• Myocardial Infarction
• Coronary Artery Disease Clinical Trials
• Interventional Techniques & Devices

In a late-breaking clinical trial that was presented at the American Heart Association 2009 Scientific Sessions in Orlando, FL, Philippe Gabriel Steg, MD, Hôpital Bichat-Claude Bernard, Paris, France, reported that ticagrelor, the first reversible oral P2Y12 receptor antagonist, was superior to clopidogrel in terms of preventing cardiovascular (CV) death, myocardial infarction (MI), or stroke in patients who presented with ST-segment elevation myocardial infarction (STEMI) and for whom PCI was planned, without causing a significant increase in major bleeding.

In this prespecified subset analysis of the larger PLATO trial (NCT00391872), presented earlier this year at the European Society of Cardiology Meeting, 8430 patients with STEMI who presented within the previous 24 hours and were planned for primary percutaneous coronary intervention (PCI) were randomly assigned to receive either 180 mg ticagrelor during PCI and stenting, followed by a maintenance dose of 90 mg twice daily, or a 300-to 600-mg loading dose of clopidogrel, followed by a maintenance dose of 75 mg daily for 6 to 12 months. In addition, all patients received daily aspirin. Patients who were previously treated with clopidogrel, either as a prerandomization loading dose or as chronic therapy (∼46%), did not receive a loading dose of the study drugs. Patients were excluded if they received fibrinolytic therapy within 24 hours prior to randomization.

The primary endpoint, a composite of CV death, MI, or stroke at 12 months, was significantly reduced in those who were randomized to ticagrelor versus clopidogrel (9.3% vs 11.0%; HR, 0.85; 95% CI, 0.74 to 0.97; p=0.02). Components of the primary endpoint were also reduced with ticagrelor, including a statistically significant reduction in MI (4.7% vs 6.1%; p=0.01) and a trend toward a lower rate of CV (4.5% vs 5.4%; p=0.09). However, there was a trend toward an increased rate of stroke (1.6% vs 1.0%; p=0.07) with ticagrelor. As was observed in the main trial result, all-cause mortality was significantly reduced from 6.0% for those on clopidogrel to 4.9% for ticagrelor (HR, 0.82; 95% CI, 0.68 to 0.99; p=0.04) among patients with STEMI. Stent thrombosis (ARC definite, definite or probable, and all ARC categories) was significantly reduced (2.5% vs 3.6% for definite or probable, HR, 0.69; 95% CI, 0.52 to 0.92; p=0.01) in the patients who were treated with ticagrelor.

Safety results were similar to the overall trial. There was no significant difference in the risk of PLATO major, TIMI major, or fatal bleeding between treatment groups. Episodes of dyspnea were more common with ticagrelor (13.8%) compared with clopidogrel (7.8%). The difference was statistically significant (p<0.0001) and led to significantly (p=0.002) more ticagrelor patients who discontinued treatment.

Ticagrelor differs from thienopyridines, such as clopidogrel, in a number of important ways. It is not a prodrug and thus does not require hepatic activation—instead, it directly inhibits the adenosine diphosphate (ADP) receptor P2Y12 (purinoceptors), which is involved in platelet activation. Ticagrelor has a rapid onset of action and can completely inhibit the sustained aggregation response to ADP; yet, it is reversible, wherein functional recovery of circulating platelets occurs within 48 hours of treatment cessation. Because patients with STEMI who undergo primary PCI require urgent and effective blockade of the P2Y12 platelet receptor and are at a greater risk of side effects from inconsistent platelet inhibition, the pharmacokinetic profile of ticagrelor is well suited for treating such patients.

One drawback, mentioned by the discussant of this trial, Lisa K. Jennings, PhD, University of Tennessee Health Science Center, Memphis, TN, was the need for twice-daily dosing due to ticagrelor's reversible binding properties and 12-hour half-life. This might cause problems for patients who are not fully compliant. In balance, however, the significant reduction in all-cause mortality and in clinically important cardiac events, without increased bleeding, makes this new agent a promising new addition to oral antiplatelet therapy for patients with STEMI who are undergoing PCI.

• © 2009 MD Conference Express