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Dual Antiplatelets or Lytics for Minor Stroke?

August 22, 2023

Written by Alex Clark

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In minor acute ischemic stroke (AIS) patients presenting within 4.5 hours of onset, dual antiplatelet therapy (DAPT) is non-inferior to intravenous alteplase for excellent neurologic outcome at 90 days.

Let me get this straight… DAPT is not, not, not worse than tPA?
Current guidelines recommend thrombolytics for AIS patients presenting within 4.5 hours. However, recent trials question tPA in minor strokes (NIHSS ≤ 5).1-3 The ARAMIS Trial4 is a multicenter, open-label, blinded endpoint, non-inferiority study (*more on this below*) in which image confirmed minor AIS patients (n = 760) were randomized to IV alteplase (followed by DAPT at 24-hours) versus DAPT-only. They determined that 93.8% of the DAPT-group had excellent neurologic outcomes at 90 days (0 or 1 modified Rankin Scale) versus only 91.4% in the alteplase-group. Significant secondary outcomes included an increased risk of both neurologic deterioration at 24 hours (adjusted risk difference of -4.6%) and bleeding events (adjusted RD -3.6%) in the alteplase group.

I found their decision to present the primary outcome as “non-inferiority” particularly interesting. These measurements can be difficult to interpret (hence the subheading not, not, not worse…) and are discussed previously on JournalFeed. To be non-inferior, or at least not worse than alteplase, the authors suggest that DAPT must have a lower 1-sided 97.5%CI margin of its risk difference ≥ -4.5%. If this number seems odd to you, you’re not alone! It’s actually derived from IST-3, a subgroup analysis that found a 9% absolute difference in favorable outcomes between alteplase and standard medical care. The ARAMIS authors extrapolate that preserving at least 50% of this difference (i.e. -4.5% as the lower margin) would provide significant results. Therefore, although this non-inferiority approach is evidence-based, they could have chosen a different value for the non-inferiority margin, which would have changed the study’s conclusion.

Ultimately, these authors calculated an adjusted risk difference of 2.3% (with an adjusted 95% CI: −1.6% to 6.1%) and a lower boundary of the CI greater than their pre-specified -4.5% value. In other words, DAPT was non-inferior and may be a reasonable alternative to alteplase in patients with minor strokes. Due to a high number of cross-over participants (20.4%), this may even be an understatement for the DAPT camp. However, interestingly this trend toward non-inferiority disappears in the subgroup analysis with NIHSS 4-5, suggesting that the scope for DAPT may be even more limited than what is proposed by the authors.

How will this change my practice?
Overall, this is a well-done RCT that attempts to address a knowledge gap in the stroke literature. I appreciate the authors’ honest self-critique and direction for future studies. As EM providers, we should be aware of the potential for DAPT as a replacement for alteplase in patients with MINOR, non-disabling strokes, as our neurologists may begin recommending this on shift.

Editor’s note: This trial was messy, with 22% crossing over from DAPT to alteplase and 16% from alteplase to DAPT. However, the per-protocol and as-treated analyses had similar results to the intention to treat analysis. My take home: For very mild strokes, don’t use alteplase (or other lytics). As NIHSS approaches 5, lytics may make more sense, though the PRISMS RCT haunts me. In fact, I just had a case like this last week (NIHSS was 1), and I recommended against TNK. She weighed her options and chose no lytics. ~Clay Smith

Dual Antiplatelet Therapy vs Alteplase for Patients With Minor Nondisabling Acute Ischemic Stroke: The ARAMIS Randomized Clinical Trial. JAMA. 2023 Jun 27;329(24):2135-2144. doi: 10.1001/jama.2023.7827.

Works Cited

  1. Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits: The PRISMS Randomized Clinical Trial. JAMA. 2018 Jul 10;320(2):156-166. doi: 10.1001/jama.2018.8496. PMID: 29998337; PMCID: PMC6583516.
  2. Platelet-oriented inhibition in new TIA and minor ischemic stroke (POINT) trial: rationale and design. Int J Stroke. 2013 Aug;8(6):479-83. doi: 10.1111/ijs.12129. PMID: 23879752; PMCID: PMC4412261.
  3. Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) trial. New England Journal of Medicine. 2013 Jul;4(369):11-19. 10.1056/NEJMoa1215340.
  4. Dual Antiplatelet Therapy vs Alteplase for Patients With Minor Nondisabling Acute Ischemic Stroke: The ARAMIS Randomized Clinical Trial. JAMA. 2023;329(24):2135–2144. doi:10.1001/jama.2023.7827

What are your thoughts?