Comparing ticagrelor versus clopidogrel in patients with a history of cerebrovascular disease: a net clinical harm?

T he PLATO trial was a phase 3, randomized, double-blind, parallel-group, multinational, clinical study comparing the efficacy of ticagrelor (formerly known as AZD6140, marketed as Brilinta) versus standard care treatment with clopi-dogrel. Patients (n=18 624) with moderate-to high-risk acute coronary syndrome undergoing coronary intervention or medically managed were randomized to ticagrelor 180 mg loading dose followed by 90 mg twice daily thereafter, or clopidogrel 300 to 600 mg loading dose followed by 75 mg once daily for 6 to 12 months. 1 The primary end point was the time of the first event of death from vascular causes, myocardial infarction or stroke, and occurred in 11.7% of patients treated with clopi-dogrel, versus 9.8% of patients randomized to ticagrelor, representing a highly significant benefit (hazard ratio [HR]=0.84; CI=0.77–0.92; P<0.001) for ticagrelor. 1 Importantly, the benefit of ticagrelor was driven equally by the reduction of vascu-lar death (P<0.001), and myocardial infarction (P<0.005) with 89 events favoring ticagrelor each, but not stroke (P=0.22) with 19 less events in the clopidogrel arm. 1 Moreover, the original PLATO data indicated a 17% increase in stroke (19 extra events; number needed to harm 491) with ticagre-1 However, the Food and Drug Administration complete response review indicates an even greater risk of stroke (24% increase) with ticagrelor versus clopidogrel (27 extra strokes; 138/9333 versus 111/9291; HR=1.24 [0.97–1.59]; number needed to harm=352) just missing statistical significance (P=0.09). 2 In summary, the original PLATO results may underestimate the risk of stroke on ticagrelor compared with clopidogrel. The Food and Drug Administration complete response review indicates that patients having a history of cerebrovas-cular disease (cerebrovascular, carotid artery disease, verte-brobasilar artery disease) had a >2-fold increase in the risk of a cerebrovascular event (stroke or transient ischemic attack [TIA]) on ticagrelor compared with clopidogrel (8.1% versus 4.0%; P=0.24) in the PLATO trial (Table 2). 2 Patients who had a history of cerebrovascular disease on ticagrelor had a >5-fold increase in the risk of a stroke or TIA compared with all patients on ticagrelor (8.1% versus 1.59%; relative risk=5.1). 2 Clopidogrel-treated patients with a history of cerebrovascular disease also had an increase in the risk of a stroke or TIA compared with all patients treated with clopidogrel (4.0% versus 1.49%; relative risk=2.5), albeit half the increased risk that was associated with ticagrelor. 2 Moreover, compared with clopi-dogrel, patients on ticagrelor had a 2-fold increase in major or life-threatening intracranial hemorrhage (n=27 [0.3%] …