The sooner brain reperfusion therapy is initiated after an acute ischemic stroke (AIS), the greater the likelihood of a better outcome. It is crucial for eligible patients to begin intravenous thrombolysis (IVT) treatment using alteplase as soon as possible within the 3- or 4.5-hour window from the stroke's onset; treatment should not be postponed until the window's end.
Similarly, mechanical thrombectomy (MT) is also time-sensitive, showing clear benefits for patients with AIS resulting from an intracranial large artery occlusion (LAO) in the proximal anterior circulation when treated within 6 hours of symptom onset. Specialized stroke centers may consider MT beyond the 6-hour window (up to 24 hours) by employing imaging-based selection for patients with anterior circulation stroke. [1,2, and 3].
Less than 3 hours — Treatment of eligible patients (clinical syndrome of acute ischemic stroke causing a potentially disabling neurologic deficit and no contraindication to IVT) should receive IVT with intravenous alteplase and should be started as soon as possible within 3 hours of onset. In this group of patients, alteplase led to a good outcome in 33% compared to 23% for the control group (odds ratio [OR] 1.75, 95% CI 1.35-2.27). The number needed to treat (NNT) for one additional patient to achieve a good outcome was 10 [2]. Patients should also be evaluated in this time window to determine if they are candidates for MT.
3 to 4.5 hours — Treatment for eligible patients is suggested to start if duration of onset was within the 3-4.5 hours. Special warning exists for patients aged >80 years old, have a National Institutes of Health Stroke Scale (NIHSS) score >25, have a combination of previous stroke and diabetes, or on oral anticoagulant use regardless of INR, but these are not absolute contraindication for IVT. The proportion with a good outcome in the alteplase was 35% compared to 30% in the control group (OR 1.26, 95% CI 1.05-1.51, NNT 20) [2]. Patients should also be evaluated in this time window to determine if they are candidates for MT.
4.5 to 6 hours — In this time period, the harm may exceed the benefit in patients with acute stroke and should not receive IVT. The proportion with a good outcome in the alteplase was 33% compared to 31% in the control group (OR 1.15, 95% CI 0.95-1.40, NNT 50) [2]. Patients in this time window should be evaluated to determine if they are candidates for MT.
6 to 24 hours — In this time period, risks outweighs benefit and patients are not eligible to receive IVT. However, mechanical thrombectomy is still an option at specialized stroke centers using imaging-based selection of patients with anterior circulation stroke.
Beyond 24 hours — No reperfusion treatment (IVT or MT) should be offered for those patients in this time period for the lack of benefit and potential harm [2].
In general, alteplase increases the risk of symptomatic intracranial hemorrhage (6.8 percent, versus 1.3 percent for control, OR 5.55, 95% CI 4.01-7.70, NNH 18.2) and fatal intracranial hemorrhage within 7 days (2.7 versus 0.4 percent, OR 7.14, 95% CI 3.98-12.79, NNH 44). This risk was the same among patients regardless of age, stroke severity, or treatment delay. However, this risk is offset by the benefit within the appropriate time window. Mortality rate at 90 days was not statistically different between the two groups (17.9% versus 16.5%, hazard ratio 1.11, 95% CI 0.99-1.25) [2].
Unwitnessed stroke onset and "wake-up" stroke — If the time of onset of symptoms is not known (patient wakes up with symptoms from sleep of more than 4.5), then imaging-based selection of patients is used to guide treatment options [5]. An acute ischemic lesion that is diffusion positive and fluid-attenuated inversion recovery [FLAIR] negative is likely to be of less than 4.5 hour-duration and patients should be considered for IVT and/or MT in specialized centers.
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Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, Brott T, Cohen G, Davis S, Donnan G, Grotta J, Howard G, Kaste M, Koga M, von Kummer R, Lansberg M, Lindley RI, Murray G, Olivot JM, Parsons M, Tilley B, Toni D, Toyoda K, Wahlgren N, Wardlaw J, Whiteley W, del Zoppo GJ, Baigent C, Sandercock P, Hacke W; Stroke Thrombolysis Trialists' Collaborative Group. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014 Nov 29;384(9958):1929-35. doi: 10.1016/S0140-6736(14)60584-5. Epub 2014 Aug 5. PMID: 25106063; PMCID: PMC4441266.
Goyal M, Almekhlafi M, Dippel DW, Campbell BCV, Muir K, Demchuk AM, Bracard S, Davalos A, Guillemin F, Jovin TG, Menon BK, Mitchell PJ, Brown S, White P, Majoie CBLM, Saver JL, Hill MD; HERMES Collaborators. Rapid Alteplase Administration Improves Functional Outcomes in Patients With Stroke due to Large Vessel Occlusions. Stroke. 2019 Mar;50(3):645-651. doi: 10.1161/STROKEAHA.118.021840. PMID: 30760169.
Thomalla G, Boutitie F, Ma H, Koga M, Ringleb P, Schwamm LH, Wu O, Bendszus M, Bladin CF, Campbell BCV, Cheng B, Churilov L, Ebinger M, Endres M, Fiebach JB, Fukuda-Doi M, Inoue M, Kleinig TJ, Latour LL, Lemmens R, Levi CR, Leys D, Miwa K, Molina CA, Muir KW, Nighoghossian N, Parsons MW, Pedraza S, Schellinger PD, Schwab S, Simonsen CZ, Song SS, Thijs V, Toni D, Hsu CY, Wahlgren N, Yamamoto H, Yassi N, Yoshimura S, Warach S, Hacke W, Toyoda K, Donnan GA, Davis SM, Gerloff C; Evaluation of unknown Onset Stroke thrombolysis trials (EOS) investigators. Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data. Lancet. 2020 Nov 14;396(10262):1574-1584. doi: 10.1016/S0140-6736(20)32163-2. Epub 2020 Nov 8. PMID: 33176180; PMCID: PMC7734592.
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