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Abstract
Mild stroke symptoms are cited as the reason for not using tissue-type plasminogen activator in 29–43% of time-eligible patients. Previous studies suggested that not all of these patients had a good recovery or even survival to hospital discharge. Since then, stroke guidelines worldwide recommended thrombolysis in minor but disabling strokes.
Dual antiplatelet treatment with aspirin and clopidogrel was more effective than aspirin alone for reducing subsequent events in patients with minor stroke if started within 24 hours of onset in both CHANCE (Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events) and POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischaemic Stroke) trials. Recently, both PRISMS (The Potential of rtPA for Ischemic Strokes With Mild Symptoms) trial and TEMPO-2(The Potential of rtPA for Ischemic Strokes With Mild Symptoms) trial showed that treatment with thrombolysis versus antiplatelet did not increase the likelihood of favourable functional outcome at 90 days among patients with minor non-disabling acute ischaemic strokes. Therefore, a narrative review on thrombolysis for patients with minor strokes from published studies may help practicing clinicians.
- Stroke
- Thrombolysis
- Asprin
- Ischemic Stroke
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Introduction
Mild stroke symptoms are cited as the reason for not using tissue-type plasminogen activator in 29–43% of time-eligible patients.1 2 Previous studies suggested that not all of these patients had a good recovery or even survive to hospital discharge.3–6 A large nationwide study (Get With The Guidelines–Stroke) showed that stroke-related disability in mild stroke is relatively common. They also illustrated the clinical outcomes at discharge were strongly associated with the initial NIHSS(National Institutes of Health Stroke Scale) scores.7 The multinational Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry observational study showed patients with a minor stroke had 71–72% favourable outcome (modified Rankin Scale, mRS 0–1) at 3 months, regardless of the time window of presentation.8 Since then, stroke guidelines worldwide recommended thrombolysis in minor but disabling strokes.9–12
Dual antiplatelet treatment with aspirin and clopidogrel were more effective than aspirin alone for reducing subsequent events in patients with minor stroke if started within 24 hours of onset in both CHANCE (Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events) and POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischaemic Stroke) trials.13 14 Recently, both PRIMS and TEMPO-2 (The Potential of rtPA for Ischemic Strokes With Mild Symptoms) trials showed that treatment with thrombolysis versus antiplatelet did not increase the likelihood of favourable functional outcome at 90 days among patients with minor nondisabling acute ischaemic strokes.15 16 Therefore, a narrative review on thrombolysis for patients with minor strokes from published studies may help the practicing clinicians (table 1)，
Different definitions of minor stroke in different studies
Different criteria of minor stroke
A NIHSS ≤3 or ≤5 were widely used to define a minor stroke, although the consensus is still lacking.17
Impact of guidelines
Most published guidelines for acute ischaemic stroke suggest thrombolytic therapy to treat patients with a disabling minor ischaemic stroke within 4.5 hours, while most guidelines do not recommend thrombolysis in patients with non-disabling minor strokes. (Table 2).However, disabling stroke has not been defined well. It is also unclear what the best treatment is in patients with acute ischaemic stroke (AIS) low NIHSS but from a large vessel occlusion. Dual antiplatelet therapy could be an option for patients with AIS with an NIHSS<3 and given within 24 hours.
Comparison of guidelines recommendation on minor stroke and level of evidence
The ceiling effects and floor effects
A ceiling effect associated with statistics in medical condition refers to the phenomenon in which the majority of the data are close to the upper limit or highest possible score of a test. This means that (almost) all of the test participants achieved the highest (or very near to the highest) score. Recently, PRIMS trial showed 122 patients (78.2%) in the alteplase group versus 128 (81.5%) in the aspirin group achieved a favourable outcome (adjusted risk difference, −1.1%; 95% CI, −9.4% to 7.3%) at 90 days.15 Additionally, ARAMIS (Antiplatelet vs R-tPA for Acute Mild Ischemic Stroke) trial demonstrated that at 90 days, 93.8% of patients (346/369) in the DAPT (dual antiplatelet treatment) group and 91.4% (320/350) in the alteplase group had an excellent functional outcome (risk difference, 2.3% (95% CI, −1.5% to 6.2%)).18 However, TEMPO-2 trial found 50% (226/452) in the control group and 58% (247/432) in the Tenecteplase group recovered to NIHSS 0 at discharge (RR 1.16, 95% CI, 1.01 to 1.31), while the difference became smaller at 90 days for favourable outcome (71% vs 69%, RR 0.97, 95% CI, 0.89 to 1.05).16 From these studies, we have learnt that the rate of 90-day mRS 0–1 in minor stroke was high, which might have already reached the ceiling effect. Since those ceiling effects can impact the quality of studies, an NIHSS of 0 at discharge might be more sensitive.
However, floor effects need to be considered as well. Floor effect is a phenomenon where participants’ scores are generally low and show no differences due to the high difficulty of the experiment. Among these three trials, the numbers of symptomatic intracerebral haemorrhage (sICH) were reported as 5 versus 0, 1 versus 3 and 2 versus 8 in each group, respectively.15 16 18 The haemorrhagic event rate was very low, which made the traditional comparative analytical method very limited.
One post-hoc analysis from the Alteplase Compared with Tenecteplase in Patients With Acute Ischaemic Stroke trial, the primary outcome (mRS score 0–1 at 90 days) among patients with minor stroke occurred in 100 participants (51.8%) in the tenecteplase group and 86 (47.5%) in the alteplase group. There were no significant differences in the rates of sICH (2.9% in tenecteplase vs 3.3% in alteplase group).19 Therefore, the safety and efficacy of thrombolysis in minor stroke from the real-world database might need to be further studied and promising.
The rate of recurrent stroke and early neurological deterioration
Early neurological deterioration (END) occurs in about 10% of patients after intravenous thrombolysis (IVT) and is related to a poor outcome. In theory, early antiplatelet therapy following IVT could reduce END by preventing re-occlusion and stroke progression.20 However, current guidelines recommend starting antiplatelet treatment at 24 hours after IVT due to concerns of haemorrhagic transformation. Other antithrombotics studied including low molecular-weighted heparin, oral anticoagulation, intravenous tirofiban did not offer a definitive answer on their benefit and risks in preventing recurrent stroke or END.20–22 The ongoing Early Antiplatelet for Minor Stroke Following Thrombolysis trial may provide more information once completed.23
Brain reperfusion and long-term mental health
In terms of mechanism of action, antiplatelet treatment is for secondary stroke prevention while thrombolysis is to open the occluded artery with brain reperfusion.24 Reperfusion may restore more brain function from strokes and preserve long-term mental health and less cognitive impairment.25 However, data to show the benefit of thrombolysis on post-stroke cognitive impairment is limited.
Conclusion
Minor stroke is not minor.26 Thrombolysis or not for patients with minor stroke is in hot debate since more data have been published recently. These data suggested that DAPT might be as good as IVT in this group of patients. However, since the definition of a minor stroke may vary, and the long-term outcome such as END and cognition is unclear, selecting DAPT versus IVT remains a choice for the treating physician.
Ethics statements
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References
Footnotes
Collaborators NA.
Contributors XW and YD drafted the manuscript, while YD, QD and DW generated the protocol and revised the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed. Commissioned by the CSA.