Outside the Window: Plan B for Acute Stroke Management

A 44 year old woman with a remote history of gastric bypass presents to the ED after a five minute episode of right sided upper extremity weakness and left sided facial droop at 18:15. On presentation to the ED at 2:55 the following morning, she was noted to have continued right sided upper extremity weakness. What can the ED provider do for her at this point?

Given the residual deficits on exam, it is possible this patient had a stroke. Alteplase (tPA) is the first-line treatment for eligible patients with stroke, but at nearly 9 hours after her symptom onset, this patient falls outside the window for tPA1. What can ED providers do to reduce adverse outcomes for acute stroke patients outside the window for tPA administration?

Background: The American Stroke Association once recommended tPA only within 3 hours of symptom onset, but now supports tPA in certain patient populations within 3 to 4.5 hours of symptom onset. Patients who meet all of the following criteria are eligible for the expanded tPA window:

Under 80 years old
No history of diabetes or prior stroke
NIH Stroke Scale score of less than 26
No oral anticoagulants
No imaging findings of ischemic injury involving over a third of the middle cerebral artery’s territory.1

Our patient falls outside even the extended the tPA window. However, we still have options – both medical and surgical – for treating acute stroke patients who are no longer eligible for tPA.

Aspirin

Aspirin given in the acute setting reduces the risk of early recurrent ischemic stroke.

International Stroke Trial: In this study of 19,435 patients with acute ischemic stroke, patients who received aspirin had a lower risk of recurrent ischemic stroke within 14 days than patients who did not (2.8 versus 3.9 percent)2.
Chinese Acute Stroke Trial: Of 21,106 acute ischemic stroke patients, those receiving aspirin as opposed to placebo had significantly fewer early recurrent ischemic strokes (1.6 versus 2.1 percent). They were also less likely to die or have another non-fatal stroke in the next four weeks (5.3 versus 5.9 percent, for an absolute risk reduction of 12 percent)3.

Aspirin plus Clopidogrel

Dual antiplatelet therapy with aspirin and clopidogrel reduces the risk of stroke at 90 days.

CHANCE trial: 5,170 acute stroke patients were assigned to either aspirin alone or aspirin + clopidogrel. Patients receiving aspirin + clopidogrel had a lower risk of stroke at 90 days than in the aspirin-only group (8.2 versus 11.7 percent)4.
POINT trial: A study involving 4,881 patients just published in the New England Journal of Medicine found that the risk of stroke at 90 days was again lower in patients receiving dual antiplatelet therapy with clopidogrel as opposed to aspirin alone (5.0 versus 6.5%)5.

Mechanical thrombectomy within 6 hours of symptom onset improves functional outcome, and in recent trials has been shown to benefit some patients within 6-24 hours of symptom onset.

DEFUSE-3 trial: This study followed 182 patients with large anterior vessel occlusion. Those treated with mechanical thrombectomy had an improved outcome with 45 percent having a modified Rankin scale score of less than 2 versus 17 percent in the control group not receiving thrombectomy8.
DAWN trial: Patients with large anterior vessel occlusion treated with mechanical thrombectomy between 6 and 24 hours of symptom onset showed improvement in functional outcome, with 49 percent having an modified Rankin scale score of less than 2 as opposed to 13 percent in the control group9. This study enrolled 206 patients.
Randomized controlled trials (RCTs) have not yet examined extended-window thrombectomy in other groups.

Recommendations for acute stroke patients outside the tPA window:

Patients should receive dual antiplatelet therapy with aspirin and clopidogrel within 24 hours of symptom onset.
Previous statin therapy should be continued.
Mechanical thrombectomy is recommended in all patients less than 6 hours from symptom onset. It is also recommended up to 24 hours from symptom onset in patients with large anterior vessel occlusion.
The American Stroke Association recommends only patients with large anterior vessel occlusion receive mechanical thrombectomy after 6 hours of onset, because RCTs have not yet examined extended thrombectomy windows in other groups. However, it is certainly possible that thrombectomy after 6 hours could benefit other patients and should be considered in these populations as well.

References

1. Powers WJ, Rabinstein AA, Ackerson T, et al., on behalf of the American Heart Association Stroke Council. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2018;49:e46-e110.

2. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet 1997;349(9065):1569-81.

3. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Lancet 1997;349(9066):1641-9.

4. Wang, Y et al. Clopidogrel With Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) Trial: One-Year Outcomes. Circulation 2015;132(1):40-6.

5. Johnston, SC et al. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. NEJM 2018; DOI: 10.1056/NEJMoa1800410.

6. Blanco, M et al. Statin treatment withdrawal in ischemic stroke: a controlled randomized study. Neurology 2007;69(9):904-10.

7. Hong, K and Lee, J. Statins in Acute Ischemic Stroke: A Systematic Review. J Stroke 2015; 17(3):282-301.

8. Albers, G, et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. NEJM 2018;378:708-18.

9. Nogueira, R, et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. NEJM 2018;378(1):11-21.