ATTEST-2 TRIAL : TENECTEPLASE IN ACUTE ISCHEMIC STROKE

1. JOURNAL CLUB
ATTEST-2 TRIAL
ALTEPLASE TENECTEPLASE TRIAL EVALUATION
FOR STROKE THROMBOLYSIS
Presenter Moderator
Dr Aviral Shah Dr Vikas Sharma
DrNB Resident, Neurology Additional Director, Neurology
FMRI FMRI

2. The Lancet Neurology
November 2024
Volume 23, Number 11
Pages 1087-1096
JIF : 46.5
5 Year IF : 51.6
Trial conducted in UK

4. AIM
To compare Tenecteplase (0.25 mg/Kg) with Alteplase
(0.9 mg/Kg) for the treatment of acute ischemic stroke
within 4.5 hours of symptom onset to establish non-
inferiority or superiority

5. METHODS
 STUDY DESIGN
 Prospective
 Randomised
 Parallel group
 Open Label
 39 UK stroke centres
 Jan 25, 2017 to May 30, 2023
 INCLUSION CRITERIA
 Previously independent adults ≥ 18 years
 Acute ischemic stroke
 Presenting within 4.5 hours of last well known

6.  EXCLUSION CRITERIA
 Evidence of ICH or non stroke intracranial pathology accounting
for presentation
 Stroke within previous 14 days
 Thrombolytic therapy within past 14 days
 Hypodensity on CT consistent with recent cerebral ischemia
other than presenting event
 SBP ≥ 185 or DBP ≥ 110 mmHg or IV pharmacotherapy to
reduce BP to these limits
 History s/o SAH
 Conditions with high risk of hemorrhage

7.  EXCLUSION CRITERIA
 Hypoglycemia (<2.8 mmol/L) or hyperglycemia (> 22.2 mmol/L)
 Seizure at onset
 Pregnancy
 Inadequate haemostasis
 INR > 1.3 if on warfarin
 Less than 12 hours from administration of any DOAC
 Use of therapeutic dose of LMWH within 48 hours
 Any major condition likely to limit survival to day 90
 Anticipated unavailability for day 90 follow up
 Endovascular thrombectomy permitted when indicated
 Initially excluded patients proceeding for EVT – removed as
exclusion criteria in 2019

9.  PROCEDURE
 Alteplase - 0.9mg/Kg – 10% bolus followed by 90 % as
infusion over 60 mins (maximum 90mg)
 Tenecteplase - 0.25 mg/Kg as iv bolus (maximum 25 mg)
 NIHSS - before randomisation , at 22-36 hours after treatment
and at day 5 ( or discharge if earlier) and if clinical worsening
 Telephone interview at Day 90 – mRS measured using Rankin
Focused Assessment structured interview
 Additional Endpoints
 Barthel Index of ADLs
 EuroQOL Quality of Life-5 Dimensions 5 Level measure (EQ 5D-5L)
 Imaging – CT or MRI before treatment , repeated at 22-36 hours
after treatment and if significant neurological worsening

10.  Outcomes
Primary
o mRS score distribution at Day 90
Secondary
o Excellent neurological recovery – mRS 0-1
o Independent neurological recovery – mRS0-2
o Early major neurological improvement ( by ≥ 8 points or return to
0-1 NIHSS score at 24 hours)
o Excellent recovery on BI – score 95-100
o Day 90 EQ5D-5L
o Whether thrombectomy done

11.  Safety outcomes
 Mortality
 sICH (SITS-MOST and ECASS-3)
 Radiologically defined PH-2
 Any post treatment intracranial bleed
 Significant Extracranial hemorrhage- requiring transfusion or Hb
fall > 2 g/L or intraocular )
 Additional - Post hoc comparison of reperfusion at first
angiographic run ( in EVT subgroup)

12. PATIENT DEMOGRAPHICS
• Mean age – 70.4 (SD 12.9) years
• Median NIHSS – 7 (IQR 5-13)
• 17% (n 303) – NIHSS > 16
• Median onset to treatment time – 145 min
• 12% (n 219) – underwent EVT
• Median follow up – 94 days

13. RESULTS
 Absolute increase in excellent outcomes 2.03% with TNK – non
inferior but not superior – adjusted OR 1.05
 Absolute increase in independent recovery 3.41% with TNK –
adjusted OR 1.15

15.  Safety outcome
 No statistically significant difference
 Numerically higher intra/extracranial bleed in TNK

16.  No interaction with treatment effect for any outcome seen for
 Age group (≤ 80 or > 80 years)
 Stroke severity by NIHSS
 Onset to treatment time
 Thrombectomy undertaken or not
 LVO presence
 Reperfusion at thrombectomy first angio run (Mtici 2b-3)
 8% (n=8) in TNK
 4% (n=5) in TPA

17.  Superiority not shown but point estimates for day 90 mRS
recovery favoured TNK
 Magnitude of benefit with TNK at 90 day smaller than
previously suggested
 Advantages
 Wider range of stroke patients across multiple sites
 Limitations
 Lower proportion of LVO patients (19%) vs other studies ( AcT
33%)
 Lower use of EVT (12.4%) vs other studies ( AcT 25%)

18. ORIGINAL TRIAL
 Published : September 2024 in JAMA
 Aim : Assess Non inferiority of TNK vs TPA in Chinese AIS
patients within 4.5 hours of symptom onset
 Multicentre, active controlled, parallel group , randomized,
open label blinded end point phase 3 study
 55 Neurology centres in China

19.  Inclusion
 18 years or more age
 NIHSS 1-25
 Symptomatic for at least 30 minutes without significant
improvement
 Received IVT within 4.5 hours
 If NIHSS <4 – measurable motor deficit required in arm or leg
of at least 1
 Thrombectomy patients eligible
 ICH excluded by NCCT

20.  Outcomes
 Primary – Day 90 mRS of 0 or 1
 Secondary
 Major neurological improvement at 24 hours (NIHSS 0 or 4
point change from baseline)
 mRS 0-2
 Distribution of mRS scores
 BI atleast 95
 Safety outcomes
 sICH upto 36 hours – ECASS III
 All cause mortality within 90 days
 mRS score 5 or 6 on day 90

21.  Results
 1346 patients – 732 TNK and 736 TPA
 Median age 66/ Median NIHSS 6/ 30% Females
 TNK was non-inferior for excellent functional outcome
 mRS 0-2 – 80.9% TNK vs 79.9% TPA
 Major neurologic improvement TNK 48% vs TPA 45%
 BI at least 95 – 75.7% TNK vs 73.9% TPA
 Mean NIHSS change from baseline -3.70 for TNK vs -3.02 for
TPA
 Mortality 4.6% TNK vs 5.8% TPA
 mRS 5-6 = 6.8% TNK vs 7.8% TPA
 TNK NOT superior to TPA

22. OTHER TRIALS
 TASTE (2024) – Tenecteplase Versus Alteplase for Stroke
Thrombolysis Evaluation
 TRACE 2 (2023) – Tenecteplase Reperfusion Therapy in Acute
Ischemic Cerebrovascular Events
 AcT (2022)- Alteplase Compared To Tenecteplase
 ORIGINAL vs AcT
 Baseline severity higher in AcT
 Higher sICH rates in AcT
 Higher Thrombectomy rates in AcT
 Higher excellent mRS in ORIGINAL

23. SYSTEMATIC REVIEW AND META-
ANALYSIS
TENECTEPLASE VS ALTEPLASE IN ACUTE ISCHEMIC
STROKE WITHIN 4.5 HOURS
 Published in Neurology ( November 2024 )
 11 RCTs – 3788 TNK patients vs 3757 TPA patients
 TNK associated with higher likelihood of excellent functional
outcome and reduced 90 day disability
 Good functional outcome , safety outcomes and mortality at 90 day
similar

26. TAKE HOME MESSAGE
 TNK is non-inferior to TPA for AIS within 4.5 hours
 Higher fibrin specificity and longer half life – single iv
bolus dosing
 May decrease inter-hospital transfers and improve
workflow for Mechanical Thrombectomy
 Avoids infusion interruption risk
 Cost efficient
 No significantly different safety risk

27. THANK YOU