WSC 2022 | Tenecteplase versus alteplase: impact of time to thrombolysis on clinical outcomes

As some of you may know, AcT was the alteplase compared to tenecteplase trial. This was a large, pragmatic, multi-center pan-Canadian, open label, registry linked, randomized, controlled trial. We enrolled around 1,600 patients with acute ischemic stroke presenting within four and a half hours of symptom onset. And they were randomized one as to one to either receive alteplase or tenecteplase. The inclusion/exclusion criteria were very pragmatic as the trial was set like that and all patients who were above 18 years of age who were otherwise eligible for IV thrombolysis were included in the trial.

So it was a non-inferiority trial with a 5% non-inferiority margin and we did prove that tenecteplase is non-inferior to alteplase in treating acute ischemic stroke within four and a half hours of symptom onset. The results were published in the Lancet a few months ago.
The analysis that I’m presenting at the meeting is equally interesting. So what we’ll be presenting is the effect of time to treatment benefit of intravenous alteplase compared to tenecteplase in patients with acute ischemic stroke. So we’ve all been following this central dogma about ‘time is brain’ and we know that there is a time effect seen with thrombolysis, as well as with endovascular treatment. However, when I say with thrombolysis, this has only been tested with alteplase so far. So there’s no data showing that is there a time effect with tenecteplase too. And if yes, is it different from alteplase?

So AcT gave us that data. So that is what we’ll be presenting, specifically looking at two times. I’ll be talking about the onset to needle times and the door to needle times to see if they differ between alteplase and tenecteplase. Having said that, it’s also important to remember that although the current guidelines do approve thrombolysis up to four and a half hours of symptom onset, the FDA does not approve thrombolysis for the three to four and a half hour window in the US, as well as in Canada. So we are all treating patients up to four and a half hours, but from a regulatory perspective, alteplase is not approved for the later time window.

Having said that, we’re analyzing the data in two groups. So we are comparing alteplase with tenecteplase in the zero to three hour window and as well as in the three to four and a half hour window. Along with that, we’re also seeing overall with time as a continuous measure if these effects are different. So for the analysis, we included patients who were enrolled or analyzed in the AcT trial, which was 1,577 patients. We excluded cases who did not receive thrombolysis, those patients who received thrombolysis beyond the four and a half hour time window or those who were in hospital strokes. So in the end we were left with 1,093 patients in the zero to three hour window and 375 patients in the three to four and a half hour window.

So when comparing the baseline characteristics between the alteplase and tenecteplase groups in the zero to three hour window, as well as in the three to four and a half hour window, given that this was a randomized, controlled trial, we totally didn’t find any differences in baseline characteristics pertaining to age, sex, baseline NIHSS, site of occlusion, and even the workflow times. And in terms of efficacy, in the zero to three hour window, we found that similar to what we found in the main trial, so alteplase and tenecteplase were very similar in terms of primary outcome mRS 0-1, as well as mRS 0-2, as well as in all the safety outcomes.

Having said that, in the three to four and a half hour window, we found that tenecteplase was doing way better as compared to alteplase and the adjusted risk ratio was 1.27 favoring the tenecteplase arm for mRS 0-1 as the primary outcome. The length of hospital stay was also shorter and we had a pragmatic outcome called return to pre-stroke status that was also significantly in favor of tenecteplase in the three to four and a half hour window.

In terms of safety outcomes, they were similar in both time windows for both thrombolytics and when we compared mortality, symptomatic ICH rates, they were all similar across all subgroups. Now, having said that, we also tried to see continuous analysis of time in comparing alteplase and tenecteplase. And we found for our onset to needle times, there was not much difference in the zero to three hour window between alteplase and tenecteplase, and again in the later half tenecteplase did slightly better as compared to alteplase. But the P value for interactions were not significant for mRS 0-1 as well as for mRS 0-2.

As again for door to needle times, we found tenecteplase to be consistently better as compared to alteplase across all the time intervals for mRS 0-1, as well as for mRS 0-2. Again, the P value for interaction however was not significant in both these groups. So by these results, we would conclude that just as with IV alteplase, faster treatment leads to better outcomes in patients who were treated with tenecteplase as well. However, tenecteplase led to significantly better excellent outcome defined by mRS 0-1 as compared to alteplase group in the later time window, which is the three to four and a half hour. And we did not find any difference in mortality or hemorrhage rates by thrombolytic across all time intervals.