International Stroke Conference: The era of tenecteplase intravenous thrombolysis has really come?

*For reference by medical professionals only, Professor Xu Anding, director of the Cerebrovascular Disease Center of the First Affiliated Hospital of Jinan University, commented at the end of the article, don't miss it! For patients with acute ischemic stroke (AIS), vascular recanalization, or reperfusion therapy, is the most important part of the recovery of nerve function.

The thrombolytic drug alteplase has been widely used, and tenecteplase has attracted more and more attention in neurology due to its potential value and usage advantages.

The 2021 International Stroke Conference (ISC) specially invited four big names in the field of Neplase research, Professor Jeffrey Saver, Professor Patrick Lyden, Professor Shelagh Coutts and Professor Steven Warach to conduct an ISC debate and discuss alternatives.
Is Napzyme ready to be used in clinical practice?
Tenecteplase: 9 all-rounder Professor Jeffrey Saver listed 9 criteria for the application of new drugs in routine clinical practice.
If a new drug meets the criteria of 5-7, it is possible for clinical application.

Tenecteplase meets these 9 criteria.

(1) The pharmacological mechanism is clear: Tenecteplase is modified from alteplase and has many physiological advantages such as longer half-life and high fibrin specificity.

(2) The evidence of pre-clinical studies is conclusive: Tenecteplase in vitro and animal tests have shown clear evidence of thrombolysis.

(3) Benefits and safety are shown in clinical studies under similar conditions: A meta-analysis of thrombolytic trials in myocardial infarction shows that tenecteplase is safer than alteplase.

(4) Advantages in clinical practice: Tenecteplase is more convenient to use because it can be bolus injected within 1 minute, especially in the era of new coronary pneumonia.
This is more important.(5) The RCT study shows that it is effective: A meta-analysis published by Professor Jeffrey Saver in 2019 showed that the efficacy of tenecteplase in the treatment of AIS is not inferior to that of alteplase [1].

(6) Guideline recognition: Multinational guidelines all recommend tenecteplase.

(7) Support from drug regulatory authorities: The U.
S.
Food and Drug Administration (FDA) passed a revised plan for thrombolysis trials in 2021, and tenecteplase is also used as one of the standard treatments for thrombolysis.

(8) Real-world diagnosis and treatment practices have shown to be effective.

(9) Clinician support.

Professor Jeffrey Saver also cited feedback from many doctors on the two conditions (8) and (9).

In short, tenecteplase can be called a nine-athlon (Figure 1), and the professor believes that it has the conditions for clinical practice.

Figure 1: Nine criteria for the application of new drugs in routine clinical practice (picture from Professor Jeffrey Saver's PPT) Professor Steven Warach introduced his team’s experience in applying tenecteplase.

Last year, Professor Steven Warach and Professor Jeffrey Saver published an article in JAMA Neurology that tenecteplase used for stroke thrombolytic therapy can reduce the transmission of emergency new crowns and alleviate the shortage of alteplase [2], and summarized tenecteplase in detail.
The advantages of General Enzyme (Figure 2) include: (1) shorter preparation time; (2) shorter injection time; (3) no need to open and maintain a second venous access; (4) no need for intravenous infusion Pump; (5) The time required for patient transfer after intravenous administration is shorter.

Figure 2: Tenecteplase use advantages [2] Need more data Professor Patrick Lyden introduced the development process of tenecteplase clinical trials.

Professor Patrick Lyden is concerned about the dosage of tenecteplase and emphasized that for the clinical trials of tenecteplase, not only the outcome of reperfusion rate should be paid attention to, but also the improvement of the neurological function of patients in 90 days.

The short-term benefits (such as within 24 hours) are not enough to support the FDA's approval for clinical treatment.

Professor Shelagh Coutts summarized the published tenecteplase thrombolytic therapy research and ongoing research.

Published trials, from the Parsons et al.
study in 2012 to the ATTEST study to the EXTEND-IA trial in 2018, there are many gratifying results, but it should also be seen that most of the trials have fewer cases [3 ] (Figure 3).
In addition, the patients enrolled in some trials included a certain proportion of transient ischemic attack (TIA) patients and stroke mimic patients (pseudo-stroke).

Professor Shelagh Coutts believes that "we still need more data.
.
.
we need good data".
At present, multiple studies on tenecteplase are underway worldwide (Figure 4); "Don't think we already know the answer.
Rather, it conducts general rigorous tests of machine operation to obtain data.
"
Figure 3: Tenecteplase thrombolytic therapy research [3] has been published.
Note the N in the rightmost column.
Most of the trials have a small sample size.
Figure 4: The ongoing Tenecteplase trial is a reminder of the ISC debate.
Tenecteplase shows a strong advantage, but more data support is still needed.
As Shelagh Coutts said, “I don’t care about receiving alteplase treatment or receiving tenecteplase treatment.
The important thing is that it is effective.
Improve symptoms".

Professor Xu Anding, director of the Cerebrovascular Disease Center of the First Affiliated Hospital of Jinan University, commented that early recanalization, including intravenous thrombolysis, intravascular interventional thrombus removal or bridging therapy based on intravenous thrombolysis, is the only effective way to reduce the disability of AIS patients.

The 1995 NINDS study laid the cornerstone of intravenous rtPA thrombolytic therapy for AIS.

So far, rtPA is still the only intravenous thrombolytic drug that has been internationally recognized and guideline I recommendation/level A evidence for the treatment of AIS.

In recent years, basic research to phase II clinical trials have revealed the advantages of tenecteplase in the treatment of AIS, whether it is intravenous thrombolysis alone or bridging therapy, and tenecteplase has also obtained evidence of safety in patients with acute myocardial infarction.
Preliminary evidence that AIS is safe and effective for real-world use.

It should be said that tenecteplase has shown good application prospects.

But is it now ready to be widely used in clinical practice (that is, to change the guidelines)? Personal opinion is still not too hasty.

Because the phase II clinical study mainly solves the safety and dosage issues, although it also shows preliminary effectiveness, it still needs verification of the results of the phase III clinical study in a strict sense.
If the guidelines are to be completely changed, the level of evidence of Class I recommendation is reached.
At least two large-scale prospective double-blind randomized controlled studies, or even evidence from international multi-center studies are needed.

In the past, there are many examples of phase II clinical studies that are very satisfactory, but phase III clinical studies have failed, such as the DIAS study and DEDAS study of desmoplase treatment of AIS (two phase II clinical studies are positive, but then phase III negative results ), the AbESTT study of abciximab in the treatment of AIS (Phase II study suggests that it is safe and effective, but Phase III found to significantly increase bleeding), and the clinical study of the brain protectant NXY059 (Phase II is very effective, but Phase III shows no effect )Wait.

As for the relevant evidence of tenecteplase in the treatment of acute myocardial infarction, it can only be used as a reminder, and it cannot be directly cited in patients with AIS.

Therefore, the existing data has ignited the light of hope for tenecteplase in the treatment of AIS, but it will take time for it to be formally used in clinical practice.
It is good to wait for the official publication of the results of several related phase III clinical studies.

Expert profile Professor Xu Anding, second-level professor/chief physician, Ph.
D.
Supervisor, Deputy Director of Jinan University Medical Department Achievements and Honors Jinan University First Affiliated Hospital/First Clinical Medical School Dean of Jinan University First Affiliated Hospital Cerebrovascular Disease Center Guangdong Province Medical leader, vice president of the Chinese Stroke Society, vice chairman of the Stroke Prevention and Control Professional Committee of the Chinese Preventive Medicine Association, president of the Guangdong Stroke Society, vice president of the Guangdong Provincial Hospital Association, vice president of the Guangdong Medical Association and Department of Neurology Chairman of the Physician Branch, Executive Director of the Guangdong Medical Association, Deputy Chairman of the Neurology Branch, Deputy Editor of the Official SCI Journal of the Chinese Stroke Society "Stroke & Vascular Neurology", responsible for the National Natural Science Foundation of China and other provincial and ministerial funds and other projects for the past ten years There are more than 30 projects with a total fund of more than 12 million yuan.

Editor-in-chief, associate editor, and co-editing 6 monographs, and 2 undergraduate textbooks.

Published more than 200 papers, including more than 60 SCI papers.

A number of national and international conference academic committee members and invited academic lecture experts participated in the formulation of the Chinese cerebrovascular disease guidelines and series of expert consensus, and presided over several expert consensus/guideline writing reference materials: [1] Burgos AM, Saver JL.
Evidence that Tenecteplase Is Noninferior to Alteplase for Acute Ischemic Stroke:Meta-Analysis of 5 Randomized Trials.
Stroke.
2019;50(8):2156-2162.
[2]Warach SJ,Saver JL.
Stroke Thrombolysis With Tenecteplase to Reduce Emergency Department Spread of Coronavirus Disease 2019 and Shortages of Alteplase[published online ahead of print,2020 Jul 20].
JAMA Neurol.
2020;10.
1001/jamaneurol.
2020.
2396.
[3]Coutts SB,Berge E,Campbell BC,Muir KW,Parsons MW.
Tenecteplase for the treatment of acute ischemic stroke:A review of completed and ongoing randomized controlled trials.
Int J Stroke.
2018;13(9):885-892.