Google+Linking To And Excerpting From Stroke's "Guidelines in Action: Dual Antiplatelet Therapy for Nondisabling Stroke Within the 4.5-Hour Window" - Tom Wade MD
Today, I review, link to, and excerpt from STROKE‘s Guidelines in Action: Dual Antiplatelet Therapy for Nondisabling Stroke Within the 4.5-Hour Window. [No abstract available] [Full-Text HTML] [Full-Text PDF]. Stroke. 2026 Jan 26. doi: 10.1161/STROKEAHA.125.053825. Online ahead of print.
All that follows is from the above resource.
A man in his 60s with a history of hypertension treated with lisinopril presented to the emergency room with 3.5 hours of acute onset of left facial numbness and left arm numbness. The patient’s systolic blood pressure was in the high 170s on presentation, and blood glucose was 91 mg/dL. He denied any headache, weakness, speech difficulties, or vision problems. His only notable finding included mild sensory loss on the left side of the face and arm. His National Institutes of Health Stroke Scale (NIHSS) score was 1. Because the patient had nondisabling symptoms with a low NIHSS score, he was not given thrombolysis. Brain and vessel imaging were unremarkable (Figure 1). Aspirin and a loading dose of clopidogrel were administered in the emergency room. The patient’s symptoms resolved several hours later. His ABCD2 score [for TIA risk of stroke] was 4. Brain magnetic resonance imaging obtained within 12 hours was negative for an acute ischemic stroke (AIS; Figure 2) but confirmed chronic small vessel disease, the likely cause of his presentation, versus cortical ischemia.
Figure 1. A patient presents within 4.5 hours of the onset of left face and arm numbness. Initial imaging of the brain (A), intracranial vessels (B), cervical vessels (C), and perfusion imaging (D) were unremarkable. Cerebral blood flow (CBF), time-to-maximum (Tmax) perfusion.
Figure 2. Magnetic brain imaging was obtained 12 hours later. A, No brain infarction was present. B, Subcortical chronic microvascular ischemic disease and chronic lacunar infarcts were present.
DISCUSSION
Our case highlights the “2026 guideline for the early management of patients with AIS: a guideline from the American Heart Association/American Stroke Association”1 recommendations on the role of dual antiplatelet therapy (DAPT) when managing thrombolysis-eligible patients with noncardioembolic minor AIS symptoms (Figure 3).1
Intravenous thrombolytics carry a small but clinically significant risk of hemorrhage, including symptomatic intracerebral hemorrhage. Accordingly, the American Heart Association guidelines generally recommend against the use of thrombolytic therapy for patients with minor ischemic strokes or nondisabling symptoms1 and recommend considering DAPT as an alternative for early initiation of secondary stroke prevention in this population with noncardioembolic AIS.1 The CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) was one of the first major studies to demonstrate that DAPT with clopidogrel and aspirin lowered the risk of another stroke compared with aspirin monotherapy.2 These findings were subsequently confirmed in the POINT trial (Platelet-Oriented Inhibition in New Transient Ischemic Attack and Minor Ischemic Stroke), which enrolled an international cohort of patients with high-risk transient ischemic attack (ABCD2 ≥4) or minor AIS symptoms (NIHSS score ≤3). Although the POINT trial’s primary end point of reduced recurrent stroke at 90 days was not met, subsequent evaluation showed a clear benefit of DAPT in reducing recurrent ischemic events within the first 21 days after the inciting event, albeit with a modest increase in bleeding risk.3 A more recent trial extended these results by demonstrating that DAPT initiated within 72 hours of symptom onset in patients with minor AIS (NIHSS score <5) significantly reduced 90-day stroke recurrence, though at the cost of an increased risk of moderate-to-severe bleeding.4 Meta-analyses of both the CHANCE and POINT trials have shown that the maximal benefit from DAPT with early initiation (ideally within 24 hours of symptom onset), with 21 days being the approximate timeframe during which the benefits are maximized compared with the risk of bleeding.5 Of note, the National Institute of Neurological Disorders and Stroke tissue-type plasminogen activator Trials reported a symptomatic hemorrhage rate of 6.4% within 36 hours of stroke onset in patients with AIS given tissue-type plasminogen activator, compared with 0.6% in those given a placebo.6 This is contrasted with POINT, which showed a 0.1% rate of symptomatic intracerebral hemorrhage in patients on DAPT.3
Interest in early initiation of DAPT to improve outcomes emerged, as evidence suggested that intravenous thrombolytic therapy for patients with minor nondisabling AIS may not provide a significant functional benefit over antiplatelet therapy, per the results of the PRISMS trial (Potential of rtPA for Ischemic Strokes With Mild Symptoms).7 The PRISMS trial compared functional outcomes (using the modified Rankin Scale) at 90 days in this group of patients, and findings concluded that for patients with minor nondisabling AIS, treatment with tissue-type plasminogen activator versus aspirin did not significantly increase the odds of a low modified Rankin Scale after 90 days.7 The trial had several limitations but was useful in showing that not only was there no significant difference in functional independence at 90 days, but that there was also a higher rate of symptomatic intracerebral hemorrhage in the alteplase group.7 Although the trial ended early, its findings paved the way for further study into antiplatelet therapy as a possible treatment for minor nondisabling AIS.1
The ARAMIS trial (Dual Antiplatelet Therapy Versus Alteplase for Patients With Minor Nondisabling Acute Ischemic Stroke) went a step further than the PRISMS trial, comparing DAPT with intravenous alteplase. Findings similar to those of PRISMS showed that DAPT was noninferior to alteplase in minor nondisabling stroke for patients presenting within 4.5 hours of symptom onset.8 The primary outcome of ARAMIS was an excellent functional outcome (defined by a modified Rankin Scale score of 0–1) at 90 days.8 Findings from this trial also reported more adverse neurological and bleeding events in the alteplase group.8 The subsequent 2024 ARTAMIS trial (Antiplatelet Therapy in Acute Mild to Moderate Ischemic Stroke) found that in the studied patient population, clopidogrel with aspirin was superior to aspirin alone with respect to reducing early neurological deterioration, while rates of bleeding events were similar between groups.9
Take-Home Points
• Limitations in activities of daily living (eg, walking, eating, driving, and employment) are important factors to include in thrombolysis decision-making because disabling versus nondisabling is not defined solely by the National Institutes of Health Stroke Scale (Figure 3).1
• For “adult patients with AIS presenting with mild nondisabling stroke deficits within 4.5 hours of symptom onset or last known well, IVT is not recommended to improve functional outcomes. Instead, dual antiplatelet therapy should be considered to reduce the risk of early recurrent stroke” for noncardioembolic AIS (Figure 3).1
These studies represent a body of emerging evidence that DAPT may be useful as an alternative to lytic in the setting of AIS stroke in the context of minor nondisabling deficits to reduce the risk of 90-day stroke recurrence.1 In clinical practice, these findings underscore that DAPT should be considered primarily for patients with minor, nondisabling strokes, where supporting evidence is the strongest. Despite these advances, important knowledge gaps remain. PRISMS, ARAMIS, and ATAMIS relied on computed tomography or magnetic resonance imaging largely to exclude hemorrhage, without stratifying outcomes by imaging modality; because magnetic resonance imaging is more sensitive for early ischemia but less widely available, it remains uncertain whether the selection method influences the treatment effect. Beyond imaging, precision in distinguishing who benefits from DAPT versus thrombolysis may come from pooled patient-level and subgroup analyses across trials, which could clarify clinical, imaging, and demographic predictors of benefit while minimizing the risk of treating stroke mimics.
Although most studies investigating the role of DAPT in the hyperacute setting have included aspirin and clopidogrel, the guidelines also provide a class 2b, level B, randomized recommendation for the use of a combination of ticagrelor and aspirin (Figure 3).1 “In patients with minor (NIHSS score ≤3) non cardioembolic AIS or high-risk transient ischemic attack (ABCD2 score ≥4) within 24 hours after symptom onset who did not receive intravenous thrombolysis and who carry the cytochrome P450 2C19 loss-of-function allele, DAPT with ticagrelor and aspirin for 21 days (followed by ticagrelor monotherapy) may be reasonable instead of DAPT with clopidogrel and aspirin to reduce the 90-day risk of recurrent stroke.”1 Patients given clopidogrel with the loss-of-function cytochrome P450 2C19 allele may lack the expected reduction in platelet aggregation as a result of an inability to convert the clopidogrel into its active metabolite.1,10 However, it is important to note that the use of DAPT with ticagrelor has been associated with a higher risk of bleeding from any source.1,10 For this reason, caution is advised for patients who have a history of recent procedures, surgery, or bleeding events such as gastrointestinal bleeding.1
References
1. Prabhakaran S. 2026 guideline for the early management of patients with AIS: a guideline from the American Heart Association/American Stroke Association. Stroke. 2026. In press. doi: 10.1161/STR.0000000000000513
2. Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, Wang C, Li H, Meng X, Cui L, et al; CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369:11–19. doi: 10.1056/NEJMoa1215340
3. Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, Kim AS, Lindblad AS, Palesch YY; Clinical Research Collaboration, Neurological Emergencies Treatment Trials Network, and the POINT Investigators. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018;379:215–225. doi: 10.1056/NEJMoa1800410
4. Gao Y, Chen W, Pan Y, Jing J, Wang C, Johnston SC, Amarenco P, Bath PM, Jiang L, Yang Y, et al; INSPIRES Investigators. Dual antiplatelet treatment up to 72 hours after ischemic stroke. N Engl J Med. 2023;389:2413–2424. doi: 10.1056/NEJMoa2309137
5. Pan Y, Elm JJ, Li H, Easton JD, Wang Y, Farrant M, Meng X, Kim AS, Zhao X, Meurer WJ, et al. Outcomes associated with clopidogrel-aspirin use in minor stroke or transient ischemic attack: a pooled analysis of Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events (CHANCE) and Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trials. JAMA Neurol. 2019;76:1466–1473. doi: 10.1001/jamaneurol.2019.2531
6. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581–1588. doi: 10.1056/NEJM199512143332401
7. Khatri P, Kleindorfer DO, Devlin T, Sawyer RN, Starr M, Mejilla J, Broderick J, Chatterjee A, Jauch EC, Levine SR, et al; PRISMS Investigators. Effect of alteplase vs aspirin on functional outcome for patients with acute ischemic stroke and minor nondisabling neurologic deficits: the PRISMS randomized clinical trial. JAMA. 2018;320:156–166. doi: 10.1001/jama.2018.8496
8. Chen HS, Cui Y, Zhou ZH, Zhang H, Wang LX, Wang WZ, Shen LY, Guo LY, Wang EQ, Wang RX, et al; ARAMIS Investigators. Dual antiplatelet therapy vs alteplase for patients with minor nondisabling acute ischemic stroke: the ARAMIS randomized clinical trial. JAMA. 2023;329:2135–2144. doi: 10.1001/jama.2023.7827
9. Chen HS, Cui Y, Wang XH, Ma YT, Han J, Duan YJ, Lu J, Shen LY, Liang Y, Wang WZ, et al; ATAMIS Investigators. Clopidogrel plus aspirin vs aspirin alone in patients with acute mild to moderate stroke: the ATAMIS randomized clinical trial. JAMA Neurol. 2024;81:450–460. doi: 10.1001/jamaneurol.2024.0146
10. Pereira NL, Cresci S, Angiolillo DJ, Batchelor W, Capers Q, Cavallari LH, Leifer D, Luzum JA, Roden DM, Stellos K, et al; American Heart Association Professional/Public Education and Publications Committee of the Council on Genomic and Precision Medicine; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Peripheral Vascular Disease; and Stroke Council. CYP2C19 genetic testing for oral P2Y12 inhibitor therapy: a scientific statement from the American Heart Association. Circulation. 2024;150:e129–e150. doi: 10.1161/CIR.0000000000001257
