Philip Chang, MD

Kim J-T, Park M-S, Choi K-H, Cho K-H, Kim BJ, Park J-M, et al. Comparative Effectiveness of Aspirin and Clopidogrel Versus Aspirin in Acute Minor Stroke or Transient Ischemic Attack. Stroke. 2018;50:101–109.

In this study, Kim et al. studied and replicated the CHANCE protocol in stroke patients via a prospective registry database in South Korea. Patients were enrolled with acute minor stroke defined as NIHSS≤3 or lesion positive TIA with a non-cardioembolic stroke mechanism based on imaging. Among the 5590 patients enrolled, they found that combination of clopidogrel-aspirin had significantly less major adverse cardiac events compared to aspirin alone (14% vs 10%, p=0.008). This was mostly due to significantly reduced risk of stroke in the 90-day follow-up period in the dual antiplatelet group (13% vs 9%, p=0.008). This would be another confirmation of the validity of early dual antiplatelet therapy in reducing recurrent stroke risk. With the publication of CHANCE and POINT, along with all this subsequent data, I suspect there will be a change in guideline recommendations to more strongly encourage early use of dual antiplatelet therapy in minor strokes. They did 6 per-defined subgroup analyses, among which showed lesser benefit associated if people were already on antiplatelet therapy, were >75 years of age, and had a non-small vessel disease stroke mechanism.

What is interesting to me is the subgroup analyses. CHANCE previously had done a subgroup analyses of their data (PMID 29582084) and had found the patients who benefited most were those with multiple acute infarction patterns on MRI. Supplementary tables showed that further analysis suggested that those with large vessel atherosclerotic disease were the ones who benefited from treatment the most. In our current South Korean study, patients were also stratified based on the TOAST criteria, and it was found that not only large vessel atherosclerotic disease, but the “other determined mechanism” of stroke and cryptogenic stroke, also benefited from early dual antiplatelet therapy. To me, this indicates that patients with large-vessel atherosclerotic disease very much benefit from dual antiplatelet therapy.

Pushing the Boundary: How can we expand the patients we can treat with dual antiplatelet therapy?

In thinking from a pathophysiological view, the criteria of NIHSS≤3 was likely implemented due to fear of possible symptomatic intracranial hemorrhage due to increase in antithrombotic therapy. With the corollary that large strokes tend to higher chances of hemorrhagic conversion, I think the NIHSS criteria was to avoid symptomatic bleeding complications. My interpretations of the dual antiplatelet studies are that, in spirit, we want to prescribe dual antiplatelet therapies in patients who are low-risk for hemorrhagic conversion, and only continue it in the highest risk period time (first month after stroke). While the NIHSS score makes the study easy to replicate, I wonder if we may be limiting the patients who may benefit due to the NIHSS favoring left hemispheric strokes. Instead of NIHSS, I wonder if MRI lesion volume would serve as a good corollary for patients who may benefit from dual antiplatelet therapy. For example, a small corona radiata or centrum semi-ovale stroke may present with a conduction aphasia along with a hemiparesis/hemisensory loss with NIHSS>3, but the same sized lesion elsewhere (especially if on R frontal lobe territory) may have an NIHSS=0. One would wonder, since the stroke lesion volume is the same, could you assume they have similar bleeding risk? The NIHSS is heavily affected by WHERE the lesion is, not how big. Conversely, one could hide a 5cc stroke in the R orbital frontal lobe or cerebellum but easily have an NIHSS<3. To me, these patients may have increased risk of hemorrhagic transformation. For the future, I wonder if MRI along with TOAST criteria will help us appropriately select patients who will benefit the most from early dual antiplatelet therapy. For example, I wonder if small, strategically placed infarctions with NIHSS>3 may also benefit from early dual antiplatelet therapy, especially if the TOAST classification is due to large artery atherosclerosis.

Clinical Scenario to Ponder: You have a 60-year-old male who recently had a stroke with an NIHSS=10 due to aphasia. He had concurrently had a pneumonia on presentation which resulted in encephalopathy, explaining a higher NIHSS score than expected. However, MRI showed only 2 punctate infarctions 1mm each in the left PCA territory. CTA shows severe bilateral V4 vertebral artery stenosis. Would this patient benefit from early dual antiplatelet therapy?