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Ischemic Stroke Literature Review

Jimmy October 25, 2021

Name of StudyPurposeDesignTime WindowPatient PopulationIntervention/comparisonOutcomesConclusion
Door-to-needle Time 
Rech MA, et al.To evaluate pharmacist impact on door to needle (DTN) time when evaluating an AISRetrospective, single-centered cohort study<4.5 hoursn=125GroupsPharmD v No PharmD45 (36%) vs 80 (64%) 
Median Age70y vs 66.5y

Pharmacist (PharmD) at bedside versus No pharmacist group (No PharmD)
Primary endpoint Median DTN in the PharmD group was 48 min compared to 73 min in the No PharmD group (P<0.01)
Secondary endpoints DTN time <60 min 71.1% vs 28.8% (p<0.01)
DTN ≤45 min44.4% vs 8.8% (p<<0.01)
Goal DTN was not only achieved, but improved in the group in which a pharmacist was involved in stroke code response
Jacoby JS, et al. To evaluate the impact that ED pharmacist have on DTN times and clinical outcomes in patients with AIS who receive tPA in the ED Retrospective cohort study <4.5 hoursn=100GroupsPharmD v No PharmD
Median Age69y
Comorbidities: HTNPharmD vs No PharmD67% vs 88% 

Pharmacist (PharmD) at bedside versus No pharmacist group (No PharmD)
Median DTN timePharmD vs No PharmD46 minutes vs. 58 minutesDTN times<60 minutes: 71% vs. 61%<45 minutes: 49% vs. 25%Two errors reported in the No PharmD group ED pharmacist involvement in stroke care helped decrease DTN time 
Alteplase (tPA) 
NINDSEvaluate morbidity and mortality in pt’s with AIS who received tPA Double blind, randomized, placebo controlled, trial 3 hoursn=624Mean-Age 77y-NIHSS 4tPA 0.9 mg/kg (max 90mg)
versus placebo
tPA within 3 hours showed improved functional outcomes at 3 months
ECASS IIITo assess disability at 3 months in pt’s with AIS who receive tPA Multi-center, double-blind, parallel-group, randomized, placebo-controlled trial3.5-4.5 hoursn=821Mean-Age 65yNIHSS tPa vs. placebo10.7 vs 11.6History of stroketPa vs. placebo7.7% vs 14.1%tPA versus placeboAlteplase within 4.5 hours of stroke onset improved neurologic outcomes. -Increase instances of ICH -No mortality benefit
WAKE-UPTo assess functional outcome in patients with unknown time of stroke onset and MRI DWI-FLAIR mismatch who receive tPARandomized, blinded, parallel assignment, multicenter trial >4.5 hoursn=503Mean -Age 65y 
Median NIHSS 6 
89% of pt’s in each group woke up with stroke sx’s
Median time from sx recognition to admin tPA ~3h
tPA 0.9 mg/kg (max 90mg)
versus placebo
Primary outcometPA group had more favorable 90-day outcome (mRS 0-1)  (53.3% vs 41.8%; p=0.02)  
Secondary outcomes
MortalitytPA vs placebo 4.1% vs 1.2%; p = 0.07
Tenecteplase (TNK)
ATTESTAssess efficacy and safety of TNK versus tPASingle center, phase II, prospective, randomized, open-label, blinded end-point evaluation study<4.5hn=104Mean-Age 71yTanderm or ICA TNK vs tPA29% vs 21% M1 occlusion TNK vs tPA46% vs 40%*TNK group with TNK 0.25 mg/kg (max 25mg)
tPA 0.9 mg/kg (max 90mg)
Penumbra salvaged at 24-48 hours  68% vs. 68%; p=0.81Secondary endpoint: sICH 24-48 hours15% vs. 27%; p=0.09No difference in outcomes
NOR-TESTTo evaluate the safety and efficacy of TNK verses tPA in patients with AIS Multicenter, prospective, randomized, open-label, blinded endpoint, superiority <4.5 hours or <4.5 hours +wake up stroken=1,107Mean-Age 77y-NIHSS 4
NIHSS 0-7 (TNK v tPA)78% v 73% 
TNK 0.4 mg/kg (max 40mg)
tPA 0.9 mg/kg (max 90mg)
Primary endpoint: mRS score of 0-1 at 3 monthsTNK vs. tPA 354 (64%) vs. 345 (63%); p=0.52 TNK was not superior to tPA for the treatment of AIS
EXTEND-IA TNKTo compare TNK with tPA in establishing reperfusion prior to thrombectomyTo test non inferiority of TNK compared to tPA Prospective, randomized, open-label, blinded-end-point study<4.5 hours of stroke onset and thrombectomy 6 hours from onsetn=204 Mean-Age 70y-NIHSS 17
Middle cerebral artery occlusion ~70%
TNK 0.25 mg/kg (max 25mg)
tPA 0.9 mg/kg (max 90mg)
TNK was non-inferior to tPA for achieving >50% reperfusion prior to thrombectomy TNK had better functional neurologic outcomes at 90 days as compared to tPA 
EXTEND IA TNK PART 2To compare efficacy and safety of 0.25mg/kg (low dose) of TNK with 0.4mg/kg (high dose) of TNK in establishing reperfusion prior to thrombectomyMulticenter, open-label, randomized<4.5 hoursn=300Median High dose vs low dose71.7y vs 73.8yLarge artery occlusion 16% vs 11% Rural setting167 vs 146 
TNK 0.25 mg/kg (max 25mg)
TNK 0.4 mg/kg (max 40mg)
Primary OutcomeRestoration of blood flow to >50% of the involved territory High vs low dose 19.3% in both groups; p=0.89Secondary OutcomeIntercranial Hemorrhage High vs low dose 7/150 (4.7%) vs 2/150 (1.3%); p=0.12A higher dose of TNK did not improve perfusion. Additionally, there was no difference in patient centered outcomes (secondary outcomes). 0.25mg/kg may be considered for the treatment of acute ischemic stroke. 


DTN: Rech MA, Bennett S, Donahey E. Pharmacist participation in acute ischemic stroke decreases door-to-needle time to recombinant tissue plasminogen activator. Ann Pharmacother. 2017;51(12):1084-1089.

DTN: Jacoby JS, Draper HM, Dumkow LE, Farooq MU, DeYoung GR, Brandt KL. Emergency medicine pharmacist impact on door-to-needle time in patients with acute ischemic stroke. Neurohospitalist. 2018;8(2):60-65.

NINDS: National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-1587.

ECASS III: Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-1329.

WAKE-UP: Thomalla G, Simonsen CZ, Boutitie F, et al. Mri-guided thrombolysis for stroke with unknown time of onset. N Engl J Med. 2018;379(7):611-622.

ATTEST: Huang X, Cheripelli BK, Lloyd SM, et al. Alteplase versus tenecteplase for thrombolysis after ischaemic stroke (Attest): a phase 2, randomised, open-label, blinded endpoint study. Lancet Neurol. 2015;14(4):368-376. 

NOR-TEST: Logallo N, Novotny V, Assmus J, et al. Tenecteplase versus alteplase for management of acute ischaemic stroke (Nor-test): a phase 3, randomised, open-label, blinded endpoint trial. Lancet Neurol. 2017;16(10):781-788.

EXTEND IA:  Campbell BCV, Mitchell PJ, Churilov L, et al. Effect of intravenous tenecteplase dose on cerebral reperfusion before thrombectomy in patients with large vessel occlusion ischemic stroke: the extend-ia tnk part 2 randomized clinical trial. JAMA. 2020;323(13):1257-1265.

EXTEND IA TNK PART 2: Campbell BCV, Mitchell PJ, Churilov L, et al. Effect of intravenous tenecteplase dose on cerebral reperfusion before thrombectomy in patients with large vessel occlusion ischemic stroke: the extend-ia tnk part 2 randomized clinical trial. JAMA. 2020;323(13):1257-1265.