Philip Chang, MD
As neurologists, we have all encountered patients with mild lacunar stroke, confirmed on MRI to be a small subcortical lesion, especially if caught early on. However, some patients, despite a small stroke seen on early MRI having waxing and waning symptoms, for example going from complete plegia to a mild hemiparesis within the same hour. Why would this be the case? CHANCE and POINT enrolled patients of minor non-cardioembolic strokes, and proved that dual antiplatelet therapy was superior in reducing recurrent strokes in minor strokes with NIHSS<3. If one thinks about the enrollment criteria, this would likely leave small vessel disease, large vessel disease, and other/cryptogenic by TOAST criteria.
In my blog entries’ ongoing discussion on dual antiplatelet data, there has been a long story about likely success of dual antiplatelet therapy in stabilizing large artery atherosclerosis, both by transcranial doppler studies as well as a newly published study in Stroke, “Dual Versus Mono Antiplatelet Therapy in Large Atherosclerotic Stroke: A Retrospective Analysis of the Nationwide Multicenter Stroke Registry.” In my opinion, this likely drives a large portion of the effect size in CHANCE/POINT. However, early neurologic deterioration was not differentiated from early recurrent stroke in these trials, and a portion of the effect size may have been from dual antiplatelet treatment of lacunar strokes with early neurological deterioration, which likely includes entities such as “stuttering lacunar syndrome” or “capsular warning syndrome.”
“Small vessel disease”, the TOAST category of most small subcortical lacunar strokes, has a variety of different causes; the etiologies are expanding recently with research into sleep, lymphatic drainage, perivascular spaces. I hypothesize that a subset of these strokes are due to the classic description of small artery occlusion due to lipohyalinosis or fibrinoid necrosis or atherosclerosis due to hypertension, diabetes, hyperlipidemia in the small vessels. While it may be very difficult to distinguish different etiologies of small vessel disease, likely the subset from small-vessel atherosclerotic lesions could be the ones that benefit from dual antiplatelet therapy. In the literature, there are many case reports of “stuttering lacune/capsular warning syndrome.” Initially described by Dr. C. Miller Fisher as one of the classical lacunar strokes with waxing and waning symptoms and a natural history to complete infarction, there has been several case reports/case series of avoiding complete infarction with dual antiplatelet therapy including a load of clopidogrel in addition to aspirin. However, there has been no large set of data to support this until this study. While it is a retrospective study, it does suggest that patients with lacunar stroke and early neurological deterioration may be up to 2 times more likely to have better functional outcome when compared to antiplatelet monotherapy. 68% improved to admission NIHSS score at discharge while on dual antiplatelet therapy when compared to 33% in the antiplatelet monotherapy group, a finding that was statistically significant (p=0.0019). I believe this study supports additional circumstantial evidence that addition of clopidogrel to aspirin in the acute setting may prevent additional neurologic deterioration.
Application: I think this study supports and helps explain mechanistically how POINT and CHANCE were successful. Using dual antiplatelet therapy in noncardioembolic strokes with NIHSS<3 is likely standard of practice now, but this study can further expand the amount of patients eligible for dual antiplatelet therapy. Unfortunately, there is no clarification or information about the baseline NIHSS of patients enrolled, making it somewhat difficult to have a black and white application policy. For now, it seems that, as many academic centers may be practicing already, in setting of early neurological deterioration from lacunar ischemic stroke, dual antiplatelet therapy may be a reasonable therapeutic consideration. Further prospective randomized controlled trials will be needed evaluate risk of intracranial hemorrhage, upper tolerable limits of dual antiplatelet therapy including MRI lesion size or NIHSS on start of dual antiplatelet therapy.