- T-FLAVOR investigators compared tenecteplase with low-dose alteplase in stroke patients scheduled for endovascular therapy (EVT).
- The trial notably took place in Japanese patients, believed to be more susceptible to bleeding, for whom low-dose alteplase is still standard of care.
- More work is needed given concerns that tenecteplase may affect clot migration and distal embolization in EVT.
Standard-dose tenecteplase (TNKase) beat low-dose alteplase as a bridge to stroke thrombectomy in bleeding-prone patients, a Japanese trial found.
Early reperfusion outcomes significantly favored patients who received tenecteplase, for whom initial angiograms were more likely to show modified Treatment in Cerebral Ischemia grade 2b to 3 or no retrievable thrombus (10.3% vs 3.6%).
This put tenecteplase over a prespecified line for superiority, reported Kazunori Toyoda, MD, PhD, of National Cerebral and Cardiovascular Center in Suita, Japan, and colleagues of the T-FLAVOR study in JAMA Neurology.
Tenecteplase and low-dose alteplase groups shared comparable functional and safety outcomes:
- 90-day modified Rankin Scale (mRS) scores numerically trended in favor of tenecteplase (common OR 1.47, 95% CI 0.92-2.35)
- Symptomatic intracranial hemorrhage within 24-36 hours was not significantly excessive with tenecteplase (2.8% vs 1.8%)
- Mortality at 90 days was also similar between tenecteplase and alteplase (6.5% vs 9.9%)
Serious adverse events and procedure-related complications were also no different between groups.
“These safety findings are critical to our ultimate goal of obtaining regulatory approval for tenecteplase in Japan, where patients have been reported to be more susceptible to bleeding complications,” wrote Toyoda’s group. “These findings are highly relevant to clinical practice in Japan and other Asian countries where low-dose alteplase is routinely used.”
T-FLAVOR thus adds to the evidence for tenecteplase as a potent thrombolytic agent in the management of acute ischemic stroke (AIS).
Granted, tenecteplase is approved by the FDA stateside but has yet to clear Japanese regulators. Study authors noted that the low-dose alteplase (0.6 mg/kg) remains the standard there and in several Asian countries.
Tenecteplase is a clot-dissolving tissue plasminogen activator that is a genetically modified variant of alteplase. It exhibits higher fibrin specificity, a longer plasma half-life, and greater resistance to plasminogen-activator inhibitors, according to Toyoda and colleagues, and it also has notable workflow advantages through its single-bolus IV administration.
Importantly, off-label tenecteplase had already become the preferred thrombolytic for AIS before the FDA approved this indication last year.
As a lytic bridge to endovascular therapy (EVT), tenecteplase is backed by the EXTEND-IA TNK and BRIDGE-TNK trials showing better preangiographic reperfusion with tenecteplase than with alteplase. In these trials, however, tenecteplase had also been associated with statistically significant improvements in mRS scores at 90 days — findings that did not pan out in the present T-FLAVOR analysis.
“Potential explanations for the lack of statistical significance in these secondary end points, despite significance of the primary end point, include the low absolute rate of prethrombectomy reperfusion and the modest sample size,” wrote Toyoda and colleagues. “Furthermore, these outcomes are substantially influenced by the procedural success and timing of thrombectomy, which may dilute the detectable impact of thrombolytic therapy alone.”
Indeed, T-FLAVOR investigators had mechanical thrombectomies performed in an open-label fashion and did not have these procedures fully standardized.
The study was conducted in 18 Japanese hospitals. Participants had large vessel occlusion strokes and were eligible for IV thrombolysis within 4.5 hours of symptom onset and subsequent mechanical thrombectomy.
The phase II study had 221 people randomized to tenecteplase 0.25 mg/kg (maximum 25-mg bolus) versus alteplase 0.6 mg/kg (maximum 60 mg over 60 minutes), of whom 218 received their assigned study drug and were included in the final analysis.
The cohort had a mean age of 77.1 years, with 42.2% women. Before the index stroke, 28.4% had been on an antiplatelet and/or oral anticoagulant and 11.0% had had a prior stroke or transient ischemic attack.
The median baseline NIH Stroke Scale score was 18, indicating a moderate-to-severe stroke. The median Alberta Stroke Program Early CT Score was 10. Occlusion sites were confirmed to include the internal carotid artery (28.9%), middle cerebral artery M1 (38.1%), middle cerebral artery M2 (26.1%), and basilar artery (6.9%).
Time from onset to randomization was a median 125 minutes.
As for the trial’s limitations, Toyoda and colleagues noted that they had to make do with a fairly low sample size because of difficulties supplying tenecteplase in Japan. Additionally, a low-dose tenecteplase regimen had been considered for the study but was ultimately not tested.
There are also concerns that tenecteplase might fragment thrombi earlier and more effectively than alteplase, leading to clot migration and distal embolization that ultimately complicates EVT procedures and harms patient outcomes.
As such, American guidelines recommend tenecteplase administration within 4.5 hours for functional improvement after stroke, but they currently stop short of explicitly endorsing tenecteplase as a bridge to mechanical thrombectomy.
