The Future of Stroke Care: Addressing Unmet Needs in Secondary Prevention

Introduction

Stroke is the third most common cause of death and disability in the world.¹ Despite recommendations for antithrombotic therapy, stroke recurrence rates remain high.^2-6 Missing from the management of a prevalent type of stroke called noncardioembolic ischemic stroke is a therapy that significantly lowers recurrent stroke and maintains a low risk of bleeding.^2-7 Investigational factor XI (FXI) inhibitors may fill this gap by preventing thrombosis and sustaining bleeding risks that are lower than those of currently approved anticoagulants.^8-9

This article describes the clinical and economic impact of ischemic stroke, including the particular burden of recurrent stroke. Thereafter, it reviews the treatment landscape for recurrent stroke, including management guidelines, unmet needs, and data surrounding asundexian and milvexian, 2 FXI inhibitors under investigation in phase 3 trials.^10-11 The article concludes with managed care considerations surrounding this costly neurological deficit.

Clinical Impact of Ischemic Stroke

Globally, approximately 1 in 4 people will experience a stroke in their lifetime.¹² In the United States, stroke is the fifth leading cause of death⁷ and a major cause of disability,1 with as many as 76% of US stroke patients reporting a disablement.¹³ The prevalence of self-reported stroke in the US, standardized for age, has increased by 7.8% (95% CI, 4.9%-10.8%) from 2011-2013 to 2020-2022.¹⁴

Clinical Impact by Stroke Type

Stroke can be classified into hemorrhagic stroke, transient ischemic attack (TIA), and ischemic stroke. Hemorrhagic stroke includes intracerebral and subarachnoid hemorrhage, which make up 10% and 3% of strokes, respectively.⁷ A TIA is a brief episode of neurological dysfunction as a result of ischemia to the brain, spinal cord, or retina in which there is no infarct.¹⁵ Annually in the US, approximately 240,000 individuals experience a TIA.¹⁶

Ischemic strokes account for 87% of all strokes and contribute to substantial burden in the US that has grown recently.^7,14 They are infarcts of the brain, spinal cord, or retina as a result of ischemia, that result in neurological dysfunction.¹⁷ Each year in the US, 795,000 individuals experience ischemic stroke, and approximately 23% of these are recurrent.⁷ In 2022 in the US, 39.5 deaths per 100,000 people were due to ischemic stroke.¹⁸

Commonly, ischemic stroke is classified into cardioembolic, large artery atherosclerosis, small-vessel occlusion, stroke of other determined etiology, and embolic stroke of undetermined source (ESUS) subtypes.^2,19 Whereas cardioembolic stroke occurs from an embolism originating in the heart, a noncardioembolic stroke may be embolic or thrombotic in nature.¹⁹ Noncardioembolic strokes account for 73% of ischemic strokes.²

Additional Impact of Recurrent Stroke

Recurrent strokes are associated with worse clinical outcomes and are costlier than index events.²⁰

Clinical Impact

Guideline recommendations seek to prevent recurrence of ischemic stroke. However, recurrence rates have remained elevated.^2-6 Approximately 4.6% to 11.4% of patients who have had an ischemic stroke will have a recurrent stroke within 90 days.^3-6 Approximately 16.8% of those who have had a TIA or minor ischemic stroke will have a recurrent event within 5 years.²¹

Mortality rates for recurrent stroke are also higher than those for index stroke.²⁰ In a 1991 sample of Medicare patients, 2-year survival rates for patients aged 65 to 69 years were lower after recurrent stroke vs after index stroke among men (51.1% vs 66.5%; P < .001) and women (53.5% vs 68.0%; P <.001).²² In a study of US managed care patients hospitalized for noncardioembolic ischemic stroke, the all-cause mortality rate was higher for 2180 patients after recurrent stroke than it was for 1808 patients after new stroke (86 vs 37 deaths/1000 patient-years).²⁰ Moreover, disability is a common sequela of stroke, and recurrent stroke is a predictor of increased disability.²³

Economic Impact

Stroke is a costly disease that results in hospitalizations associated with recurrent stroke and complications from the index stroke.^24,25 Total economic costs of stroke are estimated to have been $56.2 billion in the US in 2019-2020. Direct medical costs accounted for $34.5 billion and are projected to rise to $94.3 billion by 2035.⁷ Moreover, 13.8% of individuals discharged from certified primary stroke centers who survive an ischemic stroke are likely to experience a hospital readmission within 30 days.²⁴ Within the first year after an index stroke, some 40% (1052 of 2603) of Medicare patients discharged from Connecticut acute care hospitals in 1995 had at least 1 hospital readmission.²⁵ The indirect costs of caregiving after a stroke are also substantial. Patients with stroke-related health problems (SRHP) in 1993 had higher additional yearly costs due to caregiving that, adjusted for inflation, would total $10,155 in 2024; those without SRHP would have expenditures totaling $2108.²⁶

Although more recent studies are needed,²⁷ recurrent stroke has been shown to cost patients and the health care system 38% more than nonrecurrent stroke.²⁰ Average (SD) costs of primary and recurrent stroke in a managed care population including hospitalization, medical, and pharmacy costs in 2005 were $40,670 ($81,588) and $51,760 ($130,279), respectively.²⁰ Adjusting for inflation from January 2005 to August 2024, these costs were $67,136 ($134,681) for index vs $85,442 ($215,057) for recurrent stroke.^20,28

Risk Factors

Modifiable risk factors, most of which are behavioral and metabolic, are responsible for 90.5% of the global stroke burden.²⁹ Those for recurrent stroke include diabetes, hypertension, hyperlipidemia, and smoking cessation.²

Nonmodifiable risk factors for recurrent stroke include a history of more than 1 stroke or TIA and male sex. In an analysis of data from 5390 participants who had had an ischemic stroke with ESUS within the previous 3 months, these factors, as well as renal impairment (creatinine clearance < 50 mL/min) and elevated CHA2DS2VASc score (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke or TIA, vascular disease, age 65-74 years, sex category) increased recurrent stroke risk after a median follow-up of 19 months (IQR, 13-27 months).³⁰

Recurrent stroke risk may vary based on risk factor management rather than on race. Robinson and colleagues studied 3816 patients who had an ischemic stroke and found after adjusting for age and sex that stroke recurrence rates were 34% higher in the Black population (95% CI, 10%-64%, P = .003). However, after adjusting for risk factors, Black race was not significantly associated with recurrent stroke (HR, 1.11; 95% CI, 0.90-1.36; P = .32).³¹

Prior TIA may confer greater risk of stroke than prior stroke. In the Framingham Heart Study, a longitudinal population-based cohort study spanning 3 generations and including more than 14,000 participants, stroke was 4.81 times (95% CI, 3.82-6.06; P < .001) more likely to occur in individuals who had had a TIA (n/N = 130/435) than in those who had had a prior stroke (n/N = 165/2175).³²

Sex and age (up to 90 years) constitute nonmodifiable factors influencing stroke mortality. In 2015, the percentage of deaths in the US from cerebrovascular disease (including hemorrhagic and ischemic stroke) was higher for women than for men across all age groups 20 years and older.³³ National Center for Health Statistics data from 2018 also demonstrate increased mortality in women 65 years and older compared with men, with the largest difference in those 85 years and older. These data also show that, as age increases each decade over 65 years, the rate of mortality more than doubles.³⁴

Treatment Landscape for Recurrent Stroke

The treatment landscape for recurrent stroke has focused on risk factor management and antithrombotic therapy with a concentration largely on antiplatelet therapy.

Guideline Recommendations

In 2021, the American Heart Association and American Stroke Association issued treatment guidelines for the prevention of stroke in patients who have already had a stroke or TIA.² These guidelines focus largely on management of vascular risk factors and on antithrombotic therapy. Based on existing literature, the guidelines recommend that treatment for prevention of stroke after an ischemic stroke be similar to treatment after TIA.² Management of vascular risk factors including nutrition, physical activity, smoking cessation, substance use, hypertension, lipids, diabetes, obesity, and obstructive sleep apnea is critical to the prevention of recurrent stroke.² A summary of level 1 guideline recommendations for risk factor management can be found in the Figure.² Mitigation of vascular disease risk factors may involve many lifestyle changes at once. Thus, recommendations for behavioral changes include programs to help encourage behavioral change with proven techniques and an interdisciplinary team.²

Guideline-Recommended Antiplatelet Therapy

After ischemic stroke or TIA, antithrombotic therapy is recommended for all patients who do not have contraindications.² Patients with a recent, mild, noncardioembolic ischemic stroke (National Institutes of Health Stroke Scale score ≥ 3) or high-risk TIA (ABCD2 score ≥ 4) should be started on dual antiplatelet therapy (DAPT) with aspirin and clopidogrel ideally within 12 to 24 hours of symptom onset and continued for at least 21 days and up to 90 days (Table).² After 90 days, single antiplatelet therapy (SAPT) is recommended, as it is for patients with non–high-risk TIA, noncardioembolic stroke after 24 hours from symptom onset, or moderate to severe noncardioembolic stroke.²

Alternative antiplatelet agents including ticagrelor, cilostazol, and dipyridamole are discussed in specific scenarios throughout the guidelines.² Ticagrelor is not recommended for use after ESUS but may be considered for patients with ipsilateral greater than 30% stenosis of a major intracranial artery in addition to aspirin as an alternative to clopidogrel. The choice to use clopidogrel or ticagrelor as part of DAPT is contingent on bleed risk, patient factors including medication adherence, and cost.² The role of cilostazol is unclear for small vessel disease; however, it may be used in addition to aspirin or clopidogrel in patients with stroke or TIA secondary to 50% to 99% stenosis of a major intracranial artery.² Extended-release dipyridamole is recommended generally for use in combination with aspirin as secondary prevention of ischemic stroke.²

For many ischemic stroke subtypes, specific management recommendations exist.² It is important to note that some of these subtypes have lower incidence and have not yet been studied as comprehensively as others, thus recommendations for antithrombotic management are not as clear.² When using antiplatelet therapy such as SAPT or DAPT, the risk of bleeding vs proven efficacy must be balanced.²

Unmet Needs

Despite recommendations for antithrombotic therapy, stroke recurrence rates after noncardioembolic stroke remain high. For 73% of ischemic strokes (noncardioembolic), therapy recommendations are SAPT or DAPT.² Direct oral anticoagulants (DOACs) are used for cardioembolic stroke where there is the assumption that the stroke was caused by atrial fibrillation.² However, DOACs are FDA approved to reduce the risk of stroke and systemic embolism in adults with nonvalvular atrial fibrillation (AF), not in patients with ischemic stroke without AF.^35-37 DOAC use has been studied in patients with ESUS and is not recommended based on findings of increased bleeding.^2,38,39 For instance, Hart et al found that, among 7212 patients with ESUS, those treated with rivaroxaban were 2.72 times more likely to experience major bleeding than those treated with aspirin (95% CI, 1.68-4.39; P < .001).³⁸ Similarly, Diener et al found the annualized rate of major bleeding in patients with ESUS was 1.7 among 2695 patients treated with dabigatran vs 1.4 in the same number of patients treated with aspirin (HR, 1.19; 95% CI, 0.85-1.55).³⁹ Patients treated with rivaroxaban and dabigatran were 51% (95% CI, 13%-100%; P = .004) and 73% (95% CI, 17%-154%) more likely to experience clinically relevant nonmajor bleeding than patients treated with aspirin, respectively.^38,39 A therapy for noncardioembolic ischemic stroke that significantly lowers recurrent stroke and maintains a low risk of bleeding constitutes an unmet need.

Agents Under Investigation: Factor XI Inhibitors

Medications currently under investigation for recurrent stroke prevention include FXI inhibitors thought to prevent thrombus and to have a lower risk of bleeding compared with historically approved anticoagulants.^8,9 The possibility of FXI inhibition as a therapeutic target arose from observational data demonstrating that individuals with FXI deficiency did not have statistically significant increased rates of spontaneous bleeding and may have decreased rates of ischemic stroke.^40,41 However, high FXI levels may promote venous thrombosis.⁴² Thus, the mechanism for FXI inhibitors is thought to occur via contact activation of the coagulation cascade in which inhibition of FXI may minimally impair hemostasis while preventing thrombus.8 FXI inhibitors under investigation include asundexian and milvexian.^10,43

Asundexian

In the PACIFIC-Stroke phase 2 dose-finding trial (NCT04304508), 1808 participants with noncardioembolic ischemic stroke were randomly assigned to receive asundexian 10 mg, 20 mg, or 50 mg, or placebo with antiplatelet therapy and were followed for 26 to 52 weeks.⁴⁴ The primary outcome evaluated was covert infarct and recurrent symptomatic ischemic stroke up to 26 weeks, whereas the safety outcome of interest was major or clinically relevant nonmajor bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria.⁴⁴ Notably, there was no difference detected between the placebo group and asundexian group regarding reduction of the primary outcome.⁴⁴ Major or clinically relevant nonmajor bleeding occurred with no significant increase in those receiving asundexian vs placebo (HR, 1.57; 90% CI, 0.91-2.71).⁴⁴ Post hoc analysis demonstrated a numerical reduction in symptomatic ischemic stroke or TIA with asundexian 50 mg.⁴⁴

OCEANIC-STROKE (NCT05686070) is a phase 3 trial with estimated study completion of October 10, 2025, and a target enrollment of 12,300 participants.¹⁰ The trial is evaluating the efficacy and safety of asundexian dosed once daily vs placebo in addition to an antiplatelet for 3 to 31 months in patients at least 18 years old who have had a recent noncardioembolic stroke, or TIA with systemic or cerebrovascular atherosclerosis or acute nonlacunar infarct.¹⁰ Primary outcomes that will be assessed include time to first occurrence of ischemic stroke and time to first occurrence of major ISTH bleed.¹⁰

Milvexian

AXIOMATIC-SSP (NCT03766581) was a phase 2 dose-finding trial in which 2366 participants 40 years or older with ischemic stroke or high-risk TIA were randomly assigned to receive milvexian 25 mg daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, 200 mg twice daily, or placebo. All patients received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days.¹¹ The primary outcome evaluated was composite symptomatic ischemic stroke in the 90 days after randomization or new covert brain infarction; the safety outcome was major bleeding classified as type 3 and type 5 bleeding per the modified Bleeding Academic Research Consortium classification.¹¹ In terms of the primary outcome, a significant dose response was not found.¹¹ However, there was a decreased number of symptomatic ischemic stroke in patients receiving all milvexian doses except for 200 mg twice daily compared with placebo.¹¹ Major bleeding rates did not vary among the different milvexian doses and there was not a substantial difference in number of bleeds in milvexian groups vs placebo.¹¹

LIBREXIA-STROKE (NCT05702034) is an ongoing phase 3 trial with estimated study completion of December 9, 2026, targeting an enrollment of 15,000 participants.⁴³ The LIBREXIA-STROKE trial is evaluating the efficacy and safety of milvexian dosed at 25 mg twice daily vs placebo in addition to SAPT or DAPT for up to 41 months in participants aged at least 40 years who have had an ischemic stroke or TIA.⁴³ The primary outcome that will be assessed includes time to first occurrence of ischemic stroke.⁴³

Managed Care and Access Considerations for Secondary Stroke Prevention

The direct and indirect expenses affiliated with primary and secondary stroke management are substantial.^7,20,26 Despite progress, rates of initial and recurrent stroke remain elevated. Improved preventive care of initial and recurrent stroke may decrease patient and health care system expenditures. An analysis of investing in larger scale interventions to dissuade tobacco use, decrease sodium intake, and improve treatment of blood pressure, cholesterol, and stroke found a 10.9 benefit-to-cost ratio and predicted prevention of 13 million strokes within 15 years.⁴⁵

Stroke systems of care advocate for community education, primordial prevention, and primary prevention prior to a stroke.⁴⁶ Increasing community education and public awareness of stroke risk factors, providing tools to manage risk factors, and addressing health literacy and cultural context may be beneficial.⁴⁶ Primordial prevention programs as part of the stroke system of care in geographical areas with higher recurrent stroke can be used to improve access to resources for successful lifestyle modification, better primary care, and social conditions.^46,47 As part of primary and secondary prevention, health care professionals can encourage lifestyle modifications by using theoretical models of behavior change and leveraging members of the multidisciplinary team.²

As new medications are studied, ensuring access to those that are efficacious and cost-effective will be of the utmost importance.

Conclusions

Ischemic stroke is prevalent in the US and carries a high risk of mortality, morbidity, and recurrence; it is associated with long-term disability and economic cost. Recurrent strokes are associated with worse clinical outcomes and pose greater financial burdens for patients, caregivers, and health care organizations compared with index stroke. Although current treatment guidelines focus on managing or preventing vascular disease risk factors and optimizing antiplatelet therapy for noncardioembolic stroke, the risk of recurrent stroke remains. FXI inhibitors are a novel therapeutic option to both promote hemostasis and prevent thrombosis. Asundexian and milvexian are 2 agents undergoing clinical trials that may help prevent ischemic stroke and may pose decreased risk of bleeding. There is room to improve the risk of recurrent strokes through increased community awareness, primordial prevention, primary prevention of risk factors, access to resources, adherence to medications, and development of additional medication therapies.

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