Discussion
In this post-hoc analysis of patients with minor ischaemic stroke enrolled in the AcT trial, treatment with tenecteplase at a dose of 0.25 mg/kg resulted in similar rates of excellent functional outcome (mRS score of 0–1) at 90–120 days compared with alteplase at a dose of 0.9 mg/kg. No significant differences were observed between tenecteplase and alteplase across most safety outcomes. While there were numerically fewer deaths in patients administered tenecteplase, these differences were not evident in the adjusted analysis, with most deaths occurring beyond 7 days and, therefore, less likely to be causally related to thrombolysis.25
The study provides insights into the functional outcomes of patients who had a minor stroke treated with standard-of-care intravenous thrombolysis. The results are consistent with previous reports that the majority of patients who had a minor stroke have excellent functional outcomes at 90–120 days and low complication rates with thrombolysis.26 While not tracked, most patients in this substudy presumably had disabling deficits at presentation, given the inclusion requirement that patients should be eligible for thrombolysis according to standard-of-care indications in Canada.15 In the main AcT trial, 35.8% of patients achieved the primary outcome of mRS 0–1 at 90–120 days, while in comparison, 49.2% of the subgroup with minor stroke had an excellent functional outcome at 90–120 days. The results also highlight that the prognosis of minor stroke when disabling on presentation is not always benign. At 90–120 days, 27.2% of patients in our study had residual moderate-to-severe disability or had died (mRS 3–6). Other studies of unselected minor stroke have reported similar rates of severe disability or death ranging from 20% to 30%.12 27 28 In comparison, in trials such as ARAMIS, where enrolment was limited to non-disabling stroke, good outcomes (mRS 0–2) were seen in 95% of patients and were similar in the tenecteplase and dual antiplatelet arms.13 The differences in outcomes between trials in minor stroke presenting with versus without disability may in part reflect an increased likelihood for disabling minor strokes to harbour more proximal occlusions. Other factors, including vascular comorbidities and stroke aetiological differences in the Chinese population enrolled in ARAMIS, may also be important.
The present results align with the main AcT trial and prospective observational data22 supporting that routine thrombolysis of minor stroke based on current guidelines with tenecteplase results in similar clinical and safety outcomes to alteplase. The AcT trial demonstrated the non-inferiority of tenecteplase compared with alteplase for intravenous thrombolysis.17 The results of this substudy are qualitatively similar, with a non-significant higher proportion of patients who had a minor stroke treated with tenecteplase achieving excellent and/or good functional outcomes compared with alteplase (mRS (0–1) at 90–120 days (51.8% tenecteplase vs 47.5% alteplase); mRS of 0–2 (74.1% tenecteplase vs 69.9% alteplase)). Higher tenecteplase dosing does not seem to improve outcomes in minor strokes relative to standard-dose alteplase. The NOR-TEST trial compared tenecteplase at a dose of 0.4 mg/kg with 0.9 mg/kg alteplase.29 While not specifically a minor stroke trial, the included patients in NOR-TEST had a median NIHSS of 4, with >70% of patients having an NIHSS of <7. The NOR-TEST trial did not show that tenecteplase at this higher dose was superior to alteplase, with 64% of patients having an mRS 0–1 at 3 months in the tenecteplase group vs 63% in the alteplase group.
This study also adds data regarding the safety of tenecteplase 0.25 mg/kg in patients presenting with minor deficits. A total of 2.6% of patients in the tenecteplase group vs 3.3% in the alteplase group (RR 0.79 (0.24 to 2.54)) had sICH at 24 hours. In comparison, in the main AcT trial, sICH at 24 hours was seen in 3.4% of patients in the tenecteplase group and 3.2% in the alteplase group overall. A similar rate of sICH was seen in the PRISMS trial, which included patients who had a minor stroke (NIHSS ≤5) with non-disabling deficits, and reported sICH in 3.2% of patients in the alteplase arm.12 While definitive evidence of the superiority or non-inferiority of tenecteplase at a dose of 0.25 mg/kg versus alteplase in minor stroke requires an adequately powered randomised trial, the present data provide reassurance that tenecteplase likely provides similar efficacy and safety outcomes to alteplase in the population who had a minor stroke.
Finally, the study highlights that patients presenting with disabling minor deficits will often have visible occlusions on CT angiography. Patients who had a minor stroke with visible occlusions carry an elevated risk of early neurological deterioration and poorer functional outcomes.5 6 30 Overall, 51.3% of patients who had a minor stroke included in this secondary analysis had visible occlusions, and 5% of those were in a proximal large artery. These rates are higher than previous minor stroke studies, where the rate of any visible occlusion ranged from 5% to 15%.31–33 The reason for the higher rates of occlusions in this subgroup may reflect a bias of investigators to enrol and thrombolyse those patients with minor deficits and visible occlusions due to concerns about progression. Study screening logs were not maintained, so it is not possible to confirm specifically which minor strokes were excluded. Future studies, such as the ongoing TEMPO-2 trial (ClinicalTrials.gov: NCT02398656), will more definitively determine if tenecteplase is superior to the standard of care, specifically in the population who had a minor stroke with visible occlusions.
Limitations
Our study has several limitations. First, randomisation was not stratified by baseline NIHSS; therefore, the effect of unmeasured confounders on the analysis cannot be discounted. Second, there were baseline differences in the number of patients with vessel occlusion and utilisation of endovascular thrombectomy between the groups, both higher in the tenecteplase group. Third, due to the pragmatic nature of the trial, no screening logs were maintained, and it was left to the discretion of enrolling physicians regarding which minor strokes to enrol. Since patients were enrolled based on current Canadian guidelines for thrombolysis,23 most patients with minor strokes likely had disabling deficits, although this was not possible to confirm. Finally, this is a post-hoc secondary analysis that is inadequately powered to detect group differences in the primary and secondary outcomes. The results should be considered exploratory and hypothesis-generating.
Conclusions
In patients who had an acute stroke enrolled in the AcT Study presenting with minor deficits, safety and efficacy outcomes with tenecteplase 0.25 mg/kg were not significantly different from alteplase 0.9 mg/kg. In these patients, tenecteplase may be a reasonable alternative to alteplase for those meeting standard indications for thrombolysis; however, further adequately powered studies in the population who had a minor stroke are needed to confirm these results.