Dosage

Following hospital discharge, ticagrelor should be administered at a dose of 90 mg BID. Following ACS a loading dose of 180 mg of should be administered. Absorption is not affected by food and no dosing adjustment is required in patients with chronic renal disease or in patients with mild hepatic impairment. Patients taking ticagrelor should also take acetylsalicylic acid (ASA) daily, unless specifically contraindicated. Ticagrelor should be used with a daily maintenance dose of ASA of 75-150 mg. Doses of ASA above 150 mg daily should not be used with ticagrelor.

Mechanism of Action

Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP), a selective, reversibly bound P2Y12 receptor antagonist that prevents ADP mediated platelet activation and aggregation. It is also characterised as a non-competitive antagonist since its binding site on the platelet P2Y12 receptor is different from that of ADP. Unlike prasugrel and clopidogrel, ticagrelor is active in its unchanged form not requiring conversion to an active metabolite to inhibit this process.

Natural binding of the receptor by ADP results in inhibition of cAMP-mediated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) (VASP-P), which is known to be closely related to the inhibition of glyprotein IIb/IIIa receptor activation.

Recommendations in Vascular Prevention

Secondary CAD Prevention

Data from a large randomized controlled trial demonstrated that ticagrelor provided a significant 1.9% absolute risk reduction over clopidogrel in the combined endpoint of MI, stroke and CV death in patients with all forms of ACS treated medically, by PCI or CABG. Secondary analysis demonstrated a significant 1.1% and 1.4% absolute risk reduction in CV death and all-cause mortality respectively. Although trial defined bleeding was not significantly increased by ticagrelor over clopidogrel, the clinically relevant safety endpoint of non-CABG related bleeding was increased by a statistically significant absolute rate of 0.7%. In the subpopulation analysis subjects from North America did not benefit from ticagrelor over clopidogrel which may have been due to doses of ASA above 150 mg used in that population.

Ticagrelor has a more potent inhibitory effect on platelet aggregation than clopidogrel and is associated with a more rapid onset and offset of effect.

Recommendations

For patients with ACS, ticagrelor 90 mg twice daily may be added to ASA 75-162 mg daily for 12 months (Class I, Level B).

For patients with ACS who undergo stent implantation, ticagrelor 90 mg twice daily may be added to ASA 75-162 mg daily for 12 months (Class I, Level B).

Warnings & Special Considerations

Increased rates of dyspnea, including dyspnea at rest, exertional dyspnea, paroxysmal nocturnal dyspnea, and nocturnal dyspnea has been reported with ticagrelor. The dyspnea is usually mild to moderate in intensity and often resolves during continued treatment. The mechanism has not yet been elucidated but is felt to be due to adenosine effects and not related to pulmonary or cardiac dysfunction.

Ticagrelor has been associated with increased rates of ventricular pauses of >3 and >5 seconds. The effect is usually seen early in treatment and has not been associated with bradycardic events such as syncope, pacemaker insertion or heart block. Patients with an increased risk of bradycardic events were excluded from studies so caution should be used when ticagrelor is used in such patients.

Secondary analysis of a large randomized controlled trial suggests reduced benefit of ticagrelor in patients taking doses of ASA >150 mg OD. Doses of ASA above 150 mg daily should not be used with ticagrelor.

Small, but statistically significant, increases in serum creatinine and uric acid have been observed in patients taking ticagrelor.