Ticagrelor Monotherapy Compared to Aspirin Monotherapy in Patients With History of ACS

Overview

Antiplatelet agents are cornerstones for management of ischemic heart disease. For patients suffering from acute coronary syndrome (heart attack), treatment with aspirin and ticagrelor are typically given for one year after index heart attack and then patients will continue to take aspirin lifelong. However, these patients are still having increased risk of suffering from another heart attack. Recently data showed that adding ticagrelor to aspirin in the long term can decrease the chance of recurrent heart attack but at the cost of increased risk of major bleeding. On the other hand, ticagrelor is a potent antiplatelet agent and has been showed to have additional benefit on blood vessels and platelets. The investigator hypothesize that monotherapy with ticagrelor may have further benefit over monotherapy with aspirin in the long term management in patients with history of heart attack. The investigator plan to perform a randomized study to compare the outcome in patients taking either ticagrelor or aspirin. The primary endpoint is measurement of endothelial function by flow mediated dilatation of brachial artery which is a surrogate marker of adverse cardiovascular outcome 3 months after treatment. The investigator would also investigate secondary endpoints of patients' blood level of adenosine activity, platelet function, endothelial progenitor cell count and biomarkers

Acute coronary syndrome (ACS) is a disease with high mortality, morbidity and economic burden. Usually, it is caused by ischemic heart disease and atherosclerotic plaque rupture in the coronary arteries causing platelet activation, aggregation and thrombus formation. For decades, antiplatelet agents are the cornerstones of management of ACS and several clinical trials have confirmed greater clinical efficacy of dual antiplatelet therapy with clopidogrel and aspirin (ASA) versus ASA alone in patients with acute coronary syndromes (ACS) for up to a year of therapy. Ticagrelor (AZD6140) is a reversible, potent, oral adenosine diphosphate (ADP) P2Y12 receptor blocker which has stronger antiplatelet activity than clopidogrel. Data from PLATO, a Phase III pivotal efficacy and safety study of ticagrelor, have demonstrated superiority of ticagrelor 90 mg twice daily over clopidogrel 75 mg daily with a duration of up to 12 months in the prevention of fatal and non-fatal cardiovascular event in ACS patients on ASA. In PLATO, ticagrelor was superior to clopidogrel in reducing the rate of the composite efficacy endpoint of CV death, MI, or stroke after ACS events. Furthermore, compared to clopidogrel, ticagrelor decreased the rate of death from any cause. PLATO-defined Major bleeding (primary safety endpoint) for ticagrelor did not differ significantly from that of clopidogrel but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting. The favourable results lead to approval of use of ticagrelor as Class I indication in ACS patients for up to one year in addition to ASA in ACC/AHA and European guidelines. After one year of DAPT, patients typically remained on single antiplatelet agent with ASA monotherapy being the conventional treatment. However, these patients are still at heightened risk of recurrent atherothrombotic events. The recent PEGASUS TIMI 54 trial investigated the use of ticagrelor in addition to aspirin in stable patients with prior myocardial infarction one to three years ago. It demonstrated ticagrelor either 90mg BD or 60mg BD significantly reduced the risk of cardiovascular death, MI and stroke compared with placebo; ticagrelor 60mg BD. However, the use of ticagrelor is also associated with higher risks of major bleeding; ticagrelor 60mg BD, HR 2.32. As the antithrombotic benefit of stronger antiplatelet effects of DAPT is offset by higher bleeding risk, it is reasonable to assume that a single potent antiplatelet agent such as ticagrelor may lead to better clinical outcome than ASA with less increase in bleeding risk when compared with DAPT. In addition to its antiplatelet effects, ticagrelor has been shown to improve endothelial function, increase plasma adenosine level, increase coronary blood flow, stabilize coronary plaques and reduce inflammation. These pleiotropic effects may lead to further clinical benefit of ticagrelor over other antiplatelet agents such as ASA and clopidogrel. Endothelial function as measured by flow mediated dilatation of brachial artery is a non-invasively measurable surrogate marker of adverse cardiovascular events. Adenosine is a purine nucleoside which has favourable effects on coronary vasodilatation, endothelial progenitor cell migration and ischemia-reperfusion injury while adenosine plasma activity can be measured by liquid chromatography.