thomas jefferson university - david roshal - david... · 2020. 11. 14. · david roshal, d.o.,...

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ROLE OF TENECTAPLASE IN ACUTE ISCHEMIC STROKE:A NEW FRONTIER

DAVID ROSHAL, D.O., D.ABPN

MEDICAL DIRECTOR OF STROKE SERVICES, JEFFERSON HEALTH NJ DIVISION

NOVEMBER 17, 2020

DISCLOSURES

• None

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MECHANISM OF ACTION OF FIBRINOLYTICS

Google Images

THERAPEUTIC OPTIONS

Campbell et al. NEJM 2018.

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TNK VS ALT

• Genetically modified form of ALT. Given as a single bolus. It is not an infusion

• Longer half-life (22 min vs 8 min)

• Increased resistance to plasminogen activator inhibitor (PAI)

• Higher fibrin specificity/affinity

• Not FDA approved for acute ischemic stroke

• Less cost. $5000 vs $8300. Both made by Genentech

• No need for premixing

• TNK has replaced alteplase as standard fibrinolytic agent for acute myocardial infarction.


TNK IN CLINICAL TRIALS (ATTEST/AUSTRALIAN TNKASE STUDY)

• Hypothesis: Patients with complete vessel occlusion show greater recanalization at 24 hours and have improved outcomes at 24 hours and 90 days when treated with TNKase vs Alteplase.

• Methods: Pooled analysis of pateintsin 2 RCTs ATTEST and Australian TNKase study. 146 patients (96+50)

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TNK IN CLINICAL TRIALS(ATTEST/AUSTRALIAN TNKASE STUDY)


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RESULTS• 1. Differences in Rx responses between complete occlusion group and partial

• occlusion group.

• 2. TNK seems to have better recanalization rates @ 24hrs and 24hr NIHSS and 90 day outcome mRS with less sICH. Recan rates with TNK approaching some thrombectomy trials.

• 3. No difference btw TNK and ALT in the 24hr or 90 day clinical outcomes in the

• partial vessel occlusion group likely due to low power.

TNK IN CLINICAL TRIALS:(ATTEST/AUSTRALIAN TNKASE STUDY)

STUDY LIMITATIONS

• 1.Small data set of 146 patients in 2 pooled studies. Studies not designed for clinical benefit with significant differences in design, imaging and outcome measurements.

• 2. Open-label design can potentially introduce post-treatment biases in decision making and clinical assessment despite the follow up assessments are blinded to treatment.

• 3. Open-label study might also influenced patient motivation, compliance and subjective reporting for the mRS.

• 4. Just to generate hypotheses from the limited data sets to help design future phase III trials.

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TNK IN CLINICAL TRIALS:EXTEND‐IA TNK TRIAL


TNK IN CLINICAL TRIALS:EXTEND‐IA TNK METHODS

Hypothesis:

- Tenecteplase is non-inferior to alteplase in achieving reperfusion at initial angiogram in patients planning to undergo endovascular therapy

- Superiority testing if non-inferiority was met

Inclusion criteria:

- Eligible for thrombolytics <4.5 hours

- Patients with LVO (ICA, M1, M2, or basilar artery) and could undergo thrombectomy in < 6 hours

Randomized TNK 0.25 mg/kg or alteplase 0.9 mg/kg

Primary outcome: Initial angiogram modified TICI reperfusion score


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TNK IN CLINICAL TRIALS:EXTEND‐IA TNK RESULTS


P = 0.002 Non-InferiorityP = 0.02 Superiority

Primary Endpoint

P = 0.04

Secondary Endpoint

TNK IN CLINICAL TRIALS:EXTEND‐IA TNK CONCLUSIONS

Superior reperfusion at initial angiogram

NNT 9 to avoid thrombectomy altogether

Faster infusion / Less expensive

Two trials (TASTE and ATTEST-2) are enrolling patients for comparison of tenecteplase vs. alteplase in non-thrombectomy patients


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TNK IN CLINICAL TRIALS:(NOR-TEST)

• Phase 3, randomized, open-label, blinded endpoint, superiority trial was done in 13 stroke units in Norway

• Patients were randomly assigned (1:1) to receive intravenous tenecteplase 0.4 mg/kg (to a maximum of 40 mg) or alteplase 0·9 mg/kg (to a maximum of 90 mg) within 4.5 hours of symptom onset. 1100 patients were randomly assigned to the tenecteplase(n=549) or alteplase (n=551) groups.

• The primary outcome was excellent functional outcome defined as modified Rankin Scale (mRS) score 0-1 at 3 months.

• The median age of participants was 77 years (64-79) and the median National Institutes of Health Stroke Scale score at baseline was 4 points (2-8).

• The primary outcome was achieved by 354 (64%) patients in the tenecteplase group and 345 (63%) patients in the alteplase group (odds ratio 1·08, 95% CI 0·84-1·38; p=0.52). By 3 months, 29 (5%) patients had died in the tenecteplase group compared with 26 (5%) in the alteplase group.

• Tenecteplase was not superior to alteplase and showed a similar safety profile.

Lancet Neurol. 2017 Oct;16(10):762-763. doi: 10.1016/S1474-4422(17)30277-6.

TNK IN CLINICAL TRIALS:(NOR-TEST POST-HOC SUBGROUP ANALYSES)

• In this post hoc analysis, moderate stroke was defined as admission National Institutes of Health Stroke Scale; 6 to 14 and severe stroke as National Institutes of Health Stroke Scale; ≥15. Rates of favorable outcome at 90 days, symptomatic intracerebral hemorrhage (sICH), and mortality after 7 and 90 days were assessed.

• In patients with moderate stroke (n=261), there were no differences in rates of favorable outcome, sICH, or mortality between tenecteplase and alteplase. In patients with severe stroke (n=87), there were no differences in outcome, frequency of sICH, or mortality at 7 days, but all-cause mortality at 90 days was increased in patients treated with tenecteplase (10 [26.3%] versus 4 [9.1%]; P=0.045). One patient died of sICH in the tenecteplase group, and 2 patients died of sICH in the alteplase group.

• Rates of favorable outcome and sICH were similar between treatment groups in patients with moderate and severe stroke. Mortality after 90 days was increased in patients with severe stroke receiving tenecteplase.

8 Apr 2019https://doi.org/10.1161/STROKEAHA.119.025041Stroke. 2019;50:1279–1281

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EVIDENCE THAT TENECTEPLASE IS NONINFERIOR TO ALTEPLASE FOR ACUTE ISCHEMIC STROKE

META-ANALYSIS OF 5 RANDOMIZED TRIALS

Table 1. Characteristics of Included Trials

TNK-S2B Australian TNK ATTEST Nor-Test EXTEND-IA TNK

Countries United States Australia Scotland Norway Australia and New Zealand

Number of sites 10 3 1 13 13

Patients, n 112 75 96 1100 202

TNK dose(s), mg/kg 0.1/0.25/0.4 0.1/0.25 0.25 0.4 0.25

Age, mean (SD) 69.1 (16.6) 70 (8.23) 71 (12.5) 71 (13.8) 71.1 (14.4)

Sex, male 58 (51.8%) 39 (52%) 30.5 (31.8%) 660 (60%) 110 (54.5%)

Severity (NIHSS), mean (SD) or median (IQR)

TNK 0.1: 8 (5–11); TNK 0.25: 10 (6–15); TNK 0.4: 9−5 to 17); ALT 13 (5-17)

14.4 (2.3)TNK: 12 (9–18); ALT: 11 (8–

16)5.7 (5.3)

TNK: 17 (12–22) ALT: 17 (12–22)

Permitted time window ≤3 h ≤6 h ≤4.5 h ≤4.5 h ≤4.5 h

Onset to treatment, mins, median (IQR) or mean (SD)

…176 (48); TNK 0.1 3.1±0.9;

TNK 0.25 3.0±0.7; ALT 2.7±0.8

188 (44.5); TNK: 180 (156–215); ALT: 200 (160–220)

TNK: 118 (79–180); ALT: 111 (80–174)*

TNK: 125 (102–156); ALT: 134 (104–176)

Atrial fibrillation … 28 (37.3%) 34 (35.4%) 119 (10.8%) …

Hypertension 89 (79.5) 47 (62.7%) 48 (50%) 482 (43.8%) …

Dyslipidemia 56 (50%) 37 (49.3%) 11 (11.5%) 126 (11.5%) …

Diabetes mellitus 21 (18.8%) 15 (20%) 14 (14.6%) 144 (13.1%) …

Current smoker 16 (14.2%) 15 (20%) 23 (24%) 346 (31.5%) …

Large vessel occlusion … 77% 47% … 100%

Endovascular Rx Prohibited Prohibited Prohibited Allowed (used in 3%–4%) Planned in all patients

sICH definition NINDS Study SITS-MOST SITS-MOST ECASS III SITS-MOST

18 Jul 2019 Stroke. 2019502156-2162

• These trials enrolled a total of 1585 patients, (828 TNK, 757 ALT).

• Across all trials, mean age was 70.8, 58.8% of patients were male, mean National Institutes of Health Stroke Scale (NIHSS) at baseline was 7, and mean time from last known well to treatment start was 148 minutes.

• All patients with ALT received standard 0.9 mg/kg ALT dosing, 10% as a bolus, followed by the remaining 90% over 60 minutes. 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%.



18 Jul 2019 Stroke. 2019502156-2162

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18 Jul 2019 Stroke. 2019502156-2162

Stacked bar chart shows outcomes for 1397 patients from 3 trials, combined directly without adjustment or modeling. TNK (tenecteplase), compared with ALT (alteplase), was associated with nominally more highly desirable outcomes (mRS, 0 and mRS, 0–1), with relatively similar outcome rates for other mRSthresholds.

For the safety end point of symptomatic ICH, data were available for 1585 patients from all 5 trials. Crude summary sICH rates were TNK 3% versus ALT 3%, risk difference 0% (95% CI, –1% to 2%; Figure V in the online-only Data Supplement). For death, in 1585 patients from all 5 trials, crude mortality rates at 3 months were TNK 7.6% versus ALT 8.1%, risk difference 0% (95% CI, –3% to 2%;)



• TNK demonstrated noninferiority to ALT with comparable safety

• Findings of noninferiority are more secure for patients with milder (eg, NIHSS, 1–14) deficits than patients with more severe (eg, NIHSS ≥15) deficits. However, the one trial (EXTEND 1A-TNK) that focused solely on patients with large vessel occlusions and severe deficits did provide strong signals of noninferiority

18 Jul 2019 Stroke. 2019502156-2162



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AHA/ASA 2019 RECOMMENDATIONS FOR USE OF TNK IN ACUTE ISCHEMIC STROKE

• It may be reasonable to choose TNK (single IV bolus of 0.25mg/kg, maximum 25mg) over IV alteplase in patients without contraindications for IV fibrinolysis who are also eligible to undergo mechanical thrombectomy (COR IIb)

• TNK administered as a 0.4mg/kg single IV bolus has not been proven to be superior or non-inferior to alteplase but might be considered as an alternative to alteplase in patients with minor neurological impairment and no major intracranial occlusion (COR IIb);

30 Oct 2019https://doi.org/10.1161/STR.0000000000000211Stroke. 2019;50:e344–e418

MORE TRIALS NEEDED:

• Alteplase-TenecteplaseTrial Evaluation for Stroke Thrombolysis (ATTEST2)

• TenecteplaseVersus Alteplase for Stroke Thrombolysis Evaluation Trial in the Ambulance (TASTEa)

• A Randomized Controlled Trial of TNK-tPAVersus Standard of Care for Minor Ischemic Stroke With Proven Occlusion (TEMPO-2)

• Tenecteplase in Wake-up Ischaemic Stroke Trial (TWIST)

• Tenecteplase in Stroke Patients Between 4.5 and 24 Hours (TIMELESS)

Available data on TNK efficacy are not definitive, as the greatest weight of evidence is from atrial (NOR-TEST) that enrolled patients with mild deficits likely to havegood outcomes regardless of treatment, diminishing study informativeness about noninferiority

Larger, definitive, noninferiority trials are desirable.

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THANK YOU!QUESTIONS??

thomas jefferson university - david roshal - david... · 2020. 11. 14. · david roshal, d.o.,...

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