Advances in antiplatelet therapy: overview of new P2Y12 receptor antagonists in development
Unità di Ematologia e Trombosi Ospedale San Paolo, Università di Milano, Via di Rudinì 8 20142, Milano, Italy
* Corresponding author. Tel:/fax: +39 025 032 3095. E-mail address: marco.cattaneo{at}unimi.it
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Abstract |
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 Top Abstract IntroductionP2Y12 receptor inhibitorsTiclopidine and clopidogrelPrasugrel, a new, fast-acting...Direct P2Y12 antagonistsConclusionsFundingReferences |
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Platelets play an important role in thrombus formation. A number of new antiplatelet agents currently in development are anticipated to improve clinical outcomes and safety benefits in patients with acute coronary syndrome (ACS). This manuscript reviews the pharmacology and clinical development of three of these agents: prasugrel, cangrelor, and AZD6140. Prasugrel, a third-generation, oral thienopyridine, has been shown to be superior to clopidogrel, the current gold standard, in preventing ischaemic events in patients with ACS undergoing percutaneous coronary intervention (PCI), although the bleeding rate was higher. Cangrelor, a chemical analogue of adenosine triphosphate, is a potent direct platelet P2Y12 antagonist. In development as an intravenous agent, cangrelor is currently being evaluated in two phase III studies in patients requiring PCI. AZD6140 is the first of a novel new class of antiplatelet agents that inhibits adenosine diphosphate-induced platelet aggregation at the level of the P2Y12 receptor. AZD6140 was shown to have a good safety profile in phase II studies and is currently being studied in a phase III trial in patients with ACS.
Key Words: Acute coronary syndrome • Antithrombotic drugs • Clopidogrel • Prasugrel • Cangrelor • AZD6140
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Introduction |
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TopAbstractIntroductionP2Y12 receptor inhibitorsTiclopidine and clopidogrelPrasugrel, a new, fast-acting...Direct P2Y12 antagonistsConclusionsFundingReferences |
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Platelets play an important role in thrombus formation by adhering to exposed subendothelial structures in response to vascular injury. In this way, they become rapidly activated by their interaction with thrombogenic substrates and generated or locally released agonists, including adenosine-5'-diphosphate (ADP), thromboxane A2, and thrombin, and acquire the ability to bind soluble adhesive molecules that become the reactive surfaces for continuing platelet deposition (platelet aggregation).
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P2Y12 receptor inhibitors |
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TopAbstractIntroductionP2Y12 receptor inhibitorsTiclopidine and clopidogrelPrasugrel, a new, fast-acting...Direct P2Y12 antagonistsConclusionsFundingReferences |
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Adenosine-5'-diphosphate plays a key role in haemostasis, as documented by the observation that patients lacking releasable ADP in granule stores or with congenital abnormalities of platelet ADP receptors have a bleeding diathesis.1,2 In addition, ADP plays a key role in the pathogenesis of arterial thrombosis, because the pharmacological inhibition of ADP-induced platelet aggregation decreases the risk of arterial thrombosis.3
The transduction of the ADP signal involves its interaction with two platelet receptors, the Gq-coupled P2Y1 receptor and the Gi-coupled P2Y12 receptor, which belong to the family of purinergic P2 receptors. The concomitant activation of both the Gq and Gi pathways by ADP is necessary to elicit normal platelet aggregation (Figure 1). In contrast to P2Y1, P2Y12 has a very selective tissue distribution,4 making it an attractive molecular target for therapeutic intervention. Indeed, P2Y12 is the target of efficacious antithrombotic agents such as the thienopyridines ticlopidine and clopidogrel, which are already used in clinical practice either alone or in combination with other antithrombotic drugs.1
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Ticlopidine and clopidogrel |
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TopAbstractIntroductionP2Y12 receptor inhibitorsTiclopidine and clopidogrelPrasugrel, a new, fast-acting...Direct P2Y12 antagonistsConclusionsFundingReferences |
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Ticlopidine and clopidogrel are structurally related compounds belonging to the thienopyridine family. They are prodrugs that are inactive in vitro and need to be metabolized in vivo by the hepatic cytochrome P450 enzymatic pathway to active metabolites. Both ticlopidine and clopidogrel have very short half-lives and irreversibly and specifically inhibit the platelet P2Y12 receptor.3
Despite their proven antithrombotic activity, ticlopidine and clopidogrel have drawbacks when used clinically. Their need to be converted to active metabolites accounts for their delayed antiplatelet effects: a maximum plateau of inhibition of ADP-induced platelet aggregation is observed 4–5 days after the daily oral administration of 500 mg of ticlopidine or 75 mg of clopidogrel.1 It should be noted, however, that the delayed onset of action of clopidogrel can be reduced to about 2–5 h by using a loading dose of 300–600 mg.1 As a consequence of the irreversible inhibition of P2Y12 function, the inhibitory effect of the thienopyridines on circulating platelets lasts for 
8–10 days, which corresponds to the lifespan of a circulating platelet. Although the ability of thienopyridines to irreversibly inhibit P2Y12 with their short-lived metabolites has theoretical advantages,5 it may represent a problem for patients who need to undergo coronary bypass surgery. Clopidogrel treatment within 4–5 days of the procedure is associated with increased blood loss, re-operation for bleeding, increased transfusion requirements, and prolonged intensive care unit and hospital stays.6–8 Finally, there is a substantial inter-individual variability in platelet inhibition by ticlopidine and clopidogrel, which is due mostly to inter-individual differences in the extent of metabolism of the prodrug to the active metabolite.1,9
The limitations of ticlopidine and clopidogrel have fostered the search for new and novel P2Y12 antagonists.
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Prasugrel, a new, fast-acting thienopyridine |
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TopAbstractIntroductionP2Y12 receptor inhibitorsTiclopidine and clopidogrelPrasugrel, a new, fast-acting...Direct P2Y12 antagonistsConclusionsFundingReferences |
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Prasugrel is a new thienopyridine with a much faster onset of action than clopidogrel.1,10 The results from a crossover study showed that a 60 mg loading dose of prasugrel provided rapid and irreversible inhibition of ADP-induced platelet aggregation even in patients who responded poorly to a standard loading dose of clopidogrel.11 Additionally, the higher potency of prasugrel compared with clopidogrel reflects a more efficient conversion of the prodrug to the active metabolite (Figure 2).12,13
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In the phase II, randomized, dose-ranging, double-blind safety trial Joint Utilization of Medications to Block Platelets Optimally–Thrombolysis In Myocardial Infarction 26 (JUMBO-TIMI 26), three doses of prasugrel were compared with clopidogrel in 904 patients undergoing elective or urgent percutaneous coronary intervention (PCI).14 Clopidogrel was administered as a standard 300 mg loading dose followed by a 75 mg/day maintenance dose, while prasugrel was given as a low dose (40 mg followed by 7.5 mg/day), intermediate dose (60 mg followed by 10 mg/day), or high dose (60 mg followed by 15 mg/day). The incidence of clinically significant (TIMI major plus minor) bleeding events, the primary endpoint of the trial did not achieve statistical significance between patients treated with prasugrel and with clopidogrel.
The phase III Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction 38 (TRITON TIMI-38) evaluated 13 608 high-risk patients with acute coronary syndromes (ACS) who required PCI. Patients were randomized to receive prasugrel 60 mg loading dose followed by 10 mg/day or clopidogrel 300 mg loading dose followed by 75 mg/day for 6–15 months. Prasugrel was associated with fewer ischaemic events but a greater incidence of major and fatal bleeding complications.15 The results of TRITON TIMI-38 showed that the greater inhibition of P2Y12-mediated platelet aggregation is associated with greater protection from ischaemic events, but also with an increased incidence of bleeding complications in patients at risk.
The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation–Thrombolysis In Myocardial Infarction 44 (PRINCIPLE-TIMI 44) trial, which was not powered for clinical events, demonstrated that the 60 mg loading dose followed by 10 mg/day prasugrel therapeutic regimen was superior to high-dose clopidogrel (600 mg followed by 150 mg/day) with respect to the inhibition of P2Y12-mediated platelet function.16
It would appear that treatment with prasugrel is associated with faster and greater inhibition of platelet function, and less interindividual variability of response than is the treatment with clopidogrel, even when clopidogrel is given in higher doses than those commonly used and officially approved.
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Direct P2Y12 antagonists |
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TopAbstractIntroductionP2Y12 receptor inhibitorsTiclopidine and clopidogrelPrasugrel, a new, fast-acting...Direct P2Y12 antagonistsConclusionsFundingReferences |
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In some clinical situations, the inhibition of platelet aggregation by fast-acting and reversible antagonists with a short half-life might be preferable to irreversible inhibition. Some direct, P2Y12 antagonists are currently under development.
Cangrelor
Cangrelor, previously known as AR-C69931MX, belongs to a family of analogues of adenosine triphosphate that are relatively resistant to breakdown by ectonucleotidases and display high affinity for the P2Y12 receptor.17 Cangrelor does not require conversion to an active metabolite and is immediately active following infusion with a half-life of 3–6 min.
A large, two-part, phase II study assessed the safety and pharmacodynamics of cangrelor in patients undergoing PCI.18 In the first part of the study, 200 patients undergoing PCI were randomized to receive an 18–24 h infusion of cangrelor 1, 2, or 4 µg/kg per minute, or placebo, in addition to aspirin and heparin before beginning the procedure. In the second part of the study, 199 additional patients were randomized to receive cangrelor 4 µg/kg per minute or the anti-glycoprotein IIb/IIIa inhibitor abciximab before the procedure. In the first part of the study, combined major and minor bleeding occurred in 13% of cangrelor-treated patients and 8% of patients who received placebo (P = NS) through 7 days of follow-up in Part 1. In Part 2, combined major and minor bleeding occurred in 7% of patients receiving cangrelor and 10% of patients receiving abciximab (P = NS). Mean inhibition of platelet aggregation in response to ADP 3 µmol/L was complete both in the patients treated with cangrelor 4 µg/kg per minute and in the patients treated with abciximab.18 However, after termination of drug infusion, platelet aggregation returned to baseline values much faster in the cangrelor-treated patients than in the patients treated with abciximab, who still displayed significant inhibition of platelet aggregation 24 h after the termination of drug infusion.18
The Safety, Tolerability and Effect on Patency in Acute Myocardial Infarction (STEP-AMI) angiographic trial assessed the safety and efficacy of cangrelor as an adjunct to tissue plasminogen activator (tPA) in 92 patients with acute myocardial infarction.19 All patients were treated with aspirin and heparin, and were randomized to receive cangrelor 280 µg/min alone, full-dose tPA alone, or cangrelor 35, 140, or 280 µg/min in conjunction with half-dose tPA. The combination of cangrelor and half-dose tPA resulted in 60 minute coronary patency similar to that of full-dose tPA alone (55 vs. 50%; P = NS) and greater patency than with cangrelor alone (55 vs. 18%; P < 0.05).19 Bleeding and adverse clinical events were comparable across the groups.
Cangrelor is currently being compared with clopidogrel in two randomized, controlled, clinical phase III trials. CHAMPION PCI (Cangrelor vs. Standard Therapy to Achieve Optimal Management of Platelet Inhibition-Percutaneous Coronary Intervention) and CHAMPION PLATFORM are both designed to evaluated ischaemic events in patients requiring PCI.
AZD6140
AZD6140 is a selective P2Y12 antagonist that is being developed as an orally active antiplatelet agent.17 It confers nearly complete inhibition of ADP-induced platelet aggregation and does not require metabolic activation for activity.
The Dose-finding Investigative Study to assess the Pharmacodynamic Effects of AZD6140 in atherosclerotic disease (DISPERSE) was a double-blind, parallel-group, dose-finding trial in 200 outpatients with stable atherosclerotic disease who were receiving aspirin 75–100 mg/day. Patients were randomized to receive AZD6140 50, 100, or 200 mg bid, or 400 mg qd, or clopidogrel 75 mg qd for 28 days.20 The results showed that AZD6140 100 and 200 mg bid and 400 mg qd rapidly and nearly completely inhibited ADP-induced platelet aggregation both after the initial dose and at Day 28. At these doses, AZD6140 inhibited platelet aggregation more effectively and with less variability than clopidogrel both after the first dose and after 28 days of therapy. In addition, the inhibition of platelet aggregation by AZD6140 was very rapid (2 h post-dose, 96 ± 6.1% for 400 mg qd) compared with that of clopidogrel. Only one major, non-fatal haemorrhage occurred in a patient treated with AZD6140 400 mg qd. The remaining bleeding events were minor and of mild-to-moderate severity. Other adverse events included dyspnea, dizziness, headache, and the presence of red blood cells in the urine. The incidence of dyspnea (10–20%) was dose related.
The DISPERSE-2 study compared the safety of AZD6140 and clopidogrel in 990 patients with non–ST-segment elevation ACS who had been treated with aspirin and standard therapy. Patients were randomized to receive AZD6140 90 or 180 mg bid or clopidogrel administered as a 300 mg loading dose followed by 75 mg/day maintenance dose for up to 12 weeks.21 The rate of major bleeding was 6.9% in the clopidogrel group, 7.1% in the AZD6140 90-mg group, and 5.1% in the AZD6140 180-mg group (P = NS). In a post-hoc analysis of continuous electrocardiograms, mostly asymptomatic ventricular pauses longer than 2.5 s were more common in patients treated with AZD6140 180 mg bid (9.9%) than in patients treated with 90 mg (5.5%) or clopidogrel (4.3%; P = 0.014 and P = 0.58).21 This study also showed that dyspnea occurs more frequently with AZD6140 than with clopidogrel.
Although the DISPERSE-2 study was not powered to detect differences in the incidence of major adverse clinical events, it showed that AZD6140 180 mg bid may be more effective than clopidogrel 75 mg/day in preventing them.21 Confirmation of these data should come from the adequately powered phase III PLATO (a study of PLATelet inhibition and patient Outcomes) trial, which is ongoing.
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Conclusions |
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TopAbstractIntroductionP2Y12 receptor inhibitorsTiclopidine and clopidogrelPrasugrel, a new, fast-acting...Direct P2Y12 antagonistsConclusionsFundingReferences |
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The pharmacopoeia of drugs inhibiting the platelet P2Y12 receptor for ADP is rapidly expanding. In addition to ticlopidine and clopidogrel, which are well-known compounds of proven antithrombotic efficacy, prasugrel, a new thienopyridine, is in clinical development. Prasugrel is characterized by higher potency and a faster onset of action than clopidogrel, and has been shown to be highly effective in patients undergoing PCI. Two direct and reversible P2Y12 antagonists, cangrelor, which can be given only intravenously, and AZD6140, which can be given orally, are associated with a rapid onset and reversal of platelet inhibition, which make them attractive alternatives to the thienopyridines, especially when the rapid inhibition of platelet aggregation or its quick reversal are required. With these new agents, physicians will soon have a panel of different P2Y12 inhibitors to choose from, enabling them to tailor the most appropriate antithrombotic therapies to individual patients and risk situations.
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Funding |
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TopAbstractIntroductionP2Y12 receptor inhibitorsTiclopidine and clopidogrelPrasugrel, a new, fast-acting...Direct P2Y12 antagonistsConclusionsFundingReferences |
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Financial support provided by Daiichi Sankyo, Inc. and Eli Lilly and Company.
Conflict of interest: none declared.
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TopAbstractIntroductionP2Y12 receptor inhibitorsTiclopidine and clopidogrelPrasugrel, a new, fast-acting...Direct P2Y12 antagonistsConclusionsFundingReferences |
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