Dual antiplatelet therapy vs thrombolysis in non-disabling acute ischemic stroke

Up to 50% of patients with acute ischemic stroke (AIS) present with minor symptoms, defined as a National Institutes of Health Stroke Scale (NIHSS) score ≤5.¹ Although often considered non-disabling, one-third of such patients may experience unfavorable functional outcomes at 90-days if acute reperfusion treatment is withheld.^2,3

The role of intravenous thrombolysis (IVT) in the acute management of these patients remains uncertain. The PRIMS (Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits) randomized controlled trial (RCT) showed no significant difference in 90-day functional outcomes between treatment groups but observed a higher rate of symptomatic intracerebral hemorrhage (sICH) in the alteplase group.⁴ In contrast, an individual patient data meta-analysis of patients with minor stroke included in RCTs of IVT with alteplase suggested that IVT improved the likelihood of achieving an excellent functional outcome (modified Rankin Scale score 0–1] at 90-days.⁵ Notably, the control arms of these trials involved single antiplatelet therapy.

This lack of conclusive evidence leaves clinicians with a therapeutic dilemma: balancing the risk of bleeding with IVT against the potential harm of withholding reperfusion treatment, especially when a significant proportion of patients with minor AIS experience unfavorable outcomes without it.

Following the publication of the CHANCE and POINT trials, early initiation of dual antiplatelet therapy (DAPT) for at least 21 days is now recommended in patients with recent minor (NIHSS score ≤3–5) non-cardioembolic ischemic stroke to reduce the risk of recurrence.⁶ DAPT has emerged as a more effective and equally safe alternative to single antiplatelet therapy, and has gained traction as a potential alternative to IVT in minor AIS. Two recent RCTs have provided additional insight into this treatment strategy.

The ARAMIS (Dual Antiplatelet Therapy vs Alteplase for Patients With Minor Nondisabling Acute Ischemic Stroke) RCT, conducted at 38 hospitals in China, randomized 760 patients with acute minor non-disabling stroke (defined as a NIHSS score ≤5, with ≤1 point in specific NIHSS single-item scores) within 4.5 hours from symptom onset to receive IVT with alteplase or DAPT. Designed as a non-inferiority trial, DAPT was found to be non-inferior to IVT for achieving an excellent functional outcome at 90 days, with no significant difference in the risk of sICH between groups.⁷

The TEMPO-2 (Tenecteplase versus standard of care for minor ischemic stroke with proven occlusion) superiority RCT enrolled patients with minor AIS (NIHSS ≤5) and intracranial occlusion or focal perfusion abnormality, within 12 hours of symptom onset. Conducted at 48 hospitals across ten countries, participants were randomized to receive intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (DAPT in 57% of patients). The trial was stopped early for futility after the enrollment of 886 patients. No significant differences were observed in the primary outcome (return to baseline functioning on pre-morbid mRS), and there was a trend towards higher risk of sICH in the tenecteplase group.⁸

Despite similar findings, the ARAMIS and TEMPO-2 trials targeted different subpopulations of minor AIS patients and had distinct limitations. The ARAMIS trial focused on patients with non-disabling minor stroke and those without presumed cardioembolic cause. It had a non-inferiority design and a high crossover rate (20.4%), but results were consistent across all analyses (full-set, per-protocol, and as-treated). In contrast, the TEMPO-2 trial, enrolled patients without any NIHSS subcategory limitation (e.g. isolated severe aphasia) and targeted those with intracranial occlusion or focal perfusion abnormalities, representing a subset of patients with higher risk for early deterioration and disability. However, the trial was likely affected by selection bias due to the prolonged enrollment period, and the authors hypothesized that the majority of patients in the trial did not have disabling symptoms. Additionally, absence of a one single comparator in the control arm limits the generalizability of its conclusions.

In interpreting these trials, some considerations are important: both focused on non-disabling minor strokes, with the distinction between disabling and non-disabling strokes being often subject to the judgement of the treating physician, patient, and family. Importantly, the best treatment approach for disabling minor strokes was not categorically addressed by these trials, where IVT remains the guideline-recommended approach.⁹ Patients in the non-IVT arm of both trials did better than excepted, which could reflect selection bias or improved stroke care in recent years. Lastly, the limited sensitivity of the mRS score in detecting milder functional impairments could make it challenging to identify differences in functional outcomes between treatment strategies.

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References

1 – Saber H, Saver JL. Distributional validity and prognostic power of the national institutes of

health stroke scale in US administrative claims data. JAMA Neurol. 2020;77:606-612.

2 – Smith EE, Fonarow GC, Reeves MJ, et al. Outcomes in mild or rapidly improving stroke not treated with intravenous recombinant tissue-type plasminogen activator: findings from Get With The Guidelines–Stroke. Stroke 2011;42:3110–15.

3 – Nedeltchev K, Schwegler B, Haefeli T, et al. Outcome of stroke with mild or rapidly improving symptoms. Stroke 2007;38:2531–35.

4 – Khatri P, Kleindorfer DO, Devlin T, et al. 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;320:156–66.

5 – Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014;384:1929–35.

6 – 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:e364-e467

7 – Chen HS, Cui Y, Zhou ZH, et al. Dual antiplatelet therapy vs alteplase for patients with minor nondisabling acute ischemic stroke: the ARAMIS randomized clinical trial. JAMA 2023;329:2135–44.

8 – Coutts SB, Ankolekar S, Appireddy R, et al. Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial. Lancet. 2024;403(10444):2597-2605.

9 – Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2019;50:e344-e418.

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