SGEM#303: Two Can Make It – Less likely to have another stroke but more likely to have a bleed (THALES Trial)

Date: October 2nd, 2020 Guest Skeptic: Dr.Barbra Backus is an emergency physician at the Emergency Department of the Erasmus University Medical Center in Rotterdam, the Netherlands. She is the creator of the HEART Score and an enthusiastic researcher. Reference: Claiborne Johnston S et al. Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA. NEJM July 2020 Case:  A 65-year-old man with a history of well controlled hypertension presents to the emergency department and is diagnosed with a mild stroke (NIHSS score 3). He is a non-smoker, not diabetic and has never had a stroke before. The only medicine he takes is an angiotensin converting enzyme inhibitor. You are wondering if he should be discharged on just aspirin or aspirin plus another antiplatelet agent like ticagrelor. Background: Acute ischemic strokes are the leading cause of disability in our society and the third most common cause of death. Aspirin has been used to prevent a subsequent stroke in patients who suffered an acute ischemic stroke (AIS) or transient ischemic attack (TIA), which occur in approximately 5-10% of patients in the first few months after their primary event. Trials have shown mixed results with the combination of aspirin with clopidogrel in this population. SGEM#24 reviewed a randomized controlled trial (RCT) of aspirin vs. aspirin + clopidogrel in patients with recent symptomatic lacunar infarcts identified by MRI (Benavente et al NEJM 2012). Adding clopidogrel to aspirin did not reduce recurrent strokes but did increase risk of bleed and death. The study was stopped early due to harm and lack of efficacy. An RCT done in China on patients with minor strokes or TIAs who were treated within 24 hours after the onset of symptoms showed that aspirin plus clopidogrel is superior to aspirin alone for reducing the risk of stroke in the first 90 days and does not increase the risk of hemorrhage (Wang et al NEJM 2013). A third RCT assigned patients with minor ischemic stroke or high-risk TIA to ASA alone or the combination of both aspirin and clopidogrel. This trial was also stopped early because of lower risk of major ischemic events but higher risk of major hemorrhage with the combination therapy compared to aspirin alone (Johnston et al NEJM 2018). As an antiplatelet agent that blocks the P2Y12 receptor, clopidogrel requires hepatic conversion to its active form through a pathway that is ineffective in 25% of white and 60% of Asian patients; efficacy is therefore uncertain in these patients (Pan et al Circulation 2017). Ticagrelor is a direct-acting antiplatelet agent that does not depend on metabolic activation. A trial of ticagrelor alone did not show a benefit over aspirin in preventing subsequent cardiovascular events (Johnston et al NEJM 2016). The effect of the combination of ticagrelor and aspirin on prevention of stroke has not been well studied. Clinical Question: Is the combination of ticagrelor and aspirin superior to aspirin alone in reducing the risk of subsequent stroke or death among patients with acute non-cardioembolic cerebral ischemia? Reference:Claiborne Johnston S et al. Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA. NEJM July 2020 Population: Patients 40 years and older who experience a mild-to-moderate acute noncardioembolic ischemic stroke (NIHSS score of 5 or less), or high-risk TIA (ABCD2>5) or symptomatic intracranial or extracranial arterial stenosis (>50% lumen narrowing accounting for the TIA) Excluded: Thrombolysis or EVT was planned <24 hours before randomization or if there was planned use of anticoagulation or specific anti-platelet therapy other than ASA. Patients were also not eligible if they had “hypersensitivity to ticagrelor or ASA, a history of atrial fibrillation or ventricular aneurysm or a suspicion of a cardioembolic cause of the TIA or stroke, planned carotid endarterectomy that required discontinuation of t...