The Shifting Landscape of Secondary Stroke Prevention

 Maybe you'd rather solve stroke to 100% recovery first when you are the 1 in 4 per WHO that has a stroke! Just a thought. Getting 100% recovered would mean a better survival of that second stroke. Cognitive resilience and all.

The Shifting Landscape of Secondary Stroke Prevention

James E Siegler, MD, FAHA Publish Date August 17, 2026

James Siegler, MD, FAHA, director of the Comprehensive Stroke Center at the University of Chicago, explores the evolving landscape of post-stroke care.

Ischemic stroke remains a leading cause of mortality and long-term disability worldwide, with recurrent cerebrovascular events contributing substantially to cumulative neurologic injury, functional decline, and health care burden. Although major advances in acute stroke management have significantly improved survival, secondary prevention following an index ischemic stroke continues to represent a critical challenge in contemporary cerebrovascular care. 

Of the more than 800,000 strokes in the US every year, 1 in 4 are recurrent events.¹ The risk for recurrent stroke varies widely across patient populations and stroke phenotypes, ranging from 10% to 15% within 12 months among patients with advanced microvascular disease or large artery atherosclerosis.² This risk persists despite advances in risk factor modification and the widespread availability of evidence-based guidelines and online resources, highlighting gaps between recommended care and real-world implementation. Barriers including health care access, treatment adherence, economic burden, patient engagement, and uncertainty in individualized risk assessment continue to limit the effectiveness of secondary prevention strategies.  Closing the gap between clinical evidence and real-world implementation remains essential to reducing recurrent stroke burden and improving functional outcomes among stroke survivors. Despite these challenges, most funding in cerebrovascular research continues to emphasize innovative technologies and pharmacotherapies, with comparatively less emphasis on translational research and implementation gaps.

Present Day Stroke Care

Persistent Risk After Index Stroke

 The risk for recurrent ischemic stroke remains substantial throughout both early and late periods following the index event. After the acute period — when recurrent stroke risk is highest, typically within the first few weeks after stroke — the underlying mechanism (eg atrial fibrillation or an unstable atherosclerotic plaque) is often identified, and individualized treatment is initiated. However, long-term risk persists well beyond the immediate post-stroke period. Longitudinal cohort studies consistently demonstrate sustained elevation in recurrent stroke risk over subsequent years, driven by persistent and uncontrolled vascular risk factors, including hypertension, dyslipidemia, obesity, diabetes mellitus, atrial fibrillation, obstructive sleep apnea, substance use (including tobacco and alcohol), and systemic vascular dysfunction.³ Without effective risk factor modification, the likelihood of recurrent stroke or other vascular events remains considerable. Perhaps more importantly, recurrent cerebrovascular events often result in greater cumulative disability than the initial stroke, contributing to progressive neurologic impairment, reduced functional independence, dementia, and diminished quality of life. These events also have substantial downstream consequences, including increased caregiver burden and higher health care costs for patients and health systems. Among the many limitations in successful secondary stroke prevention strategies is fragmentation of post-discharge care delivery. Stroke survivors frequently transition from hospitalization to outpatient care characterized by delayed or unscheduled stroke specialist follow-up, inadequate coordination between inpatient and ambulatory care teams, and limited access to multidisciplinary prevention services. These structural barriers are particularly pronounced in geographically underserved and rural populations, where access to vascular neurology, cardiology, rehabilitation medicine, and comprehensive stroke centers remains limited.  Follow-up care is essential for reinforcing the benefits of antithrombotic therapy, lipid-lowering treatments, dietary and lifestyle modifications, and recognition of stroke warning signs and symptoms. Because many stroke risk factors are clinically silent, particularly hypertension, dyslipidemia, and diabetes, ongoing follow-up with primary and subspecialty care providers is necessary to ensure patients achieve target blood pressure, cholesterol, and glycemic goals. 

Economic and Structural Challenges in Long-Term Care

 The economic burden of long-term stroke management represents another important challenge to successful secondary prevention. Effective post-stroke care often requires prolonged pharmacotherapy, outpatient specialist visits, repeat diagnostic testing, rehabilitation services, and management of multiple chronic conditions. Out-of-pocket costs, insurance limitations, prescription drug costs, transportation challenges, geographic barriers to subspecialty care, and restricted access to rehabilitation services can all impair adherence to recommended care.   Although strategies such as out-of-network exemptions, teleneurology appointments, and partially subsidized pharmacy coverage may help address some barriers, they do not fully resolve challenges to effective secondary prevention. These financial and structural barriers disproportionately affect socioeconomically vulnerable populations and contribute to persistent disparities in recurrent stroke outcomes.

Future State of Stroke Care

Residual Stroke Risk Despite Optimal Care

Even if all barriers to medical care are limited for a given patient, the risk for recurrent stroke remains unacceptably high. This may reflect the chronic and progressive nature of atherosclerotic vascular disease, although the primary drivers of residual stroke risk remain incompletely understood. For example, less than 25% of carotid plaque burden is explained by traditional vascular risk factors.4 Other contributors to vascular disease, inflammation, and stroke risk may include genetic variation, pathologic metabolites originating from the gut microbiome, microplastics, and other patient-level factors. 

Although advances in pharmacotherapies for secondary stroke prevention now include individualized antithrombotic regimens, more aggressive lipid targets, and glucagon-like peptide agonists, improvements in stroke prevention remain incremental.

Expanding the Secondary Prevention Toolkit

In addition to the persistent biological drivers of stroke risk, limitations of current therapies highlight the need for continued innovation. Concerns regarding medication toxicity and growing distrust of health care providers have introduced new challenges to sustained treatment. 

Nearly a quarter century ago, aspirin became a mainstay of secondary prevention, with a number-needed-to-treat (NNT) of approximately 100 to prevent 1 stroke at 2 weeks.5 However, long-term use is associated with risks for gastrointestinal bleeding or renal dysfunction. A decade later, high-intensity statins expanded the pharmacologic armamentarium, with an NNT of 45 to prevent stroke after 5 years of sustained treatment.6 Yet, more than half of high-risk patients discontinue statins over time due to non-adherence, perceived side effects, or financial barriers.7 

Further, glucagon-like peptide agonists have been shown to promote weight loss, reduce tobacco and alcohol use, and lower stroke rates among patients with diabetes and/or obesity, but more than one-third of patients discontinue these therapies at 1 year due to a combination of adverse effects, high out-of-pocket costs, and access barriers.8 

There is no single solution or “silver bullet” for secondary stroke prevention. However, emerging therapies may offer new opportunities. Asundexian, a novel factor XIa inhibitor, has been recently shown to reduce recurrent stroke in patients with noncardioembolic stroke.9  With an NNT of 45 to prevent 1 stroke over 19 months and no significant risk for major or minor bleeding, this therapy may represent an important advance in secondary stroke prevention. The Phase III LIBREXIA-Stroke trial (ClinicalTrials.gov Identifier: NCT05702034) evaluating milvexian is ongoing and may provide additional insight into a class effect for factor XIa inhibitors. 

Toward Precision Stroke Prevention

As the understanding of stroke biology expands, future approaches will likely move toward more individualized risk prediction and treatment selection. For patients with elevated lipoprotein(a), a low-density lipoprotein molecule largely determined by genetics, Phase III trials are ongoing that are evaluating whether small molecules or small interfering RNA therapies can reduce vascular events. Phase II trials of subcutaneously administered pelacarsen, olpasiran, lepodisiran, muvalaplin, and zerlasirin have demonstrated 30 to 95% reductions in lipoprotein(a) levels, with generally mild injection site pain and flu-like symptoms.10 Whether these reductions translate into meaningful clinical benefit remains uncertain.

The future of secondary stroke prevention will be increasingly personalized. Advances in prolonged cardiac rhythm monitoring, wearable diagnostic technologies, biomarker-based risk stratification, and artificial intelligence-driven predictive modeling may improve identification of patients at highest risk for recurrent cerebrovascular events. Precision medicine approaches are also being explored to guide individualized antithrombotic therapy based on stroke mechanism and patient-specific risk profiles. 

In parallel, digital health platforms, remote physiologic monitoring, and telemedicine-based care models may improve longitudinal patient engagement, medication adherence, and access to specialist care, particularly among underserved populations.

Closing the Evidence-to-Practice Gap

Reducing recurrent ischemic stroke risk and minimizing long-term disability will require more than the continued application of established evidence-based therapies. Persistent implementation barriers, including fragmented care delivery, suboptimal adherence, financial burden, patient mistrust, and uncertainty in individualized therapeutic decisions, continue to limit the effectiveness of current prevention strategies.

Future progress in secondary stroke prevention will depend not only on therapeutic innovation but also on scalable, cost-effective health care delivery models capable of translating scientific advances into durable improvements in cerebrovascular outcomes. Closing the gap between clinical evidence and real-world implementation remains essential to reducing recurrent stroke burden and improving functional outcomes among stroke survivors.

References:

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