Prasugrel, Ticagrelor Reduced Incidence of Stent Thrombosis

SAN FRANCISCO, CALIF.—In a session devoted to pharmacologic approaches to reducing stent thrombosis, Dean J. Kereiakes, MD, of The Christ Hospital in Cincinnati, Ohio, focused on the advantages of the novel P2Y12 receptor antagonists prasugrel and ticagrelor over clopidogrel in protecting high-risk patient subsets. Evidence is strong that both prasugrel and ticagrelor significantly reduce stent thrombosis regardless of stent type.

Limitations with clopidogrel

One of the most documented predictors of stent thrombosis is on-treatment platelet reactivity. A  recent meta-analysis of six studies by Brar and colleagues involving more than 3,000 patients showed that those in the highest quartile of platelet reactivity have a stent thrombosis risk of 3.4% vs. 0.4% in the lowest quartile (P=.002). In a pooled analysis of 17 trials, high on-treatment platelet reactivity carried a risk ratio of 3.35 (95% CI 2.39-4.70) for cardiovascular mortality and 4.14 (95% CI 2.74-6.25) for stent thrombosis.

Recent results of the GRAVITAS trial suggest that dose titration of clopidogrel may not be an effective solution, Kereiakes said. Poor responders randomized to single- or double-dose clopidogrel showed no difference in the cumulative incidence of ischemic events, including stent thrombosis at 6 months. Pharmacodynamic analysis revealed only a modest increment in conversion from poor to adequate platelet inhibition (≥230 PRU).

Enhanced inhibition with novel antiplatelets

As a potential solution, prasugrel and ticagrelor have been shown to provide more rapid, intense and uniform platelet inhibition, according to Kereiakes. Moreover, patients resistant to clopidogrel are almost invariably responsive to prasugrel and ticagrelor. In the TRITON TIMI 38 trial that randomized ACS patients to prasugrel or clopidogrel, prasugrel reduced definite or probable stent thrombosis at 30 days by 59% (P<.0001) and late thrombosis by 40% (P=.03). That difference was consistent across a host of variables. A similar pattern of reduced stent thrombosis was seen for ticagrelor in the pivotal PLATO trial. Moreover, there was no interaction with the CYP2C19 loss-of-function allele. A major pooled analysis of three randomized trials showed the advantage of both P2Y12 receptor antagonists over clopidogrel for death MI, the composite of death/MI/stroke and stent thrombosis (see Figure).

In an indirect comparison of the two drugs, Keriakes reported it appeared that prasugrel was favored for reducing stent thrombosis, while ticagrelor was favored with respect to major bleeding, although potential confounding variables warrant caution. In their respective pivotal trials, prasugrel provided a 42% reduction in definite/probable stent thrombosis to ticagrelor’s 26% reduction.

In an analysis by Mega and colleagues, clopidogrel-treated carriers of a CYP2C19 loss-of-function allele showed a 2.6%  incidence of definite/probable stent thrombosis vs. 0.8% for noncarriers (P=.02). Prasugrel-treated carriers of the allele had  a lower incidence than noncarriers. Similarly, a study by Tantry and colleagues showed a markedly lower level of platelet aggregation with ticagrelor compared with double-dose clopidogrel, with the difference greatest in loss-of-function allele carriers.

In summary, evidence is strong that both prasugrel and ticagrelor provide more rapid, intensive and predictable platelet inhibition and significantly reduce stent thrombosis regardless of stent type. As a result, these agents should be used in patients at clinical high risk for stent thrombosis, including STEMI patients, diabetics, carriers of the CYP2C19 loss-of-function allele, patients who have experienced stent thrombosis despite clopidogrel compliance, and patients with demonstrated high on-treatment platelet reactivity—all provided they have no specific contraindications, Kereiakes said. Meanwhile, determination of the relative efficacy, safety and tolerability of prasugrel vs. ticagrelor will require an adequately powered randomized trial.