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Keywords:

  • acute coronary syndromes;
  • adenosine diphosphate;
  • antiplatelet drugs;
  • cangrelor;
  • clopidogrel;
  • P2Y12;
  • platelet aggregation;
  • prtasugrel;
  • thienopyridines;
  • ticagrelor

Abstract

  1. Top of page
  2. Abstract
  3. Prasugrel, a new thienopyridine
  4. Direct P2Y12 antagonists
  5. Conclusions
  6. Disclosure of Conflict of Interests
  7. References

Summary.  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 article reviews the pharmacology and clinical development of three of these agents: prasugrel, cangrelor, and ticagrelor. Prasugrel, a third-generation, oral thienopyridine, has been shown to be superior to clopidogrel, the current gold standard, in preventing ischemic events in patients with ACS undergoing percutaneous coronary intervention (PCI), although the bleeding rate was higher. Cangrelor, a chemical analog 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. Ticagrelor is the first of a new class of orally available antiplatelet agents antagonizing the effects of ADP mediated by P2Y12; it is currently being studied in a phase III trial in patients with ACS.

ADP plays a key role in the pathogenesis of arterial thrombosis, because the pharmacologic inhibition of ADP-induced platelet aggregation decreases the risk of arterial occlusion [1].

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 [2]. In addition to its role in ADP-induced platelet aggregation, P2Y12 a mediates: (i) the potentiation of platelet secretion induced by strong agonists, which is independent of the formation of large aggregates and thromboxane A2 synthesis [2]; (ii) the stabilization of thrombin-induced platelet aggregates [2]; (iii) shear-induced platelet aggregation [2]; and (iv) the inhibition of the antiplatelet effects of the natural regulator of platelet function prostacyclin [3]. In contrast to P2Y1, P2Y12 has a very selective tissue distribution, 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].

Ticlopidine and clopidogrel are pro-drugs that need to be converted in vivo to active metabolites, which irreversibly inhibit the P2Y12 receptor. Despite their proven antithrombotic activity, they have drawbacks when used clinically: (i) their antiplatelet effects are delayed, as a consequence of the need for metabolism of the pro-drug; (ii) there is a substantial inter-individual variability in platelet inhibition, which is due mostly to inter-individual differences in the extent of metabolism of the pro-drug; and (iii) as a consequence of the irreversible inhibition of P2Y12 function, the inhibitory effect of the thienopyridines on circulating platelets lasts approximately 8–10 days, which corresponds to the lifespan of a circulating platelet. The ability of thienopyridines to inhibit irreversibly P2Y12 with their short-lived metabolites 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, reoperation for bleeding, increased transfusion requirements, and prolonged intensive care unit and hospital stays [4–6]. Therefore, the availability of short-acting, reversible, direct P2Y12 antagonists would be useful for the treatment of patients who are scheduled for surgical procedures.

Prasugrel, a new thienopyridine

  1. Top of page
  2. Abstract
  3. Prasugrel, a new thienopyridine
  4. Direct P2Y12 antagonists
  5. Conclusions
  6. Disclosure of Conflict of Interests
  7. References

Prasugrel is a new thienopyridine, with rapid and consistent inhibitory effects on platelet aggregation. It has a distinct chemical structure, which permits conversion to its active metabolite with less rigorous dependence on specific cytochrome P-450 enzymes than other thienopyridines [1]. Prasugrel’s active metabolite is detected in human plasma within 15 min of dosing, and reaches maximal plasma concentration at approximately 30 min [1].

Prasugrel consistently caused inhibition of platelet aggregation (IPA) induced by ADP to a greater extent compared with clopidogrel and ticlopidine in numerous preclinical and early-phase clinical studies [1]. Indeed, prasugrel has been shown to deliver 10- to 100-fold greater potency in ex-vivo IPA tests and in vivo thrombus formation than clopidogrel and ticlopidine, respectively and the superior potency compared to clopidogrel was confirmed in several phase I clinical studies [1]. Significantly greater IPA (79%) was achieved with a loading dose of prasugrel 60 mg, between 30 min and 24 h post-administration, compared to clopidogrel 300 mg (35%), in a crossover study conducted in healthy subjects [7]; notably, even those individuals who had responded poorly to clopidogrel achieved robust platelet inhibition with prasugrel treatment. The greater mean platelet inhibition achieved with prasugrel compared with clopidogrel was proven to be a consequence of greater exposure levels to prasugrel’s active metabolite, in a comparative crossover study, in which prasugrel 60 mg achieved a higher mean IPA (54%) than clopidogrel 300 mg (3%) or 600 mg (6%) (P < 0.001) 30 min post-loading dose in healthy subjects [8]. The area under the concentration-time curve of the active metabolite of prasugrel 60 mg was 2.2 times that of clopidogrel 600 mg.

In a dose-ranging study in aspirin-treated patients with stable coronary artery disease (CAD), a doubling of mean IPA compared with clopidgrel 300 mg was achieved by both 40 and 60 mg loading dose of prasugrel, at 4 h post-loading dose (60.6% and 68.4%, respectively, versus 30.0%, P < 0.0001), and significantly higher levels of IPA were achieved with a maintenance dose of prasugrel of 10 and 15 mg, compared with clopidogrel 75 mg, at days 7–14 and day 28, at which time 45% of patients treated with clopidogrel were non-responsive, compared to zero non-responders in the prasugrel-treated groups (P = 0.0007) [9]. In another randomized double-blind study in aspirin-treated CAD patients, treatment with prasugrel 60 mg loading dose followed by 10 mg daily maintenance dose delivered faster and higher mean platelet inhibition than clopidogrel (600 mg loading dose, 75 mg maintenance dose), as the mean change from baseline in 20 μm ADP-induced maximal platelet aggregation at 2 h post-loading dose was −41.6% for prasugrel, compared with just 17.7% for clopidogrel (P < 0.001) [10]. The superior action of prasugrel was maintained throughout the 28 day study, and was again associated with earlier and greater levels of active metabolite, compared with clopidogrel (P < 0.001) [10].

The PRINCIPLE-TIMI 44, a randomized, double-blind crossover study of 201 patients undergoing cardiac catheterization for planned percutaneous coronary intervention (PCI), demonstrated that not only is 60 mg loading dose prasugrel superior to high clopidogrel loading dose (600 mg), it showed that also 10 mg maintenance dose prasugrel is superior to high maintenance dose of clopidogrel (150 mg) in inhibiting P2Y12-dependent platelet function (measured both with light transmission aggregometry and the VASP phosphorylation flow cytometric assay) [11]. The superior action of prasugrel was maintained throughout the 28 day study, and again associated with earlier and greater levels of active metabolite, compared with clopiodgrel.

Overall, phase I and phase II studies showed that treatment with prasugrel is associated with faster inhibition of platelet function and less inter-individual variability of response than is treatment with clopidogrel. All subjects treated with prasugrel exhibited good inhibition of platelet function, accounting for the higher mean inhibition of platelet function achieved with prasugrel compared with clopidogrel. This difference is simply explained by the more effective conversion of the prasugrel pro-drug into its active metabolite, while the ability of the active metabolites of the two pro-drugs to inhibit P2Y12 is absolutely identical [12].

Theoretically, the more consistent inhibition of platelet function obtainable with prasugrel should result in greater protection from atherothrombotic events, but greater incidence of bleeding complications. This hypothesis has recently been tested in the phase III trial TRITON TIMI-38, a randomized, double-blind, parallel-group, multinational trial that evaluated 13 608 high-risk patients with acute coronary syndromes (ACS) who required PCI [13]. Patients were randomized to receive prasugrel 60-mg loading dose followed by 10 mg day−1 or clopidogrel 300-mg loading dose followed by 75 mg day−1 for 6–15 months. Prasugrel was associated with fewer ischemic events, but a greater incidence of major and fatal bleeding complications. In a post-hoc analysis, three subgroups appeared to have less net clinical benefit or greater harm: patients with previous cerebrovascular accidents, patients 75 years of age or older and patients weighing <60 kg. Subsequent subgroups analysis showed that patients with diabetes, with coronary stents or with recurrences of atherothrombotic events on treatment had greater benefit from prasugrel compared with clopidogrel.

The TRILOGY-ACS study is a phase III multicenter, double-blind, randomized, controlled trial that will evaluate the safety and efficacy of prasugrel compared to clopidogrel in reducing the risk of cardiovascular death, MI, or stroke in patients with ACS who are medically managed and in whom no revascularization is planned.

Direct P2Y12 antagonists

  1. Top of page
  2. Abstract
  3. Prasugrel, a new thienopyridine
  4. Direct P2Y12 antagonists
  5. Conclusions
  6. Disclosure of Conflict of Interests
  7. References

Cangrelor

Cangrelor, previously known as AR-C69931MX, belongs to a family of analogs of adenosine triphosphate (ATP) that are relatively resistant to breakdown by ectonucleotidases and display high affinity for the P2Y12 receptor [14]. 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 [15]. In the first part of the study, 200 patients undergoing PCI were randomized to receive an 18 to 24h infusion of cangrelor 1, 2, or 4 μg kg−1 min−1, or placebo. In the second part of the study, 199 patients were randomized to receive cangrelor 4 μg kg−1 min−1 or the anti–GP IIb/IIIa inhibitor abciximab before the procedure. Combined major and minor bleeding occurred in 13% of cangrelor-treated patients and 8% of patients who received placebo (= 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 (= NS). Mean IPA in response to ADP 3 μm was complete both in the patients treated with cangrelor 4 μg kg−1 min−1 and in the patients treated with abciximab. 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.

The 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 [16]. All patients were treated with aspirin and heparin and were randomized to receive cangrelor 280 μg min−1 alone, full-dose tPA alone, or cangrelor 35, 140, or 280 μg min−1 in conjunction with half-dose tPA. The combination of cangrelor and half-dose tPA resulted in 60-min coronary patency similar to that of full-dose tPA alone and greater patency than with cangrelor alone.

Cangrelor is currently being compared with clopidogrel in two randomized, controlled, clinical phase III trials (CHAMPION PCI, CHAMPION PLATFORM) in ACS patients requiring PCI.

Ticagrelor

Ticagrelor, previously known as AZD6140, is a selective P2Y12 antagonist that is being developed as an orally active antiplatelet agent [14]. 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−1. Patients were randomized to receive ticagrelor 50, 100, or 200 mg bid, or 400 mg qd, or clopidogrel 75 mg qd for 28 days [17]. The results showed that ticagrelor 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, ticagrelor inhibited platelet aggregation more rapidly and effectively and with less variability than clopidogrel both after the first dose and after 28 days of therapy. Treatment with ticagrelor was associated with high incidence of dyspnea (10–20%), which was dose-related.

The DISPERSE-2 study compared the safety of ticagrelor and clopidogrel in 990 patients with non–ST-segment elevation ACS (NSTE-ACS). Patients were randomized to receive ticagrelor 90 or 180 mg bid or clopidogrel administered as a 300-mg loading dose followed by 75 mg day−1 maintenance dose for up to 12 weeks [18]. The rate of major bleeding was 6.9% in the clopidogrel group, 7.1% in the ticagrelor 90mg group, and 5.1% in the ticagrelor 180-mg group (= NS). Mostly asymptomatic ventricular pauses longer than 2.5 s were more common in patients treated with ticagrelor 180 mg bid (9.9%) than in patients treated with 90 mg (5.5%) or clopidogrel (4.3%; = 0.014 and P = 0.58). This study also showed that dyspnea occurs more frequently with ticagrelor than with clopidogrel. Although the study was not powered to detect differences in the incidence of major adverse clinical events, it showed that ticagrelor 180 mg bid may be more effective than clopidogrel 75 mg day−1 in preventing them. Confirmation of these data should come from the adequately powered phase III PLATO trial, which is ongoing.

Conclusions

  1. Top of page
  2. Abstract
  3. Prasugrel, a new thienopyridine
  4. Direct P2Y12 antagonists
  5. Conclusions
  6. Disclosure of Conflict of Interests
  7. References

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 a faster onset of action and more consistent IPA 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 ticagrelor, 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 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.

Disclosure of Conflict of Interests

  1. Top of page
  2. Abstract
  3. Prasugrel, a new thienopyridine
  4. Direct P2Y12 antagonists
  5. Conclusions
  6. Disclosure of Conflict of Interests
  7. References

The author received lecture honoraria from Lilly-Daiichi Sankyo, AstraZeneca and The Medicines Company.

References

  1. Top of page
  2. Abstract
  3. Prasugrel, a new thienopyridine
  4. Direct P2Y12 antagonists
  5. Conclusions
  6. Disclosure of Conflict of Interests
  7. References
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