Intravenous Thrombolysis in 2020: A Year in Review

In this podcast, Neurology Learning Network's Stroke & Vascular Section Editor Amrou Sarraj, MD, reviews major intravenous thrombolysis trial data that emerged in 2020, including data for extending thrombolysis beyond the traditional 4.5-hour window, data from the EXTEND-IA TNK Part 2 Randomized Clinical Trial, and more.

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Amrou Sarraj, MD, is an associate professor of neurology at McGovern Medical School at UTHealth in Houston, Texas.

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  1. Campbell BCV, Ma H, Ringleb PA, et al. Extending thrombolysis to 4·5–9 h and wake-up stroke using perfusion imaging: a systematic review and meta-analysis of individual patient data. 2019;394(10193):139-147. doi:10.1016/S0140-6736(19)31053-0
  2. Campbell BCV, Mitchell PJ, Churilov L, et al. Effect of intravenous tenecteplase dose on cerebral reperfusion before thrombectomy in patients With large vessel occlusion ischemic stroke: The EXTEND-IA TNK Part 2 Randomized Clinical Trial. JAMA. 2020;323(13):1257-1265. doi:10.1001/jama.2020.1511
  3. Katsanos AH, Safouris A, Sarraj A, et al. Intravenous thrombolysis with tenecteplase in patients with large vessel occlusions: Systematic review and meta-analysis. Stroke. 2021;52(1):308-312. doi:10.1161/STROKEAHA.120.030220
  4. Thomalla G, Boutitie F, Ma H, et al. Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data. Lancet. 2020;396(10262):1574-1584. doi:10.1016/S0140-6736(20)32163-2
  5. Tsivgoulis G, Katsanos AH, Malhotra K, et al. Thrombolysis for acute ischemic stroke in the unwitnessed or extended therapeutic time window. Neurology. 2020;94(12). doi:10.1212/WNL.0000000000008904


Amrou Sarraj, MD: Greetings. This is Dr. Amrou Sarraj. I'm an associate professor of neurology and vascular neurologist at UT McGovern in Houston. In this podcast, we will do a year‑end review summary of the main clinical trials and major papers that were published within the last year or so, focusing on the different main categories of our daily stroke neurology practice.

This will be an overall review of the data. We'll go over the question of the trial or the paper, the main results, and the conclusion and how this applies to the practice. There will be a summary document available with this podcast for people who would like to see the details of the numbers, with references to all of the papers and trials that I will be going over.

The second category that we will be covering is IV thrombolysis and the new data regarding extending thrombolysis beyond the traditional 4.5-hour window. As we all know, the NINDS trials showed efficacy and safety of IV alteplase up to three hours, and the ICAS3 trial showed efficacy between 3 and 4.5 hours in a subpopulation of acute ischemic stroke patients.

This has been in general the widely utilized time cutoff. In stroke practice, we have been seeing the emergence of treating patients by tissue, rather than treating them by time. If a patient comes in beyond the 4.5-hour window, they have a significant disabling neurological deficit, but with imaging that does not show irreversible damage or a contraindication, the question is why not thrombolyse them? Some of the data that come within the last year or so did show the potential of that.

The first paper was by Tsivgoulis et al, and it was a meta‑analysis of 4 clinical trials that assist the efficacy and safety of IV alteplase beyond 4.5 in patients with unknown symptom onset, wakeup strokes, utilizing advanced imaging, whether perfusion imaging or MRI/DWI‑FLAIR mismatch.

This was not a patient‑level meta‑analysis, rather a meta‑analysis of the results. The 4 trials that were included were the WAKE‑UP trial, which was a European randomized, placebo‑controlled trial that used DWI-FLAIR mismatch; the EXTEND trial, which was a trial that conducted in Australia, Finland, New Zealand, and Taiwan, using perfusion images to thrombolyse patients beyond the 4.5-hour window; the FOS trial, which was conducted in Japan (similar to the WAKE‑UP trial, it used DWI-FLAIR mismatch); and the ECASS‑4 trial, which was the European trial, and also used a perfusion‑diffusion mismatch on MRI.

The overall result of this meta‑analysis showed better functional outcomes with IV alteplase as compared to placebo. This included the excellent outcome of modified Rankin scale of zero‑to‑one, the good outcome, with modified rank and scale of 0 to 1. However, there was an increase in the symptomatic intracerebral hemorrhage rate with IV thrombolysis with alteplase beyond 4.5 hours.

This is showing—did show efficacy, however, with some safety concerns with non‑individual‑level meta‑analysis. We'll go over a little bit more detail with the individual‑level meta‑analysis, but let's say that this is the signal towards potentially treating patients beyond 4.5 hours with IV alteplase.

The individual‑level meta‑analysis was carried by Thomalla et al, which was published in The Lancet. This one had the patient‑level data of the 4 clinical trials that I just mentioned, WAKE‑UP, EXTEND, FOS, and ECASS‑4.

If you noticed, all of these used advanced imaging. They did not use only CT. They looked for a mismatch on imaging with the DWI‑FLAIR—the FLAIR change is believed to be non‑reversal—or perfusion‑diffusion mismatch, or perfusion mismatch, as I mentioned.

This individual‑level meta‑analysis showed the same results that the previous paper that we just discussed by Tsivgoulis showed with better functional outcome in almost 850 patients. There were 843 patients, 429 in the IV alteplase arm and 414 in the placebo arm.

There was a statistical significance and better, excellent outcomes with IV thrombolysis, better shift towards improved functional outcomes. However, again, the same result, higher symptomatic intracerebral hemorrhage and higher deaths.

I would like to highlight the fact that we are talking here about 3% risk of a symptomatic intracerebral hemorrhage as compared to less than, in the IV alteplase, 3%, as compared to less than 1% in the placebo arm.

The death rate, 6% in the IV alteplase, as compared to 3% in the placebo arm. This is with about 8% increase in the excellent outcome in the IV alteplase. Again, this showed a potential for IV thrombolysis benefit beyond 4.5 hours in this subpopulation, based on the advanced imaging mismatch, with risk, would increase the risk of symptomatic hemorrhage.

The numbers are not too high, and definitely not a locating for ignoring the risk of the symptomatic hemorrhage. However, this is good data that some centers already been utilizing, using advanced imaging to thrombolyse patients beyond 4.5 hours in the wakeup and on onset.

There are clinical trials looking at thrombolysis beyond 4.5 hours that are ongoing, using tenecteplase rather than alteplase. We will be going over those in the future horizons podcast later. Again, evidence for a potential benefit of IV alteplase beyond 4.5 hours, with increase in the risk of symptomatic hemorrhage.

It's important here to go back to late in 2019 and cover a paper by Campbell et al that was published in The Lancet and looked at the same question with IV thrombolysis beyond 4.5 hours of stroke onset or wakeup strokes who had specifically mismatch on perfusion, on CT perfusion, or perfusion‑diffusion MRI.

That was a systematic review that included the EXTEND, the ECASS‑4, and the IPIFIT trial. Around 414 patients, 213 in the IV alteplase and 201 in the placebo arm. This study also concluded the same, that in those patients with salvageable brain tissue on perfusion images or diffusion‑perfusion mismatch images, may have better functional outcomes than those who received placebo. Again, higher rate of symptomatic intracerebral hemorrhage, which remains a safety concern in this subpopulation, but with a potential benefit.

An important subject in IV thrombolysis is which agent to use. There will be probably a shift in practice in the next few years, going from alteplase to tenecteplase. We'll discuss more on that in the future horizons podcast, and probably some places already have shifted their practice to tenecteplase. Definitely outside the United States, Australia, and New Zealand, there is a shift there, but in our ongoing trials, that's looking into this specific question that we will be discussing further in the other podcast.

There was data within the last year or so that showed potential benefit and maybe superiority with tenecteplase, as compared to alteplase—non‑randomized, direct comparison between the 2, but some data that is hypothesis‑generating until more randomized evidence is available.

There was a paper recently in Stroke by Kitsonis et all that was a meta‑analysis of the test, the Australian TNK, the EXTEND‑IA TNK, and the NORTEST trials that aimed to compare the efficacy and safety outcomes of intravenous tenecteplase, as compared to intravenous alteplase, for patients with acute ischemic strokes and LDO.

We know that the EXTEND‑IA TNK trial looked at this question, giving tenecteplase vs alteplase in patients with large vessel occlusion, and it was associated with higher recanalization rates and better functional outcomes.

This meta‑analysis and systematic review combined the EXTEND‑IA TNK with other trials, and indeed, it showed higher rates of 90 days MRS, 0 to 2 with tenecteplase, and higher odds of success recanalization, lower mortality rates, and lower symptomatic hemorrhage rates.

The mortality in the symptomatic hemorrhages were numerically lower. Without statistical significance, but they were lower, and that's the point with tenecteplase. A single dose, probably higher efficacy, but better safety profile.

From economic standpoint, it is cheaper than alteplase. As I mentioned, there will be other trials that we will be discussing in future podcasts that are looking specifically at this question. Within the same subject, there was a dose escalating trial, the EXTEND‑IA TNK Part 2, which was published in JAMA.

It aimed, as I mentioned, the EXTEND‑IA TNK looked at giving TNK vs alteplase in patients with large vessels occlusion prior to thrombectomy. This trial, EXTEND‑IA TNK Part 2, looked at which is the better dose.

Is it 0.25 mg/kg, with a maximum of 25 mg of tenecteplase, vs a higher dose, the 0.4 mg/kg, with a maximum of 40 mg, in these patients with large vessel occlusion prior to thrombectomy?

Of course, you're looking for better reperfusion, because thrombectomy treatment and effect with be applicable in this population, and probably better functional outcomes. Looking also at the safety profile, making sure that there is no increased hemorrhage with the higher dose.

The EXTEND‑IA TNK Part 2 did not show higher rates of substantial reperfusion. Actually, the rates were identical, 19.3% vs 19.3%. It did not also show significantly higher rates of modified Rankin scale, 0 to 2, and the mortality rates were similar.

The symptomatic hemorrhage rates were a little bit higher with the 0.4-mg dose, so the primary aim here to evaluate the higher doses is associated with better outcomes was not achieved. As I mentioned, there will be a lot of data in the next few years about tenecteplase.

I believe that there will be a lot of shift in the practice towards tenecteplase, and hopefully IV thrombolysis would improve with that, would improve with the new agent, potentially would improve with identifying patients by tissue, rather than treating them by time, and giving the opportunity to treat patients well beyond the 4.5-hour window.

Thank you for listening to this year‑end review podcast. Please join us in the third one on thrombectomy major trials and new data within the last year. Thank you.