the thin film hydration method using soy-phosphatidylcholine (SPC) and sodium deoxycholate (SDC). Transfersomes were characterized for particle size, polydispersity index (PDI), zeta potential (ZP), entrapment efficiency, surface morphology, and in vitro skin permeation studies. Various chemical enhancers were screened for skin permeation enhancement of ASPM. Optimized transfersomes were incorporated into a gel base containing suitable chemical enhancer for efficient transdermal delivery. In vivo pharmacokinetic study was performed in rats to assess bioavailability by transdermal route against oral administration. RESULTS AND DISCUSSION: Optimized transfersomes with drug:SPC:SDC weight ratio of 5:75:10 were spherical with an average size of 126.0 nm, PDI of 0.232, ZP of -43.7 mV, and entrapment efficiency of 54.96%. Ethanol (20% v/v) showed greater skin permeation enhancement. The cumulative amount of ASPM permeated after 24 h (Q24) by individual effect of ethanol and transfersome, and in combination was found to be 160.0, 132.9, and 309.3 µg, respectively, indicating beneficial synergistic effect of combined approach. In vivo pharmacokinetic study revealed significant (p < 0.05) increase in bioavailability upon transdermal application compared with oral route. CONCLUSION: Dual strategy of permeation enhancement was successful in increasing the transdermal permeation and bioavailability of ASPM.

Provocation of atrial fibrillation triggers during ablation: does the use of general anesthesia affect inducibility?

INTRODUCTION: The autonomic nervous system exerts important effects upon atrial fibrillation (AF) initiation. The strategy of anesthesia used during AF ablation may impact the provocation of AF triggers. We hypothesized that the use of general anesthesia (GA) would reduce the incidence of provokable AF triggers in patients undergoing AF ablation compared to patients studied while receiving only conscious sedation (CS). METHODS AND RESULTS: We performed a prospective, case control study comparing the incidence of provokable AF triggers in a consecutive series of patients undergoing AF ablation under GA using a standard trigger induction protocol. We compared the frequency and distribution of AF triggers to a second cohort of historical controls (matched for age, gender, left atrial dimension, and AF phenotype) who underwent ablation while receiving CS. We calculated that 44 total subjects (22 patients in each group) were required to detect a 50% reduction in the incidence of AF triggers in the GA cohort. There was no difference between the 2 groups in the rate of AF trigger inducibility (77% vs. 68%, P = 0.26) or the number of triggers provoked per patient (1.2 ± 0.8 vs. 1.3 ± 0.8, P = 0.38). Patients ablated under GA required higher doses of phenylephrine during the trigger induction protocol (408.3 mg [52-600] vs. 158.3 mg [0-75]; P = 0.003), and tended to require higher doses of isoproterenol to initiate triggers (92.8 mg [20-111] vs. 63.6 mg [6-103]; P = 0.25). CONCLUSION: AF trigger induction during GA is both safe and efficacious.

Major cardiovascular adverse events in older adults with early-stage triple-negative breast cancer treated with adjuvant taxane + anthracycline versus taxane-based chemotherapy regimens: A SEER-medicare study.

BACKGROUND: Triple-negative breast cancer (TNBC) is more aggressive as compared to other subtypes of breast cancer with characteristic metastatic patterns and a poor prognosis. The standard of care for early-stage TNBC is historically anthracycline and taxane-based chemotherapy (ATAX). Despite the effectiveness of this regimen, anthracyclines carry a small but important risk of cardiotoxicity, which is specifically a concern in the older population. This study evaluates major adverse cardiovascular events (MACE) in older women with TNBC treated with ATAX compared to taxane-based chemotherapy (TAX). METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we identified women aged 66 and older with TNBC diagnosed between 2010 and 2015 (N = 2215). We compared patient and clinical characteristics according to adjuvant chemotherapy regimen (chemotherapy versus no chemotherapy and ATAX versus TAX). Logistic regression was performed to estimate the odds ratios (OR) and 95% confidence intervals (CIs), Kaplan-Meier survival curves were generated to estimate three-year overall survival (OS) and cancer specific survival (CSS). Cox proportional hazards models were used to analyze OS and CSS while controlling for patient and tumor characteristics. MACE was defined as acute myocardial infarction, heart failure, potentially fatal arrhythmia, and cerebral vascular incidence. Few patients experienced a cardiac death and therefore this was excluded in the analysis. RESULTS: Of the 2215 patients in our cohort, most patients (n = 1334; 60.26%) received TAX compared to ATAX (n = 881; 39.78%). Patients who received ATAX were not statistically significantly more likely than those who received TAX to experience acute myocardial infarction, cerebral vascular accident (CVA), or potentially fatal arrhythmia when controlling for traditional risk factors. Among patients who experienced MACE, there was no difference in OS or CSS in patients who received TAX vs ATAX. Patients who received ATAX were less likely to develop heart failure than those who received TAX (OR 0.63, 95% CI [0.45-0.88], p < 0.01). Patients who developed MACE and who were > 76 years old had worse OS compared to those who experienced MACE and were age 66-75 years old (HR 1.67, 95% CI [1.07-2.62], p = 0.02). CONCLUSION: Among older women with TNBC, receipt of adjuvant chemotherapy with ATAX was not associated with increased risk of major adverse cardiac events. For those who experienced a cardiac event, there was no difference in survival amongst those who received TAX vs ATAX. Other factors including additional chemotherapy toxicities should be investigated as a potential etiology for the inferior OS previously observed with ATAX vs TAX in older women with node negative or 1-3 positive lymph nodes.

Clinical outcomes of adjuvant taxane plus anthracycline versus taxane-based chemotherapy regimens in older adults with node-positive, triple-negative breast cancer: A SEER-Medicare study.

BACKGROUND: Triple-negative breast cancer (TNBC) is a subtype of breast cancer associated with an aggressive clinical course. Adjuvant chemotherapy reduces the risk of recurrence and improves survival in patients with node-positive TNBC. The benefit of anthracycline plus taxane (ATAX) regimens compared with non-anthracycline-containing, taxane-based regimens (TAX) in older women with node-positive TNBC is not well characterised. METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified 1106 women with node-positive TNBC diagnosed at age 66 years and older between 2010 and 2015. We compared patient clinical characteristics according to adjuvant chemotherapy regimen (chemotherapy versus no chemotherapy and ATAX versus TAX). Logistic regression was performed to estimate the odds ratios (OR) and 95% confidence intervals (CIs). Kaplan-Meier survival curves were generated to estimate 3-year overall survival (OS) and cancer-specific survival (CSS). Cox proportional hazard models were used to analyse OS and CSS while controlling for patient and tumour characteristics. RESULTS: Of the 1106 patients in our cohort, 767 (69.3%) received adjuvant chemotherapy with ATAX (364/767, 47.5%), TAX (297/767, 39%) or other regimens (106/767, 13.8%). Independent predictors of which patients were more likely to receive ATAX versus TAX included more extensive nodal involvement (≥4), age, marital/partner status and non-cardiac comorbidities. There was a statistically significant improvement in 3-year CSS (81.8% versus 71.4%) and OS (70.7% versus 51.3%) with the use of any chemotherapy in our cohort (P < 0.01). Three-year CSS and OS for patients who received ATAX versus TAX were similar at 82.8% versus 83.7% (P = 0.80) and 74.2% versus 72.7% (P = 0.79), respectively. There was a trend towards improved CSS and OS in patients with four or more positive lymph nodes who received ATAX versus TAX (hazard ratio 0.66, 95% CI: 0.36-1.23, P = 0.19 and hazard ratio 0.68, 95% CI: 0.41-1.14, P = 0.14, respectively). CONCLUSION: Among older women with node-positive TNBC, a majority of patients received adjuvant chemotherapy, which was associated with an improvement in CSS and OS. When compared with TAX chemotherapy, there was a trend towards better outcomes with ATAX for patients with ≥4 nodes.

COVID-19 severity and cardiovascular outcomes in SARS-CoV-2-infected patients with cancer and cardiovascular disease.

Background: Data regarding outcomes among patients with cancer and co-morbid cardiovascular disease (CVD)/cardiovascular risk factors (CVRF) after SARS-CoV-2 infection are limited. Objectives: To compare Coronavirus disease 2019 (COVID-19) related complications among cancer patients with and without co-morbid CVD/CVRF. Methods: Retrospective cohort study of patients with cancer and laboratory-confirmed SARS-CoV-2, reported to the COVID-19 and Cancer Consortium (CCC19) registry from 03/17/2020 to 12/31/2021. CVD/CVRF was defined as established CVD or no established CVD, male ≥ 55 or female ≥ 60 years, and one additional CVRF. The primary endpoint was an ordinal COVID-19 severity outcome including need for hospitalization, supplemental oxygen, intensive care unit (ICU), mechanical ventilation, ICU or mechanical ventilation plus vasopressors, and death. Secondary endpoints included incident adverse CV events. Ordinal logistic regression models estimated associations of CVD/CVRF with COVID-19 severity. Effect modification by recent cancer therapy was evaluated. Results: Among 10,876 SARS-CoV-2 infected patients with cancer (median age 65 [IQR 54-74] years, 53% female, 52% White), 6253 patients (57%) had co-morbid CVD/CVRF. Co-morbid CVD/CVRF was associated with higher COVID-19 severity (adjusted OR: 1.25 [95% CI 1.11-1.40]). Adverse CV events were significantly higher in patients with CVD/CVRF (all p<0.001). CVD/CVRF was associated with worse COVID-19 severity in patients who had not received recent cancer therapy, but not in those undergoing active cancer therapy (OR 1.51 [95% CI 1.31-1.74] vs. OR 1.04 [95% CI 0.90-1.20], pinteraction <0.001). Conclusions: Co-morbid CVD/CVRF is associated with higher COVID-19 severity among patients with cancer, particularly those not receiving active cancer therapy. While infrequent, COVID-19 related CV complications were higher in patients with comorbid CVD/CVRF. (COVID-19 and Cancer Consortium Registry [CCC19]; NCT04354701).

Burden of Cardiovascular Disease in Immune Checkpoint Inhibitor-Treated Patients: Reconciling Adjudicated and Coded Outcomes.

Background: There is growing recognition of the risk of cardiovascular (CV) events, particularly myocarditis, in the context of immune checkpoint inhibitor (ICI) therapy; however, true event rates in real-world populations and in the background of CV disease remain uncertain. Objectives: The authors sought to determine CV event occurrence in ICI-treated patients and assess the accuracy of diagnosis by International Classification of Diseases (ICD) code compared with adjudication using established definitions and full-source documentation review. Methods: Electronic medical record extraction identified potential CV events in ICI-treated patients in the University of Colorado Health system. Two cardiologists independently adjudicated events using standardized definitions. Agreement between ICD codes and adjudicated diagnoses was assessed using the kappa statistic. Results: The cohort comprised 1,813 ICI-treated patients with a mean follow-up of 4.6 ± 3.4 years (3.2 ± 3.2 years pre-ICI and 1.4 ± 1.4 years post-ICI). Venous thromboembolic events (VTEs) were the most common event, occurring in 11.4% of patients pre-ICI and 11.3% post-ICI therapy. Post-ICI therapy, the crude rates of myocardial infarction (MI), heart failure, and stroke were 3.0%, 2.8%, and 1.6%, respectively. Six patients (0.3%) developed myocarditis post-ICI. Agreement between the ICD code and adjudication was greater for VTE (κ = 0.82; 95% CI: 0.79-0.85) and MI (κ = 0.74; 95% CI: 0.66-0.82) and worse for myocarditis (κ = 0.50; 95% CI: 0.20-0.80) and heart failure (κ = 0.47; 95% CI: 0.40-0.54). Conclusions: ICD codes correlated well with adjudicated events for VTE and MI, but correlation was worse for heart failure and myocarditis. Adjudication with standardized definitions can enhance the understanding of the incidence of CV events related to ICI therapy.

Practical cardiovascular imaging approach to diagnose immune checkpoint inhibitor myocarditis.

Immuno-oncology employs various therapeutic strategies that harness a patient's own immune system to fight disease and has been a promising new strategy for cancer therapy over the last decade. Immune checkpoint inhibitors (ICI), are monoclonal antibodies, that increase antitumor immunity by blocking intrinsic down-regulators of immunity, such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) or its ligand, programmed cell death ligand 1 (PD-L1). Seven ICIs are currently approved by the Food and Drug Administration and have increased the overall survival for patients with various cancer subtypes. These are used either as single agents or in combination with other checkpoint inhibitors, small molecular kinase inhibitors or cytotoxic chemotherapies. There are also many other immune modifying agents including other checkpoint inhibitor antibodies that are under investigation in clinical trials.