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IntroductionBackground
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Risk Factors
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Clinical Presentation
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Assessment Scales
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DiagnosticsDiagnosis
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Differential Diagnosis
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TreatmentTreatment Goals
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Fibrinolytic Therapy
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Disposition/Monitoring
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Ischemic Stroke Literature Review
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ConclusionPharmacists Involvement
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Tenectaplase vs Alteplase with Ashley Yeh and Nadia Awad
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Landmark Trials in Ishemic Stroke with Deena Omar and Patrick Bridgeman
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Ischemic Stroke Summary
| Name of Study | Purpose | Design | Time Window | Patient Population | Intervention/comparison | Outcomes | Conclusion |
| Door-to-needle Time | |||||||
| Rech MA, et al. | To evaluate pharmacist impact on door to needle (DTN) time when evaluating an AIS | Retrospective, single-centered cohort study | <4.5 hours | n=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 hours | n=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) | |||||||
| NINDS | Evaluate morbidity and mortality in pt’s with AIS who received tPA | Double blind, randomized, placebo controlled, trial | 3 hours | n=624Mean-Age 77y-NIHSS 4 | tPA 0.9 mg/kg (max 90mg) versus placebo | tPA within 3 hours showed improved functional outcomes at 3 months | |
| ECASS III | To assess disability at 3 months in pt’s with AIS who receive tPA | Multi-center, double-blind, parallel-group, randomized, placebo-controlled trial | 3.5-4.5 hours | n=821Mean-Age 65yNIHSS tPa vs. placebo10.7 vs 11.6History of stroketPa vs. placebo7.7% vs 14.1% | tPA versus placebo | Alteplase within 4.5 hours of stroke onset improved neurologic outcomes. -Increase instances of ICH -No mortality benefit | |
| WAKE-UP | To assess functional outcome in patients with unknown time of stroke onset and MRI DWI-FLAIR mismatch who receive tPA | Randomized, blinded, parallel assignment, multicenter trial | >4.5 hours | n=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) | |||||||
| ATTEST | Assess efficacy and safety of TNK versus tPA | Single center, phase II, prospective, randomized, open-label, blinded end-point evaluation study | <4.5h | n=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=0.09 | No difference in outcomes |
| NOR-TEST | To 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 stroke | n=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 TNK | To 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 onset | n=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 2 | To 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 thrombectomy | Multicenter, open-label, randomized | <4.5 hours | n=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=0.12 | A 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. |
References
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.