You may have mastered all the latest changes affecting management of sepsis, STEMI, and opiate-use disorder, but there’s no stopping the relentless revisions to our approach to neurologic emergencies.

The first bit of news is good news, however: a “negative” study in which no change in practice is needed. This comes out of INTERACT-4, a trial testing the efficacy of blood pressure reduction in undifferentiated acute stroke syndromes.¹ Our prior INTERACT family of trials are those whose results have influenced our current practice of blood pressure control following intracranial hemorrhage, demonstrating reductions in hematoma size associated with prompt blood pressure control. The hypothesis tested in INTERACT-4 is whether antihypertensive treatment might be started even earlier, in the pre-hospital setting, reducing any time-dependent negative effects.

In this trial conducted in China, the antihypertensive of choice was urapidil, primarily an alpha-1 receptor antagonist, and provided by the trial sponsor. Without delving into too much detail, approximately half of the over 2,300 patients in the trial suffered ischemic stroke, and the remainder hemorrhagic stroke. The intervention was, indeed, successful at lowering blood pressure in those randomized. However, the overall trial itself was “negative” in that there was no overall difference between groups. Looking more closely, there is a very clear demarcation within these results in which the intensive blood pressure control harmed those patients suffering ischemic stroke, but benefitted those suffering hemorrhagic stroke. These results suggest there is yet no role for prehospital antihypertensives until the specific stroke syndrome is diagnosed, as with one of the mobile CT scanners.

The next question addressed in recent trials continues to be refinement of the thrombolytic of choice. The last few years have been consistently spotlighting tenecteplase as superior to alteplase, both with respect to efficacy and safety. This is not unwelcome in the slightest, as tenecteplase administration in stroke is more straightforward than the bolus-plus-infusion requirement for alteplase. The most recent spotlight for tenecteplase is whether it can be used in extended time windows up to 24 hours. Two recent trials have looked at this same question: TIMELESS and TRACE-III.^2,3

These trials lend themselves to discussion in the same breath because they have, effectively, the same study concept. Each trial enrolled patients presenting with acute ischemic stroke in a large-vessel territory and favorable perfusion imaging. Each trial included patients in the 4.5 to 24 hour treatment window, outside of traditional indications for thrombolysis. How these trials differ, however, is important.

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.

Finally, we have the ongoing saga of Andexxa, properly known as “coagulation factor Xa [recombinant], inactivated-zhzo”. The conditional approval for Andexxa in the United States hinged upon single-arm studies and apparent hemostatic efficacy. However, prior to the availability of this specific reversal agent for factor Xa inhibitors, clinicians have been utilizing prothrombin concentrate complexes to treat major bleeding events. The ANNEXA-I trial aimed to compare this PCC-based stopgap “standard of care” against Andexxa for the treatment of intracerebral hemorrhage.⁵

As is the fate of many trials whose procedures, enrollment, and reporting is orchestrated by pharmaceutical companies, the topline results are misleading. Looking narrowly at their primary outcome of hemostatic efficacy, defined primarily by change in intracerebral hematoma volume, the trial favors Andexxa. However, a full 15 percent of those in the “standard of care” cohort were not treated with PCCs and an excess of patients in the Andexxa cohort were lower-risk types of intracerebral bleeding such as subdural hematomas. More troubling, however, were the poor patient-oriented outcomes observed in the trial. Patients in the Andexxa cohort suffered a substantially greater number of thrombotic events, including ischemic stroke and myocardial infarction, and the mortality in patients receiving Andexxa was actually higher at 30 days. A greater number of patients randomized to “standard of care” attained modified Rankin scores of 0 to 3 than the Andexxa cohort, as well. It may be the case Andexxa clearly reduces factor Xa inhibition and attenuates hematoma growth, but the primacy of patient-oriented outcomes clearly ought to caution clinicians about its use.

In summary, continue to expect further permutations for potential treatment in extended time windows. The march towards tenecteplase continues unabated, while reteplase has re-emerged for further investigation. Prehospital blood pressure control in undifferentiated stroke syndromes should not be considered. Finally, the Andexxa marketing push continues, but it’s clear harms cannot be ignored.

Dr. Radecki (@emlitofnote) is an emergency physician and informatician with Christchurch Hospital in Christchurch, New Zealand. He is the Annals of Emergency Medicine podcast co-host and Journal Club editor.

References

1. Li G, Lin Y, Yang J, et al. Intensive ambulance-delivered blood-pressure reduction in hyperacute stroke. N Engl J Med. 2024;390(20):1862-1872.
2. Albers GW, Jumaa M, Purdon B, et al. Tenecteplase for stroke at 4. 5 to 24 hours with perfusion-imaging selection. N Engl J Med. 2024;390(8):701- 711.
3. 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(3):203-212.
4. Li S, Gu HQ, Li H, et al. Reteplase versus alteplase for acute ischemic stroke. N Engl J Med. 2024;390(24):2264-2273.
5. Connolly SJ, Sharma M, Cohen AT, et al. Andexanet for factor xa inhibitor–associated acute intracerebral hemorrhage. N Engl J Med. 2024;390(19):1745-1755.