Switching to Tenecteplase from Alteplase for Ischemic Stroke: Is it the Time for Universal Adoption?

Introduction

Chemical thrombolytic treatment in acute ischemic stroke (AIS) is dominated by Alteplase since past two decades. The advent of Tenecteplase (TNK) and its recent trials in AIS has made the medical society think about the better change. TNK is a genetically altered tissue plasminogen activator with lower systemic coagulopathy and has a practical advantage over Alteplase with a longer half-life, and stronger fibrin specificity. In addition, unlike Alteplase, Tenecteplase is administered as a single intravenous bolus rather than an infusion, which has advantages for clinical use, such as easier management during patient transportation to the hospital. ¹

Trials and Off-label Studies

Multiple doses of TNK including 0.1 mg/kg, 0.25 mg/kg and 0.4 mg/kg have been compared with standard 0.9 mg/kg dose of Alteplase in the randomized and non-randomized trials of AIS.^{2, 3} In non-randomized studies, the patients receiving TNK for AIS with median NIHSS 8–20, had higher odds of achieving good functional outcome, that is, modified rankin scale (mRS) 0–2 (crude odds ratio [OR], 1.22; 95% CI, 0.90–1.66; adjusted OR, 1.60, 95% CI, 1.08–2.37) and successful recanalization (crude OR, 2.82; 95% CI, 1.12–7.10; adjusted OR, 2.38; 95% CI, 1.18–4.81). There were no significant differences in symptomatic intracranial hemorrhage (crude OR, 0.97; 95% CI, 0.44–2.16; adjusted OR, 1.16; 95% CI, 0.13–10.50). ² Similar results were observed in randomized studies where TNK was non-inferior to Alteplase. There was higher crude cumulative rate of patients reaching good functional outcome with TNK vs Alteplase in AIS with median NIHSS 5–22, that is, 72% vs 70% (risk difference 8%, 95% CI, –4% to 20%). Symptomatic intracranial hemorrhage and crude mortality were favorable for TNK. ³ In the recent largest RCT (n 1600), 0.25 mg.kg dose of TNK was shown to be non-inferior to standard dose of Alteplase in achieving good functional outcome (mRS of 0–1) at 90–120 days, that is, 37% vs 35% (unadjusted risk difference 2.1%, 95% CI, 2.6–6.9). The benefits were across minor and major AIS and with large vessel occlusion. There were no significant differences in 24-hour symptomatic intracranial hemorrhage or 90 days mortality. ⁴ Finally, a meta-analysis of four trials, where 0.25 mg/kg of TNK was used in three of them for the treatment of large vessel occlusion had shown significantly better recanalization rate and clinical outcome at 3 months compared to Alteplase. ⁵ These data have firmly established the effectiveness of 0.25 mg/kg dosage of TNK for AIS in both minor and major stroke.

Recent Guidelines and Possibility of Adoption

As per the current guidelines across the world, Tenecteplase is endorsed as a class IIB recommendation for patients with large vessel occlusion (LVO) and minor neurological symptoms by 2019 American Heart Association and American Stroke Association guidelines. ⁶ The New Zealand Central Region Hyper-Acute Stroke Network switched to Tenecteplase because of its simplicity of administration and potential for better LVO recanalization in the context of regional constraints to thrombectomy access. The region-wide switch program was successfully implemented with evidence of benefit and no evidence of harm along with clinical satisfaction, improved patient functional outcomes at 3 months, and shorter door-to-needle (DTN) times with equivalent safety outcomes. The shorter DTN was associated with a higher rate of in-CT thrombolysis facilitated by a single bolus injection. ⁷ Thus, the practical benefits of Tenecteplase in the real-world setting cannot be denied.

When compared to Alteplase, the cost of TNK is less. The affordability of TNK mainly in low-resource countries is a plus point in universal adoption. Thus, TNK has clearly shown non-inferiority in the treatment of AIS compared to the Alteplase. The added benefit of TNK over Alteplase like easy and quick administration and cost-effectiveness, clearly puts TNK ahead of Alteplase. Thereby, based on available non-inferior studies it is a reasonable argument for the universal adoption of TNK in place of Alteplase. The switch requires a proper implementation strategy and comprehensive consultation with safety protocols. But still further evidence focusing on dose-efficacy, stroke type and severity is desirable before universal adoption.