Ticagrelor KOs Clopidogrel

A novel antiplatelet drug, ticagrelor, from AstraZeneca delivered a knockout punch to uber-drug clopidogrel (Plavix; BMS/sanofi-aventis) in a phase 3 study of patients with acute coronary syndrome (ACS). Results of the head-to-head trial were presented Sunday at the ongoing congress of the European Society of Cardiology (ESC) in Barcelona. Trial specifics were simultaneously published online in The New England Journal of Medicine.

Both ticagrelor, trade named Brilinta [oy], and clopidogrel belong to the thienopyridine class of oral antiplatelet agents; although ticagrelor, unlike clopidogrel, is a reversible inhibitor of the P2Y12 receptor on platelets. (Read on for the importance of this distinction.)

The international AZ-sponsored trial, abbreviated PLATO, enrolled 18,624 patients with ACS* who received randomly assigned ticagrelor (180-mg loading dose followed by 90 mg bid) or clopidogrel (300-600-mg loading dose followed by 75 mg qd). (Before randomization, the overwhelming majority patients had received aspirin, and about half had received clopidogrel. During the trial, everybody got aspirin, 75-100 mg/d.) The average treatment time was 278 days (range, 6-12 months), and the follow-up rate was phenomenal—better than the purity of Ivory soap: 99.97%.

Rates of the composite primary endpoint—MI, stroke, or cardiovascular death—were 9.8% with ticagrelor and 11.7% with clopidogrel. The outcome amounts to a statistically significant relative-risk reduction of 16% with ticagrelor. Moreover, investigators observed a statistical difference between the 2 drugs at 30 days of treatment. Rate differences for several secondary endpoints, including MI or cardiovascular death, also favored ticagrelor. However, both drugs performed similarly with respect to the isolated outcome of hemorrhagic or ischemic stroke (1.5% vs 1.3%).

The ho-hum stroke outcome may have something to do with the relatively reduced risk of stroke in patients with ACS (vs the stroke risk in patients with a history of stroke). There is also the possibility that some thienopyridines aren't particularly great at preventing stroke, at least in some patients.** For instance, in the mammoth pivotal trial for clopidogrel (published way back in 1996), the drug edged out aspirin with respect to the composite outcome of ischemic stroke, MI, or vascular death in at-risk patients; however, clopidogrel was no better than aspirin in the post-hoc analysis of a stroke-only outcome. Most of the overall protective benefit of clopidogrel in this study was observed in patients with peripheral arterial disease. (Although clopidogrel is still recommended as first-line therapy for preventing recurrent stroke.) 

With respect to overall major bleeding, rates with ticagrelor and clopidogrel in the PLATO trial were similar (11.6% and 11.2%). But major bleeding in a non-CABG context was higher with ticagrelor (4.5% vs 3.8%; P = .026). Dyspnea was also more frequent with ticagrelor (14.2% vs 9.2%) and led to the discontinuation of the drug in 1% of treated patients.

In addition to outperforming clopidogrel on efficacy measures, ticagrelor has the advantage of not being a prodrug—meaning that metabolic conversion is not necessary to achieve antiplatelet activity. Consequently ticagrelor is faster acting than clopidogrel. And because ticagrelor is a reversible inhibitor of platelets, its activity wears off more rapidly than that of clopidogrel. This property enables emergent CABG, should the procedure be necessary in ACS patients who don't respond to coronary stenting. (However, rates of major bleeding during CABG were not significantly different between the 2 drugs [7.4% vs 7.9%] in the PLATO trial). The downside of ticagrelor is its twice-a-day administration. 

In the United States, clopidogrel goes off patent in 2011 (according to the LA Times); there's also a recent history of several foreign generics encroaching the market.

CABG = coronary-artery bypass grafting; PLATO = PLATelet inhibition and patient Outcomes.

* With ST-segment elevation intended for primary percutaneous coronary intervention (PCI) or without ST-segment elevation intended for invasive or medical management.

** Very recent data indicate that clopidogrel's activity is reduced in patients who are poor metabolizers of the drug (ie, those patients with genetically reduced function of CYP2C19, a P450 component). The genetic variant is associated with the reduced inhibition of platelet aggregation and an increased risk of cardiovascular events or death. About 30% of the population have the CYP2C19 variant.