journal club tenecteplase.pptx by sms medical college jaipur

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1. Tenecteplase for Ischemic Stroke at 4.5 to 24 Hours from onset without Thrombectomy By Dr. Icha Gupta (SR NEUROLOGY) MODERATOR: DR. B. L. KUMAWAT SIR DR. VASUDEV SIR

2. Tissue plasminogen activator (tPA) a protease that attaches to fibrin on the surface of a clot and activates plasminogen (attached to the fibrin.) Activated plasminogen produces plasmin, the primary enzyme for clot lysis. Alteplase, reteplase , and tenecteplase , vary slightly in their fibrin specificity and half-life. Alteplase was the first ( rtPA ) that was studied and proven effective for stroke for over last 25 years

3. THROMBOLYTIC THERAPY If patients meet appropriate criteria, IV administration of alteplase , remains the only approved therapy for acute ischemic stroke by FDA. Intravenous thrombolytic therapy with alteplase is recommended within 4.5 hours from onset of ischemic symptoms OR patients with MR—DWI positive, FLAIR negative lesions The dose of alteplase is 0.9 mg/kg, with a maximum dose of 90 mg; 10% of the total dose is given as an initial bolus, and the rest is infused over 60 minutes close neurological and blood pressure monitoring

4. However, approximately 67 to 75% of patients present after 4.5 hours after stroke onset or with an unknown time of onset. Alteplase therapy is beneficial when initiated up to 9 hours after the onset of stroke if perfusion imaging results indicate the presence of salvageable ischemic brain tissue. Tenecteplase is an effective thrombolytic agent for eligible patients with stroke who are treated within 4.5 hours after the onset of stroke. However, data regarding the effectiveness of tenecteplase beyond 4.5 hours are limited.

5. TISSUE CLOCK In patients who awaken from their stroke or who have uncertain time of onset up to 9 hours from last time known well, studies have demonstrated benefit with thrombolysis, provided substantial irreversible ischemic damage is not present on imaging. “ tissue clock ” that is unique to each patient Tissue clock can be read using MRI-DWI mismatch, MRI or CT perfusion techniques demonstrating a favorable ratio of penumbral tissue volume compared with irreversibly damaged ischemic core volume.

6. Positive DW-MRI with negative FLAIR MR images obtained, infarct volume calculated by ABC/2 formula (A =maximum length in cm, B =width perpendicular to A on the same slice, C= number of slices multiplied by the slice thickness). Slice thickness kept is 5mm. Criteria for DWI-FLAIR mismatch- (DWI infarct volume- FLAIR infarct volume) divided by DWI infarct volume multiplied by 100% and >20% was regarded as DWI/FLAIR mismatch

7. Perfusion CT CBV/CBF mismatch

8. In Asian populations, however, studies have suggested that a lower dose of 0.6 mg/kg of alteplase may be equally effective. The current Chinese Stroke Association guidelines recommend full-dose IV alteplase, with lower-dose alteplase as a consideration for patients deemed at high risk of hemorrhage (Class IIb, Evidence level C) ( Dong et al., 2017 ) In Japan, the lower alteplase dose of 0.6 mg/kg is recommended for acute stroke patients ( Kern et al., 2013 )

9. While the FDA package insert still lists 3 hours as the cutoff, American Heart Association guidelines accept rtPA treatment up to 4.5 hours after symptom onset.

10. PURPOSE OF REVIEW The effect of late administration of tenecteplase (i.e., after 4.5 hours after stroke onset) in patients without immediate access to thrombectomy is currently unclear and is relevant to a majority of patients worldwide.

11. TENECTEPLASE Tenecteplase is under evaluation as an alternative to Alteplase for acute stroke treatment has a class IIb recommendation in patients with acute stroke due to large vessel occlusion before thrombectomy (dose=0.25 mg/kg) Has class IIb recommendation for thrombolysis in minor neurological impairment(NIHSS <5) and no major intracranial vessel occlusion.(dose=0.4 mg/kg)

12. TENECTEPLASE longer half-life, more fibrin specific, therefore, may lead to superior clot lysis. increased resistance to plasminogen activator inhibitor 1(PAI-1) than alteplase More convenient dosing (given as an IV bolus without infusion)

13. Several studies of tenecteplase versus alteplase are ongoing. However, the best evidence to date, based on two large randomized comparisons and three different meta-analyses of studies, shows that tenecteplase is “noninferior” to alteplase, (their outcomes and safety are similar.)

14. A small phase IIb dose-finding study of TNK in 75 patients randomized to TNK 0.1 mg/kg, TNK 0.25 mg/kg, or alteplase 0.9 mg/kg reported significantly favorable imaging and clinical outcomes for patients receiving the higher TNK dose without a significant impact on intracranial bleeding risk ( Parsons et al., 2012 ). TNK before mechanical thrombectomy (0.25 mg/kg; maximum dose 25 mg) was associated with higher reperfusion rates and better functional outcome among patients eligible for mechanical thrombectomy, as compared with standard-dose alteplase (0.9 mg//kg; maximum dose 90 mg); 22% of tenecteplase and 10% of alteplase patients met the primary outcome of reperfusion in >50% of the involved ischemic territory (difference 12% with 95% CI 2–21; P = 0.03 for superiority) ( Campbell et al., 2018 )

15. Burgos AM et al . analyzed data from five trials involving 1585 patients (828 receiving TNK and 757 receiving ALT) and found that TNK and ALT had comparable rates of achieving disability-free status at 3 months (57.9% vs. 55.4%, respectively). The combined results strongly indicate that TNK is as effective as ALT in treating acute ischemic stroke. Kheiri B et al. conducted a meta-analysis comparing tenecteplase and alteplase in acute ischemic stroke and found that tenecteplase led to significantly higher rates of complete recanalization and early neurological improvement compared to alteplase. Both drugs showed similar outcomes in terms of excellent recovery, any intracerebral hemorrhage, and mortality.

16. Yunyun  Xiong et al. conducted a trial, The Tenecteplase Reperfusion Therapy in Acute Ischemic Cerebrovascular Events–III ( TRACE-III ) trial. This article was published on 14 June 2024 at NEJM. multicenter, prospective, open-label, randomized, blinded-outcome-assessment trial at 58 centers in China. investigated the efficacy and safety of tenecteplase at a dose of 0.25 mg per kg , administered 4.5 to 24 hours after stroke onset, in patients who had had ischemic stroke resulting from large-vessel occlusion, had salvageable tissue,

17. Eligible patients had a prestroke score of 0 or 1 on mRS scale and a score of 6 to 25 on the NIHSS scale Evidence of o cclusion of the intracranial ICA or the first (M1) or second (M2) segment of MCA on CT or MR angiography; and evidence of salvageable brain tissue as identified on perfusion imaging. Patients were ineligible if endovascular thrombectomy was planned at the time of randomization or there were guideline-based contraindications to thrombolytic agents.

18. Irreversibly injured ischemic core was defined as an area with a cerebral blood flow of less than 30% of that in the normal brain as measured with the use of CT perfusion imaging. To be eligible, patients had to have an ischemic core volume of less than 70 ml, a ratio of the volume of hypoperfused tissue to the ischemic core volume of at least 1.8, and a difference in volume between the hypoperfused tissue and the ischemic core of at least 15 ml.

19. The tenecteplase group received tenecteplase intravenously as a bolus administered over a period of 5 to 10 seconds at a dose of 0.25 mg per kg (maximum dose, 25 mg) immediately after randomization. The control group received antiplatelet therapy . The primary outcome was the absence of disability ( score of 0 or 1 on the mRS scale) at 90 days . Secondary outcomes were: the functional independence (defined as a modified Rankin scale score of ≤2) at 90 days, major neurologic improvement at 72 hours after treatment (defined as a reduction from baseline of ≥8 points on the NIHSS or an NIHSS score of ≤1), reperfusion at 24 hours after treatment (defined as >90% reduction in the volume of the lesion in which there had been a delayed arrival of an injected tracer agent of >6 seconds), change from baseline in the NIHSS score at 7 days. The key safety outcomes were symptomatic intracranial hemorrhage and death

20. 516 patients; 264 were randomly assigned to receive tenecteplase and 252 to receive standard medical treatment. Treatment with tenecteplase resulted in a higher percentage of patients with a mRS score of 0 or 1 at 90 days than standard medical treatment (33.0% vs. 24.2%. Mortality at 90 days was 13.3% with tenecteplase and 13.1% with standard medical treatment incidence of symptomatic ICH within 36 hours after treatment was 3.0% and 0.8%, respectively. The percentage of patients who were functionally independent ( mRS ≤2) at 90 days was 43.6% in the tenecteplase group and 33.3% in the standard-treatment group. Complete recanalization at 24 hours after treatment occurred in 69 patients (27.9%) in the tenecteplase group and in 14 patients (5.9%) in the standard treatment group

21. The TRACE-III trial showed that, in patients with ischemic stroke due to large-vessel occlusion who had salvageable tissue and did not have access to endovascular thrombectomy, treatment with intravenous Tenecteplase between 4.5 hours and 24 hours after stroke onset led to a larger percentage of patients with no disability than that observed with standard medical care. Although there was no marked difference in survival at 90 days, the incidence of symptomatic intracranial hemorrhage within the first 36 hours after treatment appeared to be higher in the tenecteplase group than in the standard-treatment group

22. The Albers GW. et al conducted a RCT- Thrombolysis in Imaging Eligible, Late Window Patients to Assess the Efficacy and Safety of Tenecteplase (TIMELESS) trial, in Alabama, US. Involved 458 patients with ischemic stroke with large-vessel occlusion( occlusion of the middle cerebral artery or internal carotid artery) and evidence of salvageable brain tissue on perfusion imaging. 228 patients were assigned to receive Tenecteplase (0.25 mg per kilogram of body weight, up to 25 mg) , and 230 to receive placebo, administered 4.5 to 24 hours after the time that the patient was last known to be well.  77.3% of whom subsequently underwent thrombectomy; The trial showed no significant difference between tenecteplase therapy and placebo in the the mRS at 90 days( was 3 in each group) . The safety results did not differ substantially between the tenecteplase group and the placebo group. ( mortality at 90 days was 19.7% in the tenecteplase group and 18.2% in the placebo group, and the incidence of symptomatic intracranial hemorrhage was 3.2% and 2.3%, respectively.) However, immediate access to thrombectomy is limited in many geographic locations, including in developed countries, and is often unavailable in low-income or middle-income countries.

23. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: From American Heart Association/American Stroke Association

24. ENDOVASCULAR THROMBECTOMY acute stroke in patients with large vessel occlusions. “Drip and ship” concept : where patients stop first at the nearest primary stroke center for IV thrombolysis, get screened for large vessel occlusions, and if one is found, they are sent to the endovascular thrombectomy center

25. DAWN and DEFUSE trials The DAWN trial reported results of mechanical thrombectomy for patients with large-vessel occlusion (LVO) of the proximal MCA or intracranial ICA who had been last seen well 6–24 hours prior to intervention; DEFUSE-3 study reported similar results for patients last seen well 6–16 hours prior to intervention ( Albers et al., 2018 ; Nogueira et al., 2018 ). In both trials, patients were enrolled if they had LVO on CT angiography and mismatch between infarct volume and clinical severity based on DW-MRI or perfusion CT measured. Endovascular therapy was associated with a higher percentage of functionally independent patients, without an increase in serious adverse events. In the DEFUSE-3 study 45% of those who underwent thrombectomy versus 17% who did not undergo intervention ( P < .0010) were functionally independent with mRS of 0–2. There was a similar result in the DAWN study, with functional independence at 90 days of 49% in the thrombectomy group versus 13% in the control group. In both studies, there was no increase in the rate of symptomatic ICH or death in the thrombectomy groups.

26. Role of Heparin and Heparinoids Randomized studies of UFH, LMWH, or heparinoids for acute ischemic stroke treatment continue to show no proven benefits except in the case of cerebral venous thrombosis. Studies are being done on achieving more complete lysis by adding an antithrombotic agent during the thrombolytic infusion than intravenous thrombolysis alone. Concomitant heparin has been associated with increased bleeding, but GP2b3a receptor antagonists and thrombin inhibitors have proven safe in phase 2 studies and are under evaluation in an ongoing phase 3 study.

27. Also, may prevent reocclusion and could be the next step in achieving improved recanalization. In addition, inadequate reperfusion due to distal embolization and impaired microcirculatory flow may exist despite excellent recanalization of the proximal occlusion. linking IV thrombolysis with antithrombotic drugs may be effective for improving reperfusion as well as increasing recanalization

28. References Parsons M, Spratt N, Bivard A, Campbell B, Chung K, Miteff F, O'Brien B, Bladin C, McElduff P, Allen C, Bateman G, Donnan G, Davis S, Levi C. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med. 2012 Mar 22;366(12):1099-107. doi : 10.1056/NEJMoa1109842. PMID: 22435369. Campbell BCV, Mitchell PJ, Churilov L, Yassi N, Kleinig TJ, Dowling RJ, et al. Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke. N Engl J Med. 2018 Apr 26;378(17):1573-1582. doi : 10.1056/NEJMoa1716405. PMID: 29694815. Kheiri B, OsmanM , Abdalla A, et al. Tenecteplase versus alteplase for management of acute ischemic stroke: a pairwise and network meta-analysis of randomized clinical trials. J Thromb Thrombolysis 2018;46(4):440-450.doi:10.1007/s11239-018-1721-3 Burgos AM, Saver JL. Evidence that Tenecteplase Is noninferior to alteplase for acute ischemic stroke: meta-analysis of 5 randomized trials. Stroke 2019;50(8):2156-2162. doi:10.1161/ STROKEAHA.119.025080