Definitive evidence exists that certain invasive cardiac procedures can reduce morbidity and mortality in patients with acute coronary syndrome (ACS), severe valvular disease, heart failure, and ventricular arrhythmias. However, it is important to note that the randomized clinical trials (RCTs) supporting these findings excluded individuals with advanced cancer. Simultaneously, the approach to cancer treatment has undergone a paradigm shift in recent years, significantly improving patient survival rates. Until recently, patients with advanced cancer (also referred to as metastatic) were excluded as candidates for any type of cardiac procedures due to the high risk of death from cancer before benefiting from an invasive cardiac intervention. Nonetheless, changes in survival expectations for many of these patients radically challenge this outdated approach.
This review study presents an updated summary of current evidence with the aim of guiding decision-making for metastatic cancer patients who are eligible for cancer-specific treatments and simultaneously present severe cardiovascular disease. It should be noted that the cardiac interventions recommended in this review to improve survival and/or quality of life carry a Class I recommendation and Level A evidence in patients without advanced cancer.
Primary Percutaneous Coronary Intervention in the Context of STEMI
The mortality rate following a STEMI treated with percutaneous coronary intervention (PCI) ranges from 3% to 6%. Primary PCI has shown a significant reduction in short-term mortality (within 4-6 weeks) compared to thrombolytic therapy (Odds Ratio [OR]: 0.7). Additionally, there has been a decrease in the incidence of reinfarction (OR: 0.35) and stroke (OR: 0.46), along with improvements in symptoms and patient quality of life.
On the other hand, the prevalence of coronary artery disease in patients with cancer is higher than in those without it, likely due to an increased inflammatory and prothrombotic state that makes atherosclerotic plaques more vulnerable. Furthermore, primary PCI in patients with STEMI and advanced cancer has shown a lower in-hospital mortality rate compared to those who do not receive percutaneous treatment. However, the evidence on this is limited and biased, as the option of PCI tends to be contraindicated in cancer patients in a preterminal stage.
Following primary PCI for STEMI to treat the culprit lesion, a second-stage PCI targeting non-culprit lesions to achieve complete revascularization has been associated with a reduction in cardiovascular mortality and myocardial infarctions. Additionally, improvements in angina and quality of life have been recorded for at least three years of follow-up. However, it is essential to note that RCTs investigating this complete revascularization strategy exclude patients whose life expectancy unrelated to cardiovascular issues is less than five years.
Therefore, given the immediate benefits of primary PCI, it is recommended in all cases of invasive cancer undergoing first- or second-line treatment, except in terminal cases with a very short life expectancy.
Routine Invasive Strategy in Non–ST-Segment Elevation Acute Coronary Syndrome (NSTEACS)
The comparison between routine invasive and selective invasive strategies in meta-analyses of RCTs involving NSTEACS patients has shown a reduction in the incidence of nonfatal complications. Over a follow-up period of 6 to 24 months, a significant decrease in mortality, acute myocardial infarction (MI), hospital readmissions, and angina was demonstrated, with ORs in all cases below 0.8. Additionally, various RCTs have shown similar results when comparing early catheterization (within the first 24 hours) with delayed catheterization (24-72 hours), suggesting a suitable timeframe to discuss the case in an oncology patient before making a definitive decision.
Although there are no specific RCTs for patients with both NSTEACS and cancer, exploring contemporary administrative records of patients with both conditions seems to indicate that outcomes when comparing medical and invasive treatments are similar to those observed in patients without cancer. However, conducting dedicated studies addressing this population faces the challenge of significant heterogeneity across different cancer types.
In terms of access, when performing PCI, the radial approach has proven more effective than the femoral approach, with a Hazard Ratio (HR) of 0.77 for mortality and 0.55 for major bleeding. Although these findings could be applied to patients with advanced cancer, who have a higher bleeding predisposition, caution is warranted when making such extrapolations.
Dual antiplatelet therapy (DAPT) is recommended for these patients for at least 12 months. However, in situations where dual antiplatelet therapy is contraindicated due to the oncological condition, the indication for routine cardiac catheterization becomes less clear and should be individualized, considering factors such as response to oncological treatment and expected life expectancy. Most studies on NSTEACS patients with cancer are based on single-center, retrospective, or administrative cohort studies. These limitations introduce biases that favor more favorable prognostic outcomes.
According to expert opinion, patients who may benefit less from a routine invasive strategy include those with thrombocytopenia or those whose cancer treatments increase the risk of this condition, as well as patients with a life expectancy of less than six months. Conversely, patients with persistent or recurrent ischemia, signs of hemodynamic instability, or an extensive area of myocardial ischemia are more likely to benefit from an invasive approach, especially if dealing with advanced cancer under first-line treatment.
Multivessel Coronary Disease or Left Main Coronary Artery Disease
Given the comparable outcomes in terms of mortality between surgical revascularization and PCI for left main coronary artery (LMCA) disease, percutaneous revascularization stands out as the preferred option in advanced cancer patients, provided it is technically and anatomically feasible.
In asymptomatic multivessel coronary artery disease in patients with metastatic cancer, optimal medical management is considered sufficient and appropriate. However, in symptomatic patients, coronary revascularization is recommended. In this context, the pros and cons of coronary surgery versus PCI must be weighed carefully. A recent analysis of 12 RCTs reported a low 30-day mortality rate for both procedures, below 1.4%. However, five-year survival was significantly higher with coronary surgery (9.2% vs. 11.2%), especially in diabetic patients (10.7% vs. 15.7%). Consequently, in patients with multivessel disease and advanced cancer, especially those with diabetes, coronary surgery can be considered the first option, provided there is a reasonable life expectancy of at least five years (typically patients on first-line treatment). Ultimately, this determination should be based on a comprehensive assessment that considers the patient’s morbidity, individual preferences, and the potential interruption of oncological treatment due to surgical intervention, along with other relevant variables.
Considerations on Dual Antiplatelet Therapy
After an ACS, DAPT should be maintained for at least 12 months, with the option to transition to P2Y12 monotherapy after completing 1-3 months of DAPT. For patients with chronic ischemic heart disease, DAPT may be switched to P2Y12 inhibitor monotherapy after one month of treatment if there is a high risk of bleeding.
The likelihood of hemorrhage following PCI is higher in cancer patients due to bleeding risks associated with the tumor itself and/or thrombocytopenia, which may arise due to bone marrow infiltration, autoimmune factors, or as a side effect of oncological treatment. In parallel, cancer may also be associated with a prothrombotic state, potentially increasing the risk of stent thrombosis after PCI in these patients. Therefore, the choice of antiplatelet therapy should be highly individualized.
Evidence related to antiplatelet therapy in the context of ACS in patients with thrombocytopenia is limited. A recent systematic analysis indicated that thrombocytopenia (defined as a platelet count <150,000/mm³) was linked to higher in-hospital mortality (Relative Risk [RR]: 2.6), bleeding, and long-term mortality. More recent reviews have also established a connection between thrombocytosis and an increase in cardiovascular events.
Experts suggest not excluding cancer patients from invasive treatment if thrombocytopenia is mild or moderate. According to the latest expert consensus recommendations, aspirin may be initiated if the platelet count exceeds 10,000/mm³, DAPT with clopidogrel if above 30,000/mm³, and DAPT with prasugrel or ticagrelor if above 50,000/mm³. However, these recommendations lack robust supporting evidence. The most widely accepted recommendation is likely to avoid PCI and antiplatelets in platelet counts below 50,000/mm³.
evere Aortic Stenosis
Over a decade ago, the PARTNER clinical trial clearly established that, for patients with symptomatic aortic stenosis who are contraindicated for surgical aortic valve replacement due to high comorbidity levels (risk of mortality or severe irreversible complications >50%), transcatheter aortic valve implantation (TAVI) significantly reduces mortality (Hazard Ratio [HR]: 0.55) and the composite of death or hospitalization (HR: 0.46).
In cases of symptomatic severe aortic stenosis with a life expectancy of over 12 months, TAVI is considered to offer substantial benefits, regardless of whether patients are undergoing first- or second-line cancer treatments.
Implantable Cardioverter-Defibrillators (ICD) and Cardiac Resynchronization Therapy (CRT)
Ventricular dysfunction induced by oncological treatments for advanced cancer may present varying patterns of reversibility. In some cases, as with trastuzumab, it can be reversible, whereas with agents like anthracyclines, this dysfunction is irreversible.
In general, it is well-established that for cases of heart failure (HF) with reduced ejection fraction (EF), ICDs constitute an effective strategy for reducing the risk of sudden cardiac death. The most robust clinical studies on ICDs, in both the primary and secondary prevention of sudden death, do not explicitly exclude cancer patients; rather, they tend to exclude those with a life expectancy of one or two years due to other comorbidities. Alongside these results, new therapeutic approaches for HF, such as sodium-glucose cotransporter-2 inhibitors and angiotensin receptor-neprilysin inhibitors, have shown efficacy. Therefore, in cases of advanced cancer, these new HF therapies should be exhaustively optimized before considering the implantation of these devices. Additionally, non-resynchronization implantable devices appear to provide little improvement in quality of life or HF symptoms. Although they may reduce mortality, they could also increase morbidity. Hence, careful deliberation is warranted before deciding on implantation.
For patients with severe HF, EF <35%, and QRS duration >120 milliseconds, CRT has demonstrated a reduction in mortality, HF-related hospital readmissions, and symptom improvement. In cases of advanced cancer, considering the implantation of these devices may be appropriate.
One crucial consideration is the potential impact of ionizing radiation used in radiotherapy for various cancer types, which can damage implantable devices. Approximately 6.6% of these devices exhibit malfunctions after radiotherapy. Additionally, therapy-induced thrombocytopenia and neutropenia increase the risks of bleeding and infection. Therefore, when making decisions about these therapies, it is essential to factor in the scheduling of oncological therapies, particularly radiotherapy and chemotherapy.
A Conceptual Framework for Invasive Cardiac Interventions in Patients with Advanced Cancer
Similar to the transformation of HIV infection into a chronic disease, advancements in treatments for various cancer types have significantly improved life expectancy for tumors that previously had poor prognoses, effectively converting them into chronic conditions. These achievements have been made possible through advances in immunotherapy and targeted molecular therapies. This paradigm shift requires a reassessment of how we approach cardiovascular conditions in cancer patients, which, in turn, demands a more accurate understanding of the prognosis of those with advanced cancer.
This study provides an updated and valuable table (Table 3) summarizing recent advances and prognoses for the most common types of cancer treatments. It offers relevant and essential information so that cardiologists can stay informed about the most significant innovations in the field. Table 2 provides specific recommendations for cardiac interventions in common cancer types, considering the treatment line and its progression. Some specific examples include: 1) In patients with small-cell lung cancer receiving first-line therapy with oncogenic mutations, an early invasive approach should be considered if contemplating TAVI or CRT; 2) For prostate cancer with hormone-sensitive disease, invasive approaches should be considered in cases of STEMI, NSTEACS, symptomatic severe aortic stenosis, and when ICD or CRT is indicated.
COMMENTARY:
Although current evidence on the benefits of invasive cardiac interventions in patients with advanced cancer is limited, this thorough review provides an updated perspective on available evidence and successfully achieves its goal by offering solid guidance to inform decision-making in this patient group.
Based on this article, some key considerations when making decisions for these patients include: 1) Evaluating the balance between the benefits of invasive cardiac intervention and the risks of adverse cardiovascular events if not intervened; 2) Analyzing cancer prognosis and the need to continue treatment without interruptions; 3) Considering the impact of thrombocytopenia, whether actual or anticipated; 4) Clearly defining patient care goals, prioritizing improvements in quality and life expectancy.
To facilitate understanding, invasive cardiac interventions can be categorized into two groups based on their short- and long-term benefits. Interventions with notable short-term results include primary PCI in STEMI, routine invasive percutaneous strategy in NSTEACS, and TAVI in cases of symptomatic severe aortic stenosis. Meanwhile, interventions providing long-term benefits include CRT, primary prevention ICDs, and revascularization in patients with multivessel coronary artery disease. Based on this classification, a simplified approach can be established depending on the stage of advanced cancer: 1) For patients with metastatic cancer undergoing first-line treatment and a reasonable life expectancy, all the aforementioned invasive cardiac interventions could be performed; 2) In patients showing disease progression despite initial treatment, invasive cardiac interventions with short-term benefits are recommended. Among the options with long-term benefits, CRT or revascularization in cases of multivessel disease may be considered, depending on the situation. Primary prevention ICDs are not recommended; 3) For patients with disease progression during second-line treatment or in palliative situations, invasive treatments are generally not suggested, with exceptions potentially made for primary PCI or in select cases of NSTEACS.
As evident, in the final decision-making process, it is essential to consider the patient’s fragility and the presence of multiple conditions, involving the patient and a multidisciplinary team consisting, at the very least, of a cardiologist, cardiac surgeon, and oncologist.
Although it is impossible to exhaustively address advances and prognoses for all advanced cancer types in this article, this review offers a practical and highly useful consideration by providing, for the first time, an updated overview of life expectancy for the most common cancers in light of the latest available treatments. This provides an essential guide for professionals making decisions on the suitability of invasive procedures for patients with advanced cancer. The increased survival of those facing advanced tumor diseases alongside severe cardiovascular conditions has prompted a crucial reassessment of indications for invasive procedures. As a result, there has been a progressive and consistent expansion in the indications for invasive procedures in patients with advanced cancer, a trend that will undoubtedly continue in the future.
REFERENCE:
Leong D, Cirne F, Aghel N, et al. Invasive Cardiac Interventions in Patients With Active, Advanced Solid and Hematologic Malignancies. J Am Coll Cardiol CardioOnc. 2023;0(0). https://doi.org/10.1016/j.jaccao.2023.05.008
