neurology, thrombolysis

1. Journal Club

3. Overview
• Alteplase is currently the only approved thrombolytic agent for treatment of
acute ischemic stroke.
• Tenecteplase has emerged as a potential alternative thrombolytic agent that
might be preferred over alteplase because of its ease of administration and
reported efficacy in patients with large vessel occlusion.
• New treatment strategies are also emerging that aim to reduce the risk of
vessel reocclusion after intravenous thrombolysis administration.
• Other strategies like Intraarterial thrombolysis, Mechanical Thrombectomy
Mobile Stroke Van strategies are also emerging.

4. Introduction
• Intravenous thrombolysis is one approach for the treatment of acute
ischemic stroke, and alteplase is currently the only thrombolytic agent
approved by all regulatory agencies.
• In the past 5 years, tenecteplase has emerged as a potential alternative
thrombolytic agent to alteplase, due to its ease of administration (compared
with alteplase) and reported efficacy for acute ischemic stroke caused by a
large vessel occlusion.
• Other therapies for systemic reperfusion are now a major area of interest in
stroke research.
• The increase in the number of mobile stroke units, which are highly
equipped with the necessary equipment for early diagnosis and treatment of
acute ischaemic stroke, could shorten the time from symptom onset to
medical care

5. Thrombolytics in Acute Ischemic Stroke
• In 1995, intravenous thrombolysis was introduced as an acute reperfusion
therapeutic approach for patients with acute ischaemic stroke.
• Most global stroke guidelines now recommend intravenous thrombolysis
with alteplase within 4.5 h from symptom onset, after brain imaging has
ruled out intracranial haemorrhage.

7. Thrombolytic agents

8. Trials Comparing Alteplase vs Tenecteplase

13. Comparison of Dose of Tenecteplase
• Studies in which a dose of 0.4 mg/kg was used either did not result in
clinical improvement or caused major harm in terms of increased systemic
and intracranial bleeding.
• After pooling randomised clinical trial data, a 0.4 mg/kg dose of
intravenous Tenecteplase was associated with a numerically higher rate of
symptomatic intracranial haemorrhage (5.0%, 95% CI 0.9–11.4) compared
with a 0.25 mg/kg dose(1.6%, 0.4–3.3; p=0.16).
• A dose of 0.25 mg/kg appears to be safe and effective.

15. Ongoing Trials for Tenecteplase
• Ongoing phase 3 randomised clinical trials will provide further evidence for
the use of intravenous tenecteplase compared with alteplase within 4・5 h
• ATTEST 2
• TASTE
• TRACE II
• NORTEST-2b
• BRIDGE-TNK

16. • eg, TEMPO-2 (NCT02398656), and for patients with large
vessel occlusion in the extended time window (4・5–24 h), eg,
TIMELESS (NCT03785678), TRACE III (NCT05141305),
POST-ETERNAL (NCT05105633), and ETERNAL-LVO
(NCT04454788).
• Most of these randomized clinical trials are expected to be
completed within the next 2–3 years.
• These trials have the potential to establish tenecteplase as a
new standard thrombolytic agent not only in clinical care but
also in research as the standard comparator for future trials
evaluatingalternative thrombolytic agents (eg, staphylokinase).

17. Non-immunogenic recombinant staphylokinase and
recombinant human prourokinase
• FRIDA Trial- The FRIDA trial16 was a noninferiority randomised controlled
trial in Russia of patients with acute ischaemic stroke presenting within 4・
5 h from symptom onset.
• The aim was to compare non-immunogenic staphylokinase (10 mg,
regardless of bodyweight) with alteplase (0・9 mg/kg).
• The absolute difference in the primary endpoint was 9.5% (95% CI –1・7
to 20・7) and the lower 95% CI did not cross the margin of noninferiority
(16%).

18. Continued
• Recombinant human prourokinase is a thrombolytic agent that has been
used to treat patients with acute myocardial infarction.
• A phase 2a dose-finding trial in patients with acute ischaemic stroke
suggested no safety concerns,40 and a phase 3 non-inferiority randomized
clinical trial (PROST; NCT03541668) is underway.

19. Ultrasound enhanced thrombolysis
• Pilot studies have provided preliminary evidence that pulsed-wave
ultrasound in addition to alteplase (sonothrombolysis) might increase the
rate of complete recanalisation and improve functional outcome at 3 months
in patients with acute ischaemic stroke due to proximal intracranial
occlusions.
• These findings were not corroborated by two large phase 3 randomized
clinical trials
• Current international guidelines do not recommend addition of ultrasound in
patients with acute ischaemic stroke who are receiving intravenous
thrombolysis.

20. Adjunctive Therapies to Thrombolysis
 Cytoprotective Strategies:-
• Cytoprotective strategies have had good results in preclinical stroke models,
but some strategies have not worked when coupled with intravenous
thrombolysis in the clinical research setting.
• For example, in a randomised trial of hypothermia versus normothermia
after intravenous thrombolysis in patients with acute ischaemic stroke, an
increased risk of pneumonia was reported in patients who were assigned to
hypothermia

21. • Nerinetide is an eicosapeptide that was shown to have a neuroprotective
effect in preclinical stroke models of ischaemia-reperfusion, but in a phase 3
trial of this drug, outcomes were not improved in patients with large vessel
occlusion stroke undergoing endovascular thrombectomy
• Antithrombotic agents to increase efficacy of intravenous
thrombolysis
• Drugs Used are eptifibatide, tirofiban and argatroban
• Argatroban- MOST trial (NCT03735979) in North America, as adjunct
therapies to alteplase or tenecteplase.

22. Intravenous thrombolysis in addition to
endovascular thrombectomy
• Two randomised clinical trials from China (DIRECT-MT59 and DEVT60)
found that endovascular thrombectomy alone was non-inferior to
endovascular thrombectomy after bridging therapy with intravenous
alteplase.
• Randomised clinical trials from Japan (SKIP),61 Australia (DIRECT-
SAFE),62 and Europe (MR CLEAN63 and SWIFT DIRECT64) did not
show non-inferiority of endovascular thrombectomy alone compared with
endovascular thrombectomy after bridging therapy with IV thrombolysis.
• Current guidelines recommend intravenous thrombolysis administration to
eligible patients before endovascular thrombectomy;

23. Intravenous thrombolysis in the prehospital
setting
• Two large non-randomised clinical trials have shown that stroke treatment
started in a mobile stroke unit leads to improved functional outcomes at 3
months.
• The B_PROUD study (NCT02869386) in Berlin, Germany, included 1543
patients who were treated within 6 h of acute ischaemic stroke onset.
Compared with the standard ambulance to emergency department pathway,
patients treated in a mobile stroke unit had less disability at 3 months, as
measured by the shift in mRS scores (adjusted common OR [for higher
mRS scores] 0.71, 95% CI 0.58–0.86).
• BESTMSU Study in USA also showed similar results.

24. Intravenous thrombolysis in the extended time
window
• MRI with diffusion-weighted imaging– fluid-attenuated inversion recovery
(DWI-FLAIR) mismatch, or CT or magnetic resonance-based perfusion
imaging are used for Extended window thrombolysis.
• The EXTEND randomised clinical trial 74 was done in patients with acute
ischaemic stroke presenting 4.5–9 h from last known well and compared
intravenous thrombolysis with alteplase with placebo.
• Patients were eligible for the trial if the infarct core was not large (ie,
ischaemic core <70 mL) and a perfusion lesion remained that could still be
salvaged with reperfusion from intravenous thrombolysis

25. • This trial was done when endovascular thrombectomy was not the standard
of care, and approximately 70% of participants enrolled had proximal
arterial occlusions.
• The latest European Stroke Organisation guidelines, published in 2021,
recommend intravenous thrombolysis with alteplase for patients presenting
within 4・5–9 h of symptom onset, or whose time of stroke symptom onset
is unknown, and who meet the imaging criteria of the EXTEND trial.
• The WAKEUP trial 79 assessed stroke patients within 24 h of last known
well and exclusively with unwitnessed onset who could be treated within
4.5 h of symptom recognition.

26. • The results of EXTEND and WAKE-UP,74,79 coupled with the findings
from individual patient data and pairwise meta-analyses,80–82 have
suggested that patients with acute ischaemic stroke who are selected for
treatment using advanced imaging techniques might benefit from
intravenous thrombolysis beyond the threshold of 4.5 h.

28. BASICS
- Indication and Contraindication of Thrombolysis

29. Eligibility Criteria for Mechanical
Thrombectomy
• Brain imaging using computed tomography (CT) without contrast or
diffusion-weighted magnetic resonance imaging (MRI) excludes
hemorrhage and is consistent with an Alberta Stroke Program Early CT
Score (ASPECTS) ≥3.
• CT angiography or MR angiography demonstrates a proximal large artery
occlusion in the anterior circulation as the cause of the ischemic stroke.
• The patient has a persistent, potentially disabling neurologic deficit; some
guidelines require a National Institutes of Health Stroke Scale (NIHSS)
score ≥6 .
• Thrombectomy can be started within 24 hours of the time the patient was
last known to be well at a stroke center with appropriate expertise in the use
of endovascular therapy.

30. THANK YOU