tenecteplase

hidden

Tenecteplase: Is It Ready for Primetime?

Siddharth Sehgal, MD

In 1996, intravenous alteplase was approved by the FDA for treatment of acute ischemic stroke within 3 hours of time of onset of symptoms. Since then it remains the only drug approved for treatment of acute ischemic stroke. Subsequent clinical trial showed benefit of alteplase unto 4.5 hours from onset of symptoms.

Over the past few years, several trials have studied medications including anticoagulants and thrombolytics, but have not shown positive results. Tenecteplase is a bio-engineered form of alteplase, and is approved in the U.S. for acute myocardial infarction. In 2017, results of the NOR-TEST trial were published, which compared the efficacy and safety of tenecteplase and alteplase in an open label, randomized design1. 1100 patients were randomized 1:1 to receive either alteplase 0.9 mg/kg (max dose 90 mg) or tenecteplase 0.4 mg/kg (max dose 40 mg).  Most patients enrolled in this study had a mild stroke with median NIH stroke scale of 4. The primary outcome measure of 3 months modified rankin score 0-1 was achieved in 64% of the tenecteplase group and 63% of the alteplase group. The mortality rates and serious adverse event rates were also similar in the two treatment arms. In conclusion, this study showed that tenecteplase had similar safety and efficacy as compared to alteplase when administered to acute ischemic stroke patients within 4.5 hours of symptoms onset.

A subsequent subset analysis of patients presenting within 3 to 4.5 hours time window also had similar results in the two treatment groups, with rates of good functional outcomes and adverse events including mortality2.

In the last few years, several clinical trials have established efficacy and safety of mechanical thrombectomy for treatment of ischemic stroke caused by acute occlusion of an intracranial internal carotid artery or middle cerebral artery. The American Heart Association/Stroke Association guidelines recommend treatment with intravenous alteplase in eligible patients ,prior to mechanical thrombectomy. The EXTEND-IA TNK trial3 studied the efficacy of tenecteplase 0.25 mg/kg (max dose 25 mg) compared to alteplase 0.9 mg/kg (max dose 90 mg) in patients who subsequently underwent mechanical thrombectomy fo an intracranial large vessel occlusion. The thrombolytic drugs were administered within 4.5 hours from symptom onset. The trial was designed as a non inferiority study but showed tenecteplase to be superior than alteplase. The primary outcome of greater than 50% reperfusion of the occluded artery at the time of initial angiogram was achieved in 10% of the alteplase group and 22% in the tenecteplase group (P= 0.03 for superiority and P=0.02 for non inferiority). Moreover, tenecteplase resulted in better functional outcomes measured by median modified rankin scores at 90 days ( 2 vs 3, P=0.04). Both the treatment groups had similar rates of symptomatic intracerebral hemorrhage.

Tenecteplase has better fibrin specificity and a longer half life than alteplase. Tenecteplase can be administered as a bolus over a few seconds while alteplase requires a one hour infusion. A significant proportion of large vessel occlusion stroke patients receive intravenous thrombolysis at the initial hospital and then get transferred to a larger stroke center for mechanical thrombectomy; this is referred to as the drip and ship approach. The one hour infusion is usually initiated at the first emergency department and continued en route to the thrombectomy center. This approach can pose logistical challenges and cause treatment delays, which can be overcome if a thrombolytic can be rapidly administered as a bolus prior to patient getting transferred.

These results have now shown that tenecteplase is a promising alternative to the current standard of care thrombolysis with alteplase when treating acute ischemic stroke. This may be especially favorable for the patients who also require mechanical thrombectomy of an intracranial large vessel occlusion.

Further research is needed to establish the efficacy and obtain regulatory approval for tenecteplase in treatment of acute ischemic stroke. ATTEST-2 is an ongoing trial studying the efficacy of tenecteplase in ischemic stroke not caused by a large vessel occlusion. EXTEND-IA TNK-2 is going to compare two doses of the tenecteplase (0.25 mg/kg and 0.40 mg/kg) for safety and efficacy.  It is exciting to think that we may be getting close to the first new drug approved for treatment of acute ischemic stroke in more than 20 years.

References

  1. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial. Lancet Neurol. 2017 Oct;16(10):781-788.
  2. Tenecteplase Versus Alteplase Between 3 and 4.5 Hours in Low National Institutes of Health Stroke Scale. Stroke. 2019;0
  3. Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke. N Engl J Med. 2018 Apr 26;378(17):1573-1582

 
hidden

Promising Advance In Stroke Thrombolysis Research: Tenecteplase

Neal Parikh, MD

A recent New York Times article re-surfaced the ‘debate’ regarding alteplase (IV-tPA) for ischemic stroke.1 There are some who continue to argue that the data for IV-tPA are not convincing. In this context, and otherwise, it is worthwhile to discuss a recent study comparing tenecteplase versus alteplase among patients with large vessel occlusion.2

In this study, 202 patients presenting within the IV-tPA treatment window of 4.5 hours and with an ischemic stroke due to large vessel occlusion were randomized to receive IV-tPA versus IV-tenecteplase prior to proceeding with mechanical thrombectomy. The main outcomes relevant for this discussion are the primary outcome of substantial reperfusion (restoration of blood flow in the affected area) and the safety outcome of brain hemorrhage.

Whereas 10% of patients who had received IV-tPA achieved substantial reperfusion prior to undergoing mechanical thrombectomy, 22% achieved substantial reperfusion in the tenecteplase group. The number of brain hemorrhages was the same in both groups (5-6%).

If confirmed, this represents a tremendous advance in thrombolysis because many patients require lengthy transport to reach a center where thrombectomy can be performed. Achieving reperfusion without increased risk of hemorrhage, potentially in the field using stroke ambulances and telemedicine, could dramatically improve population-level care for this otherwise very disabling form of stroke.

Further, these data suggest support the stability of the 6% estimate of brain hemorrhage risk with IV-thrombolysis. The observation that the hemorrhage risk (5 vs 6%) was the same regardless of reperfusion rate (10 vs 22%) is intriguing – if the two are independent, is the risk of hemorrhage from thrombolysis from something other than reperfusion? Further, the results of this study will spur additional study and we will thus have contemporary, high-quality data regarding the efficacy and safety of thrombolysis.

References

  1. https://www.nytimes.com/2018/03/26/health/stroke-clot-buster
  2. Campbell, et al. Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke. NEJM. 2018:378:1573-82.

Neal Parikh Headshot

Neal S. Parikh, MD, earned his MD from Weill Cornell Medical College and completed residency training in neurology at the same institution. He is now an NIH T32 neuro-epidemiology and vascular neurology fellow at New York-Presbyterian Hospital/Columbia University Medical Center. He tweets @NealSParikhMD and contributes to Blogging Stroke as a blogger.