Ticagrelor in Acute Coronary Syndromes

The PLATO trial demonstrated significantly lower mortality and myocardial infarction in acute coronary syndrome (ACS) patients treated with ticagrelor and aspirin compared to clopidogrel and aspirin. Ticagrelor is a direct acting P2Y12 receptor antagonist, and is a more potent inhibitor of platelet reactivity than clopidogrel, and this is believed to be the main cause of its superior efficacy in the PLATO trial. A range of factors have been associated with high on-treatment platelet reactivity (HOTPR) on clopidogrel, including genetic factors, drug interactions and clinical risk factors. HOTPR on clopidogrel has been associated with a higher risk of adverse outcomes following ACS. On the basis of the PLATO trial results, and the theoretical limitations associated with clopidogrel, ticagrelor was funded by PHARMAC in July 2013, and has been recommended for use in patients with ACS in New Zealand. This thesis examined the use of ticagrelor in a real world ACS population being managed through Wellington Hospital cardiology department. We examined platelet reactivity in patients treated with ticagrelor compared to clopidogrel, factors associated with clinician choice to use ticagrelor versus clopidogrel and the incidence of side effects of ticagrelor that may have implications for compliance with the drug outside the setting of a randomized controlled trial. We found that ticagrelor significantly reduced both platelet reactivity (30.3 AU ± 17.5 versus 43.7 AU ± 24.8, p= 0.0001) and the proportion of patients classified as having HOTPR (15.9% versus 37.7%, p= 0.0001), in comparison to clopidogrel. The clinical variables associated with HOTPR differ between clopidogrel and ticagrelor, suggesting that different factors were driving residual platelet reactivity on the two agents. Over a 2 year period, clopidogrel (68%) was used more commonly than ticagrelor (42%), and in a different cohort of patients. Patients treated with ticagrelor were younger (61 years ± 10 versus 65 years ± 12, p=0.0001), less likely to present with STEMI (12% versus 31%, p=0.0001), less likely to have a history of prior myocardial infarction (15.8% versus 22.7%, p=0.05), and had lower GRACE (98 ± 24 versus 108 ± 28, p=0.0001) and CRUSADE (25 ± 9 versus 28 ± 12, p=0.001) risk scores compared to those treated with clopidogrel. Prescription of ticagrelor was therefore not driven by clinical risk. Antiplatelet prescription varied significantly according to the patients’ admitting hospital. Bleeding rates on ticagrelor and clopidogrel within 30 days of study enrolment were low and were not significantly different. There was 1 patient on clopidogrel who had the drug discontinued due to bleeding. At 30 day follow up, significantly more patients treated with ticagrelor reported dyspnoea (43.3% versus 27.1%, p=0.001), however discontinuation of the drug due to dyspnoea on ticagrelor was infrequent (1.7%). In this real world cohort of ACS patients, we observed that ticagrelor was associated with more potent platelet inhibition than clopidogrel, but was not associated with factors leading to increased discontinuation at 30 days. Despite the proven benefits of ticagrelor compared to clopidogrel, the majority of patients, including the highest risk patients appear to be preferentially treated with clopidogrel. The causes contributing to underuse of ticagrelor need to be examined and addressed.