Consistent Inhibition Of Platelet Aggregation Research Articles

Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Profile of the Oral Antiplatelet Agent Ticagrelor

Acute coronary syndromes (ACS) remain life-threatening disorders associated with high morbidity and mortality, despite advances in treatment over the last decade. Adenosine diphosphate-induced platelet activation via P2Y(12) receptors plays a pivotal role in the pathophysiology of ACS. The current standard of treatment involves dual antiplatelet therapy with aspirin (acetylsalicylic acid) and the thienopyridine clopidogrel. Numerous studies and wide use in clinical practice have established the value of this approach in the treatment of ACS. However, clopidogrel treatment has a number of limitations, including a delayed onset of action due to the need for metabolic activation, variable and reduced antiplatelet effects in patients with certain genotypes, and prolonged recovery of platelet function due to irreversible P2Y(12) receptor binding. Prasugrel, a new thienopyridine, has demonstrated more consistent inhibition of platelet aggregation (IPA) than clopidogrel, although this thienopyridine also requires metabolic activation and treatment is associated with a significantly increased risk of life-threatening and fatal bleeding. The recently approved oral antiplatelet agent ticagrelor has the potential to overcome some of the limitations of current therapy due to its unique pharmacokinetic and pharmacodynamic profiles. It is a member of a new chemical class, the cyclopentyltriazolopyrimidines, and is a potent P2Y(12) receptor antagonist. Ticagrelor is rapidly absorbed, with a median time to maximum concentration of 1.3-2.0 hours. Ticagrelor does not require metabolic activation to an active form and binds rapidly and reversibly to the P2Y(12) receptor. As well as exerting effects via platelet P2Y(12) receptors, ticagrelor may confer additional benefits via inhibition of non-platelet P2Y(12) receptors. The pharmacokinetic profile of ticagrelor is not significantly affected by age, gender or administration with food, nor by prior treatment with, or responsiveness to, clopidogrel. Ticagrelor is primarily metabolized via the cytochrome P450 (CYP) 3A4 enzyme, rapidly produces plasma concentration-dependent IPA that is greater and more consistent than that observed with clopidogrel, and can also enhance platelet inhibition and overcome non-responsiveness in patients previously treated with clopidogrel. Importantly, the pharmacodynamic characteristics of ticagrelor are not influenced by CYP2C19 and ABCB1 genotypes. This article summarizes our current knowledge regarding the pharmacokinetic, pharmacodynamic and pharmacogenetic profile of ticagrelor.

Which Antiplatelet Agent for Whom? Which Patient Populations Benefit Most from Novel Antiplatelet Agents (Ticagrelor, Prasugrel)?

Antiplatelet treatment is a cornerstone for patients with acute coronary syndromes treated invasively or conservatively to reduce the risk of early and late occurring ischemic complications and to improve survival. Compared to clopidogrel, the novel antiplatelet agents prasugrel and ticagrelor provide faster and more consistent inhibition of platelet aggregation and result in substantially improved clinical outcome in patients with acute coronary syndromes but also an increased bleeding risk. Therefore, balancing the rope between safety and efficacy of treatment is crucial for optimizing outcome. An understanding of the similarities but also differences in pharmacological effect, clinical trial design, and outcome is crucial for understanding which patient populations benefit the most from novel antiplatelet treatments. This review provides recommendations for their optimal use.

Prasugrel Versus Tirofiban Bolus With or Without Short Post-Bolus Infusion With or Without Concomitant Prasugrel Administration in Patients With Myocardial Infarction Undergoing Coronary Stenting: The FABOLUS PRO (Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with ST-segment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse) Trial

The authors sought to compare the effect on inhibition of platelet aggregation (IPA) of prasugrel therapy versus tirofiban bolus with or without a post-bolus short drug infusion in ST-segment elevation myocardial infarction (STEMI) patients. The degree and rapidity of IPA after prasugrel alone with or without concomitant glycoprotein IIb/IIIa inhibition in STEMI patients is unknown. A total of 100 STEMI patients randomly received prasugrel 60 mg versus 25 μg/kg tirofiban bolus with or without post-bolus 2-h infusion of tirofiban, with or without concomitant prasugrel. IPA at light transmission aggregometry was performed throughout 24 h. The primary endpoint was IPA stimulated with 20 μmol/l adenosine diphosphate (ADP) at 30 min. At 30 min, patients in the prasugrel group showed a significantly lower IPA to 20 μmol/l ADP stimulation as compared with tirofiban-treated patients (36 ± 35 vs. 87 ± 31, p < 0.0001). Similarly, patients taking prasugrel showed a suboptimal degree of platelet inhibition for at least 2 h compared with tirofiban patients. Post-bolus tirofiban infusion was necessary to maintain a high level of IPA beyond 1 h after bolus administration if concomitant clopidogrel was given, whereas the bolus-only tirofiban and concomitant prasugrel led to the higher and more consistent IPA levels after both ADP and thrombin receptor-activating peptide stimuli than either therapy alone. Our study shows that prasugrel administration leads to a suboptimal IPA for at least 2 h in STEMI patients. Yet, prasugrel, given in association with a bolus only of glycoprotein IIb/IIIa inhibitor, obviates the need of post-bolus infusion and almost completely abolishes residual variability of IPA after treatment. (Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with ST-segment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse [The FABOLUS PRO trial]; NCT01336348).

The future of platelet function testing to guide therapy in clopidogrel low and enhanced responders

Dual oral antiplatelet therapy with aspirin and clopidogrel is the therapy of choice in patients with acute coronary syndromes and in patients undergoing coronary stent placement to lower the risk of thrombotic events. Responsiveness to aspirin and especially to clopidogrel is not uniform and is subject to considerable interindividual variability. Furthermore, there is a broad consensus that clopidogrel low response or so-called high on-treatment platelet reactivity is linked to the occurrence of ischemic events. On the other hand, evidence is accumulating that enhanced clopidogrel responders are at increased risk of bleeding. Newer antiplatelet drugs, such as prasugrel and ticagrelor, are more potent and produce more consistent inhibition of platelet aggregation via the P2Y12 ADP platelet receptor. A variety of methods of platelet function testing are available for evaluating platelet inhibition in percutaneous coronary intervention-treated patients in order to help determine the individual risk for ischemic and bleeding complications. Although not yet routinely undertaken, platelet function testing offers the potential to tailor antiplatelet therapy for individual patients. Whether alteration of therapy based on platelet function testing improves patients’ outcomes remains unclear and is currently under investigation. This article reviews the impact of antiplatelet drug responsiveness on clinical outcomes with a focus on P2Y12 receptor inhibition as well as on current and future concepts for personalized antiplatelet strategies.

The Incidence of Bradyarrhythmias and Clinical Bradyarrhythmic Events in Patients With Acute Coronary Syndromes Treated With Ticagrelor or Clopidogrel in the PLATO (Platelet Inhibition and Patient Outcomes) Trial: Results of the Continuous Electrocardiographic Assessment Substudy

The aim of this study was to determine whether ticagrelor increased the risk of ventricular pauses compared with clopidogrel and whether these pauses were associated with any clinical bradycardic events in patients presenting with acute coronary syndromes. Ticagrelor, an oral reversibly binding P2Y(12) inhibitor, provides more potent and consistent inhibition of platelet aggregation than clopidogrel but in a phase II study was associated with increased risk for ventricular pauses. A prospective continuous electrocardiographic (cECG) assessment was therefore performed within the PLATO (Platelet Inhibition and Patient Outcomes) study comparing ticagrelor and clopidogrel in patients hospitalized with acute coronary syndromes. Patients in the cECG assessment had planned 7-day cECG recording initiated at the time of randomization (week 1), which was within 24 h of symptom onset, and then repeated at 1 month after randomization during the convalescent phase. The principal safety endpoint was the incidence of ventricular pauses lasting at least 3 s. Investigators also reported symptomatic bradycardic adverse events during the entire study duration (median 277 days). A total of 2,908 patients were included in the cECG assessment, of whom 2,866 (98.5%) had week 1 recordings, 1,991 (68.4%) had 1-month recordings, and 1,949 (67.0%) had both. During the first week after randomization, ventricular pauses ≥3 s occurred more frequently in patients receiving ticagrelor than clopidogrel (84 [5.8%] vs. 51 [3.6%]; relative risk: 1.61; p = 0.006). At 1 month, pauses ≥3 s occurred overall less frequently and were similar between treatments (2.1% vs. 1.7%). Most were ventricular pauses, and the greatest excess associated with ticagrelor were asymptomatic, sinoatrial nodal in origin (66%), and nocturnal. There were no differences between ticagrelor and clopidogrel in the incidence of clinically reported bradycardic adverse events, including syncope, pacemaker placement, and cardiac arrest. In the PLATO cECG assessment, more patients treated with ticagrelor compared with clopidogrel had ventricular pauses, which were predominantly asymptomatic, sinoatrial nodal in origin, and nocturnal and occurred most frequently in the acute phase of acute coronary syndromes. There were no apparent clinical consequences related to the excess in ventricular pauses in patients assigned to ticagrelor. (A Comparison of AZD6140 and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872).

ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use

This expert consensus document was developed by the American College of Cardiology Foundation (ACCF), the American College of Gastroenterology (ACG), and the American Heart Association (AHA). Expert consensus documents inform practitioners, payers, and other interested parties of the opinion of ACCF and document cosponsors concerning evolving areas of clinical practice or medical technologies. Expert consensus documents cover topics for which the evidence base, experience with technology, or clinical practice is not considered sufficiently well developed to be evaluated by the formal ACCF/AHA Practice Guidelines process. Often, the topic is the subject of considerable ongoing investigation. Thus, the reader should view the expert consensus document as the best attempt of the ACCF and document cosponsors to inform clinical practice in areas where rigorous evidence may not yet be available. To avoid actual, potential, or perceived conflicts of interest that may arise as a result of industry relationships or personal interests among the writing committee, all members of the writing committee, as well as peer reviewers of the document, are asked to disclose all current healthcare-related relationships and those existing 12 months before initiation of the writing effort. The ACCF Task Force on Clinical Expert Consensus Documents (CECD) reviews these disclosures to determine which companies make products (on market or in development) that pertain to the document under development. Based on this information, a writing committee is formed to include a majority of members with no relevant relationships with industry (RWI), led by a chair with no relevant RWI. Authors with relevant RWI are not permitted to draft or vote on text or recommendations pertaining to their RWI. RWI are reviewed on all conference calls and updated as changes occur. Author and peer reviewer RWI pertinent to this document are disclosed in Appendixes 1 and 2, respectively. Additionally, to ensure complete transparency, …

Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers

The antiplatelet agent clopidogrel is currently the recommended treatment for acute coronary syndrome (ACS). Inhibition of platelet aggregation (IPA) with clopidogrel is insufficient, which increases the risk for recurrent ischaemic events. Therefore, there is a need for antiplatelet agents with improved IPA. Ticagrelor (AZD6140) is a new antiplatelet agent in clinical development for reduction of thrombotic events in patients with ACS. This study assesses the optimal dosing schedule for ticagrelor in healthy volunteers and compares the degree of IPA with clopidogrel. Our findings illustrate that the pharmacokinetics of ticagrelor are predictable and are associated with consistent inhibition of platelet activity. IPA with ticagrelor was greater and better sustained at high levels with twice daily ticagrelor than once daily regimens. To determine the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple oral doses of ticagrelor, a P2Y(12) receptor antagonist, in healthy volunteers. This was a randomized, single-blind, placebo-controlled, ascending dose study. Thirty-two subjects received ticagrelor 50-600 mg once daily or 50-300 mg twice daily or placebo for 5 days at three dose levels in two parallel groups. Another group of 16 subjects received a clopidogrel 300 mg loading dose then 75 mg day(-1), or placebo for 14 days. Ticagrelor was absorbed with median t(max) 1.5-3 h, exhibiting predictable pharmacokinetics over the 50-600 mg dose range. Mean C(max) and AUC for ticagrelor and its main metabolite, AR-C124910XX, increased approximately dose-proportionately (approximately 2.2- to 2.4-fold with a twofold dose increase) over the dose range. Inhibition of platelet aggregation (IPA) with ticagrelor was greater and better sustained at high levels with ticagrelor twice daily vs. once daily regimens. Throughout dosing, more consistent IPA was observed at doses > or = 300 mg once daily and > or = 100 mg twice daily compared with clopidogrel. Mean IPA with ticagrelor > or = 100 mg twice daily was greater and less variable (93-100%, range 65-100%) than with clopidogrel (77%, range 11-100%) at trough concentrations. No safety or tolerability issues were identified. Multiple dosing provided predictable pharmacokinetics of ticagrelor and its metabolite over the dose range of 50-600 mg once daily and 50-300 mg twice daily with C(max) and AUC(0,t) increasing approximately dose-proportionally. Greater and more consistent IPA with ticagrelor at doses > or = 100 mg twice daily and > or = 300 mg once daily were observed than with clopidogrel. Ticagrelor at doses up to 600 mg day(-1) was well tolerated.

Abstract 5495: More Rapid and Consistent Inhibition of Platelet Aggregation is Achieved by Loading With Ticagrelor Compared to Clopidogrel in Patients With Acute Coronary Syndromes: Results From the PLATO PLATELET Substudy

Background: Ticagrelor (T) is an oral reversible P2Y 12 receptor antagonist that does not require conversion to an active metabolite for antiplatelet activity, unlike clopidogrel (C). The PLATO study compared the efficacy of T and C in patients with a broad range of acute coronary syndromes (ACS). In this substudy (PLATO PLATELET), we assessed the onset and extent of inhibition of platelet function in PLATO study patients. Methods and Results: 24 C-naive patients with NSTE ACS or STEMI undergoing primary PCI and sequentially randomised in a double blind, double dummy design to C (300mg [n=7] or 600 mg load [n=5]) or T (180mg load [n=12]) in the PLATO study in a single centre were entered into the first phase of PLATO PLATELET. Light transmittance aggregometry (LTA) with ADP (5 and 20 uM) and whole blood single platelet counting aggregometry (WBSPC) using ADP 1–100 uM was performed prior to study drug administration and 1, 2, 4, 8 and 12 hours after study drug. VerifyNow P2Y12 (VN) and VASP assays were also performed pre and 4h post study drug. Data obtained after abciximab administration was excluded except for VASP data. There was more rapid and greater inhibition of platelet aggregation with T vs C, with most T-treated patients showing a substantial effect at 1h post dose that was sustained until 12h post dose (Figure ). VN data at 4h were 273±124 and 68±97 PRU for C and T respectively (p&lt;0.01). VASP data showed a similar trend. C 300 vs 600mg doses showed the same patterns of LTA response. Conclusion: T 180mg loading dose has a faster onset of action with greater inhibition of platelet function compared to C in patients with ACS. WBSPC and VN can rapidly assess the early effects of P2Y 12 antagonists.

Abstract 5762: A Randomized Double-Blind Study to Assess the Onset and Offset of the Antiplatelet Effects of Ticagrelor versus Clopidogrel in Patients With Stable Coronary Artery Disease

Background: Rapid and consistent inhibition of platelet aggregation (IPA) confers protection against the occurrence of ischemic events, and reversible inhibition may be desirable for patients who require surgery. The ONSET-OFFSET study was conducted in patients with stable coronary artery disease (CAD) to characterize the onset and offset of IPA associated with ticagrelor (T), the first reversibly binding oral P2Y 12 receptor antagonist, and compare them with those associated with clopidogrel (C). Methods: In a multicenter, randomized, double-blind, parallel-group study, 123 patients with stable CAD currently receiving aspirin (75–100mg) were randomized to doses of T (180 mg loading, 90 mg bid maintenance [n=57]), C (600 mg loading, 75 mg qd maintenance [n=54]) or placebo (n=12) for 6 weeks. Curves for T for onset of IPA (final extent, 20 uM ADP) post loading dose and offset of IPA were compared to those for C. Onset treatment effects were analyzed by the Wilcoxon rank sum test; offset treatment effects were analyzed by random coefficients model. Results: After the loading dose, more rapid onset of IPA occurred with T compared with C at 0.5 h (41±33% vs 8±10%, p&lt;0.0001), 1 h (79±25% vs 23±26%, p&lt;0.0001), and 2 h (88±15 % vs 38±32%, p&lt;0.0001). Higher IPA for T was consistently maintained during maintenance therapy (p&lt;0.0001 at all times). More patients in the T group than in the C group achieved &gt;50% IPA (98% vs 31%, p&lt;0.0001) and &gt;70% IPA (90% vs 16%, p&lt;0.0001) at 2 h post loading dose. At 24 h after the last dose of T, mean IPA was 58% for T vs 52% for C (p=NS). A faster offset rate for IPA was observed after the last dose of T than for C from 4 to 72 h [slope (% IPA/h): −1.037 vs. −0.482, p&lt;0.0001]. Mean IPA for T at 72 h postdose (Day 3) was comparable to C at 120 h (Day 5). Mean IPA on Day 5 for T was similar to that for C on Day 7, both of which were not statistically different from placebo (p&lt;0.05). Conclusions: Ticagrelor achieves more rapid and greater sustained IPA than clopidogrel. Moreover, after drug cessation the antiplatelet effect of ticagrelor had a faster offset. These results suggest value of ticagrelor when treatment protocol calls for rapid platelet inhibition or prompt offset of effect.

Novel antiplatelet strategies in acute coronary syndromes

Antiplatelet therapies for the treatment of acute coronary syndromes (ACS) act to interrupt various pathways of platelet activation. Clopidogrel, an established thienopyridine antiplatelet medication, inhibits adenosine diphosphate (ADP)-induced platelet aggregation to a modest degree and with wide variability in platelet response. Accumulating data suggest that a 600-mg loading dose of clopidogrel may help overcome the suboptimal response to the standard 300-mg dose seen in some patients. Prasugrel is a third-generation investigational thienopyridine that demonstrates more potent inhibition of platelet aggregation and more consistent platelet response compared with standard- and high-dose clopidogrel. A large clinical trial showed prasugrel to be superior to standard-dose clopidogrel in reducing ischemic events in patients with ACS scheduled for percutaneous coronary intervention, although prasugrel was associated with a significantly higher risk of major bleeding events. Other investigational antiplatelet agents also display more potent and consistent inhibition of platelet aggregation than is seen with clopidogrel. These include AZD6140, a reversible ADP receptor blocker; cangrelor, a rapidly acting intravenous ADP receptor blocker; and the thrombin receptor antagonist SCH 530348.

Bleeding risk with AZD6140, a reversible P2Y12receptor antagonist, vs. clopidogrel in patients undergoing coronary artery bypass grafting in the DISPERSE2 trial

AZD6140, the first reversible oral P2Y(12) receptor antagonist, exhibits greater and more consistent inhibition of platelet aggregation than the irreversible thienopyridine clopidogrel. As a result of its reversible effect, AZD6140 may pose less risk for bleeding when antiplatelet treatment cannot be stopped at least 5 days before coronary artery bypass graft (CABG) surgery or other invasive procedures. The Dose conflrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in NSTEMI (DISPERSE2) trial showed overall comparable bleeding rates with antiplatelet treatment with AZD6140 90 mg twice daily or 180 mg twice daily vs. clopidogrel 75 mg once daily in 984 patients with non-ST-elevation acute coronary syndromes. A post hoc exploratory analysis of bleeding outcomes in the subset of 84 patients undergoing CABG in DISPERSE2 suggests reduced risk for total bleeding (41% and 58% vs. 62%), all major bleeding (38% and 50% vs. 62%), and life-threatening bleeding (22% and 38% vs. 54%) with AZD6140 90 mg (n = 32) and 180 mg (n = 26) vs. clopidogrel (n = 26) respectively. Trends suggested that major bleeding rates were reduced with AZD6140 (combined groups) vs. clopidogrel when treatment was stopped < or = 5 days prior to surgery (39% vs. 63%, p = 0.15) but not when treatment was stopped > 5 days before surgery (50% vs. 60%). This observation is consistent with the reversible binding of AZD6140 to the P2Y(12) receptor. Further prospective studies are planned to assess the relationship between this potential clinical benefit of AZD6140 and the reversibility of its antiplatelet effects.

Ticagrelor yields consistent dose-dependent inhibition of ADP-induced platelet aggregation in patients with atherosclerotic disease regardless of genotypic variations in P2RY12, P2RY1, and ITGB3

The platelet P2Y12 receptor is the target of clopidogrel therapy, which has been shown to reduce thromboembolic complications of atherosclerotic disease but has limitations in terms of variability of response and irreversibility of effect. This receptor is also a target for ticagrelor (AZD6140), the first reversibly binding oral P2Y12 receptor antagonist that does not require metabolic activation and yields more consistent inhibition of platelet aggregation than clopidogrel therapy. Single nucleotide polymorphisms (SNPs) have been described in the gene for this receptor (P2RY12), some of which have been associated with variability in platelet reactivity. SNPs in P2RY1 and ITGB3 have also been reported by some groups to affect platelet reactivity to adenosine diphosphate (ADP). We assessed whether SNPs in these genes influenced the pharmacodynamic response to ticagrelor in patients enrolled in both the DISPERSE study (stable atherosclerotic disease) and the DISPERSE2 study (non-ST-segment elevation acute coronary syndromes). Platelet aggregation data (at baseline and 4 weeks) and DNA samples from clopidogrel-naive Caucasian patients treated with ticagrelor were available for 151 patients. Seventy four SNPs within three genes were genotyped. After adjustment for multiple comparisons, none of these SNPs were found to significantly influence inhibition of ADP-induced platelet aggregation by ticagrelor.

Optimizing platelet inhibition

The platelet P2Y12 receptor plays a critical role in sustaining ADP-mediated platelet aggregation. Drawbacks of the thienopyridine clopidogrel, a prodrug of an irreversible P2Y12 antagonist, include the need for two-step metabolism to its active form and partial hydrolysis to its inactive metabolite. Both contribute to high variability in the degree of platelet inhibition and the irreversibility of binding complicates both acute and planned invasive treatments when rapid offset of antiplatelet activity is desired. Novel P2Y12 antagonists include the thienopyridine prasugrel and the selective, direct, reversible antagonists cangrelor (iv) and AZD6140 (oral). Prasugrel, also an irreversible antagonist, requires only one-step metabolism to active form and achieves greater inhibition of platelet aggregation (IPA) than clopidogrel. Recently published data indicate that this translates into improved efficacy. Like clopidogrel, prasugrel relies on new platelet generation for offset of effect. The direct reversible antagonists bind directly to the receptor, and the degree of IPA closely follows plasma drug concentrations. In addition to permitting more rapid offset of effect and greater and more consistent IPA than clopidogrel, direct reversible antagonists may exert additional beneficial effects via blockade of P2Y12 in vascular smooth muscle cells. Reversible antagonists also appear to exhibit a wider therapeutic window, showing reduced bleeding time prolongation per given degree of antithrombotic effect in experimental models. Ongoing large-scale Phase 3 clinical trials are examining cangrelor in patients with acute coronary syndromes (ACS) also undergoing percutaneous coronary intervention (PCI) and AZD6140 in ACS patients being treated with medical therapy, PCI, or coronary artery bypass grafting.

New developments in antiplatelet therapy

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.

Dual antiplatelet therapy in the drug-eluting stent era

Data continue to accumulate showing that implantation of coronary stents, particularly drug-eluting stents (DES), is associated with persistent, long-term risk of thrombotic events. Dual antiplatelet therapy with aspirin and clopidogrel has reduced the risk of early and late thrombosis. However, early risk persists due to implantation, stent-related factors, and suboptimal response to clopidogrel, whereas late risk persists due not only to these factors, but to the limited duration of dual antiplatelet therapy as well. Third-generation oral P2Y12 antagonists that exhibit faster onset of action and greater and more consistent inhibition of platelet aggregation than clopidogrel include the new thienopyridine prasugrel and the reversible P2Y12 inhibitor AZD6140. Prospective, randomized, long-term trials are warranted to investigate the benefits and risks of more effective P2Y12 antagonists as part of dual antiplatelet therapy after both bare-metal stent and DES implantation.

Optimizing platelet inhibition

The platelet P2Y12 receptor plays a critical role in sustaining ADP-mediated platelet aggregation. Drawbacks of the thienopyridine clopidogrel, a prodrug of an irreversible P2Y12 antagonist, include the need for two-step metabolism to its active form and partial hydrolysis to its inactive metabolite. Both contribute to high variability in the degree of platelet inhibition and the irreversibility of binding complicates both acute and planned invasive treatments when rapid offset of antiplatelet activity is desired. Novel P2Y12 antagonists include the thienopyridine prasugrel and the selective, direct, reversible antagonists cangrelor (iv) and AZD6140 (oral). Prasugrel, also an irreversible antagonist, requires only one-step metabolism to active form and achieves greater inhibition of platelet aggregation (IPA) than clopidogrel. Recently published data indicate that this translates into improved efficacy. Like clopidogrel, prasugrel relies on new platelet generation for offset of effect. The direct reversible antagonists bind directly to the receptor, and the degree of IPA closely follows plasma drug concentrations. In addition to permitting more rapid offset of effect and greater and more consistent IPA than clopidogrel, direct reversible antagonists may exert additional beneficial effects via blockade of P2Y12 in vascular smooth muscle cells. Reversible antagonists also appear to exhibit a wider therapeutic window, showing reduced bleeding time prolongation per given degree of antithrombotic effect in experimental models. Ongoing large-scale Phase 3 clinical trials are examining cangrelor in patients with acute coronary syndromes (ACS) also undergoing percutaneous coronary intervention (PCI) and AZD6140 in ACS patients being treated with medical therapy, PCI, or coronary artery bypass grafting.

Prasugrel: A Novel Thienopyridine Antiplatelet Agent. A Review of Preclinical and Clinical Studies and the Mechanistic Basis for Its Distinct Antiplatelet Profile

Prasugrel (CS-747, LY640315) is a novel member of the thienopyridine class of oral antiplatelet agents that includes ticlopidine and clopidogrel. Like other thienopyridines, prasugrel is a prodrug that is inactive in vitro. Prasugrel's distinct chemical structure permits efficient conversion to its active metabolite with a less rigorous dependence on specific cytochrome P-450 enzymes. Prasugrel is rapidly converted in vivo to an active metabolite (R-138727) that binds specifically and irreversibly to the platelet P2Y 12 purinergic receptor inhibiting ADP-mediated platelet activation and aggregation. Preclinical studies indicated that prasugrel is approximately 10- and 100-fold more potent at inhibiting ex vivo platelet aggregation and in vivo thrombus formation than clopidogrel and ticlopidine, respectively. Early clinical data in healthy subjects confirmed the greater platelet inhibition and consistency with prasugrel compared to clopidogrel. While the active metabolites of prasugrel and clopidogrel resulted in similar levels of platelet inhibition in vitro, the amount of each active metabolite generated in vivo was quite different-prasugrel (60 mg) resulting in an approximately 12-fold greater exposure to its active metabolite compared with clopidogrel (300 mg). This observation provides a mechanistic basis for the faster, greater, and more consistent inhibition of platelet aggregation observed with prasugrel. Clinical studies in patients with cardiovascular disease confirmed the potent antiplatelet effect of prasugrel compared with clopidogrel. Collectively, these phase 1/1b studies and a phase 2 study (JUMBO-TIMI 26) aided in dose selection for the recently completed phase 3 trial (TRITON-TIMI 38) in patients with acute coronary syndrome undergoing percutaneous coronary intervention.

The use of antiplatelet agents following percutaneous coronary intervention: focus on late stent thrombosis

The uptake of drug-eluting stents (DES) has been rapid since their introduction at the start of the decade, owing to their clear superiority over bare-metal stents (BMS) in reducing restenosis rates after percutaneous coronary intervention. However, with the widespread use of DES, there has been growing concern that they may also be associated with an increased risk of late stent thrombosis compared with BMS. Late stent thrombosis is a serious concern as it may lead to myocardial infarction or death. Recent analyses of clinical trials comparing the efficacy and safety of BMS and DES appear to confirm that DES may indeed be associated with a small but significant increase in the risk of late stent thrombosis and that this increased risk may continue for several years after stenting. Dual antiplatelet therapy with aspirin and clopidogrel has been shown to be effective in reducing the risk of acute/subacute stent thrombosis. On the basis of the evidence of increased risk of late stent thrombosis, guidelines now recommend extending dual antiplatelet therapy to at least 12 months after implantation of DES, and even longer in patients at high risk of stent thrombosis. Guidelines also stress the dangers of late stent thrombosis associated with premature discontinuation of antiplatelet therapy. Reduced responsiveness to clopidogrel or to aspirin is a relatively common phenomenon and may also lead to patients being inadequately protected against late stent thrombosis. New antiplatelet agents that provide significantly greater and more consistent inhibition of platelet aggregation may have benefits in reducing the risk of late stent thrombosis and the associated burden of serious adverse cardiovascular outcomes and death.

New developments in oral antiplatelet therapy

Oral antiplatelet therapy is central to the treatment of patients with thrombotic diseases. Yet, despite the proven efficacy of currently available agents such as aspirin and the P2Y12 receptor antagonist clopidogrel, and their advocacy in treatment guidelines, their efficacy and utilization remain suboptimal. This has prompted the search for more efficacious oral antiplatelet agents. Drug classes that have been, or continue to be, investigated include thromboxane A2/prostaglandin H2 (TXA2/PGH2; TP) receptor antagonists, protease-activated receptor (PAR) antagonists, and newer P2Y12 receptor antagonists. TP receptors are G-protein-coupled receptors that, on agonist binding, activate the phospholipase C signalling cascade, resulting in platelet activation. The success of TP receptor antagonists has been limited to date; the majority of agents have been discontinued at phase I/II clinical trials following efficacy and safety concerns. However, S-18886 (terutroban) remains in development. Results from preclinical investigations demonstrate S-18886 to have comparable antiplatelet effects to clopidogrel, while data from phase II studies appear promising. Inhibiting the actions of thrombin on platelets represents an emerging area of antiplatelet research, and compounds that target the PAR1 receptor are in early development. These include the PAR1-selective antagonist SCH 530348, which is currently being evaluated in phase III studies in patients with acute coronary syndromes (ACS), prior myocardial infarction, stroke, and existing peripheral arterial disease. The P2Y12 G protein receptor is predominately located on platelets and is involved in the amplification of platelet activation. Owing to limitations of first- and second-generation thienopyridine P2Y12 antagonists such as clopidogrel, new antagonists are being evaluated. The irreversible thienopyridine P2Y12 antagonist prasugrel is currently in phase III development and has the potential to provide additional benefits over clopidogrel, including faster onset of action with improved inhibition of ADP-induced platelet aggregation and fewer non-responders. The differences in response are thought to be due to the more efficient generation of the active metabolite of prasugrel. The phase II JUMBO-TIMI 26 trial, which compared prasugrel with clopidogrel in patients undergoing elective or urgent percutaneous coronary intervention (PCI), reported low rates of bleeding with both drugs and a trend towards a reduction in ischaemic events with prasugrel relative to clopidogrel. However, the trial was not powered to show clinical outcomes. Reversible, non-thienopyridine P2Y12 receptor antagonists are a further class of antiplatelet agents undergoing evaluation in clinical trials and include cangrelor, an ATP analogue. Cangrelor is a fast- and direct-acting, intravenous antiplatelet agent which has completed phase II clinical trials for the acute treatment of patients with ACS undergoing PCI. AZD6140 is a CPTP (cyclo-pentyl-triazolo-pyrimidine), and the first oral reversible antiplatelet agent in development for use in patients with ACS. Unlike the irreversible thienopyridines, AZD6140 does not require cytochrome P450 metabolic activation to exert its inhibitory effects on platelet aggregation. Data from the phase II DISPERSE trial demonstrates AZD6140 to have a more rapid onset of action and a significantly greater and more consistent inhibition of platelet aggregation when compared with clopidogrel in stable patients with atherosclerotic disease. Publication of the full analysis from the second phase II trial, DISPERSE2, is pending while recruitment is underway for the phase III PLATO (study of PLATelet inhibition and patient Outcomes). PLATO is a head-to-head outcomes study investigating the use of AZD6140 vs. clopidogrel for ACS in patients treated with medical therapy, PCI, or coronary artery bypass graft, with a planned recruitment of 18 000 patients worldwide. Data from ongoing phase II and III clinical trials on the emerging antiplatelet agents are eagerly awaited. If these agents offer improvements over those currently available in terms of patient response to therapy, safety, and convenience, they are likely to influence the current prescribing patterns and guidelines.

Optimizing Platelet P2Y12 Inhibition for Patients Undergoing PCI

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 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 cangrelor- and 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.