Can Large Vessel Strokes Be Treated with IV Thrombolysis in an Extended Time Window?

By Alan Z. Segal, MD

Associate Professor of Neurology, Weill Cornell Medicine

SYNOPSIS: In this trial involving Chinese patients with ischemic stroke caused by large vessel occlusion, treatment with tenecteplase administered 4.5 to 24 hours after stroke onset resulted in less disability and similar survival compared to standard medical treatment.

SOURCE: Xiong Y, Campbell BCV, Schwamm LH, et al. Tenecteplase for ischemic stroke at 4.5 to 24 hours without thrombectomy. N Engl J Med 2024;391:203-212.

Rapid revascularization with endovascular therapy (EVT) in acute stroke with large vessel occlusion (LVO) is the most effective means to achieve favorable neurological outcomes. EVT was proven beneficial in the anterior circulation (distal carotid or proximal middle cerebral) when used in less than six hours (MR-CLEAN, EXTEND-IA, and SWIFT-PRIME trials), with subsequent investigations extending this indication to the six- to 24-hour time window in the setting of a penumbra (DEFUSE-3 and DAWN trials). EVT not only is effective in cases with a small core infarct and a large territory of threatened tissue, but also in cases where a large core of established infarct already has occurred (> 70 cc) and in the setting of significant early infarct signs, with Alberta Stroke Progran Early CT Score (ASPECTS) scores 3-5 (SELECT2 and ANGEL-ASPECT trials).

EVT also has been shown to be effective in the basilar artery territory (BAOCHE and ATTENTION trials) and in more distal middle cerebral artery (MCA) strokes (HERMES registry).

EVT is so effective that in patients within the treatment window for intravenous thrombolysis (IVT), it is not entirely clear whether this therapy should be skipped in favor of EVT only. Multiple studies in the < 4.5-hour time window have demonstrated that EVT alone is non-inferior to IVT + EVT (DIRECT-MT, SKIP trials).

However, these questions do not address the vast majority of stroke patients who present beyond 4.5 hours and who do not have access to EVT. In the rural United States, only one in three patients has access to EVT, and worldwide, as little as 3% of patients with an LVO undergo EVT. Therefore, the most important question is not whether EVT should be accompanied by IVT, but rather whether IVT alone can effectively treat an LVO. Recently, the time window for IVT has been lengthened to nine hours (EXTEND trial) in the setting of a favorable penumbra, and patients can be favorably treated beyond 4.5 hours in the setting of a mismatch between magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) and FLAIR lesions (WAKE-UP trial).

The use of IVT in patients presenting up to 24 hours previously was addressed in the Thrombolysis in Imaging Eligible, Late Window Patients to Assess the Efficacy and Safety of Tenecteplase (TIMELESS) trial. This investigation randomized patients to IVT vs. placebo and showed no benefit for IVT. However, TIMELESS was conducted in tertiary medical centers and 73% of patients also underwent EVT. It is not clear whether IVT failed primarily because of the fact that it was not given time to work, since the average time between IVT and EVT was only 15 minutes. Regardless, TIMELESS left the issue unanswered.

In contrast, the current study, Tenecteplase Reperfusion Therapy in Acute Cerebrovascular Events (TRACE-III) study, was conducted in China where few patients are transferred for EVT (< 2% underwent IVT + EVT). In TRACE-III, 516 patients were randomized to tenecteplase vs. placebo. Patients had anterior circulation strokes (distal internal carotid artery or MCA) and had a penumbra (defined as a core infarct of < 70 cc and a penumbra at least 1.8-fold larger than the core).

Other entry criteria were similar to prior studies (such as a National Institutes of Health Stroke Scale score in the 6 to 25 range) with standard outcome measures (a modified Rankin Scale score of 0 or 1 at 90 days). Favorable outcomes occurred in 33% of tenecteplase patients compared to 24% of placebo patients (P = 0.03). This represented 87/264 tenecteplase patients compared to 61/252 patients in the placebo group, for an effect size of 1.37.

Recanalization rates also were improved. There were marginally more hemorrhages in the tenecteplase group (n = 8) compared to two patients in the placebo arm (a non-statistically significant difference, which still was low at 3%). However, this increase in hemorrhage was not associated with an increase in mortality: 13.3% with tenecteplase compared to 13.1% with placebo. Of note, there were nine patients with protocol violations (extensive areas of hypodensity on initial computed tomography scan), and five of these patients developed significant intracranial hemorrhages. Analogous to the initial “real world” data collected following the National Institute of Neurological Disorders and Stroke study in 1995, these treatments can only be beneficial when hewing closely to strict inclusion criteria.

COMMENTARY

MCA stroke is a devastating event, producing unfavorable outcomes in approximately 75% of patients. Even in the enriched population studied here, with large penumbras (good collaterals and more opportunity to salvage tissue), poor outcomes occurred in the range of 70%, whether patients were treated with tenecteplase or not. This investigation is of obvious importance from a public health point of view, since EVT therapy remains inaccessible to most patients and a viable intravenous alternative remains necessary.

This study was conducted using tenecteplase for IVT rather than alteplase. Tenecteplase has widely become the agent of choice for IVT, showing comparable safety and efficacy as compared to alteplase. Tenecteplase may be a more effective agent than alteplase, since it is more fibrin-specific and is simpler to use (it is a single bolus rather than a one-hour infusion). However, a tenecteplase bolus, as opposed to an alteplase drip, cannot be stopped if bleeding complications are suspected.

Notably, the effect of tenecteplase in this study, while statistically significant, still was of small magnitude, showing a 9% absolute benefit and about a 25% relative benefit. This effect is of similar magnitude as that of IVT < 4.5 hours (8% absolute benefit). In cases of an LVO, the effectiveness of IVT is even lower. These benefits pale in comparison to EVT, which has about a 15% absolute benefit and 40% relative benefit.

The number needed to treat (NNT) for IVT is 10 (primarily representing patients with smaller strokes), while the NNT for EVT is 2.6. Given these differences, the effect of extending IVT to a larger population of patients, while worthwhile, is a pittance compared to the benefit of expanding access to EVT (presently a massive practical and financial challenge).

In the United States, where thrombectomy-ready centers are myriad but poorly distributed, systems of care for wider use of “hub and spoke” models need to be developed. That is, start IVT (do not skip it because it is too late, even beyond 4.5 hours in selected patients), and follow this up with definitive EVT (clot extraction = grip), which is the truly necessary intervention.