This is a summary of the on-demand Roundtable discussion between Christian Ruff, MD, Mike Sharma, MD and Kori Leblanc, PharmD which you can find here. Before participating, please read our CME and disclosure information which can be found here.

This program is supported by an independent education grant from Bayer. This education program is only available to healthcare professionals in the USA.

Despite modern hyperacute treatments, approximately 10% to 17% of patients experience a recurrent stroke within the first year following an initial event. Optimizing secondary prevention requires a precise understanding of early antithrombotic optimization, emerging anticoagulation pathways, and structured multidisciplinary care coordination.

1. Evidence-Based Antithrombotic Strategies for Non-Cardioembolic Stroke and TIA

The risk of a recurrent ischemic event is highly front-loaded, making immediate, decisive antiplatelet selection crucial.

Early DAPT Optimization and Implementation

• High-Risk Window: The risk for a recurrent stroke is highest immediately following the event, highlighting the importance of early intervention.
• Standard of Care: Based on landmark data from contemporary trials like CHANCE and POINT, appropriate patients with a minor non-cardioembolic ischemic stroke or high-risk TIA should be initiated on Dual Antiplatelet Therapy (DAPT)—typically aspirin plus clopidogrel—within the first 24 hours.
• De-escalation: Because the ischemic benefit is concentrated early while bleeding risks remain continuous, patients should be transitioned from DAPT to single antiplatelet therapy (SAPT) after an initial 21-day period.

Patient Selection and Safety Exclusions
A careful risk-benefit analysis must be performed to balance ischemic prevention against the risk of intracranial hemorrhage (ICH) or major systemic bleeding.

• Minor Stroke and High-Risk TIA: These patients represent the ideal candidates for early DAPT due to high ischemic risk and a relatively low inherent risk of hemorrhagic transformation.
• Severe or Dense Strokes: These presentations carry a much higher risk for hemorrhagic transformation; therefore, DAPT should be avoided or approached with extreme caution.
• Prior Major Bleeding: Patients with a history of significant bleeding or recurrent GI bleeds are generally poor candidates for intensive DAPT.
• Hyperacute Treatment Recipients: Patients treated with thrombolytics or mechanical thrombectomy were generally excluded from major DAPT trials. As such, DAPT should not be routinely initiated in these patients.

Genetic Considerations: Clopidogrel vs. Ticagrelor

• Metabolic Limitations: Clopidogrel is a pro-drug requiring two successive cytochrome P450 (predominantly driven by CYP2C19) oxidative steps in the liver to become active.
• Loss-of-Function Variants: Genetic variants causing poor clopidogrel metabolism are common and highly heterogeneous. This reduces clopidogrel's efficacy and increases recurrent stroke risk. Notably, East and South Asian populations appear to be most impacted.
• Role of Ticagrelor: Ticagrelor does not require metabolic activation and is highly potent. It serves as an effective alternative for known CYP2C19 loss-of-function carriers or patients experiencing recurrent ischemic events despite clopidogrel therapy. However, its higher potency carries an increased risk of bleeding that must be individualized.

Clinical Note on Cardioembolic Stroke (Atrial Fibrillation): Antiplatelet therapy has no role in preventing AF-related strokes; these require immediate or early therapeutic anticoagulation (typically DOACs). Initiation timing depends strictly on infarct size: immediately for TIA, within 24–48 hours for minor strokes, days 3–4 for moderate strokes, and 6–7 days for large infarcts. Delayed anticoagulation beyond these windows unnecessarily exposes patients to high recurrence risks.

2. Emerging Clinical Evidence on Factor XIa Inhibition

The primary limitation of current antithrombotic regimens is the absolute trade-off between ischemic efficacy and bleeding complications. Factor XIa (FXIa) inhibition represents a shifting paradigm in anticoagulation.

The Concept of Uncoupling

• Pathological vs. Physiological Clotting: Current anticoagulants (DOACs, warfarin) target the final common pathway, blocking both pathological thrombus formation ("bad clotting") and adaptive hemostasis required to repair blood vessels ("good clotting").
• FXIa Mechanism: Factor XI is highly involved in the propagation of pathological thrombosis but is largely unnecessary for normal physiological hemostasis. Inhibiting FXIa effectively uncouples thrombosis from normal hemostasis, offering a way to prevent strokes without disrupting the body's natural ability to stop bleeding.

OCEANIC-STROKE Insights

• Efficacy: In the OCEANIC-STROKE trial, adding the oral FXIa inhibitor asundexian to standard antiplatelet therapy (mostly DAPT) resulted in a 26% reduction in recurrent ischemic strokes and events on top of standard care.
• Safety Profile: Remarkably, the addition of asundexian did not increase the risk of severe bleeding, particularly intracranial hemorrhage, major bleeding, or minor bleeding compared to placebo.

Class Heterogeneity and Dosing Nuances
The FXIa inhibitor landscape is highly diverse, consisting of small molecules, monoclonal antibodies (which offer monthly subcutaneous dosing), and RNA-based therapies. Dosing and potency needs vary by agent and by dose used for specific indications.

• The OCEANIC-STROKE findings suggest that, in patients receiving antiplatelet therapy after non-cardioembolic stroke or TIA, the level of FXIa inhibition achieved with asundexian was sufficient to reduce recurrent ischemic events while maintaining a favorable bleeding profile.
• Conversely, the OCEANIC-AF trial (comparing asundexian to apixaban in AF) was stopped early due to inferior efficacy. This may demonstrate that stroke prevention in AF, due to cardioembolic stroke, likely requires highly potent, near-complete FXI pathway inhibition.

3. Coordinating Multidisciplinary, Pharmacist-Inclusive Care Strategies
The clinical utility of any antithrombotic strategy relies entirely on systemic implementation and long-term medication adherence.

Key Barriers to Long-Term Adherence

• Pill Burden: The average stroke patient is discharged on at least 5 medications across 3 to 4 distinct drug classes. Increasing medication complexity directly correlates with a drop-off in patient adherence.
• Clinical Consequences: Non-adherence in the stroke population significantly increases recurrent ischemic events and all-cause mortality. In clinical trial settings, 1 in 4 patients discontinue their secondary stroke prevention therapies within 1.5 years.
• Timing Failures: In real-world observational data, 1 in 4 post-angioplasty patients fail to stop their secondary antiplatelet (P2Y12 inhibitor) at the designated timeline, exposing them to prolonged, unnecessary bleeding risks.

Pharmacist-Led and System-Level Interventions
To optimize safety and efficacy, institutions should move away from isolated protocols and implement a single, unified longitudinal pathway that follows the patient from the emergency department through chronic outpatient care.

• Rigorous Discharge Reconciliation: Transition periods carry the highest risk for medical errors. Pharmacists are in an ideal position to lead medication reconciliation at discharge, ensuring that the prescription, discharge summary, and patient-facing materials explicitly contain identical, clear stop dates for DAPT.
• Multifaceted "Bundled" Care: The literature strongly supports a bundled approach rather than single interventions. Effective bundles must combine formal medication reconciliation, patient and caregiver education (utilizing teach-back methods), and scheduled longitudinal follow-ups.
• Strategic Touchpoints: Structured check-ins should be explicitly timed around high-risk milestones, such as the exact day a P2Y12 inhibitor is scheduled to be discontinued, and again at the 6-month mark.
• Rapid-Access Infrastructure: Implementing communication tools to allow easy access to advice, such as a “frequently asked questions” one-pagers or community and regional interdisciplinary patient and provider "hotlines," enables community clinicians (e.g., dentists, primary care physicians, community pharmacists) and patients to obtain real-time guidance on antithrombotic management. This can help to preserve therapy adherence and prevent premature or unsafe cessation.

Content accurate at time of release.