Case Vignette

A 54-year-old woman with recently diagnosed triple negative breast cancer is undergoing neoadjuvant therapy with doxorubicin, cyclophosphamide, and paclitaxel. She develops acute chest pain during her third infusion of paclitaxel. Her electrocardiogram is notable for 2 mm ST-segment elevations in leads V1-V6. She is taken emergently for cardiac catheterization, and an acute occlusion of the proximal left anterior descending artery is revealed. Intravascular ultrasound-guided percutaneous coronary intervention (PCI) is performed, and an everolimus-eluting stent is deployed in the proximal left anterior descending artery. She is treated with aspirin, ticagrelor, and heparin initially, followed by aspirin 81 mg daily and ticagrelor 90 twice daily for 6 weeks. She subsequently undergoes successful tumor resection without any complications.

Introduction

The complex relationship between cancer and cardiovascular disease is increasingly being recognized. Reasons for the link between cancer and cardiovascular disease include the shared risk factors, such as obesity, diabetes, hypertension, hyperlipidemia, tobacco use, diet, physical activity, and older age.¹ The toxicities of cancer treatment also contribute to this relationship. Several chemotherapeutic agents have been associated with acute coronary syndromes (ACS), including antimetabolites (5-fluorouracil, capecitabine, gemcitabine), anti-microtubule agents (paclitaxel), alkylators (cisplatin, cyclophosphamide), anti-tumor antibiotics (bleomycin), vinca alkaloids (vincristine), proteasome inhibitors (bortezomib, carfilzomib), vascular endothelial growth factor inhibitors (bevacizumab, ramucirumab, aflibercept, sunitinib, sorafenib, pazopanib, axitinib, regorafenib), immunomodulatory drugs (lenalidomide), and BCR-ABL tyrosine kinase inhibitors (nilotinib, ponatinib) (Table 1).^2-6 For some of these agents (cisplatin, ponatinib, nilotinib, and radiation therapy), the risk for coronary disease persists even after cessation of therapy.^2,7 Cancer generates a pro-inflammatory and pro-thrombotic milieu. Tumor biology influences this, and advanced-stage cancers as well as gastric, pancreatic, lung, bladder, testicular, gynecologic, and lymphomatous cancers are considered to have higher prothrombotic potential.^3,8

Table 1: Cancer Therapies Associated With ACS and Potential Mechanisms of Toxicity^2,4-6

Despite the overlap between cancer and cardiovascular disease, data regarding PCI in patients with cancer are limited. Patients with cancer are generally excluded from PCI clinical trials and national registries. Available data, however, do indicate worse outcomes with PCI in patients with cancer compared with those without cancer.⁹ What follows is a discussion about the outcomes and risks of PCI in patients with cancer and potential considerations unique to this patient population.

Outcomes of PCI in Patients With Cancer and Cancer Survivors

As the number of patients with cancer and cancer survivors increases, so does the frequency of PCI performed in these populations^9,10 due to the high prevalence of cardiovascular disease in this subgroup.¹¹ These patients tend to be older and have more co-morbidities than non-cancer populations, which may adversely affect PCI outcomes.^9,10 Some shared risk factors between cancer and cardiovascular disease such as smoking history and diabetes mellitus may also impact post-PCI outcomes.^12,13

In patients who present with ST-segment elevation myocardial infarction, those with cancer are noted to have worse outcomes in comparison to those without cancer. This has been partly attributed to the lower utilization of PCI in patients with cancer.¹⁴ However, among patients with cancer who receive PCI, the incidence of cardiac death is higher at 1 year.¹⁵ The lower use of drug-eluting stents (DES) and glycoprotein IIb/IIIa inhibitors in patients with cancer may contribute to this outcome. In addition, there is a higher incidence of cardiovascular comorbidities among patients with cancer.¹⁵ A cancer diagnosis within the 6 months preceding a ST-segment elevation myocardial infarction is also a risk factor primarily due to higher rates of anemia and cardiogenic shock.¹⁵

Type of cancer may also play a critical role. In a recent study comparing outcomes in the four most common cancers (prostate, breast, colon, and lung), a current diagnosis of lung cancer was associated with a twofold risk of in-hospital mortality and any in-hospital complication.⁹ Colon and prostate cancer were associated with increased bleeding with PCI but a similar mortality risk to patients without cancer. Interestingly, a diagnosis of breast cancer was not associated with increased in-hospital mortality or complications.⁹ Not surprisingly, patients with metastatic cancer who undergo PCI have a higher in-hospital mortality and bleeding risk.⁹

In cancer survivors, rates of mortality and non-fatal myocardial infarction are higher during long-term follow-up after PCI when compared with patients without cancer.¹⁶ However, because malignancies are heterogenous in terms of their natural history, prognosis, and adverse systemic effects, their impact on PCI outcomes are not identical. As such, recent data stratified by cancer type indicated worse outcomes for survivors of lung cancer but not other common malignancies.⁹ This suggests that each patient with cancer may need a different approach in the setting of significant coronary disease to optimize outcomes.

Unique Considerations

In patients with cancer, the balance of coagulability can be challenging. Cancer cells can influence the expression of hemostatic proteins, inflammatory cytokines, proangiogenic factors, procoagulant microparticles, and adhesion molecules, causing hypercoagulability.⁸ It is thought that a cyclic relationship exists in which cancer cells promote thrombosis and clotting proteins support cancer growth.⁸ Patients with cancer are up to 7 times more likely to experience venous thromboembolism (VTE), and this is a leading cause of death.¹⁷ VTE is most common in cancers of the brain, pancreas, stomach, liver, lungs, and kidneys and lymphomas and myeloma.⁸ In addition, clinical factors such as anemia, leukocytosis, and thrombocytosis also play a role. Several risk assessment models have been developed to predict the risk of VTE in patients with cancer.⁸

Cancer can also lead to an increased risk for bleeding. Bleeding occurs in approximately 10% of patients with solid tumors and is even more frequent in patients with hematologic malignancies.⁸ Gastric cancer, thrombocytopenia, and high body mass index are identified risk factors for malignancy-related bleeding.¹⁸

Interventional Approach in Patients With Cancer and Cancer Survivors

In general, all patients with a current or prior history of cancer should be treated as a high-risk group while undergoing PCI. It is essential to minimize the adverse impact of PCI in patients with ongoing cancer therapy, especially when both malignancy and cancer therapy may predispose the patient to bleeding and coagulation abnormalities. Minimizing access site complications by using radial or ulnar artery access instead to femoral artery access is important to reduce bleeding complications.¹⁹ When femoral artery access must be used, safe practices such as using ultrasound and fluoroscopy to guide access should always be in place.¹⁹

Low platelet count should not preclude PCI in situations of ACS, and a platelet count of 40,000-50,000/mL may be sufficient to safely perform most interventional procedures in the absence of associated coagulation abnormalities. In the setting of extremely low platelet counts (20,000/mL or less), platelet transfusion may be considered in consultation with the hematologist or oncologist. Withholding aspirin in thrombocytopenic patients with cancer and ACS has resulted in poorer outcomes.¹⁹

Another consideration is the impact of cancer and cancer therapy on endothelialization and the risk for stent thrombosis. Circulating endothelial cells and endothelial progenitor cells may be decreased due to malignancy and cancer therapy.²⁰ Nevertheless, a recent large study suggested superior outcomes in patients with cancer who had a DES placed compared with those with a bare-metal stent (BMS) placed.⁹ This could represent selection bias, but modern DES have demonstrated excellent outcomes with relatively short (1-3 months) durations of dual antiplatelet therapy (DAPT), and certain DES platforms have shown outcomes superior to BMS with a similar duration of DAPT.²¹ Whenever possible, these new-generation DES should be used instead of BMS.

Optimizing PCI is extremely important in this patient population, particularly given the increased likelihood that shorter duration of DAPT may be required. One important strategy is liberal utilization of intracoronary imaging to avoid stent under-sizing and malapposition and residual untreated complications such as edge dissections, all of which may lead to worse outcomes, especially with shorter duration of DAPT.¹⁹ Recent data suggest that routine use of intracoronary imaging leads to superior outcomes, which is paramount when shorter durations of DAPT are required.²² When possible, bifurcation and overlapping stents should be avoided to reduce the risk of stent thrombosis.¹⁹

The overlap between cancer and cardiovascular disease is significant. As treatments and survival for both diseases continue to improve, the prevalence of patients with both conditions continues to increase. Further data regarding best practices in this patient population are needed. In addition, collaboration between multidisciplinary oncology and cardiology teams is essential to determine the best approach to minimize periprocedural adverse events in patients with cancer and cancer survivors undergoing PCI.

References

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18. Patell R, Gutierrez A, Rybicki L, Khorana AA. Identifying predictors for bleeding in hospitalized cancer patients: A cohort study. Thromb Res 2017;158:38-43.
19. 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:E202-23.
20. Ramcharan KS, Lip GY, Stonelake PS, Blann AD. Effect of standard chemotherapy and antiangiogenic therapy on plasma markers and endothelial cells in colorectal cancer. Br J Cancer 2014;111:1742-9.
21. Varenne O, Cook S, Sideris G, et al. Drug-eluting stents in elderly patients with coronary artery disease (SENIOR): a randomised single-blind trial. Lancet 2018;391:41-50.
22. Zhang J, Gao X, Kan J, et al. Intravascular Ultrasound Versus Angiography-Guided Drug-Eluting Stent Implantation: The ULTIMATE Trial. J Am Coll Cardiol 2018;72:3126-37.

Keywords: Coronary Angiography, Acute Coronary Syndrome, Adenosine, Alkylating Agents, Anemia, Antimetabolites, Arteries, Body Mass Index, Aspirin, Breast Neoplasms, Cardiovascular Diseases, Chest Pain, Comorbidity, Cause of Death, Coronary Artery Disease, Cyclophosphamide, Cytokines, Colon, Cardiac Catheterization, Diabetes Mellitus, Doxorubicin, Drug-Eluting Stents, Diet, Electrocardiography, Exercise, Factor VIII, Femoral Artery, Hematologic Neoplasms, Heparin, Hemorrhage, Hospital Mortality, Follow-Up Studies, Fluoroscopy, Hypertension, Hyperlipidemias, Leukocytosis, Hemostatics, Lymphoma, Liver, Lung Neoplasms, Neoplasms, Obesity, Myocardial Infarction, Neoadjuvant Therapy, Paclitaxel, Percutaneous Coronary Intervention, Platelet Count, Platelet Glycoprotein GPIIb-IIIa Complex, Platelet Transfusion, Prevalence, Prostatic Neoplasms, Prognosis, Proteasome Inhibitors, Referral and Consultation, Referral and Consultation, Risk Assessment, Selection Bias, Risk Factors, Shock, Cardiogenic, Stents, Smoking, Stomach Neoplasms, Thrombocytopenia, Thrombocytosis, Thrombosis, Thrombophilia, Tobacco Use, Ulnar Artery, Vascular Endothelial Growth Factors, Venous Thromboembolism, Cardiotoxicity, Cardiotoxins

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