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.

Inclusion Criteria:

1. Men and women aged 18 years or above.
2. Documented history of presumed spontaneous ACS (excluding known peri-procedural or definite secondary MI [eg, due to profound hypotension, hypertensive emergency, tachycardia, or profound anemia]) with their most recent MI occurring 18 months or more prior to randomization
3. Patient currently prescribed and tolerating ASA
4. Females of child-bearing potential (ie, who are not chemically or surgically sterilized or who are not post-menopause) must have a negative urine pregnancy test at enrollment (to be confirmed by blood pregnancy test at the central lab.) Females of child-bearing potential must be willing to use a medically accepted method of contraception that is considered reliable in the judgment of the investigator.
5. Written informed consent prior to any study specific procedures.

Exclusion Criteria:

1. Recurrent cardiovascular event (ACS, stroke and unplanned revascularization) after the index ACS

2. Planned use of ADP receptor blockers (eg, clopidogrel, ticlopidine, prasugrel), dipyridamole, or cilostazol

3. Planned coronary, cerebrovascular, or peripheral arterial revascularization

4. Concomitant oral or intravenous therapy with strong cytochrome P450 3A (CYP3A) inhibitors, CYP3A substrates with narrow therapeutic indices, or strong CYP3A inducers which cannot be stopped for the course of the study - Strong inhibitors: ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin (but not erythromycin or azithromycin), nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir, over 1 litre daily of grapefruit juice - Substrates with narrow therapeutic index: cyclosporine, quinidine, simvastatin at doses >40 mg daily or lovastatin at doses >40 mg daily

5. Concomitant use of vasoactive drugs or vasoactive drugs cannot be stopped.

6. Need for chronic oral anticoagulant therapy or chronic low-molecular-weight heparin (at venous thrombosis treatment not prophylaxis doses)

7. Patients with known bleeding diathesis or coagulation disorder

8. Patients with:

   • Concomitant active pathological bleeding,
   • A history of intracranial bleed at any time,
   • A central nervous system tumour or intracranial vascular abnormality (eg, aneurysm, arteriovenous malformation) at any time,
   • Intracranial or spinal cord surgery within 5 years, or
   • A gastrointestinal (GI) bleed within the past 6 months, or major surgery within 30 days

9. History of ischemic stroke at any time

10. Patients considered to be at risk of bradycardic events ([eg, known sick sinus syndrome or second or third degree atrioventricular (AV) block]) unless already treated with a permanent pacemaker

11. Coronary-artery bypass grafting in the past 5 years, unless the patient has experienced a spontaneous MI subsequent to the bypass surgery.

12. Known severe liver disease (eg, ascites or signs of coagulopathy)

13. Renal failure requiring dialysis or anticipated need for dialysis during the course of the study

14. Hypersensitivity to ticagrelor or any excipients

15. Pregnancy or lactation

16. Life expectancy < 1 year

17. Any condition which in the opinion of the Investigator would make it unsafe or unsuitable for the patient to participate in this study (eg, active malignancy other than squamous cell or basal cell skin cancer)

18. Concern for inability of the patient to comply with study procedures and/or follow up (eg, alcohol or drug abuse)

19. Participation in previous study with ticagrelor if treated with ticagrelor. Previous randomization in the present study

20. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)

21. Participation in another clinical study with an investigational product during the preceding 30 days