Philip Chang, MD
When your patient has a stroke while on an antiplatelet regimen, a common practice is to switch it. If they were on aspirin, change to clopidogrel. If on clopidogrel, one may think of switching to aspirin plus dipyridamole. While there has been much theory about aspirin failure, or aspirin resistance, there has been scant evidence to suggest that switching antiplatelet agents may benefit patients. Clinicians have switched antiplatelet regimens under the common philosophy, “Insanity is doing the same thing over and over again and expecting different results.” This is with the underlying theory that patients who experience recurrent stroke while on aspirin must have developed aspirin resistance, and blocking another antiplatelet pathway (like ADP) will confer some protective benefit. However, this theory has never been proven or disproven by a clinical study. This article by Lee et al is a great step into this clinical conundrum.
This meta-analysis including 8723 patients from 5 clinical trials (of which SPS3, SOCRATES, and CHANCE will be familiar) who were on aspirin while experiencing an ischemic stroke or TIA found that patients who either switched to a different antiplatelet agent or to dual-antiplatelet therapy experienced 32% reduced risk of major adverse cardiac events, and 30% reduced risk of recurrent stroke. This is exciting news to confirm my own bias on the matter, but one must proceed with caution. The trials included in the meta-analysis were quite different, and there was moderate-to-high heterogeneity of treatment effect across the models, making it somewhat difficult to apply to clinical practice.
Question 1: When would the change in antiplatelet therapy be most effective?
SPS3 enrolled patients within 180 days of stroke, while the other 4 studies enrolled patients during acute hospitalization or within 24 hours. SOCRATES and CHANCE only followed patients to 90 days, while other studies followed them for up to 3.5 years. It is common knowledge now that risk of recurrent stroke is highest in the first 90 days, and that long-term dual antiplatelet therapy is likely not beneficial after stroke. When they discarded SPS3 from their dataset, their heterogeneity score and effect size of their outcomes were improved. It seems that switching early confers a larger benefit.
Question 2: What antiplatelet agent would we switch to?
Adding up all the numbers finds that 1429 patients were switched to aspirin plus clopidogrel, 2130 were switched to ticagrelor, 246 patients were switched to some other antiplatelet agent, and 4534 were kept on aspirin monotherapy. Thus, it seems switching to an ADP may be of benefit, and switching to the combination of aspirin plus dipyridamole is still unstudied. Almost a third of the non-aspirin monotherapy group was on aspirin plus clopidogrel, and again we know this is not beneficial in the long-term. This begs the question — how long would you keep these patients on dual-antiplatelet therapy? If so, I wonder if the effect of reduced stroke in this study would be due to intensifying antiplatelet therapy in the short-term like in CHANCE rather than a long-term preventative strategy. It would be interesting to see how the hazard ratios match up for switching to ticagrelor or clopidogrel alone.
In conclusion, while this study seems to confirm our gut instinct to switch antiplatelet regimens in patients that have an ischemic stroke/TIA while on aspirin, it is important to realize that aspirin only confers an average 20% risk reduction in recurrent stroke — it is not a perfect medication. The heterogeneity and the nature of it being an observation study make it difficult to quickly apply this to clinical practice. As the authors note, these results are only a suggestion that switching antiplatelet therapy is beneficial rather than an evidence-based clinical guideline.