Meghana Srinivas, MD

Lusk JB, Xu H, Peterson ED, Bhatt DL, Fonarow GC, Smith EE, Matsouaka R, Schwamm LH, Xian Y. Antithrombotic Therapy for Stroke Prevention in Patients With Ischemic Stroke With Aspirin Treatment Failure. Stroke. 2021;52:e777–e781.

When aspirin fails, what’s next? The use of aspirin for cardiovascular disease dates back to the 1950s to 1960s. It is only until very recently that studies have shown its lack of benefit in primary prevention of cardio and cerebrovascular diseases. In the United States, more than 40% of adults over the age of 70 years take aspirin for primary prevention of cardiovascular diseases, and more than 70% of patients of any age with a history of cardiovascular disease take daily aspirin. What’s next if patients who are taking aspirin for stroke prevention experience an ischemic stroke?

What can be tried? Increasing the dose of aspirin, adding a second drug, or switching to an alternate antiplatelet agent are often considered, but there is no evidence of superiority of one over the other. This study by Jay B. Lusk et al. used data from the American Heart Association Get with the Guidelines (GWTG) Stroke Registry to study the prevalence of aspirin failure in older patients who present with acute ischemic stroke and describe their discharge prescription pattern of antithrombotic therapy for secondary prevention of stroke.

This registry-based study used GWTG stroke registry (1734 GWTG-stroke hospitals) data, which included Medicare beneficiaries without atrial fibrillation who were discharged alive between October 2012 and December 2017. The standardized registry data included patient demographics, medical history, medications before admission, in-hospital treatment outcomes and discharge medications. Aspirin treatment failure was defined as documentation of patients taking aspirin monotherapy (without any other anti-thrombotic) within 7 days before hospital arrival. The outcome of interest was discharge antithrombotic.

The authors employed median and percentages to describe the distribution of continuous and categorical variables and ordinal logistic regression to identify factors associated with escalation of discharge antithrombotic to either single antiplatelet therapy (aspirin or clopidogrel), dual antiplatelet therapy (DAPT) (aspirin and clopidogrel), and anticoagulant with or without antiplatelet therapy. The study reported 38.2% of ischemic stroke survivors were taking aspirin monotherapy before stroke (median age 78 years, 53% females, 79.4% initial stroke, 20.6% recurrent stroke). However, the percentage of interest is, amongst the discharge antithrombotic therapy, 44.4% continued to remain on aspirin monotherapy, followed by DAPT (24.6%) and clopidogrel monotherapy (17.8%). The baseline antithrombotic therapy chosen at the time of discharge varied based on patient baseline characteristics. Those discharged on monotherapy (aspirin or clopidogrel) had fewer cardiovascular risk factors than those who received dual antiplatelet therapy (aspirin plus clopidogrel). Those who received clopidogrel or DAPT had less severe strokes (NIHSS 0-3), whereas those discharged on aspirin monotherapy, warfarin or non-vitamin K antagonist oral anticoagulant (NOAC) or no antithrombotic had evidence of severe stroke (NIHSS >10).

Graphic abstract

The analysis using ordinal logistic regression showed patients with coronary artery disease or prior myocardial infarction, carotid stenosis, peripheral vascular disease, hypertension, dyslipidemia, heart failure, prior stroke or transient ischemic attack were more likely to receive high intensity antithrombotic at discharge.

The results from this study show 3 main categories of discharge antithrombotic in acute ischemic stroke patients: either monotherapy with aspirin or clopidogrel or DAPT. There has been a higher frequency in the use of DAPT, which likely reflects practice based on the CHANCE and POINT trials, but this study found that there is heterogeneity in the DAPT group as patients received treatment even with an NIHSS of 3 or greater. Why is this important in clinical practice? Having more than one antithrombotic agent either as a single agent or in combination as a treatment strategy for secondary stroke prevention in patients where aspirin alone might not be 100% effective at reducing or eliminating risk of future strokes recurrences. As there are no studies showing superiority of one treatment strategy over another in providing additional protection against future strokes, there is an urgent need to evaluate the efficacy and safety of various treatment strategies for this complex yet common scenario.

This study has resulted in some important highlights that clinicians encounter in day-to-day practice; however, there are certain limitations, including the lack of generalizability as it is limited to Medicare ischemic stroke survivors in the GWTG stroke registry, selection bias due to lack of knowledge regarding aspirin dose prior to admission, and, most importantly, GWTG documents only medications at discharge but no reasoning as to the choice of antithrombotic prescribed.

Secondary prevention of cerebrovascular disease can be challenging at times, and the treatment might not always be 100% effective. Aspirin has been used for decades now, and the results of this study are showing that clinicians continue to prescribe aspirin monotherapy for secondary prevention at discharge despite recurrence, which makes us want to interpret aspirin failure as helping in reducing the risk but cannot prevent strokes in all scenarios.