Research Advances in Timing of Anticoagulant Therapy Following Cardioembolic Stroke

Abstract

Cardioembolic stroke primarily results from thromboembolism caused by cardiac conditions such as atrial fibrillation, characterised by high recurrence rates, high rates of disability, and high mortality. Anticoagulation therapy is a key measure for the prevention of stroke recurrence, though the timing of its initiation remains debated, requiring a balance between the risk of thromboembolic recurrence and the risk of bleeding. The widely adopted “1-3-6-12-day rule” is based on expert consensus but lacks support from high-level evidence. In recent years, multiple randomized controlled trials (such as TIMING, ELAN, OPTIMAS, and START) have demonstrated that for patients with mild-to-moderate cardioembolic stroke, early initiation (within 2–4 days after stroke) of direct oral anticoagulants (DOACs) is not only safe but also significantly reduces the risk of early recurrence, without increasing the incidence of symptomatic intracranial hemorrhage. In particular, the recently completed individual participant data meta-analysis (CATALYST) has provided robust evidence for early anticoagulation. Unlike previous reviews that have focused solely on the timing of anticoagulation in non-valvular atrial fibrillation, this review provides a critical appraisal of the evidence gaps for severe stroke and post-reperfusion populations, a practical comparison of individual DOACs to guide drug selection, and a summary of management principles for other cardioembolic sources (mechanical valves, infective endocarditis, patent foramen ovale, left ventricular thrombus, and atrial flutter). This review summarises the pathophysiological mechanisms of cardioembolic stroke, clinical strategies for anticoagulation timing, characteristics of different anticoagulant agents and their indications for use. It emphasises the importance of individualised treatment and indicates that future research should further clarify the optimal timing of anticoagulation in patients with severe stroke and those undergoing reperfusion therapy.

Keywords

ischemic stroke cardioembolic stroke atrial fibrillation anticoagulation direct oral anticoagulants / DOACs treatment initiation early initiation secondary prevention

Introduction

Cardioembolic stroke is primarily caused by thrombi originating from cardiac diseases that dislodge and occlude cerebral arteries, with the most common etiology being non-valvular atrial fibrillation. Other causes encompass cardiac valvular diseases and intracardiac thrombus formation following myocardial infarction.¹ With the global aging trend, the rising prevalence of atrial fibrillation is consequently increasing the risk of cardioembolic stroke.² The incidence rate varies across different regions, which is associated with local demographic structure, healthcare standards, and lifestyle factors, among others.³ Furthermore, acute cardioembolic ischemic stroke is associated with high rates of mortality and disability. Patients often suffer from severe neurological deficits post-onset, such as limb paralysis, speech impairments, and cognitive dysfunction, which significantly impact their quality of life. This condition not only elevates the risk of complications including pulmonary infections, deep vein thrombosis, and pulmonary embolism but, in severe cases, may even result in death. This also imposes a substantial economic burden on both families and society, encompassing medical costs, caregiving expenses, and economic losses resulting from the patient’s loss of earning capacity.⁴

To reduce stroke recurrence, post-stroke anticoagulation serves as a crucial measure for secondary prevention.¹ Previously, early initiation of anticoagulation was widely believed to potentially increase the risk of hemorrhagic transformation. This concern stemmed from the fact that following an ischemic stroke, particularly in patients with large infarcts or severe neurological deficits, brain tissue may undergo hemorrhagic conversion, potentially leading to clinical deterioration or even death.^1,5 Additionally, reperfusion therapies such as thrombolysis and thrombectomy may inherently cause vascular injury, thereby increasing the risk of bleeding. Hemorrhagic transformation is a serious complication in patients undergoing intravenous thrombolysis or endovascular therapy, which may lead to clinical deterioration or even death,^6,7 the timing of anticoagulation should be determined on an individualized basis. The central issue in determining the timing of anticoagulation lies in balancing the risk of thromboembolism against the risk of bleeding.⁸ The previously widely used “1-3-6-12 rule,” while helpful in balancing risks to some extent, is overly simplistic, and delaying anticoagulation therapy may increase the risk of stroke recurrence,⁹ and the “1-3-6-12 rule” was primarily developed based on expert consensus and clinical experience, and it lacks large-scale randomized controlled trials. Further research is needed to evaluate its safety and efficacy.¹⁰ While delaying anticoagulation may reduce the risk of bleeding, it still carries a substantial risk of recurrence.¹ Additionally, there is no clear and established gold standard for determining the optimal timing of delayed anticoagulation, and individual patient variability significantly influences decision-making. However, given the high risk of early recurrence following cardioembolic stroke, the early initiation of anticoagulant therapy can rapidly mitigate this risk.¹¹ Thus, the central challenge in clinical practice is determining the optimal timing for initiating early anticoagulation.

This review aims to elucidate the core pathophysiological mechanisms of cardioembolic stroke, systematically evaluate the limitations of traditional guidelines, and discuss optimization strategies for anticoagulation timing based on recent randomized controlled trials (such as TIMING, ELAN, OPTIMAS, START) and meta-analyses (CATALYST). It also compares the characteristics and clinical rationales of different anticoagulants, with a particular focus on DOACs, and emphasizes the paramount importance of individualized treatment management.

Discussion

Pathophysiological Mechanisms

AF is the most common etiology of cardioembolic stroke. In AF, the atrium loses its effective contractile function, leading to blood stasis within the atrial chamber, particularly in areas like the left atrial appendage, which promotes thrombus formation.¹² These thrombi, once dislodged, can be carried by the systemic circulation to intracranial arteries, causing vascular occlusion. This leads to ischemia and necrosis of brain tissue, thereby triggering a stroke.

Beyond AF, other cardiac conditions can also lead to cardioembolic stroke. Structural abnormalities of heart valves or the surface of mechanical prosthetic valves can readily activate the coagulation system, leading to thrombus formation. Rheumatic valvular disease, which is valvular inflammation caused by rheumatic fever, involves chronic inflammatory processes that can result in valve thickening, fibrosis, and calcification, thereby causing structural and functional abnormalities of the valves.¹³ Such valvular pathologies can further induce alterations in atrial structure and electrophysiological properties, thereby increasing the risk of AF;during AF, the loss of effective atrial contractile function predisposes to blood stasis, which readily promotes thrombus formation. Should a thrombus dislodge, it may trigger embolic events such as stroke.¹⁴ The primary pathological feature of infective endocarditis is the formation of vegetations on cardiac valves or the endocardial surface. Dislodgement of these vegetations can lead to septic emboli, which may involve cerebral vessels causing stroke. Furthermore, erosion of the vascular wall by bacteria can result in the formation and potential rupture of mycotic aneurysms, leading to intracerebral hemorrhage.¹⁵ Common causative pathogens of this disease include Staphylococcus aureus and Streptococcus species. The former tends to infect normal heart valves, whereas the latter more commonly infects previously damaged or abnormal valves.¹⁶ Besides, cardiac valve stenosis, particularly aortic stenosis, can impair cardiac output, leading to cerebral hypoperfusion, which directly elevates the risk of stroke.¹⁷

Heart failure contributes to intracardiac thrombus formation by inducing blood stasis within the cardiac chambers, frequently coexisting with atrial fibrillation, and often accompanied by a hypercoagulable state, collectively and significantly elevating the risk of embolic stroke.¹⁸ Acute myocardial infarction, particularly involving the anterior wall, significantly increases the risk of embolic stroke by inducing left ventricular systolic dysfunction, heart failure, and endocardial injury. These factors collectively contribute to blood stasis and thrombus formation within the left ventricle.¹⁹ Dilated cardiomyopathy is often complicated by atrial arrhythmias, which increases the risk of left atrial thrombus formation. In idiopathic dilated cardiomyopathy, marked left ventricular dilation and systolic dysfunction predispose to blood stasis within the cardiac chamber, facilitating the development of mural thrombi. Dislodgement of these thrombi can lead to ischemic stroke.²⁰ Additionally, hypertrophic cardiomyopathy (HCM) increases the risk of stroke primarily through left ventricular outflow tract obstruction, left atrial enlargement, and secondary AF.²⁰ Cardiac tumors, particularly left-sided myxomas and papillary fibroelastomas, are friable in nature. The tumor tissue itself or thrombi formed on its surface can readily detach to form emboli, which may then travel through the systemic circulation and enter the cerebral arteries. This constitutes an important mechanism for embolic stroke.²¹ Patent foramen ovale-associated stroke is primarily attributed to paradoxical embolism, in which thrombi originating from the venous system bypass the pulmonary circulation via the patent foramen and directly embolize cerebral arteries. Additionally, in-situ thrombus formation within the PFO tunnel is considered a possible secondary mechanism, although current evidence remains insufficient.²²

In summary, the pathophysiological mechanisms of cardioembolic stroke are diverse, yet the core principle lies in structural or functional cardiac abnormalities leading to thrombus formation or embolic events.

Timing of Anticoagulation

Conventional Guidelines and Their Limitations

The central challenge of anticoagulation therapy following cardioembolic stroke lies in balancing the high risk of early stroke recurrence against the potentially catastrophic risk of hemorrhagic transformation in the acute phase. The traditional “1-3-6-12-day rule” has long served as an empirical guiding framework.²³ This principle stratifies patients based on stroke severity (TIA, minor, moderate, and severe) and recommends initiating anticoagulation at 1, 3, 6, and 12 days post-stroke, respectively. Its pathophysiological rationale is to mitigate the risk of hemorrhage—which arises from vascular injury in the acute infarct zone—by delaying anticoagulation.²³

However, this principle has notable limitations. It is primarily based on expert consensus and observational experience, lacking robust support from high-level evidence such as large-scale randomized controlled trials (RCTs). Furthermore, this rigid time frame is overly simplistic and may underestimate the heightened early recurrence risk associated with cardioembolic stroke.⁹ Excessively delayed initiation of anticoagulation exposes patients to potentially preventable recurrent stroke risk, particularly in those with atrial fibrillation who are at particularly high thromboembolic risk. Consequently, more proactive and individualized anticoagulation strategies are required.

Optimization of Principle and RCTs Evidence

The “1-2-3-4-day rule” applies to patients with non-valvular atrial fibrillation (NVAF) who experience an acute ischemic stroke (IS) or transient ischemic attack (TIA). It stratifies the timing for initiating direct oral anticoagulants (DOACs) based on the severity of neurological impairment.²³ This rule recommends that DOAC therapy should be initiated within ≤1 day for patients with TIA, within ≤2 days for those with minor stroke (NIHSS 0-7), within ≤3 days for moderate stroke, and may be considered within ≤4 days even for patients with severe stroke (NIHSS ≥16).

Studies have demonstrated that this strategy significantly reduces the risk of embolism (for example, in the minor stroke group, embolic events decreased from 4.3% to 2.7%) without increasing hemorrhagic complications.²³

In recent years, the publication of a series of RCTs such as TIMING, ELAN, OPTIMAS, and START has challenged the traditional belief that “early anticoagulation invariably carries a high bleeding risk,” providing a solid evidence base for early anticoagulation initiation.

TIMING is the first randomized controlled trial designed to evaluate the efficacy and safety of initiating NOAC therapy within 10 days after an acute ischemic stroke in patients with atrial fibrillation.²⁴ This study, conducted across 34 stroke centers in Sweden, enrolled 888 patients (450 in the early group, 438 in the delayed group). Participants were randomized to initiate NOAC either early (≤4 days post-stroke, mean 66.8 hours) or delayed (5–10 days post-stroke, mean 116.8 hours). The study reported that no patients experienced symptomatic intracranial hemorrhage during the 90-day follow-up period, and the overall incidence of major bleeding, including intracranial hemorrhage, was very low within the first four weeks. Early initiation of NOAC therapy in patients with atrial fibrillation after acute ischemic stroke was found to be non-inferior to delayed initiation. Therefore, acute secondary stroke prevention should be considered in patients with acute ischemic stroke and atrial fibrillation.

The ELAN trial is the largest RCT comparing early versus late initiation of DOAC therapy in patients with AF-related IS.²⁵ The timing for initiating DOAC therapy—either early or late—is defined based on the infarct size assessed via neuroimaging.²⁵ Early treatment was defined as initiating DOACs within 48 hours after stroke onset for participants with minor (infarct diameter <1.5 cm) or moderate stroke, and on day 6 or 7 for those with major stroke (infarct diameter >1.5 cm). Late treatment involved initiating DOACs on day 3 or 4 for participants with minor stroke, on day 6 or 7 for those with moderate stroke, and on day 12, 13, or 14 for those with major stroke after the index event.²⁶ Early initiation of DOACs did not increase the risk of symptomatic intracranial hemorrhage, confirming its safety profile. Although no formal test for superiority was performed, the early group showed a strong trend toward a significant reduction in the risk of early stroke recurrence. The 30-day stroke recurrence rate was significantly lower (Early group: 1.4% vs. Delayed group: 2.5%; risk difference -1.14%, 95% CI -2.41 to 0.13). The risk difference for the 30-day composite endpoint (stroke recurrence, systemic embolism, major bleeding, or vascular death) was -1.18% (95% CI -2.84 to 0.47), suggesting potential clinical benefit from early treatment. Exploratory analysis at 90 days indicated a continued trend towards reduced stroke recurrence (Early group: 1.9% vs. Delayed group: 3.1%; OR 0.60, 95% CI 0.33 to 1.06). The imaging-based stratified strategy for initiating DOACs (within ≤48 hours for minor/moderate stroke, or on days 6-7 for major stroke) is safe and may reduce the risk of early stroke recurrence. ELAN also included patients who received intravenous thrombolysis or endovascular thrombectomy and permitted the presence of petechial hemorrhage within the infarct zone, enhancing the generalizability of its results. These findings challenge the traditional ‘1-3-6-12-day rule’ and support the individualization and earlier initiation of anticoagulation when clinically indicated.²⁶ However, ELAN has certain limitations. The study excluded patients who were already on anticoagulation therapy at the time of stroke onset; therefore, the results cannot be generalized to this population.²⁷ Furthermore, the assessment of infarct size was not centralized but was performed independently at each participating site,²⁷this may introduce a certain degree of assessment bias.

The OPTIMAS (Optimal Timing of Anticoagulation After Acute Ischaemic Stroke) trial is 4-phase, multicenter, parallel-group, randomized controlled study featuring an open-label intervention with blinded outcome assessment.²⁸ The trial employed a hierarchical non-inferiority–superiority gatekeeper design—sequentially evaluating a 2-percentage-point non-inferiority margin before proceeding to superiority testing—to compare the efficacy of early initiation of DOACs within 4 days after stroke onset versus delayed initiation between 7–14 days after stroke onset in 3,621 patients with atrial fibrillation and IS.²⁸ The primary outcome of the trial was a composite of recurrent IS, symptomatic ICH, stroke of undetermined type, or systemic embolism within 90 days, based on a modified intention-to-treat analysis.²⁵ The results showed that symptomatic intracerebral hemorrhage occurred in 11 patients (0.6%) in the early DOAC initiation group and 12 patients (0.7%) in the delayed DOAC initiation group (adjusted risk difference 0.001, 95% CI -0.004 to 0.006; p=0.78). Early initiation met non-inferiority for the primary composite outcome. These findings do not support the current widespread, guideline-endorsed practice of delaying DOAC initiation after an acute ischemic stroke in patients with atrial fibrillation.²⁸ With its large-scale and high-quality evidence, the OPTIMAS trial has clearly demonstrated that early initiation of DOAC in patients with atrial fibrillation and acute ischemic stroke does not increase the risk of symptomatic intracranial hemorrhage.

ELAN provided neuroimaging-based evidence supporting the feasibility and safety of initiating anticoagulation according to the severity of individual brain injury. In contrast, OPTIMAS validated a simplified, clinical score-based approach, confirming that applying a uniform early window (≤4 days) in broader clinical practice is equally safe and reliable.

The START trial is a prospective, pragmatic, multicenter, parallel-group, timing-of-treatment, response-adaptive randomized clinical trial. It included patients with mild-to-moderate ischemic stroke due to non-valvular atrial fibrillation. The trial randomized 200 patients into four groups, initiating DOAC therapy on day 3 or 4 (Group 1), day 6 (Group 2), day 10 (Group 3), and day 14 (Group 4) after the stroke. The primary endpoint was the composite of ischemic events (stroke or systemic embolism) or hemorrhagic events (symptomatic intracranial hemorrhage or major systemic bleeding) occurring within 30 days.²⁹ Based on Bayesian posterior probability analysis, Group 1 (day 3/4) was estimated to have the highest probability of being the optimal initiation time (0.41), followed by Group 2 (0.26), Group 3 (0.17), and Group 4 (0.15) (Table 1). This trial indicates that for patients with AF-related mild-to-moderate ischemic stroke, early DOAC initiation (at 3–4 days) may be more favorable for reducing the risk of early ischemic events without increasing the risk of bleeding.³⁰

Table 1.

Summary of Key RCTs Early Anticoagulation Timing in Cardioembolic Stroke

Trial	Sample size	Baseline(age,female%,median NIHSS)	Definition of early	Definition of late	Primary outcome	Key conclusion	Key exclusion criteria
TIMING	888	78.3y, 46.2%, 4 (IQR 2-9)	≤4 days (median 66.8 h)	5–10 days (median 116.8 h)	Composite of recurrent IS, sICH, major bleeding, or death at 90 days	Early non-inferior to delayed	NIHSS >25 (later amended), pre-existing major ICH
ELAN	2013	77y, 45%, 5 (IQR 2-11)	≤48h(minor/moderate), or day 6–7 (major stroke)	Day 3–4 (minor), day 6–7 (moderate), day 12–14 (major)	Composite of IS, sICH, SE, or vascular death at 30 days	Early safe; non-inferior; trend to lower recurrence	Anticoagulation at onset, severe ICH (PH-2)
OPTIMAS	3621	78.5y, 45.3%, 5 (IQR 3-10)	≤4 days	7–14 days	Composite of recurrent IS, sICH, undetermined stroke, SE at 90 days	Early-non-inferior; safety signal	Large haemorrhagic transformation, NIHSS >25 (site discretion)
START	200	75y, 50%, 6.5 (IQR 4-14)	Day 3 or 4	Day 6, 10, or 14	Composite of ischaemic or haemorrhagic events at 30 days	Highest probability of optimality at day 3/4	Severe stroke (NIHSS>15), PH-2

Abbreviations: DOAC, direct oral anticoagulant; IS, ischaemic stroke; sICH, symptomatic intracranial haemorrhage; SE, systemic embolism; NIHSS, National Institutes of Health Stroke Scale; PH-2, parenchymal haematoma type 2. Baseline characteristics (median age, female %,NIHSS): TIMING (78.3 y, 46.2%,4)²⁴; ELAN (77 y, 45%,5)²⁶; OPTIMAS (78.5 y, 45.3%,5)²⁸; START (75 y, 50%,6.5).²⁹

The CATALYST study is a prospective individual participant data meta-analysis designed to determine the optimal timing for initiating direct oral anticoagulants (DOACs) after an acute ischemic stroke in patients with atrial fibrillation. This research pooled data from four randomized controlled trials—TIMING, ELAN, OPTIMAS, and START—enrolling a total of 5411 patients for analysis.³⁰ The results demonstrated that, compared with late initiation (≥5 days after stroke), early initiation (≤4 days after stroke) of DOACs significantly reduced the risk of the primary composite endpoint (including recurrent ischemic stroke, symptomatic intracranial hemorrhage, or unclassified stroke) at 30 days (2.12% in the early group vs. 3.02% in the late group; odds ratio 0.70, 95% confidence interval 0.50–0.98).³⁰ Moreover, the incidence of symptomatic intracranial haemorrhage was low in both groups and showed no significant difference (0.45% in the early group versus 0.40% in the late group).³⁰ This high-level evidence indicates that for atrial fibrillation-associated acute ischemic stroke, early initiation of DOAC anticoagulation confers a benefit in reducing the risk of stroke recurrence and is not associated with an increased risk of symptomatic intracranial hemorrhage. The same conclusion was highlighted in a recent neurocardiology update.²⁷

Although no harm from early anticoagulation was observed across subgroups with different NIHSS scores, including severe stroke (NIHSS ≥16), it is important to note that all included trials excluded patients with pre-existing significant hemorrhagic transformation (e.g., PH2-type hematoma) or very severe neurological deficits (e.g., NIHSS >20). Therefore, the conclusions of CATALYST primarily apply to patients with minor-to-moderate stroke, as well as those with severe stroke but without radiographic evidence of significant hemorrhagic transformation.

The CATALYST study marks a significant shift in acute anticoagulation strategies for cardioembolic stroke, transitioning from “empirical delay” to “evidence-based early intervention”. When applying its conclusions in clinical practice, physicians should adhere to the principle of individualized management: For most patients with minor-to-moderate stroke, active consideration should be given to initiating DOACs within 4 days; for patients with severe stroke or those who have undergone reperfusion therapy, the decision should be made prudently after a comprehensive assessment of infarct core, hemorrhagic transformation risk, and embolic burden. For special populations where the aforementioned evidence is insufficient, decision-making should be even more cautious, accompanied by close monitoring. These findings are consistent with a recent GRADE-based meta-analysis,³¹ which issued a strong recommendation for early DOAC initiation (within 4 days) in minor-to-moderate stroke and a weak recommendation for severe stroke.

Anticoagulation Following Thrombolysis And/or Thrombectomy

The timing of anticoagulation after thrombolysis and/or thrombectomy in cardioembolic stroke is a complex clinical issue that necessitates balancing the risk of hemorrhage against the need to prevent recurrent embolism.^1,32 Initiating anticoagulation too early raises concerns that vascular endothelial injury induced by IVT/EVT may exacerbate the risk of hemorrhagic transformation, whereas delaying anticoagulation may increase the risk of recurrent stroke.^1,33 Therefore, following thrombolysis and/or thrombectomy, traditional anticoagulation strategies typically involve a delayed initiation of anticoagulation to mitigate the risk of hemorrhagic transformation.¹ However, a study demonstrated that for atrial fibrillation patients receiving intravenous thrombolysis (IVT), prior anticoagulation therapy was associated with improved outcomes when they underwent endovascular treatment (EVT).³⁴

Notably, recent evidence offers fresh insights into this matter.An exploratory subgroup analysis of the CATALYST meta-analysis, focusing on patients who received any reperfusion therapy (thrombolysis and/or thrombectomy) (n=1763), found that early (≤4 days) DOAC initiation showed a more favorable trend toward reducing the risk of the primary composite endpoint compared to delayed initiation (OR 0.54, 95% CI 0.28–1.04), without a significant increase in the risk of symptomatic intracranial hemorrhage.³⁰

However, the above conclusion is derived from a post-hoc subgroup analysis, representing a limited level of evidence. There is currently a lack of large-scale RCTs specifically designed in a prospective manner for cardioembolic stroke patients who have undergone reperfusion therapy, to definitively establish the optimal anticoagulation time window. Therefore, for this patient population, clinical decision-making still requires a highly individualized approach, incorporating a comprehensive assessment of factors such as infarct volume, signs of hemorrhagic transformation, procedural success, and embolic risk. Consequently, major international guidelines maintain a cautious stance in their recommendations, often advising delayed anticoagulation after thorough evaluation.

The traditional “1-3-6-12-day rule” served as an empirical framework and played a significant guiding role in an era lacking high-level evidence. However, the publication of a series of RCTs such as TIMING, ELAN, OPTIMAS, and START have collectively demonstrated that for patients with minor-to-moderate cardioembolic stroke, early (within 2-4 days) initiation of DOACs does not increase the risk of symptomatic intracranial hemorrhage, challenging the traditional notion that “early anticoagulation invariably leads to high bleeding risk.” Nevertheless, most current RCTs have excluded patients with severe stroke (NIHSS >15-20) or those with pre-existing hemorrhagic transformation. This very patient population represents the highest-risk group for bleeding in clinical decision-making, and determining their optimal anticoagulation timing remains a critical focus for future research. Furthermore, although recent meta-analytic subgroup data provide preliminary support for the safety of early anticoagulation in patients receiving reperfusion therapy, the optimal timing for anticoagulation in this group still requires confirmation through specifically designed prospective randomized trials. Therefore, future research needs to further refine and individualize anticoagulation initiation strategies to optimize clinical practice guidelines for acute-phase anticoagulation in cardioembolic stroke.

Management Considerations for Non-NVAF Cardioembolic Sources

The preceding discussion has focused on patients with nonvalvular atrial fibrillation (NVAF), who account for the majority of cases of cardioembolic stroke and are the source of the highest-level evidence from randomized controlled trials. However, clinicians frequently encounter patients whose stroke is not caused by NVAF, including those with mechanical valves, rheumatic mitral stenosis, infective endocarditis, patent foramen ovale, left ventricular thrombus, and atrial flutter. The management principles for these conditions differ from those for NVAF, and the evidence supporting the timing of anticoagulation is much weaker. The following section summarizes the key management points for these important non-NVAF cardiac causes. A comprehensive summary of preferred anticoagulants for various cardiac conditions has been provided by Manorenj et al. (Table2).³⁵

Table 2.

Summary of Management Principles for Non-NVAF Cardioembolic Sources

Cardioembolic source	Anticoagulation indicated	Recommended antithrombotic strategy
Mechanical valve / moderate–to–severe mitral stenosis	YES (VKA only)	Warfarin (INR 2.0–3.0 or 2.5–3.5)
Left ventricular thrombus (post‑MI / cardiomyopathy)	YES	Warfarin (first‑line) or DOAC (alternative)
Infective endocarditis (acute phase)	Generally not recommended (except for separate strong indications)	Antibiotics ± surgery
Patent foramen ovale (cryptogenic stroke)	Not recommended	PFO closure + antiplatelet (or antiplatelet alone)
Atrial flutter	Same as NVAF	DOAC or warfarin (based on CHA ₂ DS ₂ ‑VASc)

Mechanical Valves and Moderate-To-Severe Mitral Stenosis

In patients with mechanical valves, the valve surface activates multiple coagulation pathways, whereas DOACs are single-target inhibitors and cannot effectively prevent thrombosis; the RE ALIGN and PROACT Xa trials have demonstrated that DOACs lead to more thrombotic and bleeding events.³⁶ Patients with moderate-to-severe mitral stenosis are at extremely high risk of thrombosis due to severe stasis of blood flow in the left atrium. The INVICTUS trial showed that rivaroxaban was inferior to warfarin in terms of cardiovascular mortality, and all large-scale DOAC trials have excluded this patient population, resulting in a lack of safety data.³⁷ Therefore, DOACs should not be used in either group of patients.

Left Ventricular Thrombus (Post-myocardial Infarction or Cardiomyopathy)

Left ventricular thrombus (LVT) is a common complication of acute myocardial infarction (particularly anterior wall myocardial infarction) and cardiomyopathy. It carries a high risk of systemic embolism (especially ischemic stroke) and therefore requires anticoagulant therapy.³⁸ Current AHA/ESC guidelines recommend a 3–6-month course of oral anticoagulants (warfarin or DOACs), but the evidence supporting this recommendation is limited.^38,39 Anticoagulation decisions should be individualized, based on a comprehensive assessment of thromboembolic risk (e.g. anterior wall myocardial infarction, apical motionlessness, severe left ventricular dysfunction) and bleeding risk (e.g. HAS-BLED score), while taking into account the patient’s specific circumstances (e.g. feasibility of INR monitoring, drug interactions).³⁸ The 2023 ESC Guidelines (Class IIa recommendation, Level of Evidence C) state that vitamin K antagonists or DOACs may be considered following a diagnosis of VTE; however, the duration of treatment and whether to combine them with antiplatelet therapy should be determined on an individual basis.³⁸ Warfarin remains the standard of care at present, but DOACs may be used as an alternative when INR control is poor or when the patient finds it inconvenient.

Infective Endocarditis

Anticoagulation therapy is generally not recommended during the acute phase of infective endocarditis, as patients often have concomitant intracranial microbleeds or fungal aneurysms, and anticoagulation can significantly increase the risk of intracranial hemorrhage.⁴⁰ Contraindications for thrombolytic therapy; bleeding rates as high as 20%.⁴⁰ The cornerstone of acute-phase treatment is intravenous antibiotics and cardiac surgery when necessary.⁴¹ Current guidelines do not recommend the routine use of anticoagulation in IE unless there are other clear indications (such as mechanical valves), and decisions should be made on an individualized basis following a multidisciplinary evaluation.

Patent Foramen Ovale (PFO)

Anticoagulation therapy should not be routinely used for secondary prevention of cryptogenic stroke caused solely by a patent foramen ovale (PFO). The standard approach is to use antiplatelet therapy following PFO closure or as the sole treatment option, depending on the patient’s specific circumstances.⁴² Any consideration of anticoagulation must be based on the patient’s concurrent, well-established indications for anticoagulation and must be subject to careful evaluation by a multidisciplinary team.

Atrial Flutter

Strategies for stroke prevention in isolated atrial flutter (including perioperative anticoagulation) should follow the same principles as those for atrial fibrillation. Therefore, for patients with atrial flutter, the timing of anticoagulation initiation and the choice of anticoagulant (DOACs or warfarin) should be based on the recommendations for atrial fibrillation. The only nuance is that when Class Ic antiarrhythmic drugs (such as flecainide or propafenone) are used concomitantly, caution is warranted regarding the potential for atrial flutter to transition to 1:1 conduction, leading to rapid ventricular rates; however, this does not affect the anticoagulation decision itself.⁴³

Medication

Antiplatelet Agents

Clinical guidelines recommend antiplatelet therapy for patients with non-cardioembolic stroke or transient ischemic attack (TIA).⁴⁴ Although antiplatelet agents dominate the prevention of non-cardioembolic stroke, their role in the secondary prevention of cardioembolic stroke caused by atrial fibrillation has been definitively refuted by large-scale clinical trials. Studies such as AFASAK, SPAF, and EAFT have consistently demonstrated that adjusted-dose warfarin is significantly superior to aspirin in stroke prevention for patients with atrial fibrillation.^45-47 The AVERROES trial further demonstrated that for patients with atrial fibrillation who were unsuitable for warfarin therapy, apixaban was superior to aspirin in preventing stroke or systemic embolism without increasing the risk of major bleeding.⁴⁸ Therefore, international mainstream guidelines (AHA, ESC, etc.) recommend oral anticoagulants rather than antiplatelet therapy as the first-line treatment for long-term secondary prevention in patients with cardioembolic stroke.⁴⁹

Anticoagulants

There has been a transition in the pharmacologic management for secondary prevention of cardioembolic stroke, from Vitamin K antagonists to Direct Oral Anticoagulants (DOACs).

Warfarin, as a time-honored anticoagulant, functions by inhibiting the activation of vitamin K-dependent clotting factors (II, VII, IX, and X). It has a long history of clinical use, supported by substantial evidence demonstrating that VKA therapy reduces the risk of stroke by two-thirds and mortality by one-quarter.⁵⁰ Nevertheless, it carries well-recognized limitations, including a narrow therapeutic window necessitating frequent monitoring and dose adjustments, a high rate of suboptimal INR control, and susceptibility to dietary and drug interactions—all of which can ultimately compromise its efficacy and safety.^51,52

The advent of direct oral anticoagulants (DOACs) has effectively addressed these limitations of warfarin. DOACs (including dabigatran etexilate, rivaroxaban, apixaban, and edoxaban) are typically administered at fixed doses, do not require frequent INR (International Normalized Ratio) monitoring, and have a rapid onset of action,⁵³ enhances patient convenience. Meta-analyses of large-scale phase III clinical trials have consistently demonstrated that, compared with warfarin, DOACs are non-inferior or superior in preventing stroke and systemic embolism in patients with non-valvular atrial fibrillation, while also significantly lowering the risk of intracranial hemorrhage.^54,55 This superior safety profile, particularly the lower rate of symptomatic intracranial hemorrhage, supports the early initiation of DOACs after stroke.

Dabigatran etexilate is an oral prodrug that is rapidly converted by serum esterases to dabigatran, a potent, direct, and competitive thrombin inhibitor. It has an absolute bioavailability of 6.5%, with approximately 80% of an administered dose excreted renally. Its serum half-life ranges from 12 to 17 hours, and it does not require routine monitoring.⁵⁶ The RE-LY trial was a pivotal clinical study evaluating the efficacy of dabigatran etexilate versus warfarin for stroke prevention in patients with atrial fibrillation. The trial enrolled 18,113 patients with atrial fibrillation. The results demonstrated that dabigatran etexilate 150 mg twice daily was superior to warfarin in preventing stroke and systemic embolism, while the 110 mg twice daily dose was non-inferior to warfarin in efficacy but associated with a lower risk of bleeding.^56,57 It is worth noting that the dosage of dabigatran etexilate requires adjustment based on the patient’s renal function.⁵⁸ The total clearance (CL total) of dabigatran is primarily dependent on renal excretion. A trough concentration (C trough) below 70 ng/mL is associated with an increased risk of stroke related to dabigatran. Therefore, given the relationship between dabigatran’s CL total and creatinine clearance (CLcr)—where CL total of dabigatran is estimated by the daily absorbed dose of dabigatran etexilate divided by its plasma trough concentration—it is recommended to adjust the dose of dabigatran etexilate according to the CLcr value. This adjustment aims to achieve a target trough concentration of approximately 70 ng/mL and avoid associated risks.⁵⁸ Therefore, patients with chronic comorbidities such as diabetes and hypertension, who are at higher risk of renal impairment, require cautious use. In addition, given the age-related decline in renal function in elderly patients, a lower initial dose may be more appropriate, accompanied by close monitoring of renal function and bleeding risk.⁵⁹

Rivaroxaban exerts its anticoagulant effect by directly inhibiting coagulation factor Xa.⁶⁰ Factor Xa is a key serine protease in the coagulation cascade that catalyzes the conversion of prothrombin to thrombin. Thrombin, in turn, plays a central role in the process of thrombus formation.⁶¹ By binding to Factor Xa, rivaroxaban blocks the generation of thrombin, thereby preventing thrombus formation and ultimately achieving the goal of stroke prevention.⁶² Unlike vitamin K antagonists such as warfarin, rivaroxaban does not depend on antithrombin but instead directly binds to Factor Xa.⁶³ This direct inhibitory action results in a more predictable anticoagulant effect of rivaroxaban.⁶⁴ Studies have shown that compared to warfarin, patients experiencing intracranial hemorrhage during rivaroxaban treatment tend to have smaller hematomas and better outcomes.⁶⁵ Regarding the concern that early anticoagulation after cardioembolic stroke may lead to hemorrhagic transformation, a study evaluated the safety and feasibility of initiating rivaroxaban within ≤14 days after stroke/transient ischemic attack (TIA). This prospective, open-label study enrolled patients with atrial fibrillation who had experienced an IS/TIA with a National Institutes of Health Stroke Scale (NIHSS) score <9. The results showed that early use of rivaroxaban may not lead to hemorrhagic transformation.⁶⁶ It is important to note that rivaroxaban is partially eliminated through the kidneys. Therefore, in patients with renal impairment, its clearance is reduced, leading to elevated plasma concentrations and an increased risk of bleeding. Hence, dosage adjustment based on renal function is required.⁶⁷ Additionally, a study demonstrated that rivaroxaban can reduce left atrial “smoke-like echoes” and resolve left atrial appendage thrombus in patients with acute cardioembolic stroke.⁶⁸

Apixaban is also a direct Factor Xa inhibitor. It selectively blocks activated Factor Xa, thereby inhibiting thrombin generation and preventing thrombus formation.^69,70 In the randomized controlled trial, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE), apixaban was shown to be more effective than warfarin in preventing stroke and systemic embolism in patients with atrial fibrillation, while also reducing the risk of major bleeding.⁷¹ Concurrently, the Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial demonstrated that for patients with atrial fibrillation who were unsuitable for vitamin K antagonist therapy, apixaban was superior to aspirin.⁷¹ Additionally, in patients with adult congenital heart disease (ACHD) and atrial fibrillation, apixaban is effective in preventing thromboembolic events.⁷² The PROTECT-AR study, a prospective, multicenter, observational study conducted from 2019 to 2023, demonstrated the effectiveness and safety of apixaban in patients with ACHD and concomitant AA.⁷² Although apixaban has demonstrated significant efficacy in reducing stroke risk in patients with non-valvular atrial fibrillation, it is essential to assess renal and hepatic function prior to initiation to guide appropriate dose adjustment.⁷³

Edoxaban exerts its anticoagulant effect by selectively inhibiting Factor Xa, thereby reducing thrombin generation and subsequently decreasing fibrin formation and thrombus development, which ultimately lowers the risk of cardioembolic stroke.⁷⁴ A prospective observational study (the SATES study) assessed the safety of early edoxaban initiation following acute ischemic stroke in patients with concomitant non-valvular atrial fibrillation (NVAF).⁷⁵ The study aimed to assess the incidence of symptomatic hemorrhagic events within 90 days of stroke onset in patients receiving early edoxaban treatment. The results indicated that early use of edoxaban demonstrated a reasonable safety profile within this specific patient population.⁷⁵ In addition, a study using a mouse model demonstrated that edoxaban treatment can mitigate the severity of acute stroke by reducing blood-brain barrier damage and inflammation.⁷⁶ This study found that edoxaban may reduce post-stroke neurological damage by protecting the blood-brain barrier and inhibiting the inflammatory response.⁷⁶ Furthermore, in patients with ischemic stroke accompanied by atrial fibrillation, novel direct oral anticoagulants (non-vitamin K antagonist oral anticoagulants, NOACs) such as edoxaban have been recommended for stroke prevention.⁷⁵ Similar to other novel oral anticoagulants (NOACs), its dosage requires adjustment based on renal function.

Comprehensive Assessment of DOACs

DOACs have become the first-line choice for secondary prevention in most patients with cardioembolic stroke due to non-valvular atrial fibrillation. However, nuanced differences exist among the four available DOACs, and clinical decision-making requires an individualized approach.

DOACs have a short time to peak plasma concentration, which provides a pharmacological basis for early anticoagulation, and trials such as TIMING and ELAN have validated the safety of early DOAC initiation. However, the dosing of all DOACs requires adjustment based on renal function, assessed via CrCl. Among them, dabigatran etexilate is the most renally dependent, with approximately 80% renal excretion, making it the most sensitive to renal impairment. In contrast, apixaban has a lower renal excretion proportion (approximately 27%), making it the preferred option for elderly patients or those with mild renal impairment. Additionally, DOACs should be avoided in patients with severe hepatic impairment.For individuals at high bleeding risk, apixaban is often considered the preferred option due to its favorable safety profile demonstrated in the ARISTOTLE trial. Therefore, when selecting a DOAC, clinicians must conduct a holistic assessment that incorporates stroke severity, bleeding risk, comorbidities, and pharmacologic characteristics to optimize clinical outcomes.

Limitations

This review has several limitations. First, the major RCTs (TIMING, ELAN, OPTIMAS, START) and the CATALYST meta-analysis largely excluded patients with severe stroke (NIHSS >15–20) or PH2-type haemorrhagic transformation. Thus, our conclusions mainly apply to mild-to-moderate stroke. Second, evidence on anticoagulation timing after reperfusion therapy comes from post-hoc subgroup analyses, with no dedicated prospective trials. Third, the non-NVAF subgroups discussed (mechanical valves, infective endocarditis, PFO, left ventricular thrombus, atrial flutter) have limited evidence, and clinical decisions rely largely on expert consensus. Fourth, as a narrative review, we did not perform a systematic search or meta-analysis, which may introduce selection bias.

Conclusion

For the patients with mild-to-moderate cardioembolic stroke, clinical practice should shift towards early (within 2–4 days) initiation of DOACs, supported by robust evidence demonstrating safety and superior efficacy in reducing recurrence. Treatment decision must be individualized, integrating stroke severity and patient-specific factors. Filling the evidence gap in the treatment of severe stroke and post-reperfusion remains a key priority for future research.

Footnotes

ORCID iD

Maisitula Rousidanmu

Author Contributions

Maisitula Rousidanmu: Conceptualisation, Writing – original draft, Writing – review & editing. Niao Yang: Data curation, Visualisation, Writing – review & editing. Pan Yang: Validation, Supervision. Nao Yan: Conceptualisation, Funding acquisition, Supervision, Writing – review & editing. All authors approved the final version.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the National Natural Science Foundation of China (Grant number: 82301376, Yan Nao) and the Hubei Clinical Research Center for Dementias and Cognitive Impairments.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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