Tenecteplase vs Alteplase for Patients With Acute Ischemic Stroke
The ORIGINAL Randomized Clinical Trial

Abstract

Importance

Tenecteplase is a bioengineered variant of alteplase with greater fibrin specificity and a longer half-life, allowing single-bolus administration. Evidence on the treatment effect of tenecteplase 0.25 mg/kg in Chinese patients with acute ischemic stroke (AIS) is limited.

Objective

To establish the noninferiority of tenecteplase to alteplase in patients with AIS within 4.5 hours of symptom onset.

Design, Setting, and Participants

The ORIGINAL study was a multicenter, active-controlled, parallel-group, randomized, open-label, blinded end point, noninferiority trial conducted between July 14, 2021, and July 14, 2023. Participants were recruited from 55 neurology clinics and stroke centers in China and were eligible if they had AIS with a National Institutes of Health Stroke Scale score of 1 to 25 with measurable neurologic deficit and were symptomatic for at least 30 minutes without significant improvement.

Intervention

Patients were randomized (1:1) within 4.5 hours of symptom onset to receive intravenous tenecteplase (0.25 mg/kg) or intravenous alteplase (0.9 mg/kg).

Main Outcomes and Measures

The primary outcome was the proportion of patients with a modified Rankin Scale (mRS) score of 0 or 1 (no symptoms or no significant disability) at day 90, tested for noninferiority (risk ratio [RR] margin, 0.937). Safety end points included symptomatic intracerebral hemorrhage (per European Cooperative Acute Stroke Study III definition) and 90-day all-cause mortality.

Results

Among the 1489 patients randomized, 1465 patients were included in the full analysis set (732 in the tenecteplase group; 733 in the alteplase group) and 446 (30.4%) were female. The primary outcome occurred in 72.7% (532/732) of patients receiving tenecteplase and 70.3% (515/733) receiving alteplase (RR, 1.03 [95% CI, 0.97-1.09]; noninferiority threshold met). Symptomatic intracerebral hemorrhage occurred in 9 patients (1.2%) in each group (RR, 1.01 [95% CI, 0.37-2.70]). The 90-day mortality rate was 4.6% (34/732) in the tenecteplase group and 5.8% (43/736) in the alteplase group (RR, 0.80 [95% CI, 0.51-1.23])

Conclusions and Relevance

In patients with AIS eligible for intravenous thrombolysis within 4.5 hours after stroke onset, tenecteplase was noninferior to alteplase with respect to excellent functional outcome (mRS score of 0 or 1) at 90 days and had a similar safety profile. Findings from this study support tenecteplase as a suitable alternative to alteplase in this setting.

Trial Registration

ClinicalTrials.gov Identifier: NCT04915729

Key Points

Question Is tenecteplase noninferior to alteplase for patients with acute ischemic stroke (AIS) eligible for intravenous thrombolysis within 4.5 hours after stroke onset?

Findings In this noninferiority randomized clinical trial including 1489 participants, a total of 72.7% of patients receiving tenecteplase and 70.3% receiving alteplase achieved modified Rankin Scale scores of 0 or 1 (excellent functional outcome), resulting in a risk ratio of 1.03 (95% CI, 0.97-1.09), which met the predefined noninferiority margin of 0.937.

Meaning  Findings from this study support tenecteplase as a suitable alternative to alteplase for patients with AIS eligible for thrombolysis.

요약

소개

테넥테플라제(Tenecteplase)는 알테플라제(Alteplase)의 생체공학적 변형으로, 더 높은 피브린 특이성과 긴 반감기를 가지며, 단일 볼루스(single-bolus)로 투여할 수 있다. 한편, 급성 허혈성 뇌졸중(AIS) 환자에서 테넥테플라제 0.25 mg/kg의 치료 효과에 대한 증거는 아직 제한적이다. 본 연구는 증상 발현 4.5시간 이내에 AIS 환자에서 테넥테플라제가 알테플라제에 비해 비열등성을 입증하는 것을 목표로 한다.

방법

환자들은 증상 발현 4.5시간 이내에 무작위 배정(1:1)되어 정맥 주사로 테넥테플라제(0.25 mg/kg) 또는 알테플라제(0.9 mg/kg)를 투여받았다. 주요 결과(primary outcome)는 90일 후 수정된 랭킨 척도(mRS) 0 또는 1점(증상 없거나 심각한 장애 없음)을 받은 환자의 비율로 설정되었으며, 비열등성을 검증하기 위해 위험비(RR) 마진 0.937을 사용했다. 안전성 평가로는 유럽 협동 급성 뇌졸중 연구 III(ECASS III) 정의에 따른 증상성 뇌출혈과 90일 전체 사망률을 포함했다.

결과

1489명의 참가자가 포함된 이 비열등성 무작위 임상 시험에서, 테넥테플라제를 받은 환자 72.7%와 알테플라제를 받은 환자 70.3%가 90일 후 수정된 랭킨 척도에서 0 또는 1점을 기록(우수한 기능적 결과)하였으며, 위험비는 1.03(95% CI, 0.97-1.09)로 나타났다. 이는 사전에 설정된 비열등성 마진인 0.937을 충족하는 결과다.

결론 및 의의

증상 발현 4.5시간 이내에 정맥 내 혈전 용해 치료가 가능한 급성 허혈성 뇌졸중 환자에서, 테넥테플라제는 90일 후 우수한 기능적 결과(mRS 0 또는 1)에 있어 알테플라제에 비해 비열등하며, 유사한 안전성 프로필을 보였다. 이 연구의 결과는 테넥테플라제가 이 환경에서 알테플라제의 적절한 대안이 될 수 있음을 보여준다.