Antiplatelet or Alteplase in minor stroke with nondisabling deficits: Do we have a definite answer now?

About half of acute ischemic stroke (AIS) patients experience a minor stroke, defined as a National Institutes of Health Stroke Scale (NIHSS) score of 5 or less. Based on a meta-analysis¹ current guidelines recommend the use of alteplase within 4.5 hours in patients with minor stroke and disabling deficits². But until now it remained unknown, if alteplase is also beneficial in patients with minor stroke and nondisabling deficits.

But before delving into the data, the most critical question is: How do we define a disabling vs a nondisabling stroke?

The most used definition for “disabling” is ‘a deficit that, if unchanged, would prevent the patient from performing basic activities of daily living (i.e., bathing, ambulating, toileting, hygiene, and eating) or returning to work’³. A list of examples of non-disabling deficits mentioned in previous studies included isolated mild aphasia (patient still able to communicate meaningfully), isolated facial droop, mild cortical hand (especially non-dominant: NIHSS score = 0), mild hemimotor loss, hemisensory loss, mild hemisensorimotor loss and mild hemiataxia (patient still able to ambulate).

For patients, who have this kind of nondisabling deficit current guidelines do not recommend intravenous thrombolysis. However, this recommendation is based on a relatively weak foundation, primarily relying on a subgroup analysis of the IST-3 trial⁴ and the early terminated PRISMS Trial³.

The ARAMIS (Antiplatelet vs R-tPA for Acute Mild Ischemic Stroke) trial was now the first trial to investigate if dual antiplatelet therapy (DAPT) could lead to similar efficacy and safety as alteplase in patients with minor stroke and only nondisabling deficits within 4.5 hours⁵. This multicenter, non-inferiority trial randomized 760 Chinese patients with minor (NIHSS ≤5), nondisabling stroke and premorbid mRS ≤1 in a 1:1 manner to either DAPT (aspirin + clopidogrel) or alteplase (0.9mg/kg). Nondisabling in ARAMIS was  defined as a maximum of 1 point on each single-item NIHSS score (such as vision, language, neglect, or single limb weakness, and a score of 0 in the consciousness item).

In the full analysis set the primary outcome, defined as excellent functional outcome (mRS score 0 to 1) was achieved in 93.8% of the DAPT group and 91.4% of the alteplase group. Of note, 87/393 patients in the DAPT group and 60/367 patients in the alteplase group had crossed over to the other treatment arm, but the as-treated and per-protocol analyses produced similar outcomes. The researchers had set a non-inferiority margin of -4.5%, implying that up to a 4.5% reduction in DAPT’s efficacy compared to alteplase would be acceptable, considering the convenience, better safety, and lower costs of DAPT.  The results demonstrated an overall risk difference of 2.3% in favor of DAPT over alteplase. The confidence interval for this difference ranged from -1.5% to 6.2% and though the lower boundary of the 95% confidence interval (-1.5%) fell below zero, it was still within the “accepted” margin of DAPT’s efficacy loss (-4.5%). The authors therefore could demonstrate that the effect of DAPT on an excellent outcome is non-inferior compared to Alteplase.

Parity was between many of the trial’s secondary endpoints apart from early neurological deterioration (≥2 NIHSS point decline) within 24 hours which showed a higher proportion of patients in the alteplase group (9.1%) than in the DAPT group (4.6%). As expected for the safety outcomes, there were numerically more instances of sICH and significantly more bleeding events in the alteplase group (sICH: n=3, bleeding: n=19), compared with the DAPT group (n=1, n=6). It’s noteworthy, that in the subgroup analysis with NIHSS scores of 4 or 5 (n=134) the risk ratio of excellent functional outcome favored the treatment with alteplase over DAPT (-2.6%, CI -8.7% to 1.4%) on a statistical non-significant level.

In conclusion, DAPT is currently the recommended treatment for patients with minor nondisabling stroke and considering the non-inferiority design the trial could not give clinicians a definitive answer as to whether DAPT or alteplase is the better therapy in this group.

Moreover, a critical challenge that persists is determining the precise distinction between a disabling or nondisabling deficit in both clinical practice and research. This definition cannot solely rely on the numerical NIHSS score; rather, it often hinges on the patient’s lifestyle and functional abilities.

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 References:

1. 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: 1929-1935. 20140805. DOI: 10.1016/s0140-6736(14)60584-5.
2. Berge E, Whiteley W, Audebert H, et al. European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke. Eur Stroke J 2021; 6: I-lxii. 20210219. DOI: 10.1177/2396987321989865.
3. 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: 156-166. DOI: 10.1001/jama.2018.8496.
4. Khatri P, Tayama D, Cohen G, et al. Effect of Intravenous Recombinant Tissue-Type Plasminogen Activator in Patients With Mild Stroke in the Third International Stroke Trial-3. Stroke 2015; 46: 2325-2327. DOI: doi:10.1161/STROKEAHA.115.009951.
5. 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: 2135-2144. DOI: 10.1001/jama.2023.7827.