Ticagrelor

Ticagrelor (Brilinta) AZD6140

Rationale

Acute Coronary Syndrome (ACS) is a major cause of morbidity and mortality in the United States. The management of ACS includes a combination of oral antiplatelet therapy like aspirin and clopidogrel; however, clopidogtel use is limited by a high degree of interpatient variability and inconsistent inhibition of platelets. Current limitations ofantiplatelet agents include high interpatient variability in efficacy, the occurrence of thromboembolic events despite therapy, and overall adverse events. An antiplatelet agent that is capable of producing more potent and consistent inhibition of platelets without increasing the risk of bleeding is highly wanted. Ticagrelor, a new, oral platelet P2Y12 antagonist is being studied as an alternativeantiplatelet agent to clopidogrel for the reduction of atherosclerotic events in patients with ACS.

There have been key clinical trials on ticagrelor. In the DISPERSE-2 trial the primary objective was to assess the safety and tolerability of the different doses of ticagrelor versus clopidogrel in patients with non-ST-segment elevation ACS by evaluating the total bleeding events seen within the first4 weeks of treatment. The secondary endpoints were rates for cardiovascular death or MI. In the end, the study showed similar safety and tolerability for ticagrelor compared with clopidogrel, yet there was a trend towards a lower rate of MI for patients taking ticagrelor. According to the DISPERSE-2 study, superior platelet inhibition is achieved with ticagrelor in both clopidogrel-naïve andclopidogrel -pretreated patients. In addition, the ONSET/OFFSET study further showed that ticagrelor inhibited platelets to a greater extend than clopidogrel did. Another important trial was the PLATO for which the primary efficacy end point was the composite of vascular death, MI, and stroke. The primary safety end point was major bleeding as defined by the study and TIMI criteria. The principalsecondary efficacy end point was the primary efficacy variable studied in those patients who underwent invasive management. The primary endpoint of death from vascular causes, MI, and stroke occurred less often in the ticagrelor group than in the clopidogrel group. In addition, there was no difference in CABG-related TIMI major bleeding or bleeding requiring transfusion of red blood cells in theTicagrelor and clopidogrel groups, but on the contrary there was a strong inclination towards higher rates of non-CABG-related TIMI major bleeding and intracranial bleeding with ticagrelor over clopidogrel. Rates of other types of major bleeding using other criteria like GUSTO and PLATO were fewer with ticagrelor. Ticagrelor treated patients that received a stent during the study had a lower rate ofdefinite stent thrombosis than those in the clopidogrel group. All in all, clinical studies of patients with both ST and non-ST elevation ACS have shown that ticagrelor, compared to clopidogrel, reduces the rates of vascular death, myocardial infarction, or stroke but increases the rate of non-coronary artery bypass graft-related major bleeding compared to clopidogrel.

Indications

FDAapproved indication: Unknown yet, ticagrelor is currently under review by FDA as of November 2009

A. Non-FDA approved indication: Acute myocardial infarction, percutaneous coronary intervention (PCI), and thrombosis prophylaxis 
Drug Class: First Antiplatelet Agent of the cyclo-pentyl-triazolo-pyrimidines class
Pharmacology: ACS is characterized by rupture of an atherosclerotic plaque withinthe coronary artery, with subsequent platelet aggregation, thrombus formation, and ischemia. For platelet aggregation to occur platelets must first be activated which occurs by endogenous platelet agonists like adenosine-5-diphosphate (ADP) binding to the P2Y12 receptors on the platelet surface. Ticagrelor is an oral, reversible P2Y12 receptor antagonist that exerts its antiplatelet effects by...