2026 AHA科学声明：活动性癌症患者缺血性脑卒中的分类和管理

Stroke With Known Cancer

Compared with the general AIS population, patients with comorbid cancer tend to be older and to have lower rates of hypertension and dyslipidemia but higher rates of smoking and venous thromboembolism (VTE).$^{9,28,29}$ Malignancy-associated infarcts are frequently multifocal,$^{28-30}$ manifested clinically with higher average stroke severity attributable to more widespread cerebral involvement, and encephalopathy.$^{9,29}$ Radiographically, the “3-territory sign,” describing involvement of the bilateral anterior and posterior cerebral circulations, is more common in malignancy-associated stroke, occurring in 30% to 50% of cases.$^{28,29}$

In patients with cancer and AIS, markers of systemic hypercoagulability and inflammation are often elevated, with D-dimer being the most validated hematologic biomarker to discriminate malignancy-associated AIS.$^{23,29,32,31}$ Low hemoglobin and elevated neutrophil-to-lymphocyte ratio have also been described.$^{23,29,32,32}$ On transcranial Doppler ultrasound, microembolic signals are common and often bilateral.$^{28,29}$

BIOLOGICAL PATHWAYS IMPLICATED IN HEIGHTENED STROKE RISK

Several factors are responsible for increased stroke risk in patients with cancer, including cancer treatment effects and frequent interruptions of antithrombotic therapy for procedures, thrombocytopenia, and bleeding.

However, in general, the largest driver of stroke risk in patients with cancer is cancer-mediated hypercoagulability, a complicated multifactorial process involving several linked pathways, including broad activation of the platelet, coagulation, and endothelial systems.$^{9,29}$ In the prospective Mechanisms of Ischemic Stroke in Cancer (MOST-Cancer) study, markers of platelet (P-selectin), coagulation (D-dimer), and endothelial (thrombomodulin, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1) activation were higher in patients with active cancer and AIS (n=50) than in matched controls with AIS only (n=50).$^{28}$ Of the markers tested, D-dimer had the largest absolute and relative numeric difference between groups.$^{28}$ von Willebrand factor, a glycoprotein that mediates platelet adhesion and aggregation at sites of vascular injury, is also implicated in the pathogenesis of cancer-related stroke.$^{33}$ In the prospective SCAN study (Ischemic Stroke in Patients With Cancer and Neoplasia), among 90 patients with active cancer and AIS, von Willebrand factor antigen levels were associated with stroke severity, multiterritorial infarctions, cryptogenic mechanisms, and mortality at 1 year.$^{33}$ However, because von Willebrand factor is an acute-phase reactant associated with infarct size, its relationship with cancer-related stroke may be an epi-phenomenon and not causal.$^{34}$

Thromboinflammation through neutrophil extracellular trap formation is another important contributor to AIS development in patients with cancer. Activated neutrophils release decondensed chromatin, leading to extracellular DNA lattices that can trap other blood cells and cause thrombus formation. It has been postulated that circulating cancer cells interact with neutrophils to trigger neutrophil extracellular trap formation and subsequently AIS.$^{35}$ In the prospective OASIS-Cancer study (Optimal Anticoagulation Strategy in Stroke Related to Cancer Study), compared with 100 matched controls, including those with AIS only or cancer only, 38 patients with cancer-related AIS had higher plasma DNA and nucleosome levels, and these neutrophil extracellular trap formation markers correlated with D-dimer levels.$^{35}$

The OASIS-Cancer study also highlighted the role of extracellular microvesicles in cancer-related stroke.$^{36}$ The investigators reported that cancer cell-derived extracellular microvesicle levels were higher in the cancer-related stroke group than in control groups, and the microvesicle levels were associated with hypercoagulability, measured by D-dimer, through tissue factor-independent pathways.$^{36}$ These circulating microvesicles are small spherical cell fragments shed by tumors or blood cells, often in response to inflammatory signaling, that promote activation of the coagulation cascade by expressing pro-coagulant proteins and exposing surface phospholipids. Besides these biological pathways, which likely vary by cancer type, others are probably involved in cancer-related stroke, including secretion of mucin, release of

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tissue factor, and expression of fibrinolysis inhibitors and inflammatory cytokines.$^{9}$ However, it is clear that no single factor can be targeted to eliminate cancer-mediated hypercoagulability other than the cancer itself, the driving force behind all of these pathways.

STROKE MECHANISMS

Conventional stroke mechanisms account for about half the burden of AIS in patients with active cancer, although cancer-related factors sometimes mediate these mechanisms (Figure).$^{28,32}$ Large-artery atherosclerosis is a frequent stroke mechanism in the oncological population because of high smoking rates and the long-term effects of cancer treatments. Immunotherapy with immune checkpoint inhibitors has been associated with accelerated progression of atherosclerosis and a 3-fold higher risk of ischemic cardiovascular events.$^{37}$ Radiotherapy also promotes atherosclerosis, most often affecting the cervical internal carotid arteries in patients with head and neck cancer and the intracranial vasculature in patients with primary brain tumors.$^{2,15}$ Cardioembolism is common in patients with malignancy because cancer increases the risk for atrial fibrillation,$^{38}$ and some cancer treatments, particularly anthracyclines, trastuzumab, cyclophosphamide, and taxanes, can cause cardiomyopathy.$^{39}$ In addition, immunosuppression and indwelling venous catheters are common in patients with cancer, predisposing them to infective endocarditis and septic emboli. Last, cancer greatly heightens VTE risk, and this can lead to paradoxical embolization through right-to-left shunts.$^{40}$ However, the attributable risk of patent foramen ovale for stroke may be lower in patients with cancer than in the general population. Among 2236 patients with AIS who had transesophageal echocardiography in Bern, Switzerland, patients with active cancer (n=103) had lower median Risk of Paradoxical Embolism scores (4 versus 5) and fewer right-to-left shunts (23% versus 36%) than patients without cancer, although confounding by indication was possible.$^{40}$

The remaining 50% of AISs in patients with active cancer are either of undetermined source or attributable to known cancer-specific mechanisms.$^{9,28,32}$ Many of these undetermined cases have distinctive clinical features and are likely caused by cancer-mediated prothrombotic processes.$^{9}$ The typical phenotype for what historically has been labeled cancer-related ESUS is a patient with disseminated solid cancer that is recently diagnosed and untreated or that has progressed through treatment who has embolic-appearing AIS in multiple vascular territories with elevated blood prothrombotic markers and microemboli on transcranial Doppler. When a cerebral arterial occlusion is detected on vessel imaging, the susceptibility vessel sign is usually absent on brain MRI, indicating an erythrocyte-poor thrombus.$^{41}$ Furthermore, if thrombectomy is performed,

the retrieved thrombus is generally confirmed as platelet and fibrin rich.$^{42}$

Many of these patients with cancer-related ESUS may have occult NBTE, which shares a similar clinical phenotype and is characterized by platelet-fibrin vegetations on cardiac valves.$^{43}$ However, NBTE is rarely confirmed, even when suspected, because the valvular vegetations tend to be small and friable and thus difficult to detect.$^{44}$ Therefore, attention should be paid to “valve thickening” on echocardiography, which may represent NBTE lesions in the appropriate context. Disseminated intravascular coagulation (DIC) causing in situ cerebral artery thrombosis is another possible mechanism for ESUS in patients with cancer, although formal criteria for overt DIC are rarely met.$^{9}$ Another cancer-specific stroke mechanism is tumor embolization, which arises from centrally located primary or metastatic lung cancers that invade the pulmonary veins or cardiac chambers.$^{2}$ This mechanism should be suspected if, months later, melastases form at the site of stroke. Last, nonstenos-ing large-artery atherosclerosis is an underappreciated stroke mechanism, including in patients with cancer; high-risk plaque features on imaging may help identify culprit lesions.$^{30}$

Rarely, cancer drugs can cause stroke.$^{13,14}$ This includes vascular endothelial growth factor inhibitors, vascular endothelial growth factor and BCR-ABL-tar-geting tyrosine kinase inhibitors, immunomodulatory antiangiogenic agents, and hormonal therapies.$^{39,45}$ However, assigning causality to these medications is challenging because of confounding by indication.$^{14}$ Many cancer therapeutic agents linked to stroke risk are typically administered to patients with disseminated cancers or as second-line treatment after progression of disease; therefore, delineating whether the cancer and its hematologic effects caused the stroke or whether it was the drug given to treat the cancer is difficult.$^{14}$ This is compounded by the fact that many patients with cancer receive multiple treatments in combination. We therefore stress caution in assigning causality to individual cancer therapies, which could lead to inappropriate cessation of potentially lifesaving treatments and produce a self-fulfilling prophecy. Furthermore, if one considered these relationships causal, stroke secondary prevention therapies could mitigate future AIS risk regardless of ongoing cancer treatments.

DIAGNOSTIC ALUATION

The diagnostic approach to patients with suspected stroke and active cancer must account for additional layers of complexity related to the dual disease process.$^{6}$ For example, a hypodensity on head CT could represent an infarction, metastasis, or infection; therefore, MRI is preferred, although even MRI may be insufficient for an immediate definitive diagnosis. MRI findings that favor

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 Figure. Ischemic stroke mechanisms related to cancer or its treatments and their corresponding diagnostic findings.

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AIS over tumor include true restricted diffusion (ie, bright hyperintensity on diffusion-weighted images with accompanying hypointensity on apparent diffusion coefficient images), wedge-shaped lesion(s) corresponding to cerebrovascular territories, edema that involves the cortex and is proportionate to the size of the diffusion-weighted hyperintensity, and lack of enhancement.$^{46}$ In some cases, especially when the diffusion-restricting

areas are small or the MRI is performed subacutely (when enhancement from infarcts is expected), a repeat MRI in 1 to 2 months is necessary to confirm stroke.

Given the complicated relationships among stroke, cancer, and cancer treatments, these patients often need more testing than other patients with AIS. Notably, vascular imaging should include the aortic arch among patients with prior chest radiation; thus, CT angiography

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CLINICAL STATEMENTS AND BUIDELINES

may be preferred over magnetic resonance angiography. Blood cultures should be considered to assess for infectious endocarditis, especially those that are immunosuppressed, have indwelling venous catheters, or endorse systemic symptoms. Measuring plasma D-dimer is generally advised because it can be helpful in relating the cancer to the stroke, stratifying the risk of future stroke and death, and measuring the response to treatment.$^{31,47}$ We typically measure D-dimer during the index stroke hospitalization and every few months thereafter. In patients treated with intravenous thrombolysis or thrombectomy, early D-dimer measurements may be falsely elevated, so checking toward the end of the hospitalization may be prudent. Echocardiography should generally include an agitated saline injection to assess for right-to-left shunts because the risk of VTE is markedly elevated with cancer and could lead to paradoxical embolism.$^{40,44}$ If a right-to-left shunt is identified, then venous ultrasound of the extremities may be warranted. Transesophageal echocardiography should be considered because it views the cardiac valves better than transthoracic echocardiography and is more likely to diagnose NBTE.$^{44}$ Because cancer is associated with a heightened risk of atrial fibrillation, prolonged cardiac rhythm monitoring is generally advised.$^{38}$ In select patients, chest CT might also be considered to assess a centrally located cancer that could cause tumor embolization. Conversely, it should be noted that although these tests may provide useful information, they can be burdensome, especially for patients with active cancer who may be frail and overwhelmed by their cancer treatment. Therefore, decisions about which diagnostic tests to obtain should be individualized and shared with the patient.

NEW CLASSIFICATION FOR CANCER-RELATED STROKE

About 50% of AIS in patients with cancer are currently categorized as ESUS by predominant classification systems such as TOAST (Trial of Org 10172 in Acute Stroke Treatment).$^{9,28,48}$ However, it is increasingly clear from epidemiological, translational, and histopathological studies that many of these strokes are related to the systemic effects of the cancer itself.$^{8,28,35,36,49}$ However, there is no standardized classification schema for cancer-related stroke, and existing literature is ripe with inconsistent nomenclature when referring to this phenotype. Therefore, like the PFO-Associated Stroke Causal Likelihood classification for patent foramen ovale-associated stroke,$^{50}$ we propose a novel classification system with varying degrees of certainty to attribute a stroke to cancer itself (Table 3). The different categories for certainty of causality (probable versus possible versus unlikely) have been adapted from a recent international consensus statement on subgroups of ESUS and relate to a patient's distinctive clinical features and

their estimated risk for recurrent thromboembolism.$^{27}$ The proposed criteria are based on data that are routinely available in clinical practice. The probable category encompasses standard criteria for NBTE, overt DIC, or tumor embolism; the possible category includes the most robust clinical, laboratory, and radiographic risk markers for AIS in patients with cancer.$^{9,27,28}$ A D-dimer threshold of >2500 ng/mL fibrinogen equivalent units was selected to assign possible causality because it is near most published cutoffs for identifying occult cancer or positing causation to known cancer in patients with AIS, and it is roughly 5 times the upper limit of normal.$^{23,27-29,31}$ Meanwhile, cancer therapies were omitted from the proposed criteria because strokes attributed to them have uncertain mechanisms, and their treatment may differ from therapy directed toward a cancer-related stroke; thus, we believe they should be classified separately. It is important to note that cancer-related stroke is not a homogenous entity, and some patients meeting criteria for cancer-related stroke may have stroke from nonneoplastic causes; therefore, it is imperative that clinicians comprehensively address patients' overall cardiovascular risk profile, including hypertension, smoking, diabetes, and hyperlipidemia. We hope that this novel framework will harmonize stroke classification in patients with cancer, thereby enabling consistent nomenclature across clinical practice and research and setting the stage for therapeutic trials in this growing high-risk population.

GOALS OF CARE

Patients with cancer-related stroke face high rates of disability and cancer- and treatment-related complications.$^{2}$ In a prospective survey, patients with active cancer and AIS reported that stroke disability and cancer pain had the largest impact on their quality of life, and cognitive impairment and functional dependence were their biggest concerns for the future.$^{51}$ This cohort was generally more concerned about future stroke than bleeding events and preferred a more aggressive antithrombotic strategy, although wide variability existed.$^{51}$ Given these factors, it is imperative to periodically reassess these patients' goals of care, especially because they may change over the course of their illness. In addition, palliative care to control symptoms and to enhance quality of life should always be considered along with disease-targeting medical therapies. For an in-depth discussion on palliative care for patients with cardiovascular disease, we refer readers to the scientific statement on this topic.$^{52}$

ACUTE TREATMENT

Patients with AIS and cancer should be considered for acute treatment with intravenous thrombolysis. Cancer is not a contradiction to such treatment$^{5}$; however, an additional layer of vigilance is warranted in the

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|Degree of certainty|Probable|Possible|Uncertain causal link| |---|---|---|---| |Criteria|Meeting ≥1 of the following criteria: Cardiac vegetation(s) with negative blood cultures (ie, NBTE) ISTH DIC Score ≥5 fulfilling criteria for overt DIC# Radiographic evidence for tumor invading the left atrium or ventricle, pulmonary veins, or cervicocephalic arteries with acute infarction confined to the corresponding cerebrovascular territories§|Cryptogenic ischemic stroke after standard diagnostic evaluation in a patient with active cancer that has spread beyond the primary site OR recently progressed AND meeting ≥1 of the following criteria: D-dimer >2500 ng/mL FEU in the absence of an acute venous thromboembolism Acute infarction in multiple cerebrovascular territories (ie, bilateral anterior, unilateral anterior and posterior, or bilateral anterior and posterior) Bilateral microemboli (ie, HITS) on TCD Absence of the susceptibility vessel sign on MRI despite a confirmed acute intracranial occlusion on vessel imaging§|Not meeting criteria for probable or possible causality|

DIC indicates disseminated intravascular coagulation; FEU, fibrinogen equivalent units; HITS, high-intensity transient signals; ISTH, International Society of Thrombosis and Haemostasis; MRI, magnetic resonance imaging; NBTE, nonbacterial thrombotic endocarditis; and TCD, transcranial Doppler.

*This classification is specific to patients with active cancer. The prevailing definition for active cancer in prospective studies is a pathological diagnosis or treatment of any cancer other than basal or squamous cell carcinoma of the skin within the past 6 months; known recurrent, regionally advanced, or metastatic cancer; or cancer not in complete remission.

† This proposed classification is meant to supplement prevailing classification systems such as TOAST (Trial of Org 10172 in Acute Stroke Treatment). It is intended for strokes that are currently classified as cryptogenic or those that fall under defined mechanistic categories but are directly related to the systemic effects of cancer (ie, NBTE, DIC, tumor embolism). Under this proposed schema, these "cancer-related strokes" should instead be categorized under the "stroke of other determined cause" subtype. Stroke mechanisms with defined categories that are not directly related to the systemic effects of cancer should be categorized per conventional criteria even if mediated by cancer or its treatments (ie, large-arter atherosclerosis after radiotherapy).

‡The ISTH DIC Score ranges from 0 to 8. A score ≥5 fulfills criteria for overt DIC. Points are assigned based on platelet count (2 points for values <50×10$^{3}$/µL or 1 point for values of 51 to 100×10$^{3}$/µL), fibrin-related markers such as D-dimer (3 points for severely increased values (>10×per limit of normal) or 2 points for moderately increased values (>1 to <10×per limit of normal]), prothrombin time (2 points if prolonged ≥6 seconds or 1 point if prolonged 3 to 6 seconds), and fibrinogen level (1 point if <100 mg/dL).

§Radiographic evidence can include echocardiography, computed tomography, or MRI.

||The susceptibility vessel sign describes a hypointense signal within an occluded intracranial artery seen on MRI/T2-weighted gradient-recalled echo images and is associated with erythrocyte-rich thrombolic

assessment of eligibility. Because hematologic derangements are common in patients with cancer, clinicians may want to wait for the results of complete blood counts and coagulation studies before administering treatment. Furthermore, a careful review of baseline brain imaging must exclude not only hemorrhage but also meta-static disease. If brain metastases are present, we would defer intravenous thrombolysis because of the high risk of hemorrhagic complications. In general, patients with cancer are roughly one-third less likely to receive thrombolysis because of factors such as thrombocytopenia, anticoagulation, recent invasive procedures, and concern for tumoral bleeding.$^{53}$ Short-term outcomes after intravenous thrombolysis, including symptomatic intracerebral hemorrhage and in-hospital mortality, are similar in properly selected patients with and without cancer.$^{54}$ However, long-term outcomes are typically worse in oncological patients, although this is driven primarily by the effects of the cancer, and a sizeable number achieve functional independence.$^{55}$

Similarly, patients with cancer may be eligible for mechanical endovascular thrombectomy if a large-vessel occlusion is identified. This procedure has similar rates of technical success and short-term outcomes in patients with and those without cancer.$^{56,57}$ However, patients with cancer face a greater probability of death and stroke recurrence because of their malignancy.$^{56,57}$

Overall, patients with cancer and AIS should be considered on an individual basis for these acute stroke

interventions with the aim of reducing disability and optimizing quality of life. Although all treatment decisions must be considered in the context of the long-term goals of care and perceived risks and benefits, the potential for substantial reversal of stroke-related deficits is likely to be worthwhile for most patients. Conversely, in patients who have a large core infarct on baseline imaging and are likely to have permanent severe disability even with reperfusion, a more palliative approach may be more appropriate.$^{51}$ Because patients' wishes in such scenarios may be unknown to treating neurologists acutely, we encourage emergency consultation with the involved oncologist(s) to assist with medical decision-making.

RISK OF RECURRENT STROKE AND OTHER ADVERSE EVENTS

Cancer-related stroke is one of the highest risk subgroups for stroke recurrence.$^{2,47}$ Compared with the general stroke population, patients with active cancer have a 2- to 3-fold increased risk of recurrent stroke at 1 year, with rates ranging from 14% to 29%.$^{9,58}$ Most of these events occur within 3 months, an especially high-risk period for recurrence.$^{10,47}$ These patients also face substantially increased risks of other ischemic events.$^{47}$ Among 263 patients with active cancer and AIS at a quaternary cancer center, the 6-month rate of major ischemic events was 37%, and nearly half the events were

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VTEs.$^{10}$ Patients who had a recurrent thromboembolism were twice as likely to die as those who did not.$^{10}$

There is a U-shaped curve for incident and recurrent stroke risk in patients with cancer, with the highest risk soon after cancer diagnosis (peak hypercoagulability resulting from amplified cancer activity and treatment), then a reduction in risk during the years after cancer control or cure, followed by a subsequent progressive rise in stroke risk associated with cancer recurrence or long-term effects of cancer treatments.$^{2}$ Historically, the coexistence of cancer and stroke was associated with poor prognosis and high mortality.$^{43,59}$ Fortunately, advancements in supportive care and oncological treatments, especially immunotherapy and targeted therapy, have improved survival in patients with cancer.$^{4,60}$ Paradoxically, this may also prolong the window during which thromboembolic complications can occur.

Patients with cancer and AIS are also at high risk of major bleeding because of frequent thrombocytopenia, invasive tumors, or cancer therapies impairing hemostasis.$^{29}$ In a prospective cohort of patients with active cancer and AIS, the estimated 1-year cumulative incidence of major bleeding was 24%.$^{47}$ Balancing the prevention of recurrent ischemic events through anticoagulants and antiplatelet medications with mitigating bleeding risks poses significant clinical challenges that require judicious decision-making.

SECONDARY STROKE PREVENTION

For Patients With Known Mechanisms

Secondary stroke prevention in patients with cancer should be tailored to the stroke mechanism if known.$^{6}$ For instance, antiplatelet therapy and aggressive risk factor control should be implemented for small-vessel disease, and direct oral anticoagulant (DOAC) therapy should be administered for nonvalvular atrial fibrillation. Stroke from radiation-induced atherosclerosis of the extracranial carotid artery should generally be treated with revascularization, typically endovascular stenting because of the perceived higher risks of adverse events related to open surgical dissection through fibrotic soft tissue; consultation with proceduralists with expertise in this population is suggested. In patients with confirmed NBTE or overt DIC, therapeutic-dose anticoagulants are typically prescribed, although supportive clinical trial data are admittedly lacking, and a reasonable argument could be made to administer antiplatelets to patients with confirmed NBTE because of their platelet-rich vegetations.$^{2}$ Many begin with unfractionated or low-molecular-weight heparin, particularly for overt DIC, which frequently causes bleeding, thereby favoring a short-acting anticoagulant. Long term, DOACs may be preferred because of their oral administration and safety

and efficacy comparable to those of low-molecular-weight heparin for other forms of cancer-associated thromboembolism.$^{9,29}$

For Patients With Unknown Mechanisms

When the stroke is categorized as ESUS according to current construct (or possible cancer-related stroke as proposed in this scientific statement), the optimal antithrombotic strategy is uncertain, and equipoise exists between anticoagulant and antiplatelet therapy.$^{9}$ Although theoretical considerations may prompt some physicians to use anticoagulants, current observational and clinical trial data do not indicate that is a clearly superior approach. At a major cancer center, among 172 patients with active cancer and AIS, 90 were prescribed an anticoagulant at hospital discharge, and 82 were prescribed an antiplatelet medication alone.$^{10}$ Rates of recurrent stroke, recurrent thromboembolism, and death were comparable between groups, although confounding by indication was likely.$^{10}$ Subgroup analyses of 2 large randomized trials in ESUS were similarly neutral. Among 543 patients with history of cancer enrolled in the NAVIGATE-ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source), recurrent AIS rates were 7.7% with rivaroxaban 15 mg daily and 5.4% with aspirin 100 mg daily (hazard ratio, 1.43 [95% CI, 0.71–2.87]).$^{61}$ In the ARCADIA trial (Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke), 137 patients had a history of cancer, and the risk of a major ischemic or hemorrhagic event was 21.1% in patients randomized to apixaban 5 mg twice daily versus 13.1% in patients randomized to aspirin 81 mg daily (hazard ratio, 0.61 [95% CI, 0.26–1.43]).$^{62}$ An important caveat to these subgroup analyses is that data on cancer activity, type, and stage were unavailable.

Two randomized trials have been dedicated to secondary stroke prevention in patients with cancer. The TEACH trial (Trial of Enoxaparin vs Aspirin in Patients With Cancer and Stroke) compared therapeutic-dose enoxaparin with standard-dose aspirin in patients with active cancer and AIS and no clear indication for anti-coagulant or antiplatelet therapy.$^{63}$ This trial, focused on feasibility of enrollment, demonstrated that patients and physicians are generally willing to enroll in a trial comparing these antithrombotic strategies, especially if an oral anticoagulant was used.$^{63}$ The small number of patients (n=20) prevented meaningful efficacy analyses.$^{63}$ The ENCHASE trial (Edoxaban for the Treatment of Coaguopathy in Patients With Active Cancer and Acute Ischemic Stroke) randomized 40 patients with cancer and ESUS to edoxaban 60 mg daily or enoxaparin 1 mg/kg twice daily; there was no antiplatelet arm.$^{64}$ This trial, focused on prothrombotic and embolic biomarkers,

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demonstrated that D-dimer levels at 7 days and tran-scranial Doppler microemboli rates at 90 days were similar between groups, indicating that DOACs and low-molecular-weight heparins have comparable effects in this population.$^{64}$

Vitamin K antagonists have not been studied in clinical trials focused on AIS with cancer. However, they are generally avoided in this population because of their narrow therapeutic window, interactions with cancer treatments, and inferiority to other anticoagulants for the treatment of cancer-associated VTE. Furthermore, in a retrospective study of cancer-related stroke (n=79), warfarin use was associated with higher follow-up D-dimer levels and nominally more recurrent stroke than low-molecular-weight heparin use.$^{65}$

Phase 3 randomized trials of different antithrombotic strategies, particularly DOACs versus aspirin, are needed to determine the optimal approach for ESUS with cancer. Combined anticoagulant-antiplatelet therapy should also be explored because both coagulation factors and platelets are implicated in cancer-related stroke; however, this approach could further increase an already high bleeding risk. The role of statins in cancer-related stroke is also uncertain, although observational data suggest that statins may improve survival in patients with cancer and AIS regardless of stroke mechanism.$^{66}$ In the absence of clear indications, decisions surrounding secondary stroke prevention should be individualized and guided by multidisciplinary discussions between neurologists and oncologists. Drug-drug interactions should be considered in the selection of medications, particularly DOACs because of their cytochrome P450 3A4 and P-glycoprotein metabolism.$^{67}$

Aggressive oncological treatment is critical to reduce the prothrombotic effects of cancer. Cancer activity drives the multifactorial hypercoagulable process that promotes stroke, and this is best addressed by eliminating cancer cells.$^{9}$ Therefore, chemotherapy, especially targeted agents that cause less systemic toxicity, should not be postponed in patients with AIS with reasonable performance status. One exception is when the index stroke is attributed to a cancer medication, in which case the medication should be substituted for comparable alternatives. Another occasional exception is cancer surgery, for which there are competing risks that require consideration. Operating soon after AIS will delay or interrupt antithrombotic therapy, which may trigger recurrence, especially if an active thromboembolic source is present. Conversely, postponing surgery for prolonged periods will enable cancer dissemination and progression of cancer-mediated hypercoagulability, which unquestionably will promote stroke recurrence. Therefore, we generally advise not postponing surgery beyond a few weeks unless the stroke was severely disabling or the surgical risks are too high.

CONCLUSIONS

Cancer-related stroke is a growing and high-risk subgroup of AIS, with distinctive clinical features, mechanisms, and outcomes. As cancer treatments continue to improve, the prognosis of cancer-related stroke will likely follow suit. Translational studies have increased our understanding of the molecular and cellular pathogenesis of cancer-related stroke, although much work remains, including a better delineation of the biological causal pathway from cancer to AIS. In general, if standard exclusions are absent, patients with cancer and AIS should be treated with acute reperfusion interventions. Furthermore, all management decisions, including the type of antithrombotic therapy, should be individualized and implemented according to the patient's goals of care and priorities. In this scientific statement, we propose a novel classification system for cancer-related stroke to remove it from the ESUS umbrella and to enable consistent nomenclature across clinical practice and research. We hope that this novel classification will spur dedicated controlled trials to determine the optimal strategies for acute treatment and secondary prevention for these complex patients.

ARTICLE INFORMATION

The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.

This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on October 7, 2025, and the American Heart Association Executive Committee on October 22, 2025. A copy of the document is available at https://professional.heart.org/statements by using either "Search for Guidelines & Statements" or the "Browse by Topic" area. To purchase additional reprints, call 215-356-2721 or email Meredith.Edelman@wolterskluwer.com

The American Heart Association requests that this document be cited as follows: Navi BB, Kasner SE, Cushman M, Okwuosa TM, Fleming NH, Behr JM, Yang JJ, Gupta A, DeAngelis LM; on behalf of the American Heart Association Stroke Council and Council on Cardiovascular and Stroke Nursing. Classification and management of ischemic stroke in patients with active cancer: a scientific statement from the American Heart Association. Stroke. 2026;57:e······.. doi: 10.1161/STR.0000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000

The expert peer review of American Heart Association--commissioned documents (eg, scientific statements, clinical practice guidelines, systematic reviews) is conducted by the Office of Science Operations. For more on statements and guidelines development, visit https://professional.heart.org/statements. Select the "Guidelines & Statements" drop-down menu, then click "Publication Development."

Permissions: Multiple copies, modification, alteration, enhancement, and distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at https://www.heartorg/permissions. A link to the “Copyright Permissions Request Form” appears in the second paragraph (https://www.heartorg/en/about-us/statements-and-policies/copyright-request-form).

Acknowledgments

The authors thank Anne Leonard for her invaluable guidance and support for this statement; Dr Eric Yang, Dr Gregory Goldgof, Dr Jennifer Jantz, Richard Genova, Dr Jana Ivanidze, and the New York–Presbyterian/Weill Cornell Medical Center Clinical Microbiology Laboratory for assisting in image acquisition; and Patrick Lane for designing the Figure.

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Disclosures

Writing Group Disclosures

|Writing group member|Employment|Research grant|Other research support|Speakers' bureau/honoraria|Expert witness|Ownership interest|Consultant/ advisory board|Other| |---|---|---|---|---|---|---|---|---| |Babak B. Navi|Weill Cornell Medicine|None|None|None|None|None|None|None| |Lisa M. DeAngelis|Memorial Sloan-Kettering Cancer Center|None|None|None|None|None|None|None| |Jacqueline M. Behr|University of Rochester Medical Center|None|None|None|None|None|None|None| |Mary Cushman|University of Vermont, The Robert Larner, M.D. College of Medicine|None|None|None|None|None|None|None| |Nathaniel H. Fleming|University of California, San Francisco|None|None|None|None|None|None|None| |Ajay Gupta|Columbia University Irving Medical Center|None|None|None|None|None|None|None| |Scott E. Kasner|University of Pennsylvania|Daichi Sankyo (clinical trial payments to institution)*|None|None|None|None|None|Bayer*; Bristol-Myers Squibb*| |Tochi M. Okwuosa|Rush University Medical Center|None|Abbott Labst†|None|None|None|None|None| |Jennifer J. Yang|Memorial Sloan-Kettering Cancer Center|None|None|None|None|None|None|None|

This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be "significant" if (a) the person receives $5000 or more during any 12-month period, or 5% or more of the person's gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $5000 or more of the fair market value of the entity. A relationship is considered to be "modest" if it is less than "significant" under the preceding definition. *Modest. *Significant.

*Modest.

†Significant.

Reviewer Disclosures

|Reviewer|Employment|Research grant|Other research support|Speakers' bureau/honoraria|Expert witness|Ownership interest|Consultant/ advisory board|Other| |---|---|---|---|---|---|---|---|---| |Joseph P. Broderick|University of Cincinnati|None|None|None|None|None|None|None| |James C. Grotta|Memorial Hermann Health System|None|Genentech (grant; we receive drug for a clinical trial)*|None|None|None|None|Frazer Ltd†| |Steven R. Levine|SUNY Downstate Health Sciences University|None|None|None|None|None|None|None| |Wade Smith|University of California, San Francisco|None|None|None|None|MindRhythm, Inc†|None|None| |Lawrence R. Wechsler|University of Pittsburgh Medical School|None|None|None|None|None|None|None|

This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be "significant" if (a) the person receives $5000 or more during any 12-month period, or 5% or more of the person's gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $5000 or more of the fair market value of the entity. A relationship is considered to be "modest" if it is less than "significant" under the preceding definition. *Modest. *Significant.

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