Safety and Efficacy of Low-Dose Ticagrelor in Chinese Patients With NSTE-ACS

Ticagrelor is an oral, reversibly-binding, direct-acting P2Y12 receptor antagonist used
clinically for the prevention of atherothrombotic events in patients with acute coronary
syndromes (ACS). Guideline recommendations on the use of dual antiplatelet therapy (DAPT)
have been formulated that ticagrelor 90 mg twice daily plus aspirin in preference to
clopidogrel 75mg daily plus aspirin for patients who have an ACS with or without ST-segment
elevation. These recommendations are primarily based on large, randomized, Phase III
clinical trials. However, few East Asian patients (or those of East Asian descent) have been
included in these trials to assess the use of these drugs. In addition, a growing body of
data supported that East Asian might have different adverse event profiles (thrombophilia
and bleeding) and "therapeutic window" compared with white subjects. Furthermore, "East
Asian paradox" phenomenon has been described that East Asian patients have a higher
prevalence of platelet reactivity during DAPT, but an ischaemic event rate following PCI or
ACS is similar or even lower than white patients. Therefore, the antiplatelet treatment
strategy that is most appropriate for East Asian patients is increasingly urgent. In Korea
and Japan, it has been reported that low doses of ticagrelor had a more potent inhibition of
platelet aggregation (IPA) than clopidogrel (75 mg once daily) in healthy subjects and
patients with stable coronary artery disease, respectively. But it is still not clear
whether a low dose of ticagrelor is superior to clopidogrel in a large population of Chinese
ACS patients. A recent study on pharmacokinetics and tolerability of ticagrelor has found
that maximum plasma concentration (Cmax) and area under the plasma concentration-time curve
(AUC) of ticagrelor (90 mg twice daily) and its active metabolite (AR-C124910XX) tended to
be approximately 40% higher in healthy Chinese volunteers compared with Caucasian subjects.
This data also suggested that a low dose of ticagrelor might be more appropriate for Chinese
ACS patients. In view of a large diurnal variation with a single daily dose, a lower dose
twice daily may be a better choice for Chinese patients. Therefore, we performed the current
study to observe the different effects of low-dose ticagrelor (45 mg twice daily),
conventional-dose ticagrelor (90 mg twice daily) and clopidogrel (75mg once daily) on high
platelet reactivity (HPR) and IPA, and investigated the safety and efficacy of low-dose
ticagrelor further in Chinese patients with non-ST-elevation ACS (NSTE-ACS).

Inclusion Criteria:

- hospitalized for NSTE-ACS within the preceding 48 h

- have one of the following additional criteria:

1. ischemic symptoms at rest, lasting ≥10 minutes;

2. horizontal or down-sloping ST segment depression ≥0.1 mV;

3. cardiac troponin I (cTnI), marker associated with NSTE-ACS, local laboratory
upper limit of normal values;

4. underwent percutaneous coronary intervention (PCI); (5) a history of myocardial
infarction.

Exclusion Criteria:

- ST-elevation ACS;

- planned use of glycoprotein IIb/IIIa receptor inhibitors, adenosine diphosphate (ADP)
receptor antagonists, or anticoagulant therapy during the study period;

- platelet count <100g/L;

- creatinine clearance rate < 30ml/min;

- diagnosed as respiratory or circulatory instability (cardiac shock, severe congestive
heart failure NYHA II-IV or left ventricular ejection fraction < 40%);

- a history of bleeding tendency;

- aspirin, ticagrelor or clopidogrel allergies;

- diabetes.