Ditch Alteplase for Stroke. It’s the easiest way to save $250,000/year.

For almost 25 years, rt-PA (Alteplase) has been the exclusive drug therapy for acute ischemic stroke. Despite the availability of other fibrinolytics that have established roles in cardiology by maintaining therapeutic benefits while improving safety (bleeding), agents like TNKase (aka tenecteplase) have not been a real consideration. But that has been changing over the past few years. 

In fact, a recent meta-analysis of 5 RCTs demonstrated the noninferiority of TNKase when compared to rt-PA in mRS of 0-1 at 3 months [n=1585, 57.9% vs 55.4%, respectively with a random-effect informal risk difference of 4% (95% CI -1% to 8%) meeting non-inferiority margin of -1.3%]. When extending the mRS scale to 0-2 at 3 months, the results were similar, however, the lower end of the 95% CI of -4% was within 2 of the 3 non-inferiority margins (-6.5%, -5% but not -1.3%). Furthermore, there were similar rates of symptomatic ICH between groups of 3% in each group (95% CI -1% to 2%).

One limitation of this meta-analysis was the heterogenicity of doses used for TNKase. While the accepted 0.9 mg/kg dosing was used consistently for rt-PA, TNKase doses included 0.1 mg/kg (6.85% of patients), 0.25 mg/kg (24.6% of patients), and 0.4 mg/kg (68.6% of patients). While there was no observed heterogeneity of treatment effect across the three different TNKase doses, there was insufficient power to detect a difference. Furthermore, there was a suggestion of heterogeneity in the treatment effect of TNKase in terms of the secondary endpoint of mRS of 0-2 at 3 months.

Which dose for stroke?

But with the cost savings of switching from rt-PA to TNKase is substantial. Savings are on the order of $2500 per dose, and if you’re at a typical stroke center with 100 cases/year that’s a lot of saving.  So considering the possibility of these savings, TNKase is a promising alternative in stroke. But as the evidence-based wheels keep on churning, we, in fact, have more evidence to guide us on what the most appropriate dose of TNKase is for acute ischemic stroke. The recently published EXTEND-IA TNK Part 2 Randomized Clinical Trial is just the study that could answer this question.

This study included adult patients in Australia and New Zeland with an acute ischemic stroke due to occlusion of the intracranial internal carotid, basilar, or middle cerebral artery and presented to a study site ED less than 4.5 hours after symptom onset and was going for endovascular thrombectomy. These patients also must have met standard intravenous fibrinolysis inclusion criteria.

Patients were randomized to either TNKase 0.4 mg/kg (max 40 mg) IV or TNKase 0.25 mg/kg (max 25 mg) IV. Although these patients were given the study drugs in an open-label fashion, there was a blinded radiological and clinical outcome assessment.

The primary outcome was reperfusion of greater than 50% of the involved ischemic territory prior to thrombectomy, assessed by consensus of 2 blinded neuroradiologists. Secondary outcomes included mRS of 0-1, mRS score of 0-2, substantial neurological improvement at 3 days. As far as safety endpoints go, the study authors sought to observe the incidence of symptomatic intracranial hemorrhage within 36 hours and all-cause mortality.

One hundred and fifty patients were randomized to each group (N=300) with the typical patient being a 73-year-old male with a first segment MCA occlusion and NIHSS score of 16, arriving to the hospital 78 minutes from the onset of symptoms and an onset-to-needle time of 132 minutes and a lysis-to-arterial puncture time of 45 minutes.

For the primary outcome of participants with greater than 50% reperfusion of the previously occluded vascular territory was similar between groups. Remarkably, the two groups achieved identical reperfusion (19.3% of patients (29/150) in each group, RR of 0.00, -8.9 to 8.9). Furthermore, there were no significant differences between treatment groups in any of the secondary efficacy endpoints.

With regards to safety, 17% (26/150) patients died in the 0.4 mg/kg group compared to 15% (22/150) in the 0.25 mg/kg group (RR 2.7, -5.6 to 11.0). More patients in the higher 0.4 mg/kg group experineced sICH compared to the lower dose group, although this difference did not reach statistical significance (4.7%, 7/150 vs 1.3%, 2/150; RR 3.5, 0.74 to 16.62, p=0.12). 

TNKase in, rt-PA out for stroke

The findings suggest that the 0.40 mg/kg dose of tenecteplase does not confer an advantage over the 0.25 mg/kg dose in patients with large vessel occlusion ischemic stroke in whom endovascular thrombectomy is planned.

What’s left unanswered from this study is whether patients not undergoing planned endovascular thrombectomy would see a similar benefit. Based on all the available data, I would estimate that if a difference in efficacy did exist, it would be small and not significant.

I would agree that there are relatively few patients this has been evaluated in. The EXTEND-IA TNK, was in a thrombectomy population.  But NORTEST had ~4% undergo the procedure (albeit with the low stroke severity), and ATTEST, Australian TNK, and TNK-S2B all prohibited intervention.  Although NINDS-2 included 168 patients receiving alteplase, we are approaching that number in patients randomized to TNKase. The much larger NORTEST-2 which may answer many of these questions is underway, but we won’t have results for at least a few years.
From my perspective, the designs of non-inferiority are somewhat reasonable since we aren’t considering TNKase to be more effective than alteplase. Based on the available evidence, I would predict the trend demonstrating non-inferiority with TNKase will continue. The larger unanswered question is whether it will as safe and lead to real-world care process improvements.
Since it is a single bolus, we eliminate the risk of dosing and administration errors we’ve observed from referring facilities in our network. We also reduce the risk of errors in our own facility during normal and off-hours. There’s yet another potential for improvement in the door-to-needle time since the preparation is less complex and does not require a pump. This would open the possibility of storing it safely in CT scan, for example.
Although it has a much longer physiologic half-life, there is a hypothetical risk of worse bleeding outcomes. Fortunately, this does not appear to be a reality based on the aforementioned literature. But as mentioned above, this may change too with larger sample size.

 

Related articles to Ditch Alteplase for Stroke.

Reverse anticoagulation for rt-PA in stroke

References for Ditch Alteplase for Stroke:
Burgos AM, Saver JL. Evidence that Tenecteplase Is Noninferior to Alteplase for Acute Ischemic Stroke Meta-Analysis of 5 Randomized Trials. Stroke. 2019;50:2156–2162

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. Published online February 20, 2020.