Optimizing Platelet P2Y 12 Inhibition for Patients Undergoing PCI

Transcription

1 Cardiovascular Drug Reviews Vol. 25, No. 2, pp C 2007 The Authors Journal compilation C 2007 Blackwell Publishing Inc. Optimizing Platelet P2Y 12 Inhibition for Patients Undergoing PCI Steven Steinhubl 1 and Matthew T. Roe 2 1 Gill Heart Institute, University of Kentucky, Lexington, Kentucky, USA 2 Division of Cardiology, Duke Clinical Research Institute, Duke University Medical Center, North Carolina, USA Keywords: Antiplatelet therapy AZD6140 Cangrelor Clopidogrel Coronary artery disease P2Y 12 inhibition PCI Prasugrel Thrombosis. ABSTRACT Guidelines recommend that dual antiplatelet therapy using aspirin and clopidogrel should be administered to the majority of patients with acute coronary syndromes, including those undergoing percutaneous coronary intervention (PCI). However, the results of a large randomized, placebo-controlled study suggest that a 300-mg loading dose of clopidogrel must be administered at least 15 h prior to PCI in order to achieve a significant reduction in peri-pci thrombotic events. Other data suggest that 2 h of pretreatment may be sufficient if a 600-mg loading dose is used. Since it is often difficult to achieve an adequate pretreatment goal with clopidogrel in clinical practice, more rapid achievement of platelet P2Y 12 inhibition may improve patient outcomes. Prasugrel, [6-[2-(3,4-diflurophenyl) cyclopropyl1-1-y1] amino-2-propylthio-9?-d-ribofuranosyl-9h-purine (AZD6140), and cangrelor are platelet P2Y 12 receptor antagonists currently in development that offer faster acting inhibition of adenosine diphosphate (ADP) induced platelet aggregation. These agents act upon the same platelet receptor as clopidogrel, but are distinguished by their routes of administration, reversibility, and pharmacodynamic properties. Prasugrel is an orally administered agent that provides faster, higher, and more consistent inhibition of platelet aggregation than clopidogrel. The results of Phase II testing suggest that the risk of bleeding is Address correspondence and reprint requests to: Dr. Steven Steinhubl, Gill Research Institute, University of Kentucky, Lexington, KY 40536, USA. Tel.: ; Fax: ; srstei2@ .uky.edu Conflict of interest: Steven Steinhubl has received honoraria as an advisor for Daiichi-Sankyo, Sanofi-adventis, the Medicines Company, and Eli Lilly. Matthew Roe has served as a consultant for and received research grants from Eli Lilly/Daiicho-Sankyo. 188

2 PLATELET P2Y 12 INHIBITION 189 similar in prasugrel- and clopidogrel-treated patients. AZD6140 is another orally administered platelet inhibitor with rapid and reversible action. Again, Phase II testing suggests similar bleeding risk for clopidogrel. Preliminary evidence suggests that clinical outcomes may be better in prasugrel- and AZD6140-treated patients than in clopidogrel-treated patients. Cangrelor is an intravenously administered, reversible, short-acting agent with a rapid onset of activity. Bleeding risk and clinical outcomes data are similar in cangrelorand abciximab-treated patients. The results of ongoing Phase III clinical trials involving more than 40,000 patients will demonstrate whether these agents fulfill their potential to improve outcomes in PCI-treated patients by providing faster, higher, and more consistent inhibition of platelet aggregation. INTRODUCTION Percutaneous coronary intervention (PCI) is widely used in the treatment of coronary artery disease. This procedure is recommended in suitable asymptomatic and symptomatic patients, including those with acute coronary syndromes (ACS) (Braunwald et al. 2002; Antman et al 2004; Smith et al. 2006). The current recommendation that all PCI-treated patients should receive antiplatelet therapy prior to and after the procedure (Braunwald et al. 2002; Antman et al, 2004; Smith et al. 2006; Silber et al. 2005) is based on widespread, conclusive data demonstrating that optimal inhibition of platelet activation significantly reduces cardiovascular risk in these patients (Mehta et al. 2001; Steinhubl et al. 2002; Sabatine et al. 2005). The benefits of antiplatelet therapy were first demonstrated in studies designed to determine the effects of aspirin on cardiovascular risk in various high-risk patient groups. One example is the Second International Study of Infarct Survival (ISIS-2), which showed that aspirin therapy, commenced within 24 h of pain onset and continued for 1 month, led to significant reductions in the risks of deaths due to vascular causes, nonfatal reinfarction, and nonfatal stroke in patients with suspected acute myocardial infarction. (ISIS-2 Collaborative Group 1988) The results of this and other studies (Antithrombotic Trialists Collaboration 2002; Savage et al. 1995) have led to the universal recommendation that aspirin should form the basis of antiplatelet therapy in all patients at high cardiovascular risk, including those undergoing PCI, unless contraindicated on the basis of aspirin allergy (Braunwald et al. 2002; Antman et al. 2004; Silber et al. 2005; Smith et al. 2006). Aspirin acts by inactivating cyclooxygenase (thereby reducing production of thromboxane A 2 ), but it does not prevent platelet activation via thromboxane A 2 -independent pathways. There is thus a rationale for combining aspirin with antiplatelet agents that act via complementary mechanisms. Preclinical and clinical ex vivo studies have shown that aspirin and the thienopyridine, clopidogrel (which inhibits platelet aggregation by blocking adenosine diphosphate [ADP] dependent platelet activation via the P2Y 12 receptor), have synergistic antiplatelet effects (Herbert et al. 1998; Moshfegh et al. 2000; Cadroy et al. 2000). It is this synergistic inhibition, achieved through the blockade of two separate platelet activation pathways that is believed to underlie the clinical benefits of adding clopidogrel to aspirin in patients with ACS and in those undergoing PCI (CURE Trial Investigators 2001; Mehta et al. 2001; Steinhubl et al. 2002; Chen et al. 2005; Sabatine et al. 2005). There are challenges to incorporating guideline-recommended dual antiplatelet therapy in all patients for whom this strategy is indicated. For example, clopidogrel-treated patients

3 190 S. STEINHUBL AND M.T. ROE who are likely to undergo coronary artery bypass grafting (CABG) are at increased risk of bleeding if rapid surgical revascularization is required (CURE Trial Investigators 2001; Hongo et al. 2002; Mehta et al. 2006a). For this reason, current guidelines recommend that patients scheduled for CABG should not receive clopidogrel for at least 5 days prior to the procedure, and a withholding period of 7 days is preferred (Braunwald et al. 2002; Antman et al. 2004). As a result, many physicians are reluctant to prescribe clopidogrel to eligible patients until their coronary anatomy has been defined and a decision regarding the need for PCI or CABG has been made. In contrast, recent data from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines?) initiative show that CABG is performed within 5 days of clopidogrel administration in a substantial majority of patients (Mehta et al. 2006b). Physicians who employ this strategy may do so with the belief that the reduction in cardiovascular risk associated with clopidogrel administration outweighs the increased risk of bleeding. Alternatively, physicians who administer clopidogrel before the need for CABG may feel that the benefits of reduced cardiovascular risk justify the increased costs incurred by the prolonged hospital stay, should CABG be needed. Nonetheless, electively treated and emergency patients with acute coronary syndrome (ACS) who are referred for PCI immediately after diagnostic angiography frequently do not receive clopidogrel until immediately prior to the procedure. An antiplatelet agent with a rapid onset of activity would provide these patients with maximal protection from thrombotic events during and after PCI. This article outlines the clinical implications of clopidogrel s time to onset of action, and discusses the need for rapid-acting antiplatelet agents in patients requiring PCI. PHARMACOKINETICS Time to Onset of Platelet Inhibition with Clopidogrel Clopidogrel is a prodrug which, following oral administration, is metabolized to its active metabolite in the liver by a two-step cytochrome P450-dependent process (Savi et al. 1994; Savi et al. 2000). Although clinical data have shown that both the dose of clopidogrel administered and the timing of its administration are critical in achieving an optimal effect (Steinhubl et al. 2002; Steinhubl et al. 2006), studies that have attempted to correlate pharmacodynamic and clinical effects of various clopidogrel dosing regimens have yielded contradictory results. Pharmacodynamics When administered without a loading dose, clopidogrel 75 mg daily causes some degree of inhibition of ADP-induced platelet aggregation as early as 2 h after treatment initiation, but maximal inhibition is not achieved for 3 7 days (Bates et al. 2005; Physicians Desk Reference 2006). This delay can be substantially reduced by use of a 300-mg loading dose, but pharmacodynamic studies differ widely in their estimates of the timing of the maximal effect achieved using this strategy. Thus, recent studies have reported maximal or near-maximal inhibition of platelet aggregation between 2 h and 24 h after administration of 300 mg clopidogrel, with the vast majority of studies finding that the effect is near-maximal

4 PLATELET P2Y 12 INHIBITION 191 after approximately 3 h (Savcic et al. 1999; Cadroy et al. 2000; Helft et al. 2000; Gurbel et al. 2005; Montalescot et al. 2006; Price et al. 2006). The pharmacodynamic effects of higher loading doses of clopidogrel (450 mg, 600 mg, and 900 mg) have also been assessed (Müller et al. 2001; Seyfarth et al. 2002; Angiolillo et al. 2004; Gurbel et al. 2005; von Beckerath et al. 2005; Montalescot et al. 2006; Price et al. 2006). It has become evident that even with a 600-mg loading dose, clopidogrel s full antiplatelet effect still takes 2 4 h to develop (Hochholzer et al. 2005; Montalescot et al. 2006). Increasing the dose to 900 mg has been associated with marginal increases in the magnitude and speed of platelet inhibition (Montalescot et al. 2006; Price et al. 2006), but significant differences between the 600 mg and 900 mg doses have not been demonstrated (von Beckerath et al. 2005; Montalescot et al. 2006; Price et al. 2006). This apparent ceiling in the pharmacodynamic effect of clopidogrel has been attributed to limited intestinal absorption of the drug, variability in cytochrome P450-dependent enzyme activity, and drug drug interactions (von Beckerath et al. 2005; Hochholzer et al. 2005). Thus, regardless of the size of the loading dose, pharmacodynamic studies indicate that 2 h is the minimum preintervention interval that is necessary to achieve optimal inhibition of platelet aggregation with clopidogrel. CLINICAL STUDIES The effects of clopidogrel on patient outcomes have been widely investigated in clinical studies that have involved a range of treatment regimens (e.g., clopidogrel 75 mg/day with no loading dose, clopidogrel 75 mg/day preceded by a 300-mg loading dose, and abciximab therapy preceded by a 600-mg clopidogrel loading dose) in various patient populations (e.g., PCI-treated ACS patients, PCI-treated stable angina patients, and unselected patients with ACS) (CURE Trial Investigators 2001; Mehta et al. 2001; Kandzari et al. 2004; Chen et al. 2005; Wolfram et al. 2006). In the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, 12,562 aspirin-treated patients with ACS were randomized to receive clopidogrel (300-mg loading dose followed by 75 mg/day) or placebo for 3 12 months (CURE Trial Investigators 2001). Treatment was initiated within 24 h of symptom onset. This strategy was associated with a significant 20% reduction in the risk of cardiovascular death, nonfatal myocardial infarction, or stroke (CURE Trial Investigators 2001). Interestingly, the beneficial effect of clopidogrel was evident within a few hours of randomization and was statistically significant 24 h after treatment initiation. It should be noted that only a minority of these patients (approximately 20%) underwent PCI after randomization. Although revascularized patients were shown to derive significant beneficial effect from clopidogrel pretreatment, the applicability of these data to current practice is limited, since most patients underwent PCI days after randomization to study drug (Lewis et al. 2005). Evidence from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial shows that PCI-treated patients derive clinical benefit from a 300-mg loading dose of clopidogrel, but only if the pretreatment duration exceeds approximately 15 h. In this study, 2116 aspirin-treated patients who were scheduled for or deemed likely to undergo PCI were randomized to receive a 300-mg loading dose of clopidogrel between 3 and 24 h prior to PCI, or matching placebo (Steinhubl et al. 2002). All patients subsequently received clopidogrel maintenance therapy (75 mg/day) for 28 days. In the overall cohort, administration of the clopidogrel loading dose did not significantly reduce the combined

5 192 S. STEINHUBL AND M.T. ROE FIG. 1. Duration of treatment prior to percutaneous coronary intervention and the log odds of the primary combined endpoint of death, myocardial infarction (MI), and urgent target-vessel revascularization (UTVR) in patients receiving clopidogrel (solid line) or placebo (dashed line) in the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Reprinted from J Am Coll Cardiol Vol 47(5), Steinhubl SR, et al., Optimal timing for the initiation of pretreatment with 300 mg clopidogrel before percutaneous coronary intervention, , 2006, with permission from The American College of Cardiology Foundation. risk of death, myocardial infarction, or urgent target-vessel revascularization at 28 days (Steinhubl et al. 2002). However, post hoc analysis of data from the CREDO trial found that greater than h of pretreatment was necessary to demonstrate any benefit of clopidogrel pretreatment with a 300-mg loading dose (Fig. 1) (Steinhubl et al. 2006). In fact, the optimal pretreatment duration in CREDO was the maximal duration of approximately 24 h (Steinhubl et al. 2006). Studies designed to determine whether increasing the loading dose to 600-mg is associated with improvements in outcome have provided conflicting results. For example, in the Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty (ARMYDA)- 2 trial, PCI-treated patients who received a 600-mg loading dose of clopidogrel 4 8 h before the procedure had a significantly lower risk of periprocedural myocardial infarction than patients who received a 300-mg loading dose (Patti et al. 2005). All patients without contraindications were also pretreated with aspirin, and continued to receive aspirin indefinitely postintervention. In contrast, a retrospective analysis of data from 445 patients with stable angina who underwent PCI found no difference between the effects of 300-mg and 600-mg loading doses on the risk of periprocedural events or clinical outcomes at 30 days (Wolfram et al. 2006). However, clopidogrel was administered at the time of the procedure in this study, and the pretreatment duration may have been insufficient to provide protection in either treatment group. It should be noted that the results of the ARMYDA-2 trial, in which the 600-mg loading dose was found to be beneficial, were based on a per-protocol analysis rather than an intention-to-treat analysis, a factor that has formed the basis of criticism of this trial (Tricoci et al. 2005). Moreover, ARMYDA-2 was a small trial (n = 255) and the event rate in the 300-mg clopidogrel arm was surprisingly high (composite endpoint

6 PLATELET P2Y 12 INHIBITION 193 of death, myocardial infarction, or target-vessel revascularization within 30 days of PCI, 12%). In addition, the results of the much larger, placebo-controlled, and blinded CREDO study (Steinhubl et al. 2002) would suggest that the duration of clopidogrel pretreatment in the 300-mg arm of the ARMYDA-2 trial (4 8 h) was too short to be effective. As discussed previously, the results of the CREDO trial suggest that clopidogrel loading doses of 300 mg should be administered between 15 and 24 h prior to PCI if they are to be effective in improving clinical outcome (Steinhubl et al. 2006). In contrast, the results of the Intracoronary Stenting and Antithrombotic Regimen Rapid Early Action for Coronary Treatment (ISAR REACT) trial suggest that if a 600-mg loading dose is chosen, no advantage is gained by increasing the pretreatment duration beyond 2 3 h (Kandzari et al. 2004). Thus, 30 days after randomization, clinical outcome was similar in PCI-treated patients who received 600 mg clopidogrel 2 3 h,3 6 h,6 12 h, and >12 h prior to the procedure. All patients also received aspirin, in addition to clopidogrel. It is clear from this discussion that the optimal loading dose and timing of clopidogrel initiation has been the subject of much debate and investigation in recent years. However, results of the recent Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) suggest that patients with acute myocardial infarction derive significant early benefit from clopidogrel maintenance therapy (75 mg/day), even without administration of a loading dose (Chen et al. 2005). This large, placebo-controlled study involved 45,852 patients with acute myocardial infarction, most of whom were treated medically (i.e., without revascularization). The results showed that administration of clopidogrel was associated with a significant reduction in mortality within 24 h of treatment initiation. Although these findings cannot be extrapolated directly to a population of patients undergoing PCI, they do indicate a contradiction between the results of pharmacodynamic studies (which suggest that clopidogrel takes a number of days to achieve a maximal antiplatelet effect when administered at 75 mg/day) and the drug s clinical efficacy. Use of Clopidogrel in Clinical Practice The conflicting results of these pharmacodynamic and clinical studies have been considered by a number of guidelines committees, including those of the European Society of Cardiology and the American College of Cardiology (ACC)/American Heart Association (AHA)/Society for Cardiovascular Angiography and Interventions (SCAI) (Silber et al. 2005; Smith et al. 2006). These guidelines recommend that a 300-mg loading dose of clopidogrel should be administered at least 6 h before PCI (Silber et al. 2005; Smith et al. 2006). The European guidelines further recommend that, if possible, clopidogrel therapy should be initiated the day before the procedure (Silber et al. 2005). While acknowledging that the use of loading doses >300 mg allows higher levels of antiplatelet activity to be achieved more rapidly, the guidelines point out that the efficacy and safety of administering these higher doses have not been fully established (Silber et al. 2005; Smith et al. 2006). Physicians must take these recommendations into consideration while simultaneously dealing with the realities of clinical practice. When the results of elective diagnostic angiography indicate the need for PCI, physicians usually proceed directly to the intervention, rather than delaying the procedure to allow time for clopidogrel to take optimal effect. This strategy may leave many patients at an unnecessarily increased thrombotic risk. The same time constraints apply to ACS patients, in whom the decision to proceed with PCI or CABG

7 194 S. STEINHUBL AND M.T. ROE FIG. 2. Percentage of patients with non-st-segment elevation acute coronary syndromes who received antiplatelet agents, β-blockers, heparin, and glycoprotein (GP) IIb IIIa inhibitors in the first 24 h after presentation. These data, which were collected over a 3-month period in 2004, are taken from the CRUSADE registry (Mehta et al. 2006b). is based on the results of diagnostic angiography. Given the increased risk of bleeding in clopidogrel-treated patients who proceed to CABG, many emergency physicians and cardiologists do not routinely prescribe clopidogrel until the results of the diagnostic angiogram confirming that CABG is unnecessary are known. The CRUSADE initiative, a quality improvement program designed to improve the care of patients with non-st-segment elevation ACS, has confirmed that the use of clopidogrel within the first 24 h of presentation is far from universal (Mehta et al. 2006b). During a 3-month period in 2004, 95% of eligible patients with ACS received aspirin within 24 h of presentation, but only 52% of patients received clopidogrel (Fig. 2) (Mehta et al. 2006b). Over the same period, 24% of patients with ACS underwent PCI within 24 h of presentation (Mehta et al. 2006b). This patient subset may have included a proportion of the 48% of patients who did not receive clopidogrel within 24 h of presentation. This indicates that there may be a proportion of patients who undergo early PCI without receiving clopidogrel early enough to achieve optimal inhibition of platelet aggregation. Interindividual Variability in Clopidogrel Response A further factor that has led clinicians to question the universal utility of clopidogrel is the marked interindividual variability in response (Gurbel et al. 2003; Taubert et al. 2004; Gurbel et al. 2005; Serebruany et al. 2005; O Donoghue and Wiviott 2006; Price et al. 2006; Cassar et al. 2006; Gurbel and Tantry 2006). A variety of studies have shown that between 4% and 44% of patients have an inadequate pharmacodynamic response to clopidogrel (Gurbel and Tantry 2006; O Donoghue and Wiviott 2006). This wide range is dependent on a number of factors, including the dose of clopidogrel administered, the pretreatment duration, the laboratory methods used to measure platelet aggregation, and the definition of hyporesponsiveness (Angiolillo et al. 2004; O Donoghue and Wiviott 2006; Gurbel and Tantry 2006). Potential reasons for a poor response include variations in cytochrome P450-dependent enzyme activity, variable intestinal absorption of the parent drug, and drug drug interactions (Gurbel and Tantry 2006; O Donoghue and Wiviott

8 PLATELET P2Y 12 INHIBITION ). In one small prospective study involving PCI-treated patients (n = 60), clopidogrel responsiveness showed a significant inverse relationship with risk of recurrent cardiovascular events (Matezky et al. 2004), suggesting that pharmacodynamic response is related to clinical efficacy. However, in the absence of large-scale clinical trials documenting a relationship between pharmacodynamic effect and patient outcome, the clinical utility of pharmacodynamic variability remains in question. The ACC/AHA/SCAI guidelines for PCI recognize the potential contribution to adverse clinical outcomes made by interindividual variability in the response to clopidogrel (Smith et al. 2006). As a result, these guidelines recommend that platelet aggregation studies should be considered in patients in whom subacute thrombosis may be catastrophic or lethal (e.g., those with unprotected left main, bifurcating left main, or last patent coronary vessels), and that the maintenance dose of clopidogrel should be increased to 150 mg/day in high-risk patients in whom clopidogrel 75 mg daily causes <50% inhibition of platelet aggregation (Smith et al. 2006). These recommendations remain controversial, however, since there are no published studies to support the use of increased clopidogrel maintenance doses or the use of platelet aggregation studies as a means of guiding clopidogrel therapy. Clinical evidence indicates that continuation of combination treatment with aspirin and clopidogrel following PCI reduces cardiovascular ischemic events, and current guidelines recommend that lower dose ( mg daily) aspirin is continued indefinitely following PCI, and clopidogrel is continued for up to 12 months in patients who are not at high risk of bleeding (Smith et al. 2006). Antiplatelet Agents in Clinical Development It is evident from the controversy surrounding the appropriate use of currently available antiplatelet therapies in patients whose coronary anatomy has not been defined that novel antiplatelet agents with a more rapid onset of action would provide a valuable tool in the treatment of patients destined for PCI. A number of such agents are currently in clinical development, and include an oral, irreversible thienopyridine agent (prasugrel), and two reversible non-thienopyridine agents: AZD6140 [6-[2-(3, 4-diflurophenyl)cyclopropy1-1-y1] amino- 2-propylthio-9?-D-ribofuranosy1-9H-purine and cangrelor (formerly AR-C69931MX). Prasugrel Like clopidogrel and ticlopidine, prasugrel (CS-747; 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluoro-2-fluorobenzyl-4,5,6,7-tetrahydrothieno [3,2-c]pyridine) is a thienopyridine that selectively and irreversibly inhibits the platelet P2Y 12 ADP receptor (Hasegawa et al. 2005). Inhibition of the P2Y 12 receptor inhibits platelet aggregation, and inhibition of aggregation via this pathway is complementary to the inhibition of aggregation effected by aspirin via blockade of the thromboxane A 2 pathway. Prasugrel is an orally administered prodrug that is converted to its active metabolite by cytochrome P450-dependent oxidation (Rehmel et al. 2006). However, unlike clopidogrel, prasugrel requires only one cytochrome P450-dependent oxidative step to generate the active metabolite (Jakubowski et al. 2006a), and this difference may underlie the more rapid metabolic conversion and onset of action of prasugrel compared with clopidogrel (Brandt et al. 2007).

9 196 S. STEINHUBL AND M.T. ROE FIG. 3. Mean (± SD) inhibition of adenosine diphosphate (ADP) induced platelet aggregation induced by single doses of prasugrel (60 mg) and clopidogrel (300 mg). Panel A: Platelet aggregation induced by 5 µm ADP; Panel B, 20 µm ADP. SD, standard deviation. Reprinted from Am Heart J, Vol 153, Brandt JT, Payne CD, Wiviott SD, et al, A comparison of prasugrel and clopidogrel loading doses on platelet function: Magnitude of platelet inhibition is related to active metabolite formation, E9 E16, 2007, with permission from Elsevier. Early Phase I and II trials have demonstrated the safety of prasugrel (Asai et al. 2006; Matsushima et al. 2006; Jakubowski et al. 2006a) and have shown that it provides significantly more rapid, higher, and more consistent inhibition of platelet aggregation than clopidogrel (Jernberg et al. 2006; Serebruany et al. 2006; Jakubowski et al. 2006b). In a randomized, crossover, ex vivo study, healthy subjects received a single loading dose of prasugrel (60 mg) or clopidogrel (300 mg) (Brandt et al. 2007). Inhibition of platelet aggregation with prasugrel was evident after 15 min (aggregation induced by 5 µm ADP) (Brandt et al. 2007) and 30 min (20 µm ADP) (Fig. 3) (Brandt et al. 2007). In addition, compared with clopidogrel, prasugrel achieved a significantly higher degree of platelet inhibition (5 µm ADP, 84% vs. 49%; 20 µm ADP, 79% vs. 35%, P < 0.001) and an earlier plateau of effect (1 h vs. 4 h) (Fig. 3) (Brandt et al. 2007). These results were confirmed in another recently reported study which showed that 30 min after administration, 60 mg prasugrel achieved significantly greater inhibition of platelet aggregation than clopidogrel 300 mg and 600 mg (prasugrel, 52.1%; clopidogrel 300 mg, 1.3%; clopidogrel 600 mg, 4.3%; P < 0.001) (Payne et al. 2006). Also, in healthy subjects, treatment with prasugrel 10 mg or 20 mg daily for 10 days resulted in more rapid, more consistent, and higher levels of inhibition of platelet aggregation than clopidogrel 75 mg/day administered for the same period (Jakubowski et al. 2006b). Additionally, in stable aspirin-treated patients with coronary artery disease, prasugrel (loading dose, mg; maintenance dose, mg/day) was associated with a significantly higher degree of platelet inhibition and a lower proportion of poor responders than clopidogrel (loading dose, 300 mg; maintenance dose, 75 mg/day) (Jernberg et al. 2006). These

10 PLATELET P2Y 12 INHIBITION 197 differences were apparent from 2 h after treatment initiation until the end of the study (28 days), at which time the response rate was 100% for the prasugrel-treated patients receiving maintenance doses of 10 mg and 15 mg, and 55% for the clopidogrel-treated patients. However, these studies did not examine the impact of these differences in platelet inhibition on patient outcomes. Current, albeit limited, data suggest that the effects of prasugrel on bleeding risk and clinical outcome compare favorably with those of clopidogrel. In the Joint Utilization of Medications to Block Platelets Optimally (JUMBO) Thrombolysis In Myocardial Infarction (TIMI) 26 trial, clopidogrel and prasugrel were compared in 904 patients undergoing elective or urgent PCI. There was no difference in the rate of clinically significant (TIMI major plus minor) non-cabg-related bleeding between patients treated with prasugrel and those who received clopidogrel (Wiviott et al. 2005). Compared with the clopidogrel-treated group, prasugrel-treated patients had numerically lower incidences of major adverse cardiac events at 30 days (Wiviott et al. 2005). This study provided the rationale for a large, ongoing, multinational Phase III study (TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibition with prasugrel-thrombolysis In Myocardial Infarction 38 [TRITON-TIMI 38]) designed to compare the efficacy and safety of prasugrel and clopidogrel in PCI-treated ACS patients. AZD6140 AZD6140 (6-[2-(3,4-difluorophenyl)cyclopropyl-1-yl]amino-2-propylthio-9β-D-ribofuranosyl-9H purine, formerly AR-C69931MX) is an oral, reversible, short-acting nonthienopyridine ADP receptor antagonist with a rapid onset of activity that is currently in Phase III development. Like clopidogrel and prasugrel, this agent inhibits platelet aggregation by selective blockade of the P2Y 12 receptor but, unlike the thienopyridine agents, AZD6140 has a direct action and is not a prodrug. In an early, dose-finding study (Dose-finding Investigative Study to assess the Pharmacodynamic Effects of AZD6140 in atherosclerotic disease [DISPERSE]), AZD6140 was well tolerated when administered at doses of 100 mg and 200 mg twice daily (Husted et al. 2006). At these doses, peak inhibition of platelet aggregation was achieved within 2 4 h of treatment initiation, and AZD6140 inhibited platelet aggregation more effectively than clopidogrel (75 mg/day), both immediately after administration of the first dose (Fig. 4) and after 28 days of therapy. The effects of AZD6140 on inhibition of platelet aggregation are also less variable than those of clopidogrel (Husted et al. 2005). The Dose confirmation Study assessing AntiPlatelet Effects of AZD6140 vs. clopidogrel in NSTEMI (DISPERSE-2) has found that the incidence of bleeding events was similar in NSTEMI patients who have received AZD6140 and in those treated with clopidogrel (Emanuelsson et al. 2006). A dose-dependent association between AZD6140 and dyspnea has been identified, although none of the dyspneic episodes observed were associated with congestive heart failure or bronchospasm, and none were considered to be serious (Husted et al. 2006). The relationship between AZD6140 and dyspnea is being investigated in ongoing clinical studies. Two substudies of DISPERSE-2 have shown that AZD6140 suppresses platelet aggregation in clopidogrel-naïve patients (Storey et al. 2006a), and that it provides rapid additional suppression of aggregation in patients currently receiving clopidogrel therapy (Storey et al. 2006b). Outcomes data from DISPERSE-2 suggest that at a twice daily dose of 180 mg, AZD6140 may be more effective than clopidogrel 75 mg/day in preventing thrombotic events

11 198 S. STEINHUBL AND M.T. ROE FIG. 4. Mean percentage inhibition of adenosine diphosphate induced platelet aggregation after administration of a single dose of AZD6140 (50 mg, 100 mg, or 200 mg) or clopidogrel (75 mg) to patients with atherosclerosis. Husted S, et al., Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y 12 antagonist AZD6140 with aspirin in patients with atherosclerosis: A double-blind comparison to clopidogrel with aspirin, Eur Heart J, 2006;27: , by permission of Oxford University Press. in patients with ACS (Cannon et al. 2006). However, these results require confirmation in an adequately powered clinical outcomes study. A Phase III clinical trial (PLATelet inhibition and patient Outcomes [PLATO]) designed to compare the efficacy and safety of AZD6140 and clopidogrel in ACS patients is currently underway. Cangrelor Cangrelor (AR-C NX; N6 [-2-methylthio]-2-[3,3,3-trifluoropropylthio]-5 - adenylic acid) is another reversible, short-acting, non-thienopyridine antagonist of platelet aggregation with a rapid onset of action (Storey et al. 2001). Like AZD6140, cangrelor inhibits platelet aggregation by acting directly as a selective antagonist of the P2Y 12 platelet receptor. However, unlike the prodrugs clopidogrel and prasugrel, and unlike AZD6140, cangrelor is administered intravenously. In a small, Phase II study involving aspirin- and heparin-treated patients with ACS, administration of cangrelor achieved 95% inhibition of platelet aggregation, and was safe and well tolerated at infusion rates of up to 4 µg kg 1 min 1 administered for 69 h (Storey et al.

12 PLATELET P2Y 12 INHIBITION 199 FIG. 5. Mean (± SD) platelet aggregation (measured using an impedance aggregometer) in 200 PCI-treated patients who were randomized to receive h infusions of cangrelor (1, 2, or 4 µg kg 1 min 1 ) or placebo. PCI, percutaneous coronary intervention; SD, standard deviation. Reprinted from Am Heart J, Vol 151, Greenbaum AB, Grines CL, Bitti JA, et al., Initial experience with an intravenous P2Y 12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: Results from a 2-part, Phase II, multicenter, randomized, placeboand active-controlled trial, 689.E1-689.E10, 2006, with permission from Elsevier. 2001). The safety and pharmacodynamics of intravenous cangrelor (1 4 µg kg 1 min 1 ) have been compared with abciximab (an intravenous platelet glycoprotein IIb/IIIa inhibitor) and placebo in a larger, two-part, Phase II study in patients undergoing PCI. Intravenous cangrelor (1 4 µg kg 1 min 1 ) and placebo were associated with similar rates of combined major and minor bleeding (cangrelor, 13%; placebo, 8%) (Greenbaum et al. 2006). Furthermore, cangrelor- and abciximab-treated patients showed no significant differences in the 7-day incidence of combined major and minor bleeding or in the 30-day composite incidence of adverse cardiac events. At steady state, mean inhibition of platelet aggregation was 100% for the abciximab-treated patients and for the cangrelor-treated patients who received the highest dose rate (4 µg kg 1 min 1 ). This Phase II study also demonstrated that cangrelor is characterized by rapid onset of activity and short duration of action. Maximal platelet inhibition was achieved within 15 min of infusion initiation and, at cangrelor dose rates 2 µg kg 1 min 1, inhibition returned toward baseline within 15 min of infusion discontinuation (Fig. 5) (Greenbaum et al. 2006). Abciximab also showed rapid onset of activity but, in contrast to cangrelor, nearmaximal inhibition of platelets was still apparent 24 h after treatment cessation. There was a trend for cangrelor-treated patients to have shorter bleeding times than those randomized to abciximab (Greenbaum et al. 2006). Cangrelor s short half-life and the necessity for intravenous infusion mean that the clinical utility of this agent will be limited to the inpatient setting and that an oral agent will be required for long-term protection. A Phase III clinical trial (Clinical Trial Comparing Cangrelor to Clopidogrel in Subjects Who Require PCI [CHAMPION-PCI]) designed to compare the efficacy of cangrelor and clopidogrel in patients requiring PCI is currently underway. A second trial (Clinical Trial Comparing Treatment with Cangrelor [in Combination with Usual Care] to Usual Care in

13 200 S. STEINHUBL AND M.T. ROE Subjects who Require PCI [CHAMPION PLATFORM]), which commenced late in 2006, will determine the effects of adding cangrelor to usual care in patients requiring PCI. CONCLUSIONS The benefits of early loading with clopidogrel to achieve adequate platelet inhibition before PCI have been demonstrated in a number of clinical trials. However, when the guideline-recommended loading dose of 300 mg is used, clopidogrel must be administered at least h, and preferably 24 h, before PCI to achieve its maximal beneficial effect. In clinical practice, it is rarely possible to achieve this pretreatment duration because patients frequently proceed directly from diagnostic angiography (the results of which determine treatment strategy) to PCI, leaving insufficient time between the two procedures for clopidogrel to achieve optimal antiplatelet efficacy. Moreover, because administration of clopidogrel within 5 7 days of CABG is associated with increased bleeding risk, clinicians are reluctant to administer clopidogrel prior to angiography in case CABG is later indicated. As a result, clopidogrel is often withheld until the coronary anatomy has been defined with diagnostic angiography, as demonstrated in ACS patients in the CRUSADE initiative (Bhatt et al. 2004). Thus, there is a need for a platelet P2Y 12 ADP receptor antagonist that can rapidly achieve maximum platelet inhibition in patients who proceed immediately from diagnostic angiography to PCI. Early phase trials have shown that several promising platelet P2Y 12 ADP receptor antagonists currently being tested in large-scale clinical trials may offer unique benefits. Results from these trials will help to clarify the optimal antiplatelet regimen to use for both ACS and non-acs patients who undergo PCI. REFERENCES Angiolillo D, Fernández-Ortiz A, Bernardo E, Ramírez C, Sabaté M (2004) High clopidogrel loading dose during coronary stenting: Effects on drug response and interindividual variability. Eur Heart J 25: Antithrombotic Trialists Collaboration (2002) Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324: Antman E, Anbe D, Armstrong P, Bates E, Green L (2004) ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction. J Am Coll Cardiol 44:E1-E211. Asai F, Jakubowski J, Naganuma H, Brandt J, Matsushima N (2006) Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y12 inhibitor: A single ascending dose study in healthy humans. Platelets 17: Bates E, Lau W, Bleske B (2005) Loading, pretreatment, and interindividual variability issues with clopidogrel dosing. Circulation 111: Bhatt DL, Roe MT, Peterson ED, Li Y, Chen AY, Harrington RA, Greenbaum AB, Berger PB, Cannon CP, Cohen DJ, et al (2004) Utilization of early invasive management strategies for high-risk patients with non-st-segment elevation acute coronary syndromes: Results from the CRUSADE Quality Improvement Initiative. JAMA 292: Brandt JT, Payne CD, Wiviott SD, Weerakkody GJ, Farid NA, Small DS, Jakubowski JA, Naganuma H, Winters KJ (2007) A comparison of prasugrel and clopidogrel loading doses on platelet function: Magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 153:66.e9-16. Braunwald E, Antman E, Beasley J, Califf R, Cheitlin M (2002) ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-st-segment elevation myocardial infarction summary article: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol 40:

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