EDITORIAL COMMENT
Hunting for the "Sweet Spot" in P2Y12 Receptor Blockade*
Daniel I. Simon, MD and
Sahil A. Parikh, MD*
University Hospitals Harrington-McLaughlin Heart & Vascular Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio
* Reprint requests and correspondence: Dr. Daniel I. Simon, University Hospitals Harrington-McLaughlin Heart & Vascular Institute, 11100 Euclid Avenue, Cleveland, Ohio 44106 (Email: daniel.simon{at}uhhospitals.org).
Key Words: platelet • thienopyridine • loading dose • STEMI
The addition of the P2Y12 antagonist clopidogrel to aspirin reduces ischemic events in unstable angina/non–ST-segment elevation myocardial infarction treated with medical therapy, percutaneous coronary intervention (PCI), or coronary artery bypass grafting (1), in ST-segment elevation myocardial infarction (STEMI) treated with thrombolytic therapy (2), and in elective PCI (3). Dual antiplatelet therapy also reduces major adverse cardiovascular events and stent thrombosis after PCI compared with aspirin alone or the combination of aspirin and warfarin (4). However, there are significant limitations of clopidogrel therapy. Clopidogrel is a pro-drug with a slow onset of action, requiring conversion to an active thiol metabolite by the hepatic cytochrome P450 (CYP450) system (5). The degree of platelet inhibition induced by clopidogrel is highly variable among individuals with "hyporesponsiveness" occurring in up to 30% of individuals receiving a 300-mg loading dose (6). Persistent high platelet reactivity despite clopidogrel therapy is associated with adverse clinical outcomes in a variety of clinical settings (7,8). Multiple cellular, clinical, and genetic factors likely contribute to clopidogrel nonresponsiveness (9). Increasing clopidogrel dose (10) or CYP450 activity enhances the platelet inhibitory response of clopidogrel by increasing the concentration of the active metabolite (5). Conditions or "risk factors" associated independently with clopidogrel nonresponsiveness include congestive heart failure, body weight (>100 kg), myocardial infarction presentation, and diabetes mellitus (8). Genetic polymorphisms, particularly of genes responsible for the metabolism of clopidogrel, such as the *2 allele of CYP450 2C19, result in loss of function leading to reduced conversion of clopidogrel to its active metabolite and are associated with a higher rate of adverse cardiovascular events in patients presenting with acute coronary syndromes (11). An additional limitation of clopidogrel involves drug–drug interactions. The use of drugs that inhibit the activity of CYP2C19, including several of the proton pump inhibitors (PPIs), could result in reduced drug levels of the active metabolite and a possible reduction in clinical efficacy. A retrospective cohort study of more than 16,700 patients who received clopidogrel post-stenting reported an increase in the 1-year risk of cardiovascular events in patients taking a PPI on top of clopidogrel as compared with patients not taking a PPI (hazard ratio [HR]: 1.51, 95% confidence interval [CI]: 1.39 to 1.64; p < 0.0001) (12).
Next generation P2Y12 receptor antagonists such as prasugrel, ticagrelor, and elinogrel have enhanced potency (with the potential for >80% inhibition of platelet aggregation), more rapid onset (seconds to  60 min), and markedly reduced response variability (13,14). They are currently being evaluated in phase II/III clinical trials. Determining the appropriate "sweet spot" of platelet inhibitory response—namely, the dose that achieves a concentration of drug that optimizes the balance of efficacy and safety—remains a major goal and focus of these trials. In the 1990s, trials of reversible, competitive antagonists of glycoprotein IIb/IIIa showed that 80% inhibition of adenosine diphosphate-induced platelet aggregation represented the sweet spot for this class of drugs (15). P2Y12 antagonists are of several pharmacologic subtypes: irreversible for clopidogrel and prasugrel; reversible and noncompetitive for ticagrelor; while elinogrel and cangrelor are reversible, competitive antagonists of P2Y12. Prasugrel has demonstrated superior clinical efficacy to clopidogrel (300-mg loading dose, 75-mg maintenance dose) therapy; however, enhanced efficacy was accompanied by a significant excess of major and minor bleeding (13). Tantalizing evidence from a series of small clinical trials suggests that increasing the loading dose of clopidogrel to 600 mg reduces ischemic events in-hospital and up to 30 days without increasing the rate of bleeding (16,17). Pre-clinical studies have shown that reversible P2Y12 antagonists, both noncompetitive and competitive, have an improved therapeutic index versus clopidogrel (18). It is not yet known whether the sweet spot differs for the 3 pharmacologic subtypes and whether these agents will provide improved clinical efficacy with less bleeding in patients.
In this issue of the Journal, the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) study investigators explored the potential benefits of a 600-mg loading dose of clopidogrel compared with 300 mg in the clinical setting of primary PCI for STEMI (19). The main HORIZONS-AMI trial was designed to determine the net clinical benefit of bivalirudin compared with unfractionated heparin plus glycoprotein IIb/IIIa therapy (20). Randomization was stratified by clopidogrel loading dose. Patients in the 600-mg (n = 2,158) group compared with the 300-mg (n = 1,153) clopidogrel loading dose group had significantly lower rates of death, reinfarction, and stent thrombosis. By multivariable analysis, a 600-mg loading dose was an independent predictor of lower rates of 30-day major adverse cardiovascular events (HR: 0.72, 95% CI: 0.53 to 0.98, p = 0.04). This finding suggests that the favorable pharmacodynamic properties of increasing clopidogrel dose from 300 to 600 mg—namely, greater inhibition with faster onset of action and reduced rate of nonresponsiveness/hyporesponsiveness—are associated with improved clinical outcomes.
The results of the HORIZONS-AMI trial need to be considered in the context of recent lessons from the STEMI subanalysis (21) of the TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction 38) trial comparing prasugrel (60-mg loading dose, 10-mg maintenance dose) with clopidogrel (300-mg loading dose, 75-mg maintenance dose) in patients undergoing PCI for acute coronary syndromes (22). Treatment with prasugrel significantly reduced the rate of adverse cardiovascular events compared with treatment with clopidogrel (HR: 0.68, 95% CI: 0.54 to 0.87; p = 0.0017). However, when only patients undergoing primary PCI were considered, the superiority of prasugrel over clopidogrel was less evident (HR: 0.80, 95% CI: 0.60 to 1.08; p = 0.144).
The results of the HORIZONS-AMI and TRITON–TIMI 38 STEMI substudies might lead the reader to ask a highly relevant clinical question: is clopidogrel 600 mg as effective or nearly as effective as prasugrel 60 mg? The definitive answer to this question will require a randomized comparison between these agents. Although primary end point definitions differed in the 2 substudies, it is useful to evaluate the absolute and relative risk reductions with respect to the common 300-mg clopidogrel loading dose groups in each trial (Table 1). Importantly, assignment to clopidogrel 600/75 mg compared with 300/75 mg in the HORIZONS-AMI trial was nonrandomized and left to the discretion of the physician, raising the possibility that significant measured and unmeasured variables may have contributed to the apparent clinical benefits of clopidogrel 600/75 mg despite attempts to minimize confounding by performing propensity-matched analysis.
The results of the HORIZONS-AMI substudy are provocative, as the 600-mg loading dose may have been more effective than the 300-mg loading dose for multiple reasons, as diagramed in Figure 1. First, since thrombi are dynamic, and P2Y12 signaling is known to be involved in platelet adhesion and subsequent activation as well as in thrombus growth, clopidogrel could have provided benefit by stopping platelet recruitment and favoring endogenous mechanisms (e.g., endogenous fibrinolysis) to achieve dissolution of the occlusive thrombus. Alternatively, since persistent signaling by adenosine diphosphate acting on P2Y12 is required to maintain glycoprotein IIb/IIIa in the activated state within a platelet aggregate (23), the expected doubling of the concentration of the active metabolite by the 600-mg dose could have directly induced reversal of existing thrombi. Future studies are required to determine whether the concentrations of active metabolites of the thienopyridines present after the 600-mg dose of clopidogrel, which are more abundant and form earlier after the 60-mg dose of prasugrel, are sufficient to achieve thrombus reversal and whether the new reversible P2Y12 antagonists are even more effective dethrombotic agents.
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Figure 1 Potential Role of P2Y12 Antagonism in Reversing Platelet Aggregation and Thrombosis
P2Y12 signaling after platelet stimulation by thrombin or collagen promotes activation of the receptor function of glycoprotein (GP) IIb/IIIa, fibrinogen binding, and platelet aggregation. Since continued P2Y12 signaling is required to maintain the activation state of GP IIb/IIIa and aggregate stability, addition of P2Y12 antagonists to aggregated platelets in a thrombus is capable of reversing thrombosis. ADP = adenosine diphosphate; vWf = von Willebrand factor.
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Acknowledgments
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The authors would like to thank David R. Phillips, PhD, for his critical review of the manuscript.
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Footnotes
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Dr. Simon has received consulting and lecture fees from Daichi Sankyo, Cordis/Johnson & Johnson, Eli Lilly, The Medicines Company, and Sanofi-Aventis, and serves on advisory boards for Cordis/Johnson & Johnson and Medtronic Vascular.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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