TY - JOUR
AU - Storey, Robert, F.
AB - Abstract The P2Y12 receptor plays a central role in platelet aggregation, and the clinical effectiveness of the thienopyridine clopidogrel, an irreversible P2Y12 antagonist, in preventing thrombosis provides proof that P2Y12 blockade is a sound strategy in reducing thrombotic risk. Drawbacks of clopidogrel treatment include prolonged time to onset and offset of effect and a variable inhibition of platelet aggregation (IPA). New P2Y12 antagonists have been developed to overcome these drawbacks. Prasugrel is a new thienopyridine that is more efficiently metabolized to its active form than clopidogrel, providing more rapid onset of effect and greater and more consistent IPA. AZD6140 is a reversible oral P2Y12 antagonist that does not require metabolic activation. AZD6140 provides more rapid onset and offset of effect than clopidogrel and greater and more consistent IPA, with a level of IPA depending on plasma drug concentrations. Cangrelor is a direct, reversible intravenous P2Y12 antagonist that has rapid onset and offset of action. Phase 2 trials of these agents have provided some evidence of potential clinical benefits in patients at risk of thrombotic events. Recent and ongoing Phase 3 trials will provide important information on how to improve clinical outcomes with P2Y12 inhibition: the TRITON-TIMI 38 trial comparing prasugrel with clopidogrel in 13 608 patients with acute coronary syndromes (ACS) and planned percutaneous coronary intervention (PCI); the PLATO trial comparing AZD6140 with clopidogrel in approximately 18 000 patients with ACS undergoing medical management, PCI, or coronary artery bypass grafting; and the CHAMPION PCI trial of cangrelor vs. clopidogrel in patients with ACS or stable coronary disease undergoing PCI. AZD6140, Cangrelor, P2Y12 antagonists, Prasugrel, Platelet aggregation A focus on platelet P2Y12-receptor antagonism in the development of antiplatelet therapies is supported by the central role of this receptor in platelet function. As shown in Figure 1, numerous agonists can interact with platelet surface receptors to induce platelet activation.1 Platelet activation induces conformational change; activates αIIbβ3 (glycoprotein (GP) IIb/IIIa); stimulates thrombin generation and alpha-granule release of coagulation factors and inflammatory mediators; and stimulates dense-granule release of adenosine triphosphate (ATP), 5-hydroxytryptamine (5HT), and adenosine diphosphate (ADP). Binding of ADP to P2Y12 results in amplification of these responses including not only aggregation but further procoagulant response and secretion from alpha- and dense-granules. P2Y12 inhibitors block the binding of ADP to P2Y12, preventing these procoagulant responses. The antiplatelet effects of aspirin reflect blockade of thromboxane A2 secretion, which has a limited overall role in platelet activation. Platelet GP IIb/IIIa inhibitors block the final pathway of aggregation, but complete blockade is associated with intolerable bleeding, such that it has proved difficult to optimize a use of these agents in clinical practice. The active metabolites of thienopyridines irreversibly bind to the P2Y12 receptors. The established clinical efficacy of these agents (e.g. ticlopidine, clopidogrel) in antiplatelet therapy has provided proof that P2Y12 inhibition is an effective strategy in inhibiting thrombosis. Thienopyridines The variable inhibition of platelet aggregation (IPA) observed with clopidogrel treatment is a major drawback of antiplatelet therapy with the agent. The mechanism underlying this variability in inhibitory effect appears to be that receptors are left unbound by the active metabolite of the agent. As shown in Figure 2, in a study in eight patients undergoing percutaneous coronary intervention (PCI) who had received a clopidogrel 300 mg loading dose followed by 75 mg/days for 4–7 days, inhibition of ADP-induced platelet aggregation at steady state was moderate and marked by wide inter-individual variation in response.2 The addition of the selective reversible P2Y12 antagonist cangrelor in vitro provided a further significant reduction in final aggregation response to ADP, suggesting that this agent blocked the P2Y12 receptors left unblocked by the clopidogrel active metabolite. This notion is supported by findings in a radioligand binding study in healthy subjects receiving clopidogrel at a 300 mg loading dose followed by 75 mg/day for 7 days.3 To quantify P2Y12 binding, 33P-2MeSADP binding to platelets in samples from these subjects was measured in the presence of an excess of the selective P2Y1 antagonist MRS 2179 (to ensure that the binding of P2Y1 did not contribute to and confound results) and in the presence or absence of cangrelor. Clopidogrel administration reduced radioligand binding to P2Y12 by 80% and complete inhibition was observed only in the presence of cangrelor, indicating that the administered regimen of clopidogrel only partially blocked the P2Y12 receptors. The third-generation thienopyridine prasugrel is an irreversible P2Y12 inhibitor that also acts through an active metabolite, to which it is converted via a different pathway than clopidogrel. Prasugrel exhibits more rapid onset of effect and produces greater mean IPA compared with clopidogrel. In a two-way crossover study, IPA was measured in 68 healthy subjects receiving a loading dose of 300 mg clopidogrel or 60 mg prasugrel.4 IPA at 20 µM ADP with prasugrel was significantly higher (P < 0.01) than with clopidogrel from 30 min to 24 h, with a maximum IPA of 78.8 ± 9.2% with prasugrel vs. 35.0 ± 24.5% with clopidogrel (P < 0.001). As shown in Figure 3, a response to prasugrel, defined as IPA response greater than the background (20%), was observed in subjects who did not respond to clopidogrel. Overall, the lower IPA response to clopidogrel was associated with lower plasma concentrations of its active metabolite compared with prasugrel (P < 0.001). There is now robust evidence that prasugrel reduces ischaemic events following PCI, albeit at the expense of increased bleeding complications. The Phase 2 JUMBO-TIMI 26 trial5 was a dose-ranging safety trial comparing prasugrel (loading doses of 40, 60, and 60 mg/day and maintenance doses of 7.5, 10, and 15 mg, respectively) with clopidogrel (300 mg followed by 75 mg/day) for 30 days in 904 patients undergoing elective or urgent PCI (all patients received concomitant aspirin therapy). There was no difference between prasugrel and clopidogrel with regard to the primary endpoint of TIMI major/minor bleeding not related to coronary artery bypass grafting (CABG) (1.7 vs. 1.2%, P = 0.59) and no difference in the primary efficacy composite endpoint of 30-day major adverse cardiac events (7.2 vs. 9.4%, P = 0.26) (Figure 4). However, there was a significant reduction in target vessel thrombosis among prasugrel patients (0.6 vs. 2.4%, P = 0.02) and numerically lower rates of myocardial infarction (MI) and ischaemia. In the TRITON-TIMI 38 Phase 3 trial,6 13 608 patients with acute coronary syndromes (ACS), consisting of ST-segment elevation MI (STEMI) or unstable angina (UA)/non-STEMI (NSTEMI), with planned PCI were randomized to prasugrel 60 mg followed by 10 mg/day or clopidogrel 300 mg followed by 75 mg/day in addition to aspirin therapy for a median of 12 months (Figure 5A). The primary endpoint was the composite of cardiovascular death, MI, or stroke; secondary endpoints included the composites of cardiovascular death/MI/stroke/reischaemia and cardiovascular death/MI/urgent target vessel revascularization. The rate of occurrence of the primary endpoint was lower in the prasugrel group (9.9%) compared with the clopidogrel group (12.1%; 95% confidence interval 0.73–0.9, P < 0.001). There was an impressive reduction in the stent thrombosis rate from 2.4% in the clopidogrel group to 1.1% in the prasugrel group, confirming the importance of effective P2Y12 blockade in preventing this serious complication following PCI. However, major bleeding was increased in the prasugrel group (2.4 vs. 1.8% in the clopidogrel group; P = 0.03) and the increase in fatal bleeding (0.4 vs. 0.1% in the clopidogrel group) offset the beneficial effect of prasugrel on mortality due to ischaemic events such that there was no difference in mortality between the two groups. On post hoc subgroup analysis, it was noted that patients with a previous history of cerebrovascular disease fared worse on prasugrel compared with clopidogrel suggesting that particular caution may be required in these patients. Many of the patients in TRITON may have received study treatment post-angiogram, just prior to undergoing PCI, whereas many of those with STEMI may have received it prior to angiography on the basis of electrocardiogram (ECG) evidence of STEMI. Further studies are necessary to determine any difference in efficacy between prasugrel and more effective pretreatment with clopidogrel, such as clopidogrel 600 mg more than 2 h prior to angiography in patients with UA and NSTEMI. Direct, reversible P2Y12 antagonists AZD6140 AZD6140 is the first reversible oral ADP-receptor antagonist; it represents a new class of P2Y12 inhibitors, the cyclopentyltriazolopyrimidines, which differ from both thienopyridines and ATP analogues. The agent is direct acting (does not require metabolic activation) and exhibits reversible binding to all exposed circulating platelets, with the degree of inhibition reflecting plasma drug levels. The agent thus exhibits more rapid offset of effect than thienopyridines; and on cessation, a full recovery of platelet function. AZD6140 reaches peak plasma drug levels within 2–3 h of dosing, which directly correlate to IPA, and has a greater and more consistent IPA than clopidogrel. Figure 6 shows the area under the curve (AUC) for IPA over 0–12 h (final extent) on Day 28 in patients with atherosclerosis receiving various maintenance doses of AZD6140 vs. 75 mg/day of clopidogrel in the Phase 2 DISPERSE trial.7,8 These data indicate high and consistent IPA with AZD6140 doses of 100 mg twice daily and greater, with more variable and lesser response observed with the 50 mg twice daily and with the standard clopidogrel 75 mg maintenance dose. In the Phase 2 DISPERSE2 trial,9 patients with NSTEMI ACS were randomized to AZD6140 90 or 180 mg twice daily or clopidogrel 300 mg followed by 75 mg once daily for up to 12 weeks; approximately half of the patients in each AZD6140 group received a loading dose of 270 mg, followed 12 h later by their assigned maintenance dose, with the remainder of patients beginning therapy at the maintenance dose. As shown in Figure 7, a substudy in 45 clopidogrel-naïve patients showed more rapid onset of effect and markedly greater IPA with all doses of AZD6140 compared with the clopidogrel 300 mg loading dose after the first dose of study treatment.8,10 As can be seen in Figure 6, after 4 weeks of treatment, the ranges of AUC for IPA over 0–12 h in the DISPERSE2 patients were similar to those in the DISPERSE trial in patients with stable disease,8 suggesting that the acute nature of ACS did not influence response to AZD6140 treatment. At 4 weeks, 4-h post-dose IPA was 64 ± 22% with clopidogrel, 79 ± 22% with AZD6140 90 mg, and 95 ± 8% with AZD6140 180 mg.8,10 In DISPERSE2,9 a total of 990 patients were randomized to AZD6140 90 mg twice daily (n = 334), 180 mg twice daily (n = 329), or clopidogrel 75 mg once daily (n = 327) with all patients receiving aspirin. There were no differences between AZD6140 groups and the clopidogrel group in the primary outcome measure of major and minor bleeding (Figure 8A). The bleeding rate in patients undergoing CABG between 1 and 5 days of stopping study drug was numerically lower in AZD6140 patients. Rates of the composite clinical endpoint (cardiovascular death, MI, or stroke) were numerically lower in the AZD6140-treated groups (6.0% with AZD6140 90 mg, 3.5% with AZD6140 180 mg, and 6.2% with clopidogrel) (Figure 8A). A trend towards a lower rate of MI was observed with the higher dose of AZD6140, with MI occurring in 5.6% of clopidogrel patients, 3.8% of AZD6140 90 mg patients (P = 0.41 vs. clopidogrel), and 2.5% of AZD6140 180 mg patients (P = 0.06 vs. clopidogrel) (Figure 8B). Overall, AZD6140 had similar safety and tolerability compared with clopidogrel, with similar proportions of patients discontinuing study treatment in the three groups (6–7%).9 DISPERSE2 confirmed the earlier finding of dyspnoea associated with AZD6140 treatment, with dyspnoea occurring in 15.8% of AZD6140 180 mg patients (P < 0.0002 vs. clopidogrel), 10.5% of AZD6140 90 mg patients (P = 0.07 vs. clopidogrel), and 6.4% of clopidogrel patients. Dyspnoea was reported as mild to moderate and was frequently self-limited: 27% of patients reporting dyspnoea had resolution within 24 h. A post hoc analysis of continuous ECGs identified a greater frequency of ventricular pauses >2.5 s in AZD6140 patients, with rates of 9.9% in the 180 mg AZD6140 group (P = 0.014 vs. clopidogrel), 5.5% in the 90 mg-dose group (P = 0.058 vs. clopidogrel), and 4.3% in the clopidogrel group. The mechanism for these side effects is not known but one hypothesis is that they may be mediated by endogenous adenosine. Recent data supporting this hypothesis indicate that AZD6140 inhibits adenosine uptake by erythrocytes and consequently may affect coronary blood flow in response to adenosine infusion or local ischaemia in canine studies.11 The safety and effectiveness of AZD6140 is currently being evaluated in the large-scale PLATO trial (Figure 5B). In this trial, a target population of approximately 18 000 patients with UA, NSTEMI, or STEMI undergoing PCI, medical management, or CABG are being randomized to clopidogrel or AZD6140. Clopidogrel-naïve patients will be randomized to either a 180 mg loading dose of AZD6140 and placebo clopidogrel, followed by AZD6140 90 mg twice daily and matching placebo, or to a 300 mg loading dose of clopidogrel (over-encapsulated), followed by clopidogrel 75 mg once daily and matching placebo AZD6140 for up to 12 months. An additional 300 mg of clopidogrel study drug may be given prior to PCI. Patients already receiving clopidogrel will be randomized to either a loading dose of 180 mg AZD6140 and matching placebo, followed by 90 mg twice daily or clopidogrel 75 mg (over-encapsulated) followed by 75 mg once daily and placebo AZD6140, for up to 12 months. The primary endpoint is the composite of cardiovascular death/MI/stroke. Secondary endpoints include cardiovascular death/MI/stroke/revascularization with PCI and cardiovascular death/MI/stroke/severe recurrent ischaemia. Cangrelor Cangrelor is an IV ATP analogue that binds reversibly to the P2Y12 receptor. It has onset of action within minutes of administration, IPA determined by plasma drug levels, and an ultra-short half-life of approximately 5 min. As part of a Phase 2 study, 12 patients with UA/NSTEMI in the first part of the study received cangrelor at stepped-dose increments starting at 0.05 µg/kg/min and increasing to 0.2, 0.5, and 2.0 µg/kg/min at 0.5, 1.5, 2.5, and 3.5 h after the start of infusion and remaining at the latter dose for 21 h.12 As shown in Figure 9, plasma cangrelor levels increased with increasing dose, were reduced by nearly 50% at 20 min after stopping infusion and were undetectable in most patients by 1 h. IPA increased to a peak at the highest infusion rate and mean IPA at 24 h was 96%; mean IPA was approximately 50% at 20 min after infusion and 36% at 1 h after infusion. As part of a Phase 2 trial, 199 patients undergoing PCI were randomized to cangrelor 4 µg/kg/min infusion for 18–24 h or the GP IIb/IIIa inhibitor abciximab 0.25 mg/kg bolus followed by 0.125 µg/kg/min up to 10 µg/min for up to 12 h, with all patients receiving concomitant aspirin.13 By 7 days, major bleeding had occurred in 1% of cangrelor patients and 2% of abciximab patients; minor bleeding had occurred in 6 and 7%, respectively (Figure 10). Rates of the composite endpoint of death/MI/reintervention at 7 days were 5.7% in cangrelor patients and 5.4% in abciximab patients; 30-day rates were 7.6 and 5.3%, respectively. This early study provided some proof of principle that P2Y12 inhibition could supplant GP IIb/IIIa inhibition in at least some patient subsets. Cangrelor is currently being examined in two Phase 3 trials. The CHAMPION PCI trial is comparing cangrelor with clopidogrel in a target population of 9000 patients with ACS or stable coronary artery disease undergoing PCI, with a focus on ischaemic events during the first 48 h (Figure 5C). The primary clinical endpoint is all-cause mortality, MI, and ischaemia-driven revascularization in the 48 h after randomization, with secondary endpoints including all-cause mortality/MI at 48 h. The CHAMPION PLATFORM trial is comparing cangrelor plus usual care vs. placebo plus usual care in a target population of more than 4000 patients undergoing PCI. Summary The P2Y12 receptor plays a major and central role in platelet activation, aggregation, granule secretion, and procoagulant and pro-inflammatory responses. Standard regimens of clopidogrel achieve partial P2Y12-receptor blockade, leading to suboptimal protection against arterial thrombosis in some patients. Three new P2Y12 antagonists are being compared with clopidogrel in large-scale Phase 3 trials. Prasugrel is a new thienopyridine that is more efficiently converted to its active metabolite than clopidogrel, leading to more consistent P2Y12 inhibition and, in the TRITON study, more effective prevention of ischaemic events at the expense of increased bleeding. AZD6140 is a reversible oral P2Y12 antagonist that yields greater and more consistent P2Y12 inhibition than clopidogrel. Cangrelor is an IV reversible P2Y12 antagonist that has rapid onset and offset of action. Findings in these trials will provide valuable information on how best to use P2Y12 antagonism to improve clinical outcomes in ACS patients. Conflict of interest: Dr. Storey has received institutional research grant support and/or honoraria from AstraZeneca, Eli Lilly, Daiichi Sankyo, and The Medicines Company. Figure 1 Open in new tabDownload slide Platelet-activation mechanisms and role of the P2Y12 receptor. Platelet activation leads to dense-granule secretion of ADP, which activates P2Y12, inducing amplification of aggregation, procoagulant, and pro-inflammatory responses. Novel P2Y12 antagonists include the new thienopyridine prasugrel, the oral reversible antagonist AZD6140, and the reversible IV antagonist cangrelor.10 Figure 1 Open in new tabDownload slide Platelet-activation mechanisms and role of the P2Y12 receptor. Platelet activation leads to dense-granule secretion of ADP, which activates P2Y12, inducing amplification of aggregation, procoagulant, and pro-inflammatory responses. Novel P2Y12 antagonists include the new thienopyridine prasugrel, the oral reversible antagonist AZD6140, and the reversible IV antagonist cangrelor.10 Figure 2 Open in new tabDownload slide Mean percentage of platelet aggregation at 20 µM ADP before (baseline) and after clopidogrel 300 mg loading dose followed by 75 mg once daily for 4–7 days in patients undergoing PCI. The addition of cangrelor in vitro further inhibited platelet aggregation, indicating blockade of P2Y12 receptors left unblocked by clopidogrel at steady state.10 Figure 2 Open in new tabDownload slide Mean percentage of platelet aggregation at 20 µM ADP before (baseline) and after clopidogrel 300 mg loading dose followed by 75 mg once daily for 4–7 days in patients undergoing PCI. The addition of cangrelor in vitro further inhibited platelet aggregation, indicating blockade of P2Y12 receptors left unblocked by clopidogrel at steady state.10 Figure 3 Open in new tabDownload slide IPA at 20 µM ADP at 24 h in healthy subjects receiving clopidogrel 300 mg or prasugrel 60 mg in a crossover study. Reprinted from Am Heart J, 153, Brandt JT, et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation, 66.e9–66.e16, 2007, with permission from Elsevier.4 Figure 3 Open in new tabDownload slide IPA at 20 µM ADP at 24 h in healthy subjects receiving clopidogrel 300 mg or prasugrel 60 mg in a crossover study. Reprinted from Am Heart J, 153, Brandt JT, et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation, 66.e9–66.e16, 2007, with permission from Elsevier.4 Figure 4 Open in new tabDownload slide Thirty-day rates for major adverse cardiac events (MACE), target vessel thrombosis, and major and minor non-CABG bleeding in patients receiving clopidogrel (CLOP) or prasugrel (PRAS) in the Phase 2 JUMBO-TIMI 26 study. HR, hazard ratio; RR, relative risk (95% confidence interval). Data are from Wiviott et al.6 Figure 4 Open in new tabDownload slide Thirty-day rates for major adverse cardiac events (MACE), target vessel thrombosis, and major and minor non-CABG bleeding in patients receiving clopidogrel (CLOP) or prasugrel (PRAS) in the Phase 2 JUMBO-TIMI 26 study. HR, hazard ratio; RR, relative risk (95% confidence interval). Data are from Wiviott et al.6 Figure 5 Open in new tabDownload slide Large-scale Phase 3 trials comparing the new P2Y12 antagonists prasugrel (TRITON-TIMI 38 trial) (A), AZD6140 (PLATO trial) (B), and cangrelor (CHAMPION-PCI trial) (C) with clopidogrel. ASA, aspirin; CAD, coronary artery disease; CV, cardiovascular; CVD, cardiovascular death; IDR, ischaemia-driven revascularization; ld, loading dose; UTVR, urgent target vessel revascularization. Figure 5 Open in new tabDownload slide Large-scale Phase 3 trials comparing the new P2Y12 antagonists prasugrel (TRITON-TIMI 38 trial) (A), AZD6140 (PLATO trial) (B), and cangrelor (CHAMPION-PCI trial) (C) with clopidogrel. ASA, aspirin; CAD, coronary artery disease; CV, cardiovascular; CVD, cardiovascular death; IDR, ischaemia-driven revascularization; ld, loading dose; UTVR, urgent target vessel revascularization. Figure 6 Open in new tabDownload slide Area under the curve for IPA (final extent) over 0–12 h with various AZD6140 maintenance doses and clopidogrel in the Phase 2 DISPERSE trial in patients with atherosclerosis (A) and Phase 2 DISPERSE2 trial in patients with NSTEMI ACS (B). Reprinted from J Am Coll Cardiol, 50, Storey RF, et al. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes, 1852–1856, 2007, with permission from Elsevier.8 Figure 6 Open in new tabDownload slide Area under the curve for IPA (final extent) over 0–12 h with various AZD6140 maintenance doses and clopidogrel in the Phase 2 DISPERSE trial in patients with atherosclerosis (A) and Phase 2 DISPERSE2 trial in patients with NSTEMI ACS (B). Reprinted from J Am Coll Cardiol, 50, Storey RF, et al. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes, 1852–1856, 2007, with permission from Elsevier.8 Figure 7 Open in new tabDownload slide Mean IPA (final extent) at 20 µM ADP after first study dose of AZD6140 or clopidogrel in 45 clopidogrel-naïve patients in the DISPERSE2 trial. SEM, standard error of the mean. Reprinted from J Am Coll Cardiol, 50, Cannon CP, et al. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndromes, 1844–1851, 2007, with permission from Elsevier.10 Figure 7 Open in new tabDownload slide Mean IPA (final extent) at 20 µM ADP after first study dose of AZD6140 or clopidogrel in 45 clopidogrel-naïve patients in the DISPERSE2 trial. SEM, standard error of the mean. Reprinted from J Am Coll Cardiol, 50, Cannon CP, et al. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndromes, 1844–1851, 2007, with permission from Elsevier.10 Figure 8 Open in new tabDownload slide Adjudicated major and minor bleeding rates at Weeks 4 and 12 (A) and adjudicated clinical endpoints (B) among patients receiving AZD6140 or clopidogrel in the DISPERSE2 trial. CV, cardiovascular. *Minor bleeding without major bleeding. Adapted with permission from Cannon (2007). Bleeding classifications: Major—fatal/life-threatening (based on the TIMI major bleeding category), Major—other (based on the TIMI minor bleeding category), Minor (requiring medical intervention or transfusion of one or more units). Figure 8 Open in new tabDownload slide Adjudicated major and minor bleeding rates at Weeks 4 and 12 (A) and adjudicated clinical endpoints (B) among patients receiving AZD6140 or clopidogrel in the DISPERSE2 trial. CV, cardiovascular. *Minor bleeding without major bleeding. Adapted with permission from Cannon (2007). Bleeding classifications: Major—fatal/life-threatening (based on the TIMI major bleeding category), Major—other (based on the TIMI minor bleeding category), Minor (requiring medical intervention or transfusion of one or more units). Figure 9 Open in new tabDownload slide Plasma levels of cangrelor (AR-C69931XX) (A) and mean IPA (B) during and after cangrelor infusion in patients with NSTEMI ACS. Reproduced with permission from Storey et al.2 Figure 9 Open in new tabDownload slide Plasma levels of cangrelor (AR-C69931XX) (A) and mean IPA (B) during and after cangrelor infusion in patients with NSTEMI ACS. Reproduced with permission from Storey et al.2 Figure 10 Open in new tabDownload slide Composite endpoint rate and major and minor bleeding rates at 7 days in PCI patients receiving cangrelor or abciximab in the Phase 2 trial. Revasc, revascularization. Data are from Greenbaum et al.13 Figure 10 Open in new tabDownload slide Composite endpoint rate and major and minor bleeding rates at 7 days in PCI patients receiving cangrelor or abciximab in the Phase 2 trial. Revasc, revascularization. Data are from Greenbaum et al.13 References 1 Storey RF . Biology and pharmacology of the platelet P2Y12 receptor. Curr Pharm Des ( 2006 ) 12 : 1255 –1259. 2 Storey RF , Wilcox RG, Heptinstall S. Comparison of the pharmacodynamics effects of the platelet ADP-receptor antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease. Platelets ( 2002 ) 13 : 407 –413. 3 Judge HM , Buckland RJ, Sugidachi A, Jakubowski JA, Storey RF. The active metabolite of prasugrel effectively blocks the platelet P2Y12 receptor and inhibits procoagulant and pro-inflammatory platelet responses. Platelets ( 2008 ) 19 : 125 –133. 4 Brandt JT , Payne CD, Wiviott SD, Weerakkody G, Farid NA, Small DS, Jakubowski JA, Naganuma H, Winters KJ. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J ( 2007 ) 153 : 66.e9 –66.e16. 5 Wiviott SD , Antman EM, Winters KJ, Weerakkody G, Murphy SA, Behounek BD, Carney RJ, Lazzam C, McKay RG, McCabe CH, Braunwald E, JUMBO-TIMI 26 Investigators. Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention. Results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation ( 2005 ) 111 : 3366 –3373. 6 Wiviott SD , Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM, the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med ( 2007 ) 357 : 2015 –2021. 7 Husted S , Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J ( 2006 ) 27 : 1038 –1047. 8 Storey RF , Husted S, Harrington RA, Heptinstall S, Wilcox RG, Peters G, Wickens M, Emanuelsson H, Gurbel P, Grande P, Cannon CP. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol ( 2007 ) 50 : 1852 –1860. 9 Cannon CP , Husted S, Harrington RA, Scirica BM, Emanuelsson H, Peters G, Storey RF, for the DISPERSE2 Investigators. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral ADP-receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndromes: primary results of the DISPERSE2 trial. J Am Coll Cardiol ( 2007 ) 50 : 1844 –1851. 10 Storey RF , Husted S, Harrington RA Heptinstall S, Wilcox RG, Gurbel PA, Grande P, Sanders N, Peters G, Emanuelsson H, Cannon CP. AZD6140 yields greater inhibition of platelet aggregation than clopidogrel in patients with acute coronary syndromes without previous clopidogrel treatment. J Am Coll Cardiol ( 2006 ) 47 ( Suppl. A ): 204A . Abstract 821-3. 11 Björkman JA , van Giezen JJJ, Zachrisson H. Reduced bleeding time prolongation for the reversible P2Y12 antagonist AZD6140 compared with the thienopyridine clopidogrel in both a rat and a dog model of combined thrombosis and haemostasis. Presented at: The XXIst International Society on Thrombosis and Haemostasis Congress, 6–12 July 2007: Geneva, Switzerland. 12 Storey RF , Oldroyd KG, Wilcox RG. Open multicenter study of the P2T receptor antagonist AR-C69931MX assessing safety, tolerability and activity in patients with acute coronary syndromes. Thromb Haemost ( 2001 ) 85 : 401 –407. 13 Greenbaum AB , Grines CL, Bittl JA, Becker RC, Kereiakes DJ, Gilchrist IC, Clegg J, Stankowski JE, Grogan DR, Harrington RA, Emanuelsson H, Weaver WD. Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: results from a 2-part, phase II, multicenter, randomized, placebo- and active-controlled trial. Am Heart J ( 2006 ) 151 : 689.e1 –689.e10. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org
TI - New developments in antiplatelet therapy
JO - European Heart Journal Supplements
DO - 10.1093/eurheartj/sun008
DA - 2008-05-01
UR - https://www.deepdyve.com/lp/oxford-university-press/new-developments-in-antiplatelet-therapy-SfNXYrR0li
SP - D30
VL - 10
IS - suppl_D
DP - DeepDyve
ER -