Clinical Insights Into Recurrent Stroke

ANDREW RUSSMAN, DO
Head, Cleveland Clinic
Enterprise Stroke Program
Vascular Neurologist
Cleveland Clinic
Cleveland, OH

AJMC®: In your experience, what are the most significant long-term clinical effects of a recurrent stroke?

RUSSMAN: Recurrent strokes tend to have more severe long-term clinical effects than initial strokes and impact physical, cognitive, and emotional health. Physically, they often lead to increased disability that requires more intensive rehabilitation as brain damage compounds. This can worsen mobility and functional independence, while cognitive decline—including vascular dementia—becomes more likely. Emotional health can also decline; recurrent strokes often exacerbate depression and anxiety. Unfortunately, mental-health care often is neglected in favor of physical rehabilitation, although both are crucial for comprehensive recovery. Additionally, recurrent strokes can lead to complications such as obstructive sleep apnea, swallowing dysfunction, and reduced social engagement, all of which further diminish quality of life.

AJMC: How do the challenges of preventing recurrent stroke shape your clinical approach?

RUSSMAN: Prevention presents several challenges. The management of risk factors drives prophylaxis. While factors like age and genetics cannot be changed, key risks such as hypertension, high cholesterol, diabetes, smoking, and atrial fibrillation (AF) are critical targets for intervention. Hypertension is the most important modifiable factor due to its prevalence and the significant risk reduction achieved through control. Managing diabetes, cholesterol, and AF can substantially lower the likelihood of a recurrent stroke, as well.

Two major challenges in preventing recurrent stroke are treatment adherence and cost management. Newer therapies such as PCSK9 inhibitors for hyperlipidemia and diabetes medications like semaglutide reduce stroke risk, but they often have high costs and complex insurance preauthorization processes. To shape our clinical approach, we balance the best evidence-based treatments with affordability.

Balancing stroke prevention and the risk of bleeding presents another challenge as we select antithrombotic therapies, whether antiplatelet agents or anticoagulants. For this, tailoring treatment to each patient is essential.

AJMC: How do the American Heart Association/American Stroke Association (AHA/ASA) guidelines1 influence your treatment strategies?

RUSSMAN: The AHA/ASA guidelines provide a strong foundation for secondary stroke prevention, particularly in addressing noncardioembolic strokes. They are heavily evidence based and offer clear recommendations for managing risk factors like hypertension, hyperlipidemia, diabetes, smoking, and AF. For noncardioembolic strokes, especially those caused by large artery atherosclerosis, the guidelines support revascularization procedures such as carotid artery stenting or endarterectomy for patients with severe symptomatic carotid stenosis. However, there are gaps in evidence for other conditions like vertebral artery stenosis for which clear treatment protocols are still lacking. In areas where evidence is limited, treatment decisions often rely on clinical judgment.

Regarding antiplatelet therapy for secondary prevention, short-term dual antiplatelet therapy (DAPT) has been shown to benefit most patients with non-cardioembolic stroke. The current evidence suggests that a 21- to 30-day course of DAPT (typically aspirin and clopidogrel or ticagrelor) strikes a balance between reducing ischemic stroke risk and minimizing bleeding complications. Beyond this period, continuing DAPT offers little additional benefit, with single-agent aspirin being sufficient for most patients.

While the guidelines provide a robust framework for secondary stroke prevention, real-world practice often involves balancing evidence-based treatments with individual patient needs, especially in areas where evidence is scarce.

AJMC: In the current treatment landscape, what are the most pressing unmet needs in preventing recurrent strokes?

RUSSMAN: One of the most pressing needs is understanding underlying stroke etiology. Without a clear understanding of the cause, we often apply a generic approach to risk reduction, which may not be most effective for all patients. For instance, patients with small-vessel disease may benefit more from aggressive risk factor modification than from other therapies like dual antiplatelet treatment.

Another critical need is better access to advanced diagnostic tools, particularly for identifying AF in patients with recurrent strokes of unknown cause. Cardiac rhythm monitoring, including the use of implantable loop recorders, has shown that up to 30% of these patients may have undiagnosed AF after 3 years of monitoring. However, there are challenges in securing payer support for these tools despite their proven value in guiding the most effective anticoagulant therapy.

There’s also a need for more efficient screening tools such as patch-based monitors to identify AF and other conditions early. This early identification allows clinicians to apply guideline-driven therapies that significantly reduce stroke risk.

Finally, addressing social determinants of health is crucial. Many patients face barriers to accessing advanced therapies due to cost, which can affect their ability to manage risk factors and recover fully after a stroke. The affordability and support for newer, more effective therapies remain significant gaps in stroke prevention efforts.

AJMC: What future research or developments in stroke prevention are you most excited about, and how do you anticipate that they will impact clinical practice?

RUSSMAN: I’m particularly excited about the development of new antithrombotic therapies such as factor XI inhibitors and the growing emphasis on understanding optimal treatment intervals and agents for individual patients. A one-size-fits-all approach to stroke prevention is inadequate, especially when we know that stroke recurrence risk is highest in the first 90 days after an initial event. This calls for more tailored treatment strategies based on each patient’s specific etiology and risk profile over time.

Precision medicine is the future of stroke prevention. By applying the right antithrombotic therapy to the right patient for the right duration, we can reduce the risk of stroke recurrence while minimizing adverse effects like increased bleeding. Rather than using a generic approach, precision medicine considers individual factors—like genetic predispositions that affect a patient’s response to certain medications such as anticoagulants and antiplatelet agents. This could be further enhanced by artificial intelligence (AI) models, which can help clinicians analyze vast amounts of data to make more precise treatment decisions.

Beyond antithrombotic therapy, there’s potential for innovation in other areas like optimal blood pressure and lipid management. For example, combining statins with PCSK9 inhibitors or using antihyperglycemic agents that reduce stroke and heart attack risk can be personalized to each patient’s needs. Coupling these medical advancements with effective strategies for smoking cessation and addressing social determinants of health will further enhance stroke prevention.

AJMC: You mentioned factor XI inhibitors. What potential do you see for these agents in the treatment landscape, and how might they change current practices?

RUSSMAN: Current antithrombotic therapies, such as direct oral anticoagulants like apixaban, are quite effective; they balance ischemic risk reduction with a lower risk of bleeding complications. Apixaban has become a market leader due to its efficacy and safety profile, especially for conditions like AF. Any new therapy, including emerging factor XI inhibitors, will need to demonstrate a comparable or superior balance of efficacy and safety to challenge apixaban and other established treatments. The bar is high, and it remains unclear whether factor XI inhibitors will outperform apixaban in AF.

That said, factor XI inhibitors show significant promise in other areas, particularly noncardioembolic stroke. If they prove to be both effective in reducing stroke risk and safer with lower bleeding risks, they could reshape stroke prevention strategies. However, the key will be identifying which patients will benefit most and for how long. This aligns with the growing shift toward precision medicine.

While there’s enthusiasm for these new therapies, cost and affordability will also play a significant role in their adoption. To fully integrate factor XI inhibitors or other novel treatments into clinical practice, we’ll need robust clinical trial data demonstrating long-term benefits and safety. Additionally, emerging tools like AI could enhance our ability to tailor therapies to individual patients.

AJMC: How do you involve patients in the decision-making process regarding stroke prevention therapy, particularly when discussing treatment risks and benefits?

RUSSMAN: Involving patients starts with a thorough understanding of their stroke’s etiology. As clinicians, we need to investigate and explain the diagnostic approach, which includes MRI, vessel imaging, laboratory tests, and cardiac monitoring. Effective stroke prevention relies on understanding the underlying cause, which can lead to more targeted and effective treatment.

For patients with recurrent strokes and unknown etiology, we need to discuss the benefits and risks of further investigation. For example, if AF is suspected, we might recommend a surface monitor or an implantable loop recorder. It’s essential to clearly communicate that while these investigations have minimal risks, they can significantly impact treatment outcomes. Identifying AF and initiating anticoagulant therapy can drastically reduce the risk of subsequent strokes from around 7% to 10% annually to 1.5% to 2%.

Engaging patients involves addressing their specific concerns and explaining how tailored treatments can alleviate their worries. For instance, if patients are hesitant about medication adherence, exploring their underlying concerns—such as affordability, adverse effects, or lifestyle impacts—can help in addressing those issues effectively. Discussing the importance of self-care in the context of caregiving responsibilities can also be a powerful motivator.

Addressing social determinants of health is also crucial. This includes helping patients navigate issues like transportation, medication affordability, and access to support services. Ensuring that patients are aware of financial assistance programs or insurance adjustments can improve adherence and overall outcomes.

AJMC: What key takeaways or advice would you offer to health care professionals and managed care organizations focused on optimizing secondary stroke prevention?

RUSSMAN: I’d offer 5 key takeaways. First, health care professionals should prioritize understanding and applying clinical practice guidelines. It’s not just about using the latest medications—it also involves effectively using proven strategies to reduce stroke risk.

Second, smoking cessation is a critical component of secondary stroke prevention. It significantly reduces risk but requires time and commitment from health care providers to discuss and implement effective quit strategies. Managed care organizations should support these efforts by providing robust smoking cessation programs through medication or other strategies.

Third, health care systems need to support smoking cessation and other preventive measures by creating infrastructure and programs that enable providers to deliver effective care. Managed care organizations should facilitate access to these resources and build strong relationships with smoking cessation programs.

Fourth, managed care organizations should negotiate rates that reflect the benefits of secondary prevention strategies. Effective interventions, even if initially costly, can lead to long-term savings by reducing downstream health care expenditures. Ensuring that these strategies are affordable for patients is crucial.

Fifth and finally, health care professionals and managed care organizations should use available data and guidelines to inform prevention strategies. This will help to ensure that interventions are not only personalized but also cost-effective and aligned with the latest evidence. By integrating these practices, health care professionals and managed care organizations can enhance stroke prevention efforts and ultimately improve patient outcomes and reduce overall health care costs.

REFERENCE

1. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 guideline for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline from the American Heart Association/American Stroke Association. Stroke. 2021;52(7):e364-e467. doi:10.1161/STR.0000000000000375