Earlier this year, results from the Canadian AcT (Alteplase compared to tenecteplase) randomised controlled trial (RCT) were delivered for the first time at the European Stroke Organisation Conference (ESOC 2022; 4–6 May, Lyon, France). And, alongside other first-time data presentations from studies like NOR-TEST 2 and TWIST, these results represented a major step towards validating the benefits of tenecteplase, a newer-generation intravenous thrombolysis (IVT) drug, over alteplase, the longstanding ‘go-to’ in thrombolytic stroke treatments. That is according to AcT principal investigator Bijoy Menon (University of Calgary, Calgary, Canada), who recently sat down with NeuroNews to discuss these findings and their wider implications—as well as what the future of IVT treatments may look like globally.
Firstly, could you briefly summarise the purpose, design and key results of the AcT trial?
Although tenecteplase was of increasing interest as a thrombolytic agent in patients with acute ischaemic stroke, because of its use as a single bolus, there was no phase 3 RCT showing evidence that it could replace alteplase as the thrombolytic agent of choice in our routine practice. The AcT trial sought to generate this evidence that would help change practice. The primary goal of the trial was to show that tenecteplase at a dose of 0.25mg/kg body weight was comparable to alteplase in all acute stroke patients otherwise eligible for thrombolysis as per Canadian acute stroke guidelines. The Canadian acute stroke guidelines are very similar to the European, American or Australian acute stroke guidelines.
The design of the trial was therefore pragmatic, with all acute ischaemic stroke patients who would otherwise be thrombolysed as part of standard care being eligible for enrolment. Comparability was to be shown via non-inferiority—if the lower 95% confidence interval [CI] of the difference in primary outcome rates between tenecteplase versus alteplase was greater than −5%, then tenecteplase would be considered non-inferior. The trial had a prospective randomised open blinded-endpoint (PROBE) design with blinded-endpoint assessments. The primary efficacy outcome was 90-day modified Rankin Scale (mRS) 0–1 rate collected centrally in a blinded manner, and key safety outcomes included symptomatic intracerebral haemorrhage rates at 24 hours and 90-day mortality. Other pragmatic outcomes included return to baseline function at 90 days and ambulatory status at discharge.
The trial enrolled 1,600 patients. The primary outcome rate with tenecteplase was 36.9% compared to 34.8% with alteplase (unadjusted risk difference 2.1%; 95% CI, −2.6 to 6.9), with the −2.6% lower 95% CI for the risk difference easily being greater than the −5% non-inferiority margin. The two drugs were comparable for all secondary and safety outcomes too. No statistical heterogeneity was seen across any relevant subgroups. The AcT trial therefore provides robust evidence that we can switch standard of care within 4.5 hours of stroke symptom onset to tenecteplase, given its ease of use when compared to alteplase.
What is the relevance of these findings and how are they set to impact clinical practice?
The AcT trial was designed to build evidence that would be considered robust and generalisable (i.e. evidence that mirrors real-world practice). This is why large, pragmatic trials are important—their results can be directly applied to your practice. This impact of the trial’s pragmatic design is reflected by the fact that practice is now changing in Canada and across the world.
What are the major benefits tenecteplase offers, and why they are so crucial in stroke care?
The major benefits with tenecteplase are a) ease of use as a single intravenous bolus injection administered over 5–10 seconds, compared to a bolus and an hour-long infusion with alteplase, and b) easy workflow given that patients need not be transferred within and between hospitals when being administered thrombolysis using complicated intravenous lines and infusion pumps. These advantages would translate to faster treatment times, reduced overall treatment costs and, potentially, better outcomes for acute stroke patients.
Other studies have investigated a higher dose of tenecteplase than the one seen in AcT and produced more negative results. What is the significance of this?
Thrombolysis has risks; the most important amongst them being bleeding that is dose related. The evidence from the NOR-TEST 2 trial (Norway) and from the earlier phase 2 trials suggest that a higher dose of tenecteplase (0.4mg/kg body weight) causes more harm without any additional benefit. The body of evidence up to now, including from AcT, therefore suggests that we should be using tenecteplase at a dose of 0.25 mg/kg body weight for IVT.
How important do you think further recent/ongoing studies are in building on the positive data seen in AcT?
The recent study out of Dell Medical School (Austin, USA) is a real-world observational study—rather than an RCT—that is showing the efficacy and safety of tenecteplase. Such studies show the real-world benefits of tenecteplase in different settings and are therefore very helpful. The TECNO trial (Switzerland) is testing the utility and safety of intra-arterial tenecteplase. Such studies are important in helping expand indications and use of tenecteplase. Other studies like the recent TWIST trial (Norway), and the ongoing TIMELESS (USA and Canada) and ETERNAL (Australia) trials, help us understand the utility of tenecteplase in the extended time window too. The ongoing ATTEST 2 (UK) and TASTE (Australia) phase 3 trials—along with the recently completed TRACE phase 3 trial (China)—will provide more evidence around tenecteplase use in acute stroke patients. All these trials are likely to help us transition globally to a more efficient thrombolysis paradigm in acute stroke.
For acute stroke treatments, is tenecteplase likely to replace alteplase completely in the future?
Yes, and we only have to look at the practice in cardiology to understand why. After the large ASSENT-2 RCT, which was published in The Lancet in 1999 and compared tenecteplase to alteplase in patients with acute myocardial infarction, demonstrating that mortality and bleeding risks were equivalent, practice changed completely to using tenecteplase because of tenecteplase’s ease of use. I see no reason why this will not happen in stroke given the AcT results—also published in The Lancet earlier this year. Transition always take time though as systems have to adapt; but this is a matter of time.
Some centres are already making the switch, but how long do you think it may be before, globally, tenecteplase becomes more widely used?
There is a supply shortage of tenecteplase in Europe and some other parts of the world that is limiting this switch; otherwise, I see this transition happening very soon. In Canada and the USA, where there is no shortage of tenecteplase, this switch is happening right as we speak. Many hospitals and health systems have already moved to a tenecteplase-only IVT protocol, with others following suit. The transition will also accelerate once national guidelines reflect this new evidence, and the supply issues are being addressed too. Overall, I see us having moved to tenecteplase globally as the IVT drug of choice in acute stroke patients within the next 2–3 years.
Can you provide insight on which direction you feel tenecteplase research should now take in order to further bolster these promising findings?
We need to develop robust evidence for thrombolysis in many conditions where, previously, because of restrictive trial criteria within the initial alteplase thrombolysis trials, evidence was weak. We also need to better understand the utility and safety of tenecteplase in patients undergoing endovascular therapy (EVT); those who may be on newer anticoagulants or anti-thrombotics; those with other risk factors like renal dysfunction, high blood pressure or high blood glucose; and even in the elderly. We need to better understand how to use thrombolysis when modern imaging information of risk and futility is available. And we need to understand if the effect of thrombolysis with tenecteplase can be enhanced and whether concomitant therapies might improve outcomes further. As Dickens said: “These are the best of times…”; we have an incredible opportunity here, if only we can make use of it.