coronary syndromes Advances in antiplatelet treatment for acute

Context: Recent publications of TRITON-TIMI (prasugrel) as well as PLATO (ticagrelor) have introduced new and potent antiplatelet agents, but at the same time have left clinicians with multiple choices without clear directions regarding the most appropriate use of these agents. Objective 1. To review the randomized controlled trial evidence examining the role of the three antiplatelet gents in acute coronary syndromes is presented. 2. To provide recommendations for the practicing physician for their optimal use in clinical practice. Data Sources: CURE, TRITON-TIMI 38 and PLATO trials. Study Selection: Large randomized placebo controlled trials of dual antiplatelet therapy in acute coronary syndromes. Data Extraction: From original trials. Results and Conclusions: Both prasugrel and ticagrelor are potent antiplatelet agents with improved ischaemic benefits in comparison with clopidogrel. The improved benefit, however, comes at the price of increased bleeding. As such, careful patient selection and balancing of benefit-risk is warranted to optimise their use in clinical practice. Dual antiplatelet inhibition with aspirin and clopidogrel has been shown to result in a reduction in cardiovascular events in a variety of settings. Attempts to improve outcomes further have led to the development of more potent antiplatelet agents, but at a cost of increased bleeding complications. The bleeding risk is especially highlighted in patients undergoing urgent coronary artery bypass grafting (CABG) or other invasive procedures. The search for an antiplatelet agent with optimal ischaemic protection and an acceptable bleeding risk remains the ‘holy grail’ of antiplatelet drug development. With the advent of new agents such as prasugrel and ticagrelor in addition to clopidogrel, physicians are left with many choices but without a clear direction regarding the most appropriate use of these agents. Three randomised controlled trials have evaluated the superiority of adenosine diphosphate (ADP) antagonists (table 1 & 2). We herein review the randomised controlled trial evidence examining the role of these three agents in acute coronary syndromes (ACS), and provide recommendations for the practising physician for their optimal use in clinical practice. CLOPIDOGREL Clopidogrel is a thienopyridine, which irreversibly blocks the ADP receptor P2Y12 on platelets. It is a prodrug and requires dual hepatic activation. This results in delayed onset of action and large individual variability in platelet response. As a result of its irreversibility, the effect lasts for the life of the bound platelet and requires discontinuation for at least 5 days before surgery (table 1). The CURE Trial first established the superiority of dual antiplatelet therapy with aspirin and clopidogrel compared with aspirin alone. A statistically significant reduction in the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction (MI), or non-fatal stroke was observed with dual antiplatelet treatment (9.3% vs 11.4%, p<0.001; figure 1a). The majority of the benefit stemmed from a reduction in nonfatal MI (5.2% vs 6.7%, p<0.001). This was associated with an increase in bleeding (figure 1b), especially in patients undergoing urgent CABG surgery less than 5 days after treatment discontinuation. Based on the favourable benefiterisk profile, the US Food and Drug Administration approved it for the reduction of atherothrombotic events in patients with non-ST-elevation (NSTE) ACS who are managed medically or with percutaneous coronary intervention (PCI). No warnings for increased bleeding risk were issued. Clinical practice guidelines have endorsed dual antiplatelet therapy with aspirin and clopidogrel as class I, level of evidence A recommendation in ACS. PRASUGREL Prasugrel is a new and more potent thienopyridine. Similar to clopidogrel, it irreversibly binds and blocks the ADP P2Y12 receptor. It has a more rapid onset of action and a stronger inhibitory effect than clopidogrel. Its activation requires enzymatic hydrolyses and hepatic activation of the prodrug. As a result of its irreversibility, the effect lasts for the life of the bound platelet and requires cessation of use for at least 7 days before surgery (table 1). The evidence for the efficacy of prasugrel is derived from the TRITON-TIMI 38, a phase III double-blind randomised controlled trial, which revealed a statistically significant reduction in the primary outcome (a composite of cardiovascular death, non-fatal MI, or non-fatal stroke) in the prasugrel group compared with clopidogrel (9.9% vs 12.1%, p<0.001). However, the loading dose of clopidogrel used in the study was lower than the dose commonly used in clinical practice, and only a quarter of the patients received the loading dose of prasugrel before PCI. The differences between the treatment groups were mainly due to a significantly lower incidence of non-fatal MI, half of which were non-clinical MI (identifiable only by elevated cardiac biomarker criterion). Differences in the majority of the secondary outcomes also Division of Cardiology, Cedars-Sinai Medical Center, David Geffen School of Medicine, University of California, Los Angeles, California, USA Correspondence to Dr Sanjay Kaul, Division of Cardiology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA; kaul@cshs.org Accepted 14 October 2009 656 Heart 2010;96:656e661. 10.1136/hrt.2009. 185983 Review group.bmj. com on May 1, 2010 Published by heart.bmj. com Downloaded from