ESJ Featured Article of the Month – June 2025

Intravenous thrombolysis or antiplatelet therapy for acute nondisabling ischemic stroke: A systematic review and network meta-analysis

This month’s issue of the European Stroke Journal includes an interesting meta-analysis from Francois Lun and colleagues.¹ They address the question – what is the optimal treatment approach for acute minor stroke with nondisabling symptoms – dual antiplatelet therapy (DAPT) or intravenous thrombolysis (IVT)?

Approximately half of all acute ischaemic strokes can be classified as mild or minor – where the patient appears not to have a significant disability, which is generally defined by a National Institute of Health Stroke Scale (NIHSS) score of less than 5. High quality evidence exists from the CHANCE and POINT randomised controlled trials that the risk of early recurrent stroke and major cardiovascular events (MACE) is reduced by dual antiplatelet therapy given early after minor stroke or high risk TIA.^2,3 However, acute treatment with IVT may be able to curtail infarct growth and may have other benefits in maintaining physical function or preventing long term cognitive decline. We must also acknowledge the crudeness of the NIHSS score. While physicians may classify patients with a low NIHSS score as having a ‘non-disabling’ stroke, it is important to remember that surveys of stroke patients show us that over half of those who achieved an ‘excellent’ outcome had residual cognitive symptoms at 2-3 years. More than half had not resumed their usual activities and a third reported symptoms of depression. ⁴ The rationale of the TEMPO-2 trial was that acute treatment with tenecteplase would be better than antiplatelet therapy at returning patients to their baseline function, defined as the pre-morbid modified Rankin Scale (mRS) score, however there was no significant difference in the primary outcome between the two treatment approaches. ⁵ Whether this approach may prove beneficial to reduce infarct size or protect against cognitive decline or functional impairment long term, remains unknown.

In this meta-analysis, using the PRISMA approach, investigators searched for studies (both RCTs and observational studies were eligible) which compared IVT (alteplase) with antiplatelet strategies, either aspirin alone or aspirin in combination with clopidogrel, in patients with minor stroke (NIHSS 0-5) which were considered nondisabling. The primary outcome was excellent functional outcome at 3 months, defined as a mRS of 0-1. After performing a systematic search of studies up to July 2024, identified research papers were screened, and finally 6 studies (4 RCTs and 2 observational studies) were included in the analysis.

Risk of bias of the included studies was assessed using the Cochrane Risk of Bias tool. Three of the 4 trials were a low probability of bias, while the observational studies were at low and moderate risk of bias.

The meta-analysis was performed in data from 5,897 patients. The median age ranged from 62-71 years, and the NIHSS scores ranged from 0-5. Dual antiplatelet therapy was commenced within 24 hours in the DAPT studies and thrombolysis within 4.5 hours in the IVT studies. Most participants  (>80%) achieved an excellent functional outcome, defined as mRS of 0-1.

When compared with alteplase, DAPT was significantly associated with a higher odds of excellent function outcome (OR 1.52, 95% CI 1.09-2.35), but aspirin monotherapy was not (OR 1.36, 95% CI 0.87-2.3).

There were no differences between IVT or dual antiplatelet therapy in the odds of any of the secondary outcomes, which included good functional outcome (defined as mRS 0-2), symptomatic intracranial haemorrhage, all cause death or recurrent stroke at 3 months. It is interesting to observe that DAPT was not associated with reduced risk of recurrent stroke in these data, although that was the primary outcome of CHANCE and POINT and that is the rationale upon which early DAPT is based. We need to consider how or why DAPT may be associated with a better odds of functional recovery at 3 months, if not mediated by a reduced risk of recurrent stroke.

Further research needs to be conducted to explore whether there is any benefit to using acute thrombolysis followed by DAPT. The stroke community also needs to consider whether the current outcomes (like the modified Rankin Scale) are appropriately representative and meaningful to stroke patients. Cognitive and executive dysfunction, fatigue and depression are all commonly reported by stroke survivors and are frequently disabling symptoms. In addition, return to work or driving can be a meaningful metric of functional outcome for patients. With the development of new neuroprotective agents and the targeting of acute stroke treatments at ‘milder nondisabling’ strokes, we need to consider whether the choice of primary outcome in these studies is appropriate. For now, the highest level of evidence supports DAPT as the first choice therapy for acute minor nondisabling ischaemic stroke.

Intravenous thrombolysis or antiplatelet therapy for acute nondisabling ischemic stroke: A systematic review and network meta-analysis

Lun et al.

Online first June 2025

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References:

1. Lun F, Palaiodimou L, Katsanos AH, Tsivgoulis G, Turc G. Intravenous thrombolysis or antiplatelet therapy for acute nondisabling ischemic stroke: A systematic review and network meta-analysis. European Stroke Journal 2025; 10(2): 330-8.
2. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 2013; 369(1): 11-9.
3. Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N Engl J Med 2018; 379(3): 215-25.
4. Kapoor A, Lanctôt KL, Bayley M, et al. “Good Outcome” Isn’t Good Enough: Cognitive Impairment, Depressive Symptoms, and Social Restrictions in Physically Recovered Stroke Patients. Stroke 2017; 48(6): 1688-90.
5. 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. The Lancet 2024; 403(10444): 2597-605.