Inside the Stroke Window: Back to Basics

Author: Marie Murphy, MD
Editor: Nicole Anthony, MD

“Stroke Code to the Stroke Assessment Area”

A 60-year-old, left-handed man with a past medical history of type 2 diabetes mellitus and hyperlipidemia is brought in by EMS for persistent sudden onset, left arm weakness that began 20 minutes ago. On exam, the BP  is mildly elevated, and there is left upper extremity weakness. The non-contrast CT shows no evidence of an acute hemorrhage. CT Angiography is negative for any signs of large vessel occlusion, but there are demonstrated areas of intracranial stenosis.

The patient returns from CT and on reassessment, the deficits persist. You suspect acute ischemic stroke (AIS). After assessing patient stability, among your initial thoughts is whether or not thrombolytics (tPA) are indicated.

WHY is this important?

According to the CDC, nearly 800,000 Americans per year suffer from stroke, with ischemic strokes accounting for the vast majority of cases. Stroke is a leading cause of mortality and morbidity in the United States, costing the healthcare system over $40 billion annually. The evidence is far from definitive, but thrombolytics have been associated with decreased morbidity/disability in a few RCTs. Acute Ischemic Strokes have also been identified as a neurovascular complication of SARS-CoV-2 infection, reaffirming the importance of understanding the use of thrombolytics in acute management in eligible patients.[1,2]

WHO can I give tPA to? WHAT are the absolute contraindications for patients within the window?

The criteria are lengthy and always changing. For the full detailed list of recommendations/absolute and relative contraindications: 2019 AHA Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.

First questions to ask:

1. Is your patient over 18? Not recommended in pediatric population.
2. What is the glucose? Hypoglycemia (<50mg/dL) or hyperglycemia can be a stroke-mimic.
3. Any History of intracranial hemorrhage? If so, ineligible. Done.

Here are some of the other absolute contraindications (Class III) that are harder to remember:

Figure 1. Original Figure.

Between 3.0 and 4.5 hours (“extended window”), e  should be taken in patients > 80 years old, severe stroke (NIHSS>25), diabetes + prior stroke, any anticoagulation use, or CT with multilobar infarction. These patients were excluded from the industry-supported ECASS III Trial.

WHEN: How did we get the 3 and 4.5 hour cutoffs? What is the evidence?

NINDS Trial was a randomized, double-blind study that compared outcomes of neurological symptoms in patients that received alteplase versus placebo when administered within 3 hours.

[Editor-in chief: The NINDS trial has a fragility index of 3. The fragility index is a measure of reproducibility and is equal to the number of patients who would need to have a different outcome in order for the results to become statistically insignificant (i.e. for the p-value to increase above 0.05). Not surprisingly, NINDS is an outlier among a preponderance of trials that showed no benefit or even harm.]

 

	Part I (n=291)	Part II (n=333)
Primary Outcome:	Improvement in NIHSS at 24 hours or resolution of neurological symptoms within 24 hrs after the onset of stroke.	Clinical outcome at 3 months based on a global test statistic (Barthel index, Modified Rankin Score, Glasgow Outcome, NIHSS)
Results:	No statistically significant differences were detected between treatment & placebo groups. Benefit at 3 months was observed in post-hoc analysis	– OR 1.7 (95%CI 1.2 to 2.6; P = 0.008) for a favorable outcome in the t-PA group -12% absolute increase in the number of patients with minimal or no disability (determined by Barthel index) in the t-PA group. -11% absolute increase in the number of patients with a favorable NIHSS score (0 or 1) in t-PA group

Figure 2. Original Figure 

ECASS III Trial was a double-blinded, multicenter RCT that compared the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke compared to placebo. Previous studies (ECASS II and ATLANTIS) which reported null results were smaller and underpowered. The authors reported favorable outcomes at 90 days in the intervention group compared to placebo based on NIHSS and modified Rankin scale.

[Editor-in chief: ECASS III has a fragility index of 1!]

Both studies found a statistically significant increase in initial symptomatic ICH (P < 0.001 and P=0.008, respectively) without any significant difference in mortality between treatment groups (P = 0.30 and P=0.68, respectively).

If there is an ECASS III, there must be a I & II, right?!

ECASS was a randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial comparing placebo vs. t-PA. The authors found a statistically significant difference favoring tPA in the speed of neurologic recovery and Modified Rankin score in the target population analysis, however NOT in the Intent to Treat Analysis. The authors concluded t-PA could be beneficial in a select group of patients (moderate to severe neurologic deficits without extended infarct signs on CT), but should not routinely be used in all suspected ischemic strokes because of the risk of intracranial hemorrhage.

Similarly, in ECASS II, there was no statistically significant absolute difference in favor for tPA based on modified rankin score, the primary endpoint of the study. However, a benefit was found in the median change in NIHSS score from baseline to day 30.

Numerous studies suggest a null or uncertain level of benefit. A systematic review of tPA for Acute Ischemic Stroke found that “among 26 trials, 24 research groups found no benefit in their selected primary outcome, five of which were stopped early for futility or harm”. The combined small sample size of both NINDS 2 and ECASS III is concerning and may overestimate the benefit of the intervention. Additional large scale studies are required to prove benefit, particularly since the serious complications, such as hemorrhage or angioedema, are well described.  A full discussion on all of the studies related to tPA is beyond the scope of this post.

WHAT are my options? Alteplase vs tenecteplase:

Figure 3. Alteplase vs. Tenecteplase 

There are few studies comparing these agents directly. A systematic review and metaanalysis of tenecteplase vs alteplase given in large vessel occlusion prior to thrombectomy showed a higher rate of recanalization and higher odds of improved modified rankin score at 3 mos for tenecteplase compared to alteplase for patients presenting within the 4.5hr window. This study was limited by variation in patient populations, variability in tenecteplase dosing, low power in subgroup analyses and wide confidence intervals.

My patient states he just woke up with these symptoms (unable to verify last known well). Can I use imaging to help determine if he is still in the window for tPA treatment?

The WAKE-UP Trial was a multicenter trial that looked at whether MR was a useful tool in determining time of onset of stroke to ascertain tPA eligibility. The authors found that an ischemic lesion that was visible on MR diffusion-weighted imaging without parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR) indicated that the stroke may have occurred approximately within the previous 4.5 hours. Administering tPA based on these findings resulted in a neurological improvement in functional status at 90 days based on modified rankin score compared to placebo.[3] It is important to note, this study was   due to limited funding and under-enrollment, limiting the interpretation of the findings and under-powering the study. Mortality was 4.1% with alteplase group and 1.2% with placebo (adjusted odds ratio, 3.38; 95% CI, 0.92 to 12.52; P = 0.07), which raises the question if there is a potential harmful effect masked by bias introduced by early cessation of the trial (reviewed in detail by Dr. Morgenstern in Stroke thrombolytics update 1: The WAKE UP trial).

Currently, there is a Phase III clinical trial entitled Tenecteplase in Wake-up Ischemic Stroke (TWIST) investigating the use of tenecteplase in wake-up stroke and whether CT, CTA +/- CT perfusion can be used as a tool to identify patients earlier who can benefit from intervention. The primary outcome is improved neurological status/disability at 90 days.

Should tPA be given in mild stroke? Should we just give Aspirin?

It depends on what you consider a “mild stroke”. The PRISMS Trial investigated whether administering IV alteplase in eligible patients with minor CVA (NIHSS < 5 without disabling features) had an improved functional outcome based on modified Rankin score at 90 days when compared to aspirin. Disabling deficits were defined as severe aphasia, complete hemianopia or any deficit that could interfere with a patient’s activities of daily living or livelihood. The study, although limited by under-enrollment and early termination, demonstrated no benefit of tPA over aspirin in the study population.

Takeaways

1. Within the 3 hour window, thrombolytics may have a small benefit in disability in 3 months but does cause short-term adverse effects.

2. Between 3 and 4.5 hours, extra caution should be taken in administering tPA to patients > 80 years old, severe stroke (NIHSS>25), diabetes + prior stroke, on any anticoagulation use or have multilobar infarction on CT.

3. Tenecteplase is potentially non-inferior to alteplase, more cost effective, and possibly safer pending further trials.

4. There may not be sufficient evidence to suggest a benefit of tPA, and we need to familiarize ourselves with the limitations of current studies driving clinical practice.

Resources

– Read more on how the NNT rates tPA as an intervention here.
– NINDS Trial
– ECASS I, ECASS II, and ECASS III
– WAKE UP Trial
– Tenecteplase in Wake-up Ischaemic Stroke Trial (TWIST)
–  PRISMS Trial

References

Yaghi S, Ishida K, Torres J, et al. SARS-CoV-2 and Stroke in a New York Healthcare System [published correction appears in Stroke. 2020 Aug;51(8):e179]. Stroke. 2020;51(7):2002-2011. doi:10.1161/STROKEAHA.120.030335. Pubmed.

Beyrouti R, Adams ME, Benjamin L, et al. Characteristics of ischaemic stroke associated with COVID-19. J Neurol Neurosurg Psychiatry. 2020;91(8):889-891. doi:10.1136/jnnp-2020-323586. Pubmed. 

Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clarifications of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms [published correction appears in Stroke. 2014 Mar;45(3):e52]. Stroke. 2013;44(9):2500-2505. doi:10.1161/STROKEAHA.113.000878. Pubmed.

Katsanos AH, Safouris A, Sarraj A, et al. Intravenous Thrombolysis With Tenecteplase in Patients With Large Vessel Occlusions: Systematic Review and Meta-Analysis. Stroke. 2021;52(1):308-312. doi:10.1161/STROKEAHA.120.030220. Pubmed.

Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274(13):1017-1025. Pubmed.

Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998;352(9136):1245-1251. doi:10.1016/s0140-6736(98)08020-9. Pubmed.

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. doi:10.1056/NEJMoa0804656. Pubmed.

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. doi:10.1056/NEJM199512143332401. Pubmed.

Zitek T, Ataya R, Brea I. Using Tenecteplase for Acute Ischemic Stroke: What Is the Hold Up?. West J Emerg Med. 2020;21(2):199-202. Published 2020 Feb 24. doi:10.5811/westjem.2020.1.45279. Pubmed.

Baird AE, Jackson R, Jin W. Tenecteplase for Acute Ischemic Stroke Treatment. Semin Neurol. 2021;41(1):28-38. doi:10.1055/s-0040-1722722. Pubmed.

Kvistad CE, Novotny V, Kurz MW, et al. Safety and Outcomes of Tenecteplase in Moderate and Severe Ischemic Stroke. Stroke. 2019;50(5):1279-1281. doi:10.1161/STROKEAHA.119.025041. Pubmed.

Rønning OM, Logallo N, Thommessen B, et al. Tenecteplase Versus Alteplase Between 3 and 4.5 Hours in Low National Institutes of Health Stroke Scale. Stroke. 2019;50(2):498-500. doi:10.1161/STROKEAHA.118.024223. Pubmed.

Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators, Van De Werf F, Adgey J, et al. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet. 1999;354(9180):716-722. doi:10.1016/s0140-6736(99)07403-6. Pubmed.

Oliveira M, Fidalgo M, Fontão L, et al. Tenecteplase for thrombolysis in stroke patients: Systematic review with meta-analysis.Am J Emerg Med. 2021;42:31-37. doi:10.1016/j.ajem.2020.12.026 Pubmed.

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. doi:10.1056/NEJMoa1804355. Pubmed.