TIMELESS enrolled patients with the expectation they would receive endovascular intervention following enrollment, 77 percent of whom ultimately underwent thrombectomy. TRACE-III, on the other hand, enrolled patients without access to endovascular intervention, testing the idea that tenecteplase may be suitable as an alternative in such cases. This distinction represents the crux of their differing results.

The foundation of the paradigm for endovascular intervention lies in the established observation intravenous thrombolysis is grossly ineffective at dissolving large vessel occlusions. Therefore, in TIMELESS, a trial where the overwhelming majority receive thrombectomy per the standard of care, all clots are expunged, irrespective of the pre-intervention treatment with tenecteplase. There are a few clots teneteplase dissolves prior to endovascular intervention. However, the sorts of patients who have salvageable tissue in late time windows turn out to be those whose “time is brain” clock is running the slowest, already, due to strong collateral perfusion. Therefore, TIMELESS is a “negative” trial, showing no advantage to tenecteplase when subsequent endovascular intervention is expected.

In contrast, TRACE-III does not have the endovascular backstop following intravenous thrombolysis. In this case, because outcomes are so dismal already from large-vessel occlusions, there is some benefit to treatment with tenecteplase, 33 percent versus 24 percent advantage for good or excellent functional outcomes. The authors report an excess bleeding events in the tenecteplase cohort, likely leading to the neutral effect on overall survival. It is reasonable to consider the use of tenecteplase in extended time windows, then, in systems of care where endovascular intervention is not readily available.

Now, just when you’ve gotten used to the idea of tenecteplase replacing alteplase as your preferred agent, should we be reconsidering reteplase? Reteplase is not “new” by any stretch of the imagination. It should sound familiar from its use in the early days for STEMI. However, in those trials, it was associated with higher rates of bleeding than alteplase and tenecteplase, and thusly it fell into disfavor. The RAISE trial in China tested reteplase versus alteplase in, generally, mild strokes with a median NIHSS of 6.⁴ Overall, good or excellent outcomes were seen in 79 percent of the reteplase cohort versus 70 percent of those receiving alteplase. Unfortunately, consistent with other trials, excess bleeding events were seen with reteplase, leading to increased mortality and other extra-cranial complications. Further evaluation and replication of these results will be necessary to even begin reconsideration of reteplase in the coming years.