TNK for Ischemic Stroke at 4.5-24 hours without Thrombectomy (TRACE-III) - Article Summary

Summary Author: Loren Marino

Brief Summary:

Intravenous (IV) thrombolytic therapy such as tenecteplase (TNK) is used in the acute management of ischemic stroke in eligible patients up to 4.5 hours after the onset of symptoms. Patients with large vessel occlusions are also typically eligible for endovascular thrombectomy within 24 hours of onset of symptoms. However, hospitals in low or middle income countries may not have immediate access to thrombectomy. Additionally, an estimated 67-75% of patients present after the 4.5 hour window for IV thrombolytics. A prior study in 2018 found that alteplase reduced neurologic deficits in patients with ischemic stroke compared to placebo if used within 9 hours of symptom onset. However, the efficacy of using TNK after 4.5 hours is not currently known. Therefore, this study aimed to assess the degree of disability and rate of adverse effects in patients with ischemic stroke who present after 4.5 hours and receive TNK.

Study Design:

This study was a phase 3 open-label, randomized trial that took place across 58 medical centers in China. Key inclusion criteria included: patients who presented between 4.5 and 24 hours after last known well, had a pre-stroke score of 0-1 on the modified Rankin scale, had an NIHSS score of 6-25, had occlusion of the internal carotid artery (ICA) or the M1 or M2 segment of the middle cerebral artery (MCA), and had salvageable brain tissue as determined by perfusion imaging. Patients were excluded if they had contraindications to TNK, were scheduled to undergo thrombectomy, or had hypodensity (visible infarct) in more than 1/3rd of the MCA territory on imaging. A total of 516 patients were randomized to receive either TNK (n = 264) or standard medical management with anti-platelet therapy alone (n = 252). Outcomes as described below were assessed using the intention to treat principle.

Findings:

Primary outcome: absence of disability as defined by a score of 0-1 on the modified Rankin scale at 90 days post-stroke.

Secondary outcomes: ordinal distribution of modified Rankin scale scores at 90 days, functional independence at 90 days, major neurologic improvement at 72 hours, the change from baseline in the NIHSS score at 7 days, and evidence of reperfusion at 24 hours based on perfusion imaging.

As shown in the figure below, 33% of patients who received TNK achieved absence of disability, compared to 24.2% in the control group (p = 0.03). The number of patients receiving TNK needed to prevent one disability at 90 days was 11.

The study was not sufficiently powered to draw conclusions regarding secondary outcomes. However, results were consistent with the primary outcome. 16% of patients who received TNK achieved major neurologic improvement at 72 hours, compared to 6% in the control group. The mean change in NIHSS score at 7 days was -4 in the TNK group and -2 in the control group.

For safety outcomes, 3% of patients in the TNK group had symptomatic intracranial hemorrhage, compared to 0.8% in the control group. Importantly, several of these patients had protocol violations due to extensive areas of hypodensity on imaging. However, the overall difference in rate of hemorrhage was not statistically significant. Additionally, the survival rate between groups was similar.

Limitations:

• The study was open-label, where only clinicians assessing the outcomes were blinded to the treatment groups.

• The study was limited to China, where there is more intracranial atherosclerosis and less atrial fibrillation than in Western countries. Therefore, the generalizability of these results is less certain, as the main mechanism of stroke may differ appreciably by geography.

• Patients on average had strokes of moderate severity based on NIHSS score. They also had relatively low volumes of ischemic cores (irreversibly injured tissue). Therefore, these results may not be as applicable to patients with more severe strokes.

• The study only extended to 90 days post-stroke, so longer term effects are not known.

Conclusions:

In patients with mild to moderate ischemic strokes involving the ICA or M1/M2 segment of the MCA, the use of TNK after 4.5 hours of symptom onset led to less disability at 90 days as compared to standard medical therapy alone. Therefore, the use of TNK may be a viable option for patients who are unable to access endovascular thrombectomy, which is still considered optimal management. However, it is crucial that the extent of the infarct is evaluated prior to administering TNK, as late administration may be associated with increased rate of intracranial hemorrhage in patients with larger strokes.

Main Takeaway

There is preliminary evidence to show that the use of TNK in patients with ischemic stroke due to large vessel occlusion after the typical 4.5 hour window may still be effective at reducing future disability.

References:

Xiong Y, Campbell BCV, Schwamm LH, et al. Tenecteplase for ischemic stroke at 4.5 to 24 hours without thrombectomy. New England Journal of Medicine. 2024;391(3): 203-212.

DOI: 0.1056/NEJMoa2402980.