Dual Antiplatelet Therapy as an Alternative to Thrombolysis in Minor Acute Ischemic Stroke

Author: Jane Morris, MD

There is a new option for treatment for minor, non-disabling stroke!

Are you ever on the fence about given thrombolysis to a patient who you think is having a stroke, but you aren’t sure if the benefit will outweigh the risk? The ARAMIS Trial provides good data that you have an alternative to offer patients.

Trial Design:

The ARAMIS Trial1 was a multicenter, prospective, randomized, open-label, blinded end point noninferiority clinical trial (PROBE design) to assess the efficacy and safety of dual antiplatelet therapy (DAPT) compared with intravenous alteplase (tPA) in patients presenting with minor stroke and nondisabling deficits within 4.5 hours of symptom onset.

Minor stroke was defined as: NIHSS score ≤ 5, including 0 on LOC 1a (no depressed level of consciousness) AND ≤ 1 point on any single-item score (mild symptoms only)

Non-disabling was adjudicated by: All investigators were trained with regards to adjudicating a deficit as nondisabling by consultation with patients and their available family members based on the patient’s career and hobbies to adjudicate whether the neurologic deficit would affect the patient’s activities of daily living and work

The trial was conducted at 38 hospitals in China, enrolling 760 patients, 393 patients to DAPT (300 mg clopidogrel load followed by 75 mg daily x12 days plus aspirin 100 mg daily) and 367 patients to standard dose tPA. The primary end-point was no disability at 90 days (defined as a modified Rankin Scale score of 0-1.) The primary safety endpoint was symptomatic intracranial hemorrhage (ICH).

Outcomes:

Efficacy: mRS 0-1 at 90 days: 93.8% in the DAPT group 91.4% in the alteplase group ARR 2.3% [95% CI −1.5% to 6.2%] p for noninferiority <0.001.

Safety: Symptomatic ICH at 90 days: 0.3% (1 of 371) in the DAPT group 0.9% (3 of 351) in the alteplase group Not statistically significant (p = 0.63) No difference in any bleeding events

Other data on early antiplatelet use in acute stroke:

The ARAMIS Trial built upon data obtained in the PRISMS Trial2, which was terminated early due to slow enrollment so definitive conclusions were not drawn after completion of this trial. PRISMS compared aspirin 325 mg to standard dose tPA with similar inclusion criteria and outcome measures as used in the ARAMIS Trial. Among the 313 patients enrolled, there was no difference in the favorable clinical outcomes, though a higher bleeding rate was seen in the alteplase group.

DAPT has already achieved widespread acceptance as treatment for minor stroke/TIA (NIHSS ≤ 3 in CHANCE3, POINT4; NIHSS ≤ 5 in THALES5) given within 12 (POINT) to 24 (CHANCE and THALES) hours of symptoms onset. Whether or not administering DAPT in < 4.5 hours compared with these longer time windows makes a clinical difference is not yet known.

The 2019 AHA/ASA Guidelines for the Early Management of Patients with Acute ischemic Stroke6 do not recommend tPA for patients with mild nondisabling stroke; However, there is some subjectivity to this assessment and cases that are in a gray zone.  ARAMIS provides efficacy and safety data on early administration of DAPT as an evidenced-based alternative to thrombolysis in this subpopulation of stroke patients.

Caveats:

Times I would recommend one treatment over the other:

DAPT may be preferred  Concerns about bleeding complications that aren’t absolute contraindications to thrombolysis in patient with modest deficits Patients in whom thrombolysis is not strongly recommended who present to a hospital that does not manage post-thrombolysis patients and who prefer not to be transferred to a larger center Patients with modest stroke deficits who do not consent to thrombolysis Suspected stroke mimic with low NIHSS

Thrombolysis is preferred Acute vascular occlusion seen on CT angiogram (as these patients have a higher risk of early neurological deterioration) Suspected atrial fibrillation as mechanism of stroke (as thrombus composition in cardioembolic stroke is more sensitive to tPA)

What we are doing at Maine Medical Center?

As the 100 mg aspirin is not a common dosage in the United States, and the duration of DAPT over 12 days is well accepted from the POINT, CHANCE and THALES trials, the protocol we have adopted at MMC for this population is:

·       300 mg clopidogrel load, then 75 mg daily x 21 days

·       325 mg aspirin load for patients who are not already taking aspirin

·       For those on aspirin already, and post-load, continue aspirin 81 mg daily

Summary

DAPT is as effective as tPA for minor, nondisabling strokes and use should be considered in this patient population.

References:

1. ARAMIS: JAMA. 2023;329(24):2135-2144. doi:10.1001/jama.2023.7827

2. PRISMS: JAMA.2018;320(2):156-166. doi:10.1001/jama.2018.8496

3. CHANCE: NEJM.2013;369:11-19. doi: 10.1056/NEJMoa1215340

4. POINT NEJM.2018;379:215-225. doi: 10.1056/NEJMoa1800410

5. THALES: NEJM.2020;383:207-17. doi: 10.1056/NEJMoa1916870

6. AHA/ASA Stroke Guidelines. Stroke. 2019;50:e344–e418. doi: 10.1161/STR.0000000000000211