Cancer-Associated Atherothrombosis: The Challenge

Abstract

The association between venous thrombosis and malignancy, having typical features of a paraneoplastic syndrome, has been established for a century. Currently, it is recognized that arterial thromboembolism (ATE) may also behave as a paraneoplastic syndrome. Recent matched cohort studies, systematic reviews, and observational studies concur in showing an increased incidence of acute coronary events, ischemic stroke, accelerated peripheral arterial disease, and in-stent thrombosis during the 6-month period before cancer diagnosis, peaking for 30 days immediately before cancer diagnosis. Cancer patients with ATE are at higher risk of in-hospital and long-term mortality as compared with noncancer patients. In the present review, we focus on the epidemiology, clinical variants and presentation, morbidity, mortality, primary and secondary prevention, and treatment of cancer-associated ATE. The awareness that cancer can be a risk factor for ATE and that cancer therapy can initiate cardiovascular complications make it mandatory to identify high-risk patients, modify preexistent cardiovascular risk factors, and adopt effective antithrombotic prophylaxis. For ATE prophylaxis, modifiable patient-related risk factors and oncology treatment–related factors are levers for intervention. Statins and platelet antiaggregants have been studied, but their efficacy for prevention of cancer-associated ATE remains to be demonstrated. Results of revascularization procedures for cancer-associated ATE are worse than for ATE in noncancer patients. It is important that a multidisciplinary approach is adopted for making informed decisions, by involving the vascular surgeon, interventional radiologist, oncologist, and palliative medicine, as well as the patients and their family.

The association between thrombosis and cancer is the earliest documented paraneoplastic syndrome. Armand Trousseau, in 1865, was the first to associate thrombosis with malignancy, the first to suggest screening for malignancy in recurrent or idiopathic thromboembolic disease, and the first to advocate that the responsible mechanism was a change in the properties of the coagulation system. ¹ Next, a series of observational studies revealed the increased prevalence of venous thromboembolism in patients with cancer, an association that was later called Trousseau's syndrome. In 1977, Sack et al distinguished a widened spectrum of Trousseau's syndrome, including venous thromboembolism, arterial thromboembolism (ATE), nonbacterial thrombotic endocarditis, and chronic disseminated coagulopathy. ² While the association between venous thrombosis and cancer, featuring characteristics of paraneoplastic syndrome, has been established over decades, ATE presenting at times as a paraneoplastic syndrome has been recognized and accepted only recently. ^{2 3 4 5 6 7} The awareness that cancer can be a risk factor for ATE and that cancer therapy can initiate cardiovascular complications make it mandatory to identify high-risk patients, modify pre-existent cardiovascular risk factors, and adopt effective antithrombotic prophylaxis. ^{8 9}

Early Studies

Paraneoplastic arterial disorders include arterial thrombosis, arterial embolism, arteritis, and the accelerated course of atherothrombosis. ¹⁰ The latter came into attention in a retrospective study of 300 patients with intermittent claudication; in 15 among them, cancer was revealed. The diagnosis of cancer was preceded by an aggressive course of the peripheral arterial disease. Subsequently, patients who responded favorably to cancer treatment exhibited stabilization of claudication, while patients who were unresponsive to cancer treatment deteriorated and necessitated surgery for limb-threatening ischemia ( Figs. 1 and 2 ).

Fig. 1.

Deterioration of stable intermittent claudication to rest pain. The patient underwent femoral-popliteal artery bypass surgery. Then the graft occluded. The vascular events proceeded to the diagnosis of gastric carcinoma. After cure of cancer, the ABI returned to baseline levels and remained stable over years of follow-up. Open arrows show emergency vascular surgery, while black arrow shows cancer diagnosis ABI, ankle brachial index. (Reproduced with permission from Naschitz et al. ¹¹ )

Fig. 2.

This patient had a long history of stable intermittent claudication. Then lung cancer was diagnosed followed by deterioration of leg ischemia. Under oncology treatment, there was no improvement. The patient lived another 2 years with worsening leg ischemia. Black arrow represents cancer diagnosis and black rhombus represents patient's demise.

In the 15 patients studied, the association between peripheral arterial disease and cancer presented features consistent with a paraneoplastic syndrome ¹¹ : cancer-associated claudication had a more accelerated course and required vascular surgery more often, and lasting relief depended on the efficiency of cancer therapy. The authors postulated that cancer-associated claudication is predetermined by atherosclerosis and aggravated by the hypercoagulable state induced by cancer. Further, the hypothesis was tested that cancer, being a thrombotic diathesis, may accelerate the course of ischemic heart disease. ¹² The study focused on the period before cancer diagnosis, so cancer treatment did not interfere in this period. Data obtained from files of patients with the diagnosis of malignant tumors and admitted to a general hospital during a 3-year period were reviewed for coronary risk factors, coronary events, and characteristics of cancer. Indices of coronary instability were studied: the incidence of first coronary events, the incidence of all coronary events, and the burden of coronary events. These indices were calculated for 366 patients with cancer. Included were 166 consecutive patients from the department of medicine with cancer of several primary sites ( Fig. 3 ). Also reviewed were surgical ward files of 100 consecutive patients with colorectal cancer, 100 consecutive patients with cancer of the prostate or bladder, and 100 patients with benign prostatic hypertrophy, with the last group serving as controls. In all groups of patients with cancer, the rate of coronary events began to rise in the 2-year period before cancer diagnosis, with a steep increase 6 months before cancer diagnosis. Patients with colorectal cancer presented the highest rates of coronary events in the 2-year period before cancer diagnosis, with unstable ischemic heart disease in 18% and first coronary events in 10% of the cases. The lowest rates of coronary events among patients with cancer were noticed in patients with prostatic and bladder cancer: unstable ischemic heart disease in 6% and first coronary events in 4%. In control patients, the indices were several times lower: unstable ischemic heart disease in 3% and first coronary events in 2%. Factors other than cancer were not significantly related to the increased frequency of coronary events in the 2-year period before cancer diagnosis, particularly the known coronary risk factors and anemia. On the basis of this epidemiologic data, the authors concluded that there may be causality in the association between occult cancer and coronary events.

Fig. 3.

Retrospective review of acute coronary event frequency as well as noncoronary vascular events before and after cancer diagnosis, in the subgroup of 166 consecutive patients admitted to the department of medicine. Two years before cancer diagnosis, the rate of coronary events began to rise, with a steep increase 6 months before cancer diagnosis. After cancer diagnosis, the frequency of coronary events remained elevated in relation to the dwindling number of patients remaining in follow-up: 104 during the first year, 77 in the second year, 63 in the third year, 58 in the fourth, and 52 in the fifth year. CD, time of cancer diagnosis. (Reproduced with permission from Naschitz et al. ¹² )

Survey of the Recent Literature: Epidemiology

On a PubMed search, we recovered 4,439 articles under the keywords “cancer & arterial thrombosis,” 1,946 articles under “cancer & arterial thromboembolism,” 118 articles under “paraneoplastic & arterial disease,” 68 articles under “Trousseau & arterial thrombosis,” and 48 articles under “paraneoplastic arterial thrombosis.” In our review, we gave priority to matched cohort studies, retrospective cohort studies, prospective observational studies, and systematic reviews ( Table 1 ).

Table 1. Recent studies of the association between cancer and ATE, arranged according to the sequence of the diagnoses: (1) cancer diagnosis before ATE and (2) ATE before cancer diagnosis.

Sequence of cancer diagnosis vs. ATE	Reference	Design	Myocardial infarction	Ischemic stroke	Peripheral artery occlusion
Cancer first
Navi et al, 2017	3	RMC	+	+
Grilz et al, 2018	6	PO	+	+	+
Zöller et al, 2012	16	RC	+
Navi et al, 2014	18	RC	+	+
Yu et al, 2019	21	SR	+	+	+
ATE first
Sundbøll et al, 2018	4	RMC			+
Navi et al, 2019	13	RMC	+	+	+
Kaschwich et al, 2020	17	RMC			+

Abbreviations: ATE, arterial thromboembolism; PO, prospective observational study; RC, retrospective cohort study; RMC, retrospective matched cohort study; SR, systematic review.

Navi et al ³ analyzed the Surveillance, Epidemiology, and End Results database to appraise the incidence of ATE, myocardial infarction (MI), or stroke in cancer patients across the United States. The study included 279,719 pairs of elderly patients with a new diagnosis of cancer and matched controls. The cancer types included breast, lung, prostate, colorectal, bladder, pancreatic, gastric carcinoma, and non-Hodgkin lymphoma. The incidence of ATE, MI, or stroke at 6 months after cancer diagnosis was 4.7% in the cohort comprising all cancer patients, compared with 2.2% in the cohort of matched control patients. Patients with lung, gastric, or pancreatic cancers had the highest rates of ATE, MI, or stroke (8.3, 6.5, and 5.9%, respectively). Ischemic stroke was less common than MI in cancer patients (at 6-month follow-up, 2.0% stroke vs. 3.0% MI). Advanced stage of cancer was associated with a significant higher rate of ATE, MI, or stroke (at 6 months, 2.3% incidence for stage 0, compared with 7.7% for stage 4). One year after cancer diagnosis, the risk for ATE was significantly attenuated in most cancer types. ATE was associated with increased mortality even after matching for all factors and stage of cancer (hazard ratio [HR], 3.1; 95% confidence interval [95% CI], 3.0–3.1). The 30-day cumulative incidence of death after ATE was 17.6% in patients with cancer versus 11.6% in controls. In this large, heterogeneous, population-based sample, patients newly diagnosed with any of the common solid or hematologic cancers faced a considerably increased short-term risk of ATE. Advanced cancer stage was associated with increased risk, directly relating ATE to tumor burden and extent of disease. Finally, ATE among patients with cancer carried a poor prognosis, with a threefold increased hazard for death. In a similar study, Navi et al reviewed the rate of ATE before cancer diagnosis . ¹³ Using the population-based Surveillance Epidemiology and End Results-Medicare linked dataset, 374,331 patients 67 years or older were identified with a new primary diagnosis of breast, lung, prostate, colorectal, bladder, uterine, pancreatic, or gastric cancer or non-Hodgkin lymphoma from 2005 through 2013. Cancer patients were individually matched by demographics and comorbidities to Medicare beneficiaries without cancer, who served as controls. From day 360 to day 151 before cancer diagnosis, the risks of ATE were similar between cancer patients and controls. From day 150 to 1 day before cancer diagnosis, the risks of ATE were higher in cancer patients versus matched controls, progressively increasing as the date of cancer diagnosis approached and peaking during the 30 days immediately before cancer diagnosis, when 2,313 (0.62%) cancer patients were diagnosed with an ATE versus 413 (0.11%) controls (odds ratio, 5.63; 95% CI, 5.07–6.25). In the National Heart, Lung, and Blood Institute Dynamic Registry, patients who presented with an acute MI as an indication for percutaneous coronary intervention (PCI) were studied. At 1-year follow-up, a history of cancer was a significant predictor of myocardial reinfarction . ¹⁴ In contrast to the study, a retrospective analysis from the Mayo Clinic did not find that cancer history portends increased cardiac mortality after PCI for acute ST-segment elevation MI (STEMI). ¹⁵ In the prospective Vienna Cancer and Thrombosis Study (CATS), ⁶ the peak of ATE soon after cancer diagnosis was modest and was subsequently constant over the entire follow-up period, in contrast to venous thromboembolism, which peaked during the first 6 months after cancer diagnosis. The constant rate of ATE over time was ascribed to the role of the common cardiovascular risk factors acting independently of the course of cancer. ⁶ On the other hand, attenuation of the incidence of ATE over time, or persistence up to 10 years from the diagnosis, has been variously described according to different cancers. ¹⁶ In Sweden, all individuals with a diagnosis of cancer between January 1, 1987, and December 31, 2008, were followed for first hospitalization for coronary heart disease . ¹⁶ The reference population was the total population of Sweden without cancer. Standardized incidence ratios (SIRs) for coronary heart disease were calculated. Most cancers were associated with an increased risk of coronary heart disease during the first 6 months after cancer diagnosis. The overall coronary heart disease risk during the first 6 months after diagnosis of cancer was SIR 1.70. For 26 out of the 34 cancers studied, the risk of coronary heart disease was increased during the first 6 months after diagnosis of cancer. The overall coronary heart disease risk decreased rapidly, but remained slightly elevated even 10+ years after diagnosis of cancer (SIR, 1.07). The cancer sites/types for which the risk of coronary heart disease was highest during the first 6-month period were small intestine (SIR, 2.88), leukemia (SIR, 2.84), kidney (SIR, 2.65), lung (SIR, 2.56), and liver (SIR, 2.28). Metastatic cancer was associated with an increased risk of coronary heart disease (SIR, 1.46). Lower limb ATE was also associated with an increased incidence of occult cancer. ⁴ Data from the nationwide Danish medical registries showed that among 6,600 patients with lower limb arterial thrombosis, cancers were diagnosed subsequently in 772 cases. During the first 6 months after lower limb ATE, the SIR of any cancer was 3.28 and remained elevated during 7 to 12 months (1.42) and beyond 12 months (1.14). The strongest associations were found for lung cancer and other smoking-related cancers. ⁴ An analysis of health insurance claims from Germany ¹⁷ followed symptomatic peripheral arterial disease until an incident cancer diagnosis was recorded to appraise whether there is an increased incidence of cancer in patients with peripheral arterial disease. SIRs were computed for 96,528 patients of the study. The mean age of the patients was 72 years. When compared with the overall population, patients with peripheral arterial disease had a significantly increased risk of incident cancer of the lung (SIR, 3.5 vs. 2.6), bladder, pancreas, and colon during 10 years of follow-up. The risk of ATE recurrence in cancer patients is not well described. One study evaluated cancer patients with acute ischemic stroke and showed that ATE recurrence rate (stroke or MI) was 21, 31, and 37% at 1, 3, and 6 months, respectively. Among different cancers, adenocarcinoma had the highest rates of ATE recurrence (HR, 1.65; 95% CI, 1.02–2.68). ¹⁸ In-stent thrombosis after PCI appears to be markedly increased by malignancy. ¹⁹ The current drug-eluting stents have been proven to reduce the risk of restenosis and stent thrombosis as compared with bare-metal stents. However, out of concern for increased bleeding risk and expectant need for cancer-directed surgery, operators often prefer to use bare-metal stents in patients with cancer. The current evidence with newer-generation stent technology demonstrates the feasibility of shorter duration of dual-antiplatelet therapy (DAPT), without increasing the risk of stent thrombosis and bleeding, while maintaining improved efficacy compared with bare-metal stents. ²⁰ A systematic review of the frequency of ATE in patients with cancer searched the MEDLINE, Embase, CENTRAL, and Web of Science data to 28 January 2019. ²¹ Included were studies comparing the frequency of ATE in populations with cancer versus controls. Studies examining the frequency of ATE in the context of cancer therapies were excluded. Twelve retrospective cohort studies involving 1,260,237 patients were included in the analysis. Ten studies concluded that there is an increased risk of ATE in populations with malignancies, with the highest risk immediately after cancer diagnosis. The highest ATE risk was noticed in patients with lung and pancreatic cancer. The ATE risk diminished around 1 year after cancer diagnosis, except in patients with lung or pancreatic cancers. Heterogeneity within and between studies precluded meta-analysis.

Pathophysiology

The consistent association between vascular events and cancer provided by epidemiologic data suggests a causal linkage of their association. The state-of-the-art proof of causality between cancer and ATE is provided by Bradford Hill criteria of causation, ⁷ which are mostly useful where traditional meta-analyses of randomized controlled trials are not appropriate. In a classic study, Bradford Hill proposed a set of nine criteria to evaluate whether there is a causal link between an exposure of interest and a health outcome. The criteria of causality are strength of the association, consistency of findings, specificity of the association, temporal sequence, biological gradient, biological plausibility, coherence, analogy, and experiment. The Bradford Hill criteria have stayed virtually unchanged since their first publication and are used by epidemiologists to test causal hypotheses. We have reviewed the Medline database in a search for articles on vascular disorders preceding the diagnosis of cancer. ⁷ The following disorders were reviewed: venous thromboembolism, ATE, nonbacterial thrombotic endocarditis, migratory superficial thrombophlebitis, vasculitis, thrombotic microangiopathy, and leukothrombosis. Seven Bradford Hill criteria were fulfilled by the association of cancer with venous thromboembolism, six criteria by superficial phlebitis associated with cancer, and five criteria by ATE associated with cancer as well as by each of the other disorders studied. The data support that the association between various vascular disorders and cancer may be causally determinated. ⁷ While both venous thromboembolism and ATE are associated with cancer and both satisfy criteria of causality, it is of interest that venous and arterial thrombosis share common risk factors besides cancer, such as advanced age, obesity, smoking, diabetes mellitus, arterial hypertension, hypertriglyceridemia, and metabolic syndrome. Moreover, several disorders account for venous as well as for arterial thrombosis, such as the antiphospholipid antibody syndrome, hyperhomocysteinemia, infections, and the defined hormonal treatments. Finally, studies have consistently shown that patients with venous thromboembolism are at a higher risk of ATE than matched control individuals. ²² Therefore, it is probable that the propensity to develop venous and arterial thrombosis is affected by the same biological stimuli. Among the mechanisms involved in the pathophysiology of paraneoplastic ATE, evidence favors hypercoagulability due to high levels of circulating microvesicles, elevated heparanase procoagulant activity, alteration in platelet activity, and endothelial dysfunction. ^{23 24 25 26} The circulating levels of several different cytokines are elevated in cancer patients. ²⁷ In response to interleukin-1 and tumor necrosis factor, endothelial and platelet microvesicles are released, inducing procoagulant activity and endothelial dysfunction. ²⁸ Deregulation of cell proliferation and therefore cell cycle progression, changes in the synthesis of transcription factors as well as adhesion molecules, an alteration in the control of angiogenesis, and the molecular similarities that follow chronic inflammation are involved in both ATE and cancer. ^{29 30} Tissue factor (TF) is widely considered to be the major molecular driver of cancer-associated coagulopathy and thromboembolic disorders. Membrane bound and intravascular TF expression and activity have been shown to be upregulated in many human cancers, often correlating with thromboembolic complications and poor prognosis. The highest levels of TF expression have been reported in cancers that are most strongly associated with a high incidence of thrombotic events. The increased expression of TF in tumor is considered to be the result of the activation of dominant-acting oncogenes or loss of recessive tumor suppressors rather than dictated by genetic aberrations of the TF gene. ³¹ Tumor cell–induced platelet aggregation has been demonstrated in several experimental models. A study of human small cell cancer cell lines revealed that in vitro platelet aggregation can be induced by direct cellular interactions as well as indirect cellular interactions via secreted thrombin and adenosine diphosphate. ³² Cancer cells express adhesion molecules binding to the receptors of endothelial cells. Endothelial dysfunction in the setting of cancer fosters procoagulant activity and vasoconstriction, and reduces fibrinolytic activity, all of which contribute to ischemic vascular disease. ³³ Increased circulating levels of von Willebrand factor in cancer patients may not only be a marker of endothelial injury, but also facilitate thrombosis by promoting platelet–platelet and platelet–subendothelium interaction. Loss of expression of thrombomodulin on the endothelial surface in cancer reduces the capacity to activate the anticoagulant protein C, thereby adding to the prothrombotic state. ³³ Chemotherapeutic agents , immunomodulatory drugs, vascular endothelial growth factor pathway inhibitors, tyrosine kinase inhibitors, and radiotherapy impart increased risk for ATE that results from specific therapy-related mechanisms, often involving endothelial injury. ³⁴ All types of cancer therapies contribute to the development of coronary artery disease, including chemotherapy, radiotherapy, and targeted drug therapy. Anticancer therapies cause not only coronary artery injury, but also dysfunction in the coronary microcirculation. It is important to be aware that approximately 10% of cancer patients with an acute coronary event have takotsubo cardiomyopathy. Early identification of takotsubo cardiomyopathy can prevent the risk of bleeding caused by pointless antithrombotic treatment. ³⁵

Prevention of Cancer-Associated ATE

It would be important if cancer-associated ATE could be prevented. Modifiable patient-related common cardiovascular risk factors and oncology treatment–related risk factors are levers for intervention. ³⁶ Statin medications are protective against arterial thrombosis in the setting of atherosclerotic disease and have been shown to decrease venous thromboembolism in patients with cancer. ³⁷ Statins have an anti-inflammatory effect component that contributes to decreased thrombus formation. The precise mechanism of action is not clear but multiple biomarkers have been shown to be affected by statin therapy as well as to be associated with thrombus formation and resolution. Yet the Breast Cancer in Northern Israel Study is a case–control study that enrolled 3,585 patients with breast cancer who experienced 261 venous thromboembolism found no reduced risk of venous thromboembolism in patients receiving statin treatment. ³⁸ We could not find studies concerning statin effects on cancer-associated ATE. positron emission tomography–computed tomography (PET-CT) scans might be helpful to identify at least some of the patients who should be started on a statin prior to chemotherapy, based on the presence of coronary and vascular calcium that may be predictive of cardiac events. ^{39 40} The role of other medications, platelet antiaggregants and β-blockers , in the pharmacoprophylaxis of ATE in cancer patients has been assessed in a small number of studies. An analysis of 456 cancer patients with acute MI showed that long-term aspirin (HR, 0.77) and β-blocker (HR, 0.64) treatment significantly reduced mortality. ⁴⁰ Despite an elevated bleeding risk, many cancer patients may benefit from American College of Cardiology/American Heart Association (ACC/AHA) guideline-directed management for acute coronary syndrome including aspirin, P2Y ₁₂ inhibitor, statin, and β-blocker therapies. ⁴¹ Combining anticoagulant with antiplatelet therapy might be indicated for treatment of cancer-associated venous thromboembolism and prevention of ATE. While anticoagulants alone may be insufficient for patients at high risk for ATE, concomitant anticoagulant and antiplatelet treatment increases the risk of bleeding. There is ample experience in combining anticoagulation therapy with DAPT in other settings, e.g., in patients with atrial fibrillation who also have arterial stents. Such “triple antithrombotic therapy” has been more often associated with bleeding events with nonsignificant reduction in thrombotic events. However, in patients with active cancer, there is hardly any evidence concerning triple antithrombotic therapy for prevention of recurrent venous thromboembolism and ATE. Currently, there are no guidelines for thromboprophylaxis of MI and stroke in patients with cancer-associated venous thromboembolism. ⁴² Careful consideration of the bleeding risk is needed because thrombocytopenia is common in cancer patients. In general, guidelines recommend shorter duration of triple antithrombotic therapy, especially in patients with high risk of bleeding. ⁴³ A recent expert consensus statement from the Society of Cardiovascular Angiography and Interventions recommends that aspirin can be given if the platelet count is more than 10,000, and dual-antiaggregant treatment with aspirin and clopidogrel is reasonable for platelet counts between 30,000 and 50,000. Ticagrelor and prasugrel, which have a higher bleeding rate, should generally be avoided when the platelet count is less than 50,000. ⁴⁴ McCarthy et al, on the other hand, recommend a more conservative approach and advise against all antiplatelet agents in patients having PCI and if their platelet count is less than 50,000. ⁴⁵ It should be mentioned that risk scores validated for the definition of the risk/benefit profile of short versus prolonged DAPT in patients undergoing PCI did not include cancer. This potential shortage concerns the DAPT, the PREdicting/predicting bleeding Complications in patients undergoing Stent implantation and subsequent DAPT (PRECISE-DAPT), and the Patterns of Non-Adherence to Anti-Platelet Regimen in Stented Patients (PARIS) scores. ⁴⁶ Cancer patients with ATE are a uniquely vulnerable population who are often undertreated, and with improved cancer treatments, this population is expected to increase. ³⁹ These patients should be included in future randomized trials to better understand how to balance the complexities of increased bleeding and thrombosis risks during ATE.

Revascularization

Revascularization is imperative in patients with critical ischemia. Depending on the territory at risk, treatment options include thrombectomy, PCI, percutaneous peripheral angioplasty, or bypass surgery. Patients with critical limb ischemia due to atherosclerotic disease have an expected survival of approximately 80% at 1 year. ⁴⁷ Much worse is the outcome of patients with arterial thrombosis associated with cancer. In a series of 20 patients with cancer-associated ATE, thrombosis involved the leg in 19 cases and the arm in 1 case. Four patients also had venous thromboembolic events, and one had carotid artery thrombosis. Eight patients underwent surgical treatment for their thrombosis. Five out of six thromboembolectomies and two out of three bypass procedures failed. Twelve patients received conservative or palliative treatment. Outcomes were generally poor: 2 patients had major amputations and 17 died at median follow-up of 8 weeks. ⁴⁷ A counterpart to this observation, it has been suggested that a search for occult cancer may be productive in the case of the iterative thrombosis of an arterial bypass. ⁴⁸ Acute coronary syndrome in cancer patients, more often non-STEMI (NSTEMI), presents differently than in the general population. The prevalence of silent ischemia is higher, and the most common symptom is dyspnea, followed by chest pain, hypotension, and heart failure. ⁴⁹ Cancer patients experiencing acute coronary syndromes are at higher risk of in-hospital and long-term mortality as compared with noncancer patients. ⁵⁰ The management of acute coronary syndromes in patients with cancer is challenging due to the cancer's unique pathophysiology, which makes it difficult to balance thrombotic and bleeding risks. Due to their exclusion from large clinical trials, there is a paucity of data regarding how to best treat these complex and high-risk patients. Based on the SCAI expert consensus, there is no platelet count limit for diagnostic left heart catheterization. ⁴⁴ DAPT should be continued for the least safe time if the platelet count is less than 50,000, meaning 4 weeks for bare metallic stents or 6 months for drug-eluting stents. In patients who have platelet count less than 30,000, a multidisciplinary discussion involving cardiology and oncology is recommended prior to pursing PCI. ⁴⁴ The outcome of PCI in patients with metastatic cancer has been studied by reviewing the National Inpatient Database of the United States between 2000 and 2009. ⁵¹ There were 15,964 patients with STEMI and 33,551 with NSTEMI. PCI has been provided to 3,981 patients with STEMI (24.9%) and 3,209 patients with NSTEMI (9.6%). The adjusted odds of receiving PCI in patients with metastatic cancer have gradually increased in the last decade by 1.14 every year and this has remained unchanged for STEMI patients. The beneficial effect of PCI on in-hospital mortality has declined in NSTEMI such that, by 2009, there was no significant difference between patients who received PCI and those who did not receive PCI. It was concluded that metastatic cancer patients with NSTEMI may perform equally well without PCI in terms of in-hospital mortality. An expert consensus on coronary interventions in cancer patients ⁵² concluded that cardiologists performing PCI on cancer patients should be aware of the increased risk of bleeding, thrombosis, possible need for interruption of DAPT, and the increased risk of target lesion revascularization in this cohort. These risks may be partially mitigated by utilization of radial artery access, intravascular imaging for lesion assessment and stent optimization, and avoidance of complex stenting strategies. The BleeMACS project was a multicenter observational registry enrolling patients with acute coronary syndrome undergoing PCI worldwide in 15 hospitals. There was evidence that certain medications were beneficial in cancer patients, including β-blockers (relative risk [RR], 0.6), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (RR, 0.5), statins (RR, 0.3) and DAPT (RR, 0.5). ⁵³ In general, these patients should be approached placing the acute coronary syndrome in the context of the expected cardiac and oncologic prognosis and tailoring their treatment accordingly. It is important to have a multidisciplinary approach consisting of the treating cardiologist, medical and/or surgical oncologist, and palliative medicine; the patient and their family should also be involved in making informed decisions. ^{54 55}

Perspectives

Prevention and treatment of cancer-associated ATE may benefit from greater awareness, optimizing the management of conventional cardiovascular risk factors, careful monitoring of vascular toxicity of cancer treatments, and use of antiplatelet and antithrombotic agents in selected patients. Which patients having an ATE should be screened for a possible occult cancer, and which patients with cancer should be screened for a silent ATE, and at what time intervals are unknown. These issues are targets for future studies. ^{8 9 56}

Conclusions

Cancer patients have an increased risk of arterial thrombosis that is likely due to the cancer-associated procoagulant state as well as to adverse effects of oncology treatments. More studies are needed to investigate optimal means of ATE prophylaxis in cancer patients, surveillance strategies, and treatments of cancer-associated ATE.

Funding Statement

Funding There was no funding to this work.