Authors: Karen L. Furie, MD, MPH, and Peter J. Kelly, MD
February 18, 2026
N Engl J Med 2026; 394: 784–792VOL. 394 NO. 8
Summary
The risk of recurrent ischemic stroke can be reduced by managing modifiable risk factors and implementing a stroke prevention plan tailored to the underlying cause of the stroke. Early implementation of secondary prevention strategies is crucial, along with ongoing monitoring of risk factors, lifestyle, and medication recommendations.
This article begins with a clinical case highlighting a common medical challenge. It then presents evidence supporting various strategies, followed by a review of formal clinical guidelines where available. The article concludes with the authors’ clinical recommendations. A 74-year-old man was brought to the emergency department by ambulance after experiencing sudden weakness on the right side of his face, arm, and leg, along with difficulty speaking, which began six hours prior. His score on the National Institutes of Health Stroke Scale was 4 (on a scale of 0 to 42, with higher scores indicating more severe neurological impairment), and a physical exam revealed mild weakness in his face and upper and lower extremities, as well as slurred speech. A head CT scan showed no significant findings, and a head and neck CT angiogram did not reveal any large vessel stenosis or occlusion. A subsequent head MRI revealed a 1 cm infarct in the left internal capsule posterior limb, with hyperintensity on diffusion-weighted sequences. The patient has hypertension and hyperlipidemia, treated with lisinopril (10 mg) and atorvastatin (10 mg) daily, and his most recent hemoglobin A1c level was 6.5%. He does not smoke, drinks alcohol occasionally, and maintains a healthy diet, but has been less active in recent years due to joint pain. His body mass index (weight in kilograms divided by the square of height in meters) is 32. How would you treat this patient to reduce the risk of another ischemic stroke?
The Clinical Problem
Ischemic stroke, defined as injury to the central nervous system caused by loss of blood flow, is most often due to arterial thromboembolism.1 Globally, the incidence of stroke was estimated at nearly 12 million in 2021, with 94 million prevalent cases worldwide.2 Stroke was the third leading cause of death and the fourth leading cause of years of healthy life lost. Each year, approximately 795,000 people in the United States experience a stroke, with 87% being ischemic.2 However, the incidence of ischemic and hemorrhagic stroke varies internationally, and nearly 30% of all strokes in low- and middle-income countries are due to intracerebral or subarachnoid hemorrhage. The incidence of ischemic stroke subtypes also varies internationally. For example, intracranial atherosclerosis is reported more frequently in Brazil and China, and lacunar stroke is described more frequently in China, Pakistan, and Taiwan.3 Due to population growth, increased life expectancy, and exposure to risk factors, the global burden of stroke has nearly doubled since 1990. Incidence is similar between men and women, although prevalence is higher among women, likely related to women’s longer life expectancy.
Key Points
Secondary Prevention After Ischemic Stroke
•After an ischemic stroke, the risk of recurrence can be reduced by modifying risk factors related to the specific mechanism of the stroke.
•Diagnostic studies help identify the stroke mechanism and provide targets for intervention.
•Secondary prevention strategies should be implemented as early as possible to improve treatment adherence and prevent recurrence.
•Post-stroke monitoring of risk metrics, lifestyle behaviors, and medication recommendations is vital.
The 2016 Global Burden of Disease Study showed that the five leading risk factors for ischemic stroke were high systolic blood pressure, high levels of low-density lipoprotein (LDL) cholesterol and fasting blood glucose, particulate matter air pollution, and smoking.4 In the INTERSTROKE study, approximately 90% of ischemic strokes were attributable to potentially modifiable risk factors (Figure 1).
Four main pathophysiological categories underlie ischemic stroke: atherosclerosis of large arteries, cardioembolism, small-vessel disease, and cryptogenic stroke (including embolic stroke of undetermined source). Understanding these categories is key to tailoring treatment plans and improving patient outcomes.
The Trial of Org 10172 in Acute Stroke Treatment (TOAST) system describes classification criteria based on presumed mechanism (Table 1). The ASCOD (atherosclerosis [A], small-vessel disease [S], cardiac [C], other [O], dissection [D])7 and Causative Classification of Stroke8 systems further refine the likelihood of these mechanisms based on available information after investigation.
Approximately 80% of patients with ischemic stroke return to community living. These patients have increased risks of recurrent stroke, myocardial infarction, and cardiovascular death.9 The risk of stroke recurrence is highest in the first week, but persists for years after the initial stroke. A meta-analysis including 138,000 patients showed the annual risk of recurrent stroke was 4.3%, myocardial infarction 0.9%, and cardiovascular death 0.5%.9 In the Oxford Vascular Study, the 5-year risk of any stroke recurrence was 23% after cryptogenic stroke, 20% after small-vessel stroke, 23% after large-artery stroke, and 25% after cardioembolic stroke.10 Increased risks of disability, death, dementia, and cognitive impairment are common consequences of recurrent stroke. Modifying cardiovascular risk factors and mechanism-specific interventions can substantially reduce this risk.
evaluation should include relevant blood tests and cardiovascular and cardiac investigations (Table 2).
Strategies and Evidence
The approach to secondary stroke prevention includes lifestyle modification, pharmacological treatment, and revascularization procedures in appropriately selected patients. The transition from hospital to community provides an opportunity to initiate treatment early, which is associated with better treatment adherence and improved outcomes. The STROKE-CARD trial, an open-label, randomized, controlled trial with blinded outcome assessment, assigned 2149 patients with acute transient ischemic attack (TIA) or stroke to receive either STROKE-CARD intervention or standard care.12 The intervention was a disease management program comprising standardized visits every three months and web-based patient support, including risk factor management and education. At 12 months, major cardiovascular events occurred in 78 patients (5.4%) in the STROKE-CARD group and 59 patients (8.3%) in the standard care group (instantaneous risk ratio, 0.63; 95% confidence interval [CI], 0.45 to 0.88; P = 0.007), although no significant difference was observed in the combination of stroke or TIA (6.3% and 6.5% of patients, respectively). Quality of life, measured by the EuroQol 5-Dimensions 3-Levels (EQ-5D-3L) general utility score, was higher in patients in the STROKE-CARD group than in the standard care group (P < 0.001). These findings suggest that a structured program may be beneficial for improving overall cardiovascular outcomes in patients with recent stroke, even if it does not reduce the risk of specific stroke complications.
Lifestyle Modification
Continued smoking is associated with a doubling of the risk of stroke recurrence, and randomized trials of multi-component interventions after stroke have shown higher smoking cessation rates than observed in the control group.13 Complete smoking cessation is recommended, supported by nicotine replacement therapy, counseling, and bupropion or varenicline therapy when appropriate.14 In the medical group of the SAMMPRIS (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) trial, physical activity lasting at least 20 minutes at moderate-to-vigorous intensity at least twice weekly was independently associated with a 40% lower risk of recurrent cardiovascular events than lower physical activity, as reported on the PACE (Physician-Based Assessment and Counseling for Exercise) questionnaire.15 Although there are no high-quality trials specific to stroke on dietary changes, epidemiological studies and randomized trials in high-risk patient groups indirectly support dietary interventions for preventing cardiovascular events after stroke. In the PREDIMED (Prevention with Mediterranean Diet) trial, the risk of stroke was lower in high-risk individuals on a Mediterranean diet enriched with olive oil or nuts than on a control diet (1.6% vs. 3.0%).16 The American Heart Association recommends a Mediterranean diet (rich in vegetables, fruits, whole grains, poultry, fish, low-fat dairy, olive oil, and nuts, and low in processed foods, high-fat dairy, and red meat) and a low-sodium diet (<2.3 g per day).17
Medical Management
Antithrombotic Therapy
Randomized trials have shown a benefit of short-duration dual antiplatelet therapy (DAPT) for early recurrent stroke prevention in patients with minor non-cardioembolic ischemic stroke (National Institutes of Health Stroke Scale score ≤3) or high-risk TIA (ABCD2 score ≥4, on a scale of 0 to 7, with higher scores indicating greater risk) who were not candidates for thrombolysis, thrombectomy, or carotid revascularization. In the POINT (Platelet-Oriented Inhibition in New Transient Ischemic Attack and Minor Stroke) trial (which included 4881 patients), aspirin plus clopidogrel initiated within 12 hours of symptom onset and continued for 90 days led to a lower risk of major ischemic events than aspirin plus placebo (5.0% vs. 6.5%, P = 0.02).18 The CHANCE (Clopidogrel in High-Risk Patients with Acute Non-Disabling Stroke or Transient Ischemic Attack) trial showed that among patients randomized within 24 hours of an acute stroke, aspirin plus clopidogrel for 21 days followed by aspirin alone led to a lower risk of recurrent stroke within 90 days than aspirin alone (8.2% vs. 11.7%, P < 0.001).19 Pooled analyses of trials indicated a maximal benefit of DAPT during the first 10 to 21 days after a stroke, with a greater risk of major bleeding observed with longer durations of treatment.20 The addition of ticagrelor to aspirin led to a lower risk of stroke or death than aspirin monotherapy at 90 days (5.5% vs. 6.6%, P = 0.02), but the benefit was offset by a greater risk of fatal bleeding and intracranial hemorrhage (0.4% vs. 0.1%).21 In the CHANCE-2 trial, which included 6412 Chinese patients with acute minor stroke or TIA and loss-of-function CYP2C19 alleles, DAPT with ticagrelor plus aspirin led to a lower risk of stroke at 90 days than DAPT with clopidogrel plus aspirin (6.0% vs. 7.6%, P = 0.008).22 Long-term DAPT is generally not superior to aspirin, based on trial results.23,24 Aspirin monotherapy is generally recommended for long-term treatment in patients with symptomatic intracranial large-artery stenosis (50–99%).25 Prolonged cardiac monitoring with external or implantable monitors leads to better detection of atrial fibrillation than 24-hour monitoring.26 Biomarkers such as N-terminal pro-B-type natriuretic peptide (NT-proBNP) have been associated with atrial fibrillation burden, but are not recommended in stroke guidelines.27 In patients with established non-valvular atrial fibrillation, thrombin or factor Xa inhibition with a direct oral anticoagulant (DOAC) is the first-line therapy. A meta-analysis of randomized trials comparing a DOAC (dabigatran, apixaban, rivaroxaban, or edoxaban) with warfarin showed that the combined risk of stroke or systemic embolism was 19% lower in patients treated with a DOAC (relative risk, 0.8; P < 0.001). The benefit was due to a substantial reduction in the risk of hemorrhagic stroke, which was halved in patients treated with a DOAC, without a significant reduction in the risk of ischemic stroke.
Multiple trials have confirmed the safety of early DOAC initiation after ischemic stroke. In particular, the OPTIMAS trial demonstrated that initiating a DOAC at ≤4 days is as effective as doing so at 7 to 14 days in patients with recent stroke and atrial fibrillation, with no significant differences in the incidence of recurrent ischemic stroke, intracranial hemorrhage, or systemic embolism at 90 days. Approximately one-quarter of participants had paroxysmal atrial fibrillation, while those with other high-risk sources of cardioembolism are typically treated with vitamin K antagonists.
Hypertension
A meta-analysis of 14 randomized trials comparing more intensive versus less intensive blood pressure treatment in 42,736 patients with stroke or TIA showed that the combined risk of recurrent stroke was 27% lower with more intensive treatment (P < 0.001) and the risk of cardiovascular death was 15% lower (P = 0.01).17 Patients with a systolic blood pressure below 130 mm Hg had lower rates of stroke and death than those with a systolic blood pressure of 130 to 140 mm Hg or > 140 mm Hg, and the degree of blood pressure reduction correlated with a lower risk of stroke. Long-term blood pressure reductions can be achieved with a combination of lifestyle modifications and medication.
Hyperlipidemia
The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial compared atorvastatin (80 mg daily) with placebo in 4731 patients with non-cardioembolic ischemic stroke (67% of patients), TIA (31%), or intracranial hemorrhage (2%).31 At a median follow-up of 4.9 years, the risk of recurrent stroke was 16% lower in the atorvastatin group than in the placebo group (adjusted hazard ratio, 0.84; P = 0.03) and the risk of major cardiovascular events was 20% lower with atorvastatin (hazard ratio, 0.80; P = 0.002). A greater risk of hemorrhagic stroke was observed in the atorvastatin group than in the placebo group (instantaneous hazard ratio: 1.66; 95% CI: 1.08 to 2.55), but a net benefit was observed in preventing ischemic events. A meta-analysis of randomized trials found that per 1000 patients with stroke treated, statin therapy was associated with approximately 40 fewer major ischemic cardiovascular events and 6 more hemorrhagic strokes, findings indicating a net benefit of statin therapy.32 The Treat Stroke to Target trial, which included 2860 patients with atherosclerotic disease and a prior stroke or TIA, showed that over a median follow-up of 3.5 years, patients who had been randomized to a target LDL cholesterol level of less than 70 mg/dL and received statin and ezetimibe therapy as needed had an absolute risk of cardiovascular events (primarily ischemic stroke) that was 2.4 percentage points lower than those who had been randomized to a target of 90 to 110 mg/dL (8.5% vs. 10.9%).33 While statins are generally safe, a meta-analysis of randomized trials found a greater risk of diabetes that appeared to be dose-related (absolute risk increase of 0.1 percentage points per year with low- or moderate-intensity statin use and 1.3 percentage points per year with high-intensity statin use).34
Lifestyle changes and intensive statin therapy (e.g., atorvastatin 40–80 mg or rosuvastatin 20–40 mg) to achieve an LDL cholesterol target of less than 70 mg/dL are recommended. If LDL cholesterol remains elevated or patients cannot tolerate a statin, other LDL-lowering agents (e.g., a proprotein convertase subtilisin-kexin type 9 [PCSK9] inhibitor, ezetimibe, or small interfering RNA therapies) may be indicated.35,36 Some patients with hypertriglyceridemia may benefit from treatment with icosapent ethyl.37,38 In a secondary analysis of the REDUCE-IT trial,38 which included 8179 patients with hypertriglyceridemia who were at high risk for ischemic events (71% of whom had a prior cardiovascular event), icosapent ethyl therapy led to a lower risk of nonfatal or fatal stroke than placebo (2.4% vs. 3.3%).
Diabetes
Type 2 diabetes mellitus is present in 30% of patients with ischemic stroke and is associated with at least a 50% increased risk of recurrent cardiovascular events.39 Although there have been no stroke-specific trials in people with type 2 diabetes, the target hemoglobin A1c level for people with diabetes is less than 7%, with a level of 7 to 8% being a reasonable target for those with limited life expectancy or multiple coexisting conditions. Lifestyle modifications, including weight loss or maintenance, exercise, smoking cessation, and metformin therapy, should be prioritized in all patients. A meta-analysis including 56,251 patients in eight randomized, placebo-controlled trials showed that glucagon-like peptide 1 (GLP-1) receptor agonists reduced the risk of nonfatal stroke by 16% (odds ratio, 0.84; P = 0.002) and any stroke by 16% (odds ratio, 0.84; P = 0.001).40 Evidence of benefit from sodium-glucose cotransporter 2 (SGLT2) inhibitors is greater for prevention of progression of renal disease and heart failure, but these agents may be considered as an adjunct to metformin therapy in selected patients with stroke and diabetes.41
Carotid Revascularization: Endarterectomy and Stenting
Symptomatic atherosclerotic extracranial carotid artery stenosis (lumen stenosis of 50–99%) benefits from revascularization with carotid endarterectomy or carotid artery stenting.42-44 A meta-analysis of 13 randomized controlled trials including 7484 patients with carotid stenosis (symptomatic in 80% of patients) showed that stenting was associated with a greater risk of any stroke than carotid endarterectomy (relative risk, 1.45; 95% CI, 1.06 to 1.99) but a lower risk of periprocedural myocardial infarction (relative risk, 0.43; 95% CI, 0.26 to 0.71).45 Consideration of procedure choice should include technical feasibility, a risk-benefit assessment, and patient preference. Revascularization should generally occur within 2 weeks of symptom onset.46 In patients with asymptomatic carotid stenosis of 50–99%, stenting, but not carotid endarterectomy, was found to be superior to medical therapy alone.47
Guidelines
Recommendations from the American Heart Association and the European Stroke Organisation (ESO) recommend a blood pressure target of less than 130/80 mm Hg for most patients after ischemic stroke. In selected patients with non-cardioembolic TIA or minor stroke, DAPT with aspirin and clopidogrel (loading dose of 300 mg, followed by 75 mg daily) or aspirin and ticagrelor (180 mg day 1, followed by 90 mg twice daily) for 21–30 days is recommended, generally followed by long-term antiplatelet monotherapy with aspirin or clopidogrel.19,21,48 In patients with persistent or paroxysmal atrial fibrillation, DOAC therapy is appropriate. An LDL cholesterol target of less than 70 mg/dL is recommended. In patients with type 2 diabetes, a target hemoglobin A1c level of less than 7% is generally recommended, along with lifestyle modifications associated with cardiovascular risk, metformin therapy, and the addition of a GLP-1 agonist or SGLT2 inhibitor.
Areas of Uncertainty
The role of anti-inflammatory agents for secondary stroke prevention remains unclear.49 Whether treatment of sleep apnea after stroke reduces recurrence is also uncertain.50 Ongoing trials (e.g., ClinicalTrials.gov numbers NCT05963698 and NCT04394546) are evaluating strategies for left atrial appendage occlusion in patients with atrial fibrillation who are at high risk for bleeding.51,52 Effective therapy for carotid and vertebral artery dissection, aortic arch atheroma, and patent foramen ovale in older adults remains uncertain.
Conclusions and Recommendations
The
