This presentation looks at the evolving role of Tenecteplase in the management of acute ischemic stroke and comparison with Alteplase.

1. Evolving landscape in the
management of Acute Ischemic
Stroke: Tenecteplase
Dr Pramod Krishnan
Consultant Neurologist
Head of the Department of Neurology,
Manipal Hospital, Bengaluru
June 20th 2020

2. Objectives
1. To compare recombinant tissue plasminogen activator-Alteplase
(ALT) and Tenecteplase (TNK) in acute ischemic stroke (AIS).
2. To review current literature for the use of TNK in the setting of AIS.
3. To review the current practice guidelines/recommendations for AIS.

3. Generation of
thrombolytic drug
Fibrin specific Nonfibrin specific
First …………… Urokinase∗
…………… Streptokinase∗
Second • Recombinant tissue
plasminogen activator∗ (t-
PA) Alteplase (ALT)
• Prourokinase (scum-PA)
• Sk-plasminogen activating
complex∗ (APSAC)
Third • Tenecteplase∗ (TNK-tPA)
• Reteplase∗
• Monteplase
• Lanoteplase
• Pamiteplase∗Approved for clinical use
ALT and TNK-t-PA are
approved for the
treatment of AIS
Ref. Hindawi Publishing Corporation, The Scientific World Journal Volume 2014, Article ID 586510
TNK-tPA is a three-point-mutated variant of ALT bioengineered to achieve longer
half-life, higher fibrin specificity, and increased resistance towards plasminogen
activator inhibitor-1.

4. Tenecteplase vs Alteplase
Tenecteplase Alteplase
Fibrin specificity +++ ++
Thrombolytic potency +++ +
PAI-1 resistance ++ --
Fibrinogen depletion + ++
PRT activity +++ ++
Clearance (ml/kg/min) 1.9 16.1
Plasma Half life 18 min 4-6 min
Ref. Intravenous tenecteplase in acute ischemic stroke: an updated review, Journal of Neurology · September 2013 DOI: 10.1007/s00415-013-7102-0 ·
PAI-1 plasminogen activator inhibitor type 1, PRT platelet-rich thrombus
TNK-tPA has 15-fold greater fibrin
specificity in vitro than Alteplase. This
reduces bleeding complications and
enhances effective lysis of older clots.
So TNK-tPA can be delivered as single
bolus dose over 5 seconds at 0.25mg/kg.
TNK-tPA is 80-fold more resistant to PAI-1 than
Alteplase. PAI-1 inhibits fibrinolysis and higher
resistance may help in dissolving platelet rich
clots and improve thrombolysis.

5. Tenecteplase Vs Alteplase

6. Lancet Neurol 2017; 16: 781–88
• Superiority trial done in 13 stroke units in Norway.
• Adults with suspected AIS who were eligible for thrombolysis.
• Admitted within 4·5 h of symptom onset/ awakening with symptoms (with
DWI- FLAIR mismatch).
• Patients were randomly assigned (1:1) to receive IV TNK 0·4 mg/kg (maximum
of 40 mg) or IV ALT 0·9 mg/kg (maximum of 90 mg).

7. • Excellent (0–1 points) functional
outcome at 3 months measured with
mRS
Primary end point
• Major neurological improvement at
24 h measured with NIHSS,
• Ordinal shift analysis of mRS at 3
months.
Secondary end point
• Any intracranial haemorrhage occurring
within 24–48 h.
• Symptomatic intracranial haemorrhage
occurring within 24–48 h.
• Death within 3 months after inclusion.
Safety end point

9. Conclusion
• TNK is not superior to ALT and showed similar safety profile.
• TNK at 0.4 mg/kg is as safe as ALT 0.9 mg/kg.
• Most of the patients in this study had mild stroke. So the results cannot be
generalized to patients with large infarcts.
• This study can be generalized to routine practice as inclusion criteria did not
require any advanced radiological assessment and even patients > 80 yrs,
diabetics and those with previous stroke were enrolled.

10. • Multicenter, prospective, randomized, open-label, blinded-outcome trial.
• AIS with occlusion of the ICA, MCA or basilar artery and were eligible to
undergo thrombectomy.
• 101 received Tenecteplase (0.25 mg/kg of body weight; maximum dose, 25 mg).
• 101 received Alteplase (0.9 mg/kg; maximum dose, 90 mg).
• Thrombolysis done within 4.5 hours of symptoms onset.
• Non-inferiority of TNK was tested, followed by superiority.

11. • Restoration of blood flow to greater
than 50% of the involved territory, or,
• Absence of retrievable thrombus in
the target vessel at the time of the
initial angiographic assessment.
• mRS score at 90 days,and,
• Early neurologic improvement,
defined as a reduction of at least 8
points or a score of 0 or 1 on the
NIHSS at 72 hours.
• Death due to any cause.
• Symptomatic intracranial hemorrhage,
which included SAH, and ICH that was
adjudicated centrally by a panel as
parenchymal hematoma type 2 within 36
hours after treatment, combined with an
increase from baseline in the NIHSS score
of at least 4 points.
Primary end point Secondary end point
Safety end point

13. Primary and secondary endpoints
22
10
0
5
10
15
20
25
Primary efficacy outcome
%ofpatients
Tenecteplase Alteplase
64
51
71
10
1
51
43
68
18
1
0
10
20
30
40
50
60
70
80
Functional
independent
outcome
Excellent outcome Early neurologic
imrovement
Deaths sICH
%ofpatients
Tenecteplase Alteplase

14. Patients in the TNK-tPA group had a median
score of 2, as compared with a median score
of 3 among patients in the ALT group
(common odds ratio, 1.7; 95% CI, 1.0 to 2.8; P
= 0.04).
The horizontal line in each box represents the
median, and the top and bottom of the boxes
the interquartile range. I bars indicate 1.5
times the interquartile range, and the dots
outliers.

15. Summary
• The trial was powered for noninferiority, not for superiority.
• IV TNK-tPA resulted in a higher incidence of reperfusion of the
occluded vascular territory before endovascular thrombectomy.
• Patients in the TNK group had significantly better functional outcomes.
• The ability to administer TNK-tPA in a single bolus, as compared with
the 1-hour infusion of ALT, may be of practical benefit.

16. • Single centre, retrospective, comparative study.
• Patients 18 years or older with AIS presenting within 3 hours of symptom onset.
• NIHSS score > 4, and a modified Rankin score (mRS) of 2 or less.
• Primary efficacy outcome: A good functional recovery (mRS score of 0-2) at the end
of 3 months.
• Primary safety outcome: Development of symptomatic intracerebral hemorrhage
(with change in NIHSS>4, or death) in the first 24 hours.

17. Study design
• 120 patients were thrombolysed: 55 received TNK-tPA 0.2 mg/kg,
(maximum of 20 mg);
• 65 received ALT 0.9 mg/kg (maximum 0.9 mg/kg).
• All patients underwent CT angiogram. Those with LVO were taken up
for thrombectomy after TNK bolus or ALT (drip and ship).

18. Results
Conclusion: No significant difference between the two groups in terms of efficacy
and safety.

19. Tenecteplase dose trials

20. • Study I: Open label, randomized. TNK-tPA 0.1 and 0.2 mg/kg were compared.
• Study II: Open label. TNK-tPA 0.2 mg/kg compared with historical controls.
1. Primary endpoint: Improvement of ≥ 8 points or a score of 0 on NIHSS at 24 h.
2. Secondary endpoint: Neurological improvement assessed using NIHSS score,
mRS score, Barthel Index (BI) on days 7, 30 and 90.
• Safety: Assessed by determining symptomatic intracranial hemorrhage (sICH)
within 36 h and asymptomatic intracranial hemorrhage at 48 h after treatment.

22. Efficacy and Safety of I.V. Tenecteplase Bolus in AIS: Results
of two open label, multicenter trials.
Outcome TNK-tPA study, 0.2mg/kg
(N=91)
NINDS study, rt-PA
(N=144 part 1; N=168,part 2)
P value
Primary Outcome
MNI (Reduction in NIHSS Score ≥ 8 Points or
a score of 0 at 24 hrs)
20 ( 22%) NA __
Reduction in NIHSS Score ≥ 4 Points or a
score of 0 at 24 hrs
53 ( 58.2%) 67 (47%) 0.083
Secondary Outcomes
mRS 0-1 at 3 months 64 ( 70.3%) 66 (39%) <0.001
mRS 2-3 at 3 months 13 ( 14.3%) 35 (21%) 0.24
mRS 4-5 at 3 months 9 ( 9.9%) 39 (23%) 0.01
BI score 95-100 at 3 months 46 ( 50.5%) 84 (50%) 1.0
BI score 50-90 at 3 months 33 ( 36.3%) 27 (16%) <0.001
Safety Outcomes
sICH at 36 hrs 1(1.1%) 20 (6.4%) 0.05
Mortality at 3 months 5 ( 5.5%) 28 (17%) 0.01
POOLED ANALYSIS RESULTS : Comparison with NINDS
Am J Cardiovasc Drugs; DOI 10.1007/s40256-018-0284-1

23. Study design similar to the EXTEND-IA, with similar selection criteria and endpoints.
Aim: To study if TNK 0.4 mg/kg (n=150) is superior to TNK 0.25 mg/kg IV (n=150).
Conclusion:
• In large vessel occlusion AIS, TNK 0.40 mg/kg, compared with 0.25mg/kg, did not
significantly improve cerebral reperfusion prior to thrombectomy.
• TNK 0.40-mg/kg does not confer an efficacy or safety advantage over 0.25-mg/kg
dose.

24. Results

25. Modified Rankin Scale Scores at 90 Days
• mRS scores were not statistically different between dose groups.
• Generalized odds ratio (gOR) 0.96, 95% CI (0.74 to 1.24), p = 0.73

26. Stroke. 2019;50:2156-2162.
• Five independent randomized trials with a total of 1585 patients, (828 TNK, 757
ALT).
• Across all trials, mean age was 70.8 years, 58.8% of patients were male, mean
NIHSS at baseline was 7.
• Mean time from last known well to treatment start was 148 minutes.
• All patients with ALT received 0.9 mg/kg ALT dosing.
• TNK dosing was one-time bolus only, at doses of 0.1 mg/kg in 6.8% of patients,
0.25 mg/kg in 24.6%, and 0.4 mg/kg in 68.6%.

27. Conclusion
• TNK is noninferior to ALT in the treatment of AIS in terms of both
safety and efficacy.
• The available data are not definitive, as the greatest weight of evidence
is from a trial that enrolled patients with mild deficits likely to have
good outcomes.
• TNK-tPA 0.25 mg/kg was the most commonly used dose, followed by
0.4 mg/kg.

29. Guidelines for Prevention and Management of Stroke
Directorate General of Health Services Ministry of Health and Family Welfare,
Government of India 2019 (NPCDCS)
Intravenous (IV) thrombolysis:
For adults arriving within 4.5 hours
• 0-3 hours: IV tenecteplase (TNK) or
IV rtPA.
• 3-4.5 hours: IV rtPA (For 3 to 4.5
hours: additional criteria to be met:
age <80 years; no history of diabetes
AND previous stroke; Not on
anticoagulation; and NIHSS < 25).

30. Summary
Tenecteplase
Vs Alteplase
Comment
Efficacy TNK is non inferior to ALT. ALT is not superior to TNK.
Neurological improvement at 24 hours and at 3 months may be better
with TNK.
Safety No difference, but trend towards less bleeding complications with
TNK
Pharmacology TNK is more fibrin specific, more resistant to PAI-1, with longer half
life.
Administration Easy, as bolus over few seconds, does not need infusion pump. Door to
thrombolysis completion time is less. Easier for patients requiring
thrombectomy (‘Give and Go’ approach).
Cost TNK 20 mg Rs 30-40,000/-. ALT 60 mg Rs 60-70,000/- .

31. Questions
• Views regarding current clinical data.
• Current practice with regard to Tenecteplase.
• Role of Tenecteplase in LVO, high NIHSS score.
• Role of Tenecteplase in patients presenting between 3 to 4.5 hours.
• Ease of use of Tenecteplase compared to Alteplase.
• Should Tenecteplase replace Alteplase considering the advantages?

32. THANK YOU