Critical appraisal of ticagrelor in the management of acute coronary syndrome

Abstract

Ticagrelor is a novel P2Y₁₂ receptor antagonist which, like clopidogrel and prasugrel, functions by blocking adenosine diphosphate-mediated platelet aggregation. However, unlike the aforementioned agents, the binding of ticagrelor to this receptor is reversible. Ticagrelor is also believed to mediate some of its beneficial effects by augmenting the effects of adenosine, which is another unique pharmacologic property of this drug. In terms of antiplatelet effect, ticagrelor is more potent than clopidogrel and produces a faster and stronger inhibition of platelet aggregation. This may also be an advantage of ticagrelor over prasugrel, but this has not been adequately studied. Due to the reversible nature of the binding of ticagrelor to the platelet receptor, ticagrelor has a relatively fast offset of effect, with platelet aggregation approaching pretreatment levels about 3 days after discontinuation of therapy. This has advantages in patients requiring invasive procedures, but also makes medication adherence very important in order to be able to maintain an effective antiplatelet effect. Ticagrelor has been shown to be clinically superior to clopidogrel when given to patients with an acute coronary syndrome, resulting in significantly lower rates of myocardial infarction and vascular death. However, ticagrelor is indicated to be administered with aspirin, and the clinical benefits of ticagrelor may be less when daily dosages of aspirin exceed 100 mg. As expected, bleeding is the most common adverse effect with ticagrelor, although it occurs at rates comparable with those seen for clopidogrel with the exception of noncoronary artery bypass graft-related major bleeding and fatal intracranial bleeds, the latter of which occurs only rarely. Dyspnea is another common adverse effect with ticagrelor, although this is usually not severe and resolves with drug discontinuation. Unlike clopidogrel, there are no known pharmacogenomic concerns with ticagrelor, and emerging data suggest ticagrelor to be effective in patients resistant to clopidogrel, although more study is needed on this topic. While preliminary data suggest ticagrelor to be cost effective when compared with generic clopidogrel, the acquisition cost of ticagrelor is not insignificant and this will likely be an issue for many health care organizations. Currently, ticagrelor is well positioned to assume an active role in the treatment of coronary artery disease due to an impressive efficacy profile and reasonable safety. Its ultimate role in therapy will continue to evolve as studies on this drug continue eg, (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin, PEGASUS) and more information hopefully becomes available on its use in clopidogrel nonresponders and relative safety and efficacy compared with prasugrel.

Keywords: P2Y12; adenosine receptor antagonist; ticagrelor.

Figure 1

Adenosine diphosphate (ADP) binds to the P2Y₁₂ receptor. This binding results in activation of the platelet which causes a conformational shape change, activation of the glycoprotein (GP) IIb/IIa receptors, and platelet aggregation. Ticagrelor binds at a site on the P2Y₁₂ receptor that is separate from the ADP binding site and produces a non-competitive inhibition, while the thienopyridines, clopidogrel and prasugrel, bind directly to the ADP binding site on the P2Y₁₂ receptor permanently blocking this site. Antiplatelet agents that block the P2Y₁₂ receptor have complementary effects with aspirin in terms of platelet inhibition because their mechanism of action is different than that of aspirin, which blocks cyclo-oxygenase-1 causing a decrease in thromboxane A2. Abbreviations: 5HT, 5-hydroxytryptamine; α, alpha granules; ™, dense granules; ADP, adenosine diphosphate; ATP, adenosine triphosphate; COX-1, cyclo-oxygenase-1; GP, glycoprotein; TPα, thromboxane A2 receptor; TxA2, thromboxane A2.

Figure 2

Chemical structures of clopidogrel, prasugrel, ticagrelor, and adenosine.

Figure 3

Hazard ratios and 95% confidence intervals (in parentheses) for the PLATO study population with regards to the primary efficacy endpoint subdivided by daily aspirin dosage and geographic region. Daily dosages of aspirin > 300 mg were associated with a blunting of the benefit of ticagrelor, whereas dosages < 100 mg were associated with benefit of ticagrelor compared to clopidogrel. This finding was seen regardless of geographic region, but was most pronounced in the United States population which tended to use higher daily dosages of aspirin compared to the rest of the world. Note: *Insufficient data in the United States population.