SEARCH

SEARCH BY CITATION

Keywords:

  • Acute coronary syndrome;
  • ADP P2Y12 Inhibitors;
  • Antiplatelet therapy;
  • Cangrelor;
  • Clop Dorel;
  • Elinogrel;
  • Prasugrel;
  • Ticagrelor

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Search Method
  5. Prasugrel
  6. Clinical Trials
  7. Ticagrelor
  8. Clinical Trials
  9. Cangrelor
  10. Clinical Trials
  11. Elinogrel
  12. Clinical Trials
  13. Conclusion
  14. Conflicts of Interest
  15. References

Inhibition of the platelet P2Y12 receptor plays an important role in the prevention of thrombotic complications of acute coronary syndrome and percutaneous coronary interventions. Despite clinical benefits with clopidogrel therapy in these high risk patients, efficacy of clopidogrel is limited by slow onset of action, variability in platelet inhibitory response and potential drug–drug interactions. Importantly, suboptimal platelet inhibition by clopidogrel is associated with worse prognosis. This underscores the need for alternate antiplatelet treatment strategies. A number of novel P2Y12 antagonists are approved or in advanced development and some have demonstrated superior platelet inhibition effect, clinical outcomes, and safety profile than clopidogrel in patients with acute coronary syndrome. The aim of this manuscript is to provide an overview on the current status in P2Y12 receptor inhibition and to review the pharmacology and clinical development of four of these agents: prasugrel, cangrelor, ticagrelor, and elinogrel.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Search Method
  5. Prasugrel
  6. Clinical Trials
  7. Ticagrelor
  8. Clinical Trials
  9. Cangrelor
  10. Clinical Trials
  11. Elinogrel
  12. Clinical Trials
  13. Conclusion
  14. Conflicts of Interest
  15. References

The activation of platelet adenosine diphosphate (ADP) P2Y12 receptors plays an important role in platelet aggregation and activation during acute coronary syndrome (ACS) (Figure 1). Ticlopidine and clopidogrel are the first- and second-generation thienopyridines that inhibit platelet aggregation via the ADP P2Y12 receptor. Dual antiplatelet therapy with clopidogrel and aspirin is well established in the treatment of ACS and after coronary artery stent implantation [1–4].

image

Figure 1. Platelet activation receptors. TXA2 = thromboxane A2; ADP = adenosine diphosphate; TP = thromboxane receptor; PAR = protease-activated receptor; COX = cyclooxygenase.

Download figure to PowerPoint

The efficacy of clopidogrel is limited by a number of issues. Firstly, clopidogrel is a prodrug which requires hepatic conversion to its active metabolite by various cytochrome (CYP) enzymes leading to delayed inhibition of platelet activity (IPA) (Figure 2). Furthermore, treatment response is prone to interindividual variation largely due to genetic polymorphisms of the CYP 450 enzymes, most notably the CYP2C19 [5]. It is estimated that 20–50% of the population are carriers of one or two of the loss of function CYP2C19 genes which result in lower level of active clopidogrel metabolite, reduced IPA, and possible increased risk of major adverse cardiovascular events, particularly among patients undergoing percutaneous coronary intervention (PCI) [6–10].

image

Figure 2. Metabolisms of ADP P2Y12 inhibitors.

Download figure to PowerPoint

Secondly, concerns have been raised recently over potential drug–drug interaction of clopidogrel with drugs that are also metabolized by CYP450 such as proton pump inhibitors (PPI) [11]. A number of observational studies have shown reduction in IPA when clopidogrel and PPIs are concurrently administered [12,13]. However, the recently published clopidogrel and the optimization of gastrointestinal events trial (COGENT) showed that coadministration of clopidogrel and omeprazole did not increase the risk of adverse cardiovascular events [14]. Nevertheless, in March 2010, the United States Food and Drug Advisory (FDA) issued a “black box” warning to consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.1

Thirdly, clopidogrel inhibition of the P2Y12 receptor is irreversible. The inhibitory effect lasts for the lifespan of platelets which is approximately 8–10 days [15]. This may be undesirable for patients who need to undergo urgent surgery because of increased risk of perioperative bleeding. The absolute increase in major bleeding with clopidogrel compared with control was approximately 1%, and perioperative use of clopidogrel was significantly associated with more hemorrhage in patients undergoing coronary artery bypass graft (CABG) [16,17].

Several novel P2Y12 blockers are emerging as alternatives that overcome the limitations of clopidogrel. This review aims to provide an overview on the current status of and future directions in P2Y12 receptor inhibition, and to review the pharmacology and clinical development of four of these agents: prasugrel, cangrelor, ticagrelor, and elinogrel.

Search Method

  1. Top of page
  2. Summary
  3. Introduction
  4. Search Method
  5. Prasugrel
  6. Clinical Trials
  7. Ticagrelor
  8. Clinical Trials
  9. Cangrelor
  10. Clinical Trials
  11. Elinogrel
  12. Clinical Trials
  13. Conclusion
  14. Conflicts of Interest
  15. References

MEDLINE, EMBASE, and Cochrane library were searched with the search terms “Clopidogrel” or “Prasugrel” or “Ticagrelor” or “Cangrelor” or “Elinogrel” or “P2Y12 receptor blocker.” The searches included papers published up until October 2010, and only English papers were included.

Prasugrel

  1. Top of page
  2. Summary
  3. Introduction
  4. Search Method
  5. Prasugrel
  6. Clinical Trials
  7. Ticagrelor
  8. Clinical Trials
  9. Cangrelor
  10. Clinical Trials
  11. Elinogrel
  12. Clinical Trials
  13. Conclusion
  14. Conflicts of Interest
  15. References

Prasugrel is a thienopyridine that inhibits platelet aggregation by irreversibly blocking the ADP P2Y12 receptor. It is an orally active drug which is first hydrolyzed by esterases and then metabolized by the CYP450 system to its active metabolite which has a similar potency as the metabolites of clopidogrel but reaches peak concentration in 30 min of dosing, as compared to 5 h of clopidogrel [18,19, Table 1]. The main CYP isoenzymes taking part in the conversion of prasugrel are CYP3A and CYP2B6, with less dependence on CYP2C9 and CYP2C19. As a result, prasugrel is less susceptible to the loss-of-function mutations of these CYPs and exhibit greater and faster IPA compared to clopidogrel [20]. Prasugrel is removed by firstly hydrolysis and inactivation of its active metabolites into downstream inactive metabolites, and secondly excretion of these inactive metabolites through urine and a small part in faeces [19,21].

Table 1. Characteristics of various ADP P2Y12 inhibitors
 ClopidogrelPrasugrelTicagrelorCangrelorElinogrel
  1. CYP450, cytochrome p450; IPA, inhibition of platelet activity; IV, intravenous.

ProdrugYesYesNoNoNo
CYP450 activationYesYesNoNoNo
Interaction with PPIYesUnknownNoNoNo
Time to peak IPA6–12 h2 h2 hSeconds4–6 h
ReversibilityNoNoYes, in 3–5 daysYes, in 60–90 minYes, in 8 h
Plasma half-life7–8 h7–8 h7–12 h2.9–5.5 min11–12 h
PreparationOralOralOralIVOral/IV
AdministrationOnce dailyOnce dailyTwice dailyContinuous infusionInfusion/twice daily

Clinical Trials

  1. Top of page
  2. Summary
  3. Introduction
  4. Search Method
  5. Prasugrel
  6. Clinical Trials
  7. Ticagrelor
  8. Clinical Trials
  9. Cangrelor
  10. Clinical Trials
  11. Elinogrel
  12. Clinical Trials
  13. Conclusion
  14. Conflicts of Interest
  15. References

Early phase I studies have demonstrated prasugrel to have 10 times more potent IPA than clopidogrel [22]. This was confirmed in a crossover study by Payne et al. on 41 healthy, aspirin-free subjects [23]. In addition, this study also showed that prasugrel had quicker onset of action and more consistent level of IPA. Within poor responder to clopidogrel, prasugrel exhibited a significantly higher degree of platelet inhibition in a study by Jernberg on 101 aspirin-treated patients [24]. In this study, greater IPA by prasugrel was not associated with an increase incident of bleeding.

The risk of bleeding complications was studied in the phase II, Joint Utilization of Medications to Block Platelets Optimally (JUMBO) TIMI 26 study [25]. It was a randomized, dose-ranging, double-blind safety trial on 904 patients undergoing elective or urgent PCI. Patients were randomized to receive either standard clopidogrel or one of three different prasugrel dosing regimens (40 mg loading dose (LD)/7.5 mg maintenance dose (MD), 60 mg LD/10 mg MD, or 60 mg LD/15 mg MD) in coadministration with aspirin. This study did not show any differences in clinically significant hemorrhagic complication between prasugrel and clopidogrel, although an increased rate of TIMI minimal bleeding events was noted in the high dose prasugrel group. In this study, treatment with prasugrel attained a nonsignificantly lower rate of adverse cardiac events at 30 days. Another phase II randomized double-blind crossover study, the PRasugrel IN ComparIson to CloPidogrel for Inhibition of PLatelet Activation and Aggregation (PRINCIPLE) TIMI 44 study, was conducted to assess the antiplatelet effects of prasugrel versus high-dose clopidogrel in patient undergoing PCI [26]. In this study, the level of IPA was shown to be consistently greater with both loading and MDs of prasugrel than clopidogrel. Overall, these two phase II trials demonstrated that prasugrel had higher level of IPA than clopidogrel and comparable bleeding risk.

The TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON) TIMI 38 study was a phase III randomized double-blinded parallel group multinational trial that evaluated the clinical effectiveness of prasugrel [27]. It randomized 13,608 patients undergoing PCI to receive prasugrel or clopidogrel for 6–15 months. In this study, prasugrel was associated with significantly lower rates of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (hazard ratio (HR) 0.81, 95% CI 0.73 – 0.90). The rates of myocardial infarction, need for urgent revascularization, and stent thrombosis were also significantly lower in the prasugrel group (HR 0.66, 95% CI 0.54–0.81). However, the prasugrel group was associated with an increased risk of life-threatening bleeding (HR 1.52, 95% CI 1.08–2.13), and a 3.5 times greater risk of CABG-associated bleeding. All cause mortality was similar among the two groups. However, in the subgroup analysis, the side effect of bleeding was shown to outweigh the clinical benefits of prasugrel in patients with a history of stroke, aged ≥75 years and those with a body weight less than 60 kg. In this study, some criticisms have been raised over the choice of prasugrel dose (equivalent to the intermediate dose used in JUMBO-TIMI 26), which might favor more potent IPA but at the cost of increased bleeding risk.

Another study, the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage ACSs (TRILOGY) trial is currently underway to compare the efficacy of prasugrel with clopidogrel in ACS patients who are managed medically. In this study, patients aged over 75 and patients <65 kg in weight will receive a reduced dose of prasugrel. This study may shed light on the efficacy and bleeding risks of reduced dose of prasugrel compared with clopidgrel. In FDAs secondary review of prasugrel, there were some concerns over excess neoplasm observed in the prasugrel group compared with clopidogrel. However after reviewing “tumor-progression” studies in vitro and in vivo in mice, the FDA concluded that causality of cancer was unlikely [28].

Ticagrelor

  1. Top of page
  2. Summary
  3. Introduction
  4. Search Method
  5. Prasugrel
  6. Clinical Trials
  7. Ticagrelor
  8. Clinical Trials
  9. Cangrelor
  10. Clinical Trials
  11. Elinogrel
  12. Clinical Trials
  13. Conclusion
  14. Conflicts of Interest
  15. References

Ticagrelor (previously known as AZD 6140) is a cyclo-pentyl-triazolo-pyrimidine. It is an orally active, selective, and reversible P2Y12 inhibitor. In addition to platelet inhibition, ticagrelor also blocks ADP-mediated vasoconstriction of vascular smooth muscle [29] and enhances the adenosine-induced coronary blood flow through inhibition of adenosine uptake by erythrocytes [30]. Ticagrelor differs from clopidogrel or prasugrel in that it does not require hepatic biotransformation and binds directly to the P2Y12 receptor. Ticagrelor is eliminated in the feces, with less than 1% found in the urine, suggesting that renal dose adjustment is not necessary. The plasma half-life of ticagrelor is about 7–12 h and hence requires twice daily dosing to achieve optimal platelet inhibition [31].

Clinical Trials

  1. Top of page
  2. Summary
  3. Introduction
  4. Search Method
  5. Prasugrel
  6. Clinical Trials
  7. Ticagrelor
  8. Clinical Trials
  9. Cangrelor
  10. Clinical Trials
  11. Elinogrel
  12. Clinical Trials
  13. Conclusion
  14. Conflicts of Interest
  15. References

Early phase I studies in healthy subjects demonstrated that ticagrelor was well tolerated and exhibited maximal IPA only 2 h postdose [32]. Another study comparing different ticagrelor dosing regimens with clopidogrel found greater and more consistent IPA and a modest prolongation of bleeding time with ticagrelor [33].

In a phase II, double-blind study, ticagrelor was compared with clopidogrel in 200 stable outpatients with atherosclerosis in addition to aspirin therapy [34]. Ticagrelor at a dose higher than 100 mg was shown to have more pronounced IPA than clopidogrel, but was associated with higher incidence of bleeding. The subsequent Dose confIrmation Study assessing antiPlatelet Effects of AZD6140 versus clopidogRel in non-ST-segment Elevation myocardial infarction (DISPERSE) 2 study, which was conducted on 990 patients with non-ST elevation MI, showed that the total bleeding rates for ticagrelor 90 mg and 180 mg twice daily did not differ significantly with that in the clopidogrel group [35], and both doses of ticagrelor provided greater level of IPA than clopidogrel [36]. However, several adverse events were noted with ticagrelor, particularly dyspnea and bradycardia, which are attributed to its adenosine enhancement effect [37]. Another multicenter, randomized, double blind study, the ONSET/OFFSET study, compared the level of IPA of ticagrelor at a LD of 180 mg with a high LD (600 mg) of clopidogrel in 123 patients with stable coronary artery disease who were also taking aspirin therapy [38]. This study again showed that ticagrelor achieved more rapid and greater IPA than high-loading-dose clopidogrel with a quicker offset of action (109.19 h to 10% of IPA for ticagrelor vs. 195.66 h for Clopidogrel), but at the expense of higher incidence of bleeding (28.1% vs. 13.0%, respectively).

In the recently published phase III, multicenter, randomized, double blind, double dummy PLATelet inhibition and patient outcomes (PLATO) trials, ticagrelor was compared with clopidogrel in more than 18,500 patients with ACS [39]. Patients were randomized within 24 h post-ACS to receive either ticagrelor 180 mg loading followed by 90 mg twice daily or clopidogrel 300–600 mg loading followed by 75 mg daily for 6–12 months, on top of aspirin. The primary outcome measured was the time to first occurrence of cardiovascular or cerebrovascular death, nonfatal MI, or nonfatal stroke. Patients in the ticagrelor group experienced fewer primary outcomes compared to the clopidogrel group at 12 months (HR 0.84, 95% CI 0.77–0.92). The primary safety outcome measured was the time to first occurrence of any major bleeding event, and this was not significantly different between ticagrelor and clopidogrel groups. Notably, the all-cause mortality, although not being the primary endpoint, was significantly lower in the ticagrelor group than in the clopidogrel group (HR 0.78, 95% CI 0.69–0.89). In a subgroup analysis of the PLATO trials, ticagrelor was compared with clopidogrel in 13,408 patients planned for invasive strategy [40]. Patients given ticagrelor had significant less cardiovascular death and death from all causes. The incident of total major bleeding was similar between the two groups. Among this, CABG-related bleeding was notably similar between the two groups, with a trend toward less bleeding related to CABG with ticagrelor, but non-CABG-related major bleeding including instance of fatal intracranial hemorrhage was higher in the ticagrelor group (4.5% vs. 3.8%). In the PLATO trial, ticagrelor was noted to be associated with several adverse side effects including dyspnea, bradyarrhythmia, and more patients in the ticagrelor group discontinued study drug due to adverse events (mostly dypsnoea) compared to the clopidogrel group. An important observation of PLATO was that patients in North America which comprised around 10% of the 18,500 study population showed a statistically insignificant trend toward worse outcomes with ticagrelor. The FDA review panelists generally agreed that this observation was probably related to the difference in aspirin dose (325 mg in United States versus 100 mg outside the United States). However, the reason behind such an association was unclear.

Overall, in comparison with clopidogrel, ticagrelor exhibited greater potency in platelet inhibition and this translated into greater clinical efficacy in the phase III trial. Its safety profile in terms of total major bleeding rate was similar to clopidogrel, but had higher incidence of non-CABG-related bleeding and a worse adverse effect profile.

Cangrelor

  1. Top of page
  2. Summary
  3. Introduction
  4. Search Method
  5. Prasugrel
  6. Clinical Trials
  7. Ticagrelor
  8. Clinical Trials
  9. Cangrelor
  10. Clinical Trials
  11. Elinogrel
  12. Clinical Trials
  13. Conclusion
  14. Conflicts of Interest
  15. References

Cangrelor (previously known as AR-C69931MX) is an adenosine triphosphate analog that has a potent, direct, and reversible ADP P2Y12 receptor inhibition. It is the first P2Y12 inhibitor that is available in intravenous form. It acts directly on the P2Y12 receptor without the need for hepatic conversion to an active metabolite, in contrast to prasugrel and clopidogrel. It has a rapid onset of action (few seconds) after the administration of a bolus dose. It also has a short half-life of 2.6 min and its platelet inhibitory effect is reversed within 60 min after discontinuation of the drug infusion [41]. After binding to the P2Y12 receptor, Cangrelor is rapidly inactivated by an ADPase located on the surface of vascular endothelial cells [42].

Clinical Trials

  1. Top of page
  2. Summary
  3. Introduction
  4. Search Method
  5. Prasugrel
  6. Clinical Trials
  7. Ticagrelor
  8. Clinical Trials
  9. Cangrelor
  10. Clinical Trials
  11. Elinogrel
  12. Clinical Trials
  13. Conclusion
  14. Conflicts of Interest
  15. References

Preclinical study of cangrelor showed a 20-fold reduction of ADP-induced platelet aggregation during its infusion, and bleeding times were significantly extended [43]. An open-label study assessed the safety, tolerability, and platelet aggregation of various dosing regimens of cangrelor in 39 patients with unstable angina and non-Q wave MI, as an adjunct to heparin and aspirin therapy [44]. Cangrelor was well tolerated, with no serious adverse events or deaths. Platelet aggregation in all patients was inhibited by more than 80%. A rapid normalization of 60% of baseline platelet aggregation function was observed in 1 h following discontinuation of infusion.

A phase II study assessed the inhibition of platelet function with cangrelor compared with standard therapy with clopidogrel in patients with ischemic heart disease [45]. This study demonstrated that nearly complete IPA was achieved by adding cangrelor in vitro to the blood from the clopidogrel group and cangrelor achieved more sustained IPA than clopidogrel. Another phase II, multicenter, randomized, placebo- and active-controlled trial assessed the safety and pharmacodynamics of cangrelor in patients undergoing PCI [46]. In part I of this study, cangrelor was compared with placebo in patients who received aspirin and heparin before PCI. The composite incidence of major and minor bleeding was similar between the two groups. In part II of this study, cangrelor was compared with abciximab in patients before PCI. The incidences of adverse cardiac events were similar between those receiving cangrelor and those receiving abciximab. The mean IPA ex vivo was similar for both groups, but platelet aggregation returned to baseline more rapidly with cangrelor compared with abciximab.

In two recently published phase III study, the Cangrelor versus standard tHerapy to Achieve optimal Management of Platelet InhibitiON (CHAMPION) PCI [47] and the CHAMPION PLATFORM [48] trials, cangrelor was compared with 600 mg of clopidogrel in patients undergoing PCI. The main difference of the two trials was the timing of the administration of the study drug. In CHAMPION PCI, both cangrelor and clopidogrel were administered within 30 min before PCI, while in the CHAMPION PLATFORM, cangrelor was started at the beginning of PCI, whereas clopidogrel was administered at the end of PCI. In both trials, cangrelor did not have a significant effect on the incidence of death from any cause, MI, or ischemia-driven revascularization. Severe bleeding complications were similar in both groups, and in the CHAMPION PLATFORM, cangrelor was shown to have a marginal reduction of secondary end points of stent thrombosis and death. Both trials were terminated prematurely because the interim analysis showed that the estimated conditional power to demonstrate superiority for cangrelor was low.

In summary, despite a favorable profile of having a more potent and rapid onset and offset of platelet inhibition in the preclinical and early clinical studies, cangrelor failed to prove its clinical superiority over conventional treatment in phase III trials, underscoring the complexity of platelet activation in vivo that leads to thrombosis. However, given its unique quality of being an intravenous P2Y12 inhibitor, and with its potent and rapid onset and offset of action, cangrelor deserves a further study aiming to identify a more suitable patient group. A phase III study, the maintenance of platelet inihiBition with cangRelor after dIscontinuation of ThienopyriDines in Patients Undergoing surGEry (BRIDGE) trial is currently underway to investigate the use of cangrelor in patients before coronary artery bypass grafting.

Elinogrel

  1. Top of page
  2. Summary
  3. Introduction
  4. Search Method
  5. Prasugrel
  6. Clinical Trials
  7. Ticagrelor
  8. Clinical Trials
  9. Cangrelor
  10. Clinical Trials
  11. Elinogrel
  12. Clinical Trials
  13. Conclusion
  14. Conflicts of Interest
  15. References

Elinogrel (previously known as PRT060128 or PRT128) is a new direct, reversible P2Y12 inhibitor that is currently under investigation for its use in treatment of ACS. It is available in both intravenous and oral form, and this unique dual formulation provides the potential benefit for smooth transition from short-term intravenous to long-term oral antiplatelet therapy [49]. The average plasma half-life of elinogrel at the 40 mg dose was about 11 h.

Clinical Trials

  1. Top of page
  2. Summary
  3. Introduction
  4. Search Method
  5. Prasugrel
  6. Clinical Trials
  7. Ticagrelor
  8. Clinical Trials
  9. Cangrelor
  10. Clinical Trials
  11. Elinogrel
  12. Clinical Trials
  13. Conclusion
  14. Conflicts of Interest
  15. References

Early phase I studies demonstrated that intravenous bolus dose of elinogrel of up to 40 mg was well tolerated, and complete IPA was immediately achieved with dose of >10 mg, and the platelet function is fully reversible within 8 h of discontinuation of the infusion [50]. A study to investigate the antiplatelet effect of a single 60 mg oral dose of elinogrel on patients with high platelet reactivity (HPR) to clopidogrel and aspirin therapy has shown that the HPR can be reversibly overcome by elinogrel [51].

A phase IIa study, the Elinogrel before PCI to Optimize REperfusion in acute Myocardial Infarction (ERASE MI) trial, was conducted to assess the safety and tolerability of escalating doses of elinogrel. In this study, intravenous elinogrel was found to be well tolerated and a feasible treatment for patient before primary PCI [52]. Elinogrel was shown to have a similar rate of bleeding events as placebo, and there was no difference in ischemic outcomes between the two groups. However, this trial was terminated prematurely for administrative reason and its small sample size precluded any conclusion regarding the safety profile of elinogrel. Another larger, multicenter, randomized, double-blind, triple-dummy, clopidogrel-controlled study of IV and oral elinogrel compared to clopidogrel in patients undergoing nonurgent PCI (INNOVATE PCI) is now underway to examine the clinical efficacy, biological activity, and tolerability and safety of elinogrel.

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Search Method
  5. Prasugrel
  6. Clinical Trials
  7. Ticagrelor
  8. Clinical Trials
  9. Cangrelor
  10. Clinical Trials
  11. Elinogrel
  12. Clinical Trials
  13. Conclusion
  14. Conflicts of Interest
  15. References

Antiplatelet therapy with clopidogrel is well established in the treatment of ACS. However, efficacy of clopidogrel is impeded by several limitations, and its monopoly is now challenged by a number of new P2Y12 receptor inhibitors. Each of these new agents has its own individual characteristics and its unique pharmacological advantages over clopidogrel (Table 1). The availability of these new agents opens a gateway to a new era of personalized medicine. While the evidence for their clinical efficacy are not as strong as clopidogrel, some of these agents have already proven themselves in clinical trials to be as effective (if not more effective than) as clopidogrel, and with similar bleeding risk (Table 2). Clopidogrel will likely remain to be the mainstay of antiplatelet agent in the treatment of ACS for the time being. Nevertheless, physicians need to be aware of the availability of these new agents. With the proper risk stratification and consideration of other clinical factors such as concomitant prescription of PPI, a personalized approach to antiplatelet therapy might be adapted in patients with high risk for recurrent ACS or/and stent thrombosis or/and requiring CABG. More prospective studies are needed in the future to evaluate and validate a strategy of personalized antiplatelet therapy.

Table 2. Summary of efficacy and bleeding risks of new P2Y12 blockers
 Prasugrel [21]Ticagrelor [33])Cangrelor [40,41]
  1. aMortality as the primary end point measured in each study.

  2. bBleeding risk defined as TIMI major bleeding.

Mortality (HR)a[DOWNWARDS ARROW]0.82[DOWNWARDS ARROW]0.84≈1.05/≈0.87
Bleeding risk (HR)b[UPWARDS ARROW]1.32≈1.03≈1.36/≈ 0.44

Conflicts of Interest

  1. Top of page
  2. Summary
  3. Introduction
  4. Search Method
  5. Prasugrel
  6. Clinical Trials
  7. Ticagrelor
  8. Clinical Trials
  9. Cangrelor
  10. Clinical Trials
  11. Elinogrel
  12. Clinical Trials
  13. Conclusion
  14. Conflicts of Interest
  15. References

The manuscript has not been published and is not under consideration for publication elsewhere. All authors have read and approved the manuscript and have no real or perceived conflicts of interests.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Search Method
  5. Prasugrel
  6. Clinical Trials
  7. Ticagrelor
  8. Clinical Trials
  9. Cangrelor
  10. Clinical Trials
  11. Elinogrel
  12. Clinical Trials
  13. Conclusion
  14. Conflicts of Interest
  15. References
  • 1
    CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet1996;348:13291339.
  • 2
    Yusuf S, Zhao F, Mehta SR, et al. CURE Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med2001;345:494502.
  • 3
    Gibson CM, Ly HQ, Murphy SA, et al. Usefulness of clopidogrel in abolishing the increased risk of reinfarction associated with higher platelet counts in patients with ST-elevation myocardial infarction (results from CLARITY-TIMI 28). Am J Cardiol2006;98:761763.
  • 4
    Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction. J Am Coll Cardiol2007;50:e1–e157.
  • 5
    Shuldiner AR, O’Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA2009;302:849857.
  • 6
    Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol2008;51:19251934.
  • 7
    Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med2009;360:354362.
  • 8
    Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med2009;360:363375.
  • 9
    Marín F, González-Conejero R, Capranzano P, et al. Pharmacogenetics in cardiovascular antithrombotic therapy. J Am Coll Cardiol2009;54:10411057.
  • 10
    Mega JL, Simon T, Collet JP, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: A meta-analysis. JAMA2010;304:18211830.
  • 11
    Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: The randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol2008;51:256260.
  • 12
    Siller-Matula JM, Spiel AO, Lang IM, et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J2009;157:148.e1–148.e5.
  • 13
    O’Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: An analysis of two randomised trials. Lancet2009;374:989997.
  • 14
    Bhatt DL, Cryer BL, Contant CF, et al; COGENT Investigators. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med2010;363:19091917.
  • 15
    Savcic M, Hauert J, Bachmann F, et al. Clopidogrel loading dose regimens: Kinetic profile of pharmacodynamic response in healthy subjects. Semin Thromb Hemost1999;25(Suppl 2):1519.
  • 16
    Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost2005;3:692694.
  • 17
    Picker SM, Kaleta T, Hekmat K, et al. Antiplatelet therapy preceding coronary artery surgery: Implications for bleeding, transfusion requirements and outcome. Eur J Anaesthesiol2007;24:332339.
  • 18
    Niitsu Y, Jakubowski JA, Sugidachi A, et al. Pharmacology of CS-747 (prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y12 receptor antagonist activity. Semin Thromb Hemost2005;31:184194.
  • 19
    Farid NA, Smith RL, Gillespie TA, et al. The disposition of prasugrel, a novel thienopyridine, in humans. Drug Metab Dispos2007;35:10961104.
  • 20
    Brandt JT, Payne CD, Wiviott SD, et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: Magnitude of platelet inhibition is related to active metabolite formation. Am Heart J2007;153:66.e9–66.e16.
  • 21
    Sugidachi A, Asai F, Ogawa T, et al. The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties. Br J Pharmacol2000;129:14391446.
  • 22
    Jakubowski JA, Matsushima N, Asai F, et al. A multiple dose study of prasugrel (CS-747), a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy humans. Br J Clin Pharm2006;63:421430.
  • 23
    Payne CD, Li YG, Small DS, et al. Increased active metabolite formation explains the greater platelet inhibition with prasugrel compared to high-dose clopidogrel. J Cardiovasc Pharmacol2007;50:555562.
  • 24
    Jernberg T, Payne CD, Winters KJ, et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J2006;27:11661173.
  • 25
    Wiviott SD, Antman EM, Winters KJ, et al. Randomized comparison of prasugrel (CS-747,LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: Results of the Joint Utilizationì of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation2005;111:33663373.
  • 26
    Wiviott SD, Trenk D, Frelinger AL, et al. PRINCIPLE-TIMI 44 Investigators. Prasugrel compared with high loading and maintenance dose clopidogrel in patients with planned percutaneous coronary intervention: The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation2007;116:29232932.
  • 27
    Wiviott SD, Braunwald E, McCabe CH, et al. TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med2007;357:20012015.
  • 28
    Unger EF. Weighing benefits and risks—The FDA's review of prasugrel. N Engl J Med2009;361:942945.
  • 29
    Wihlborg AK, Wang L, Braun OO, et al. ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels. Arterioscler Thromb Vasc Biol2004;24:18101815.
  • 30
    Bjorkman JA, Kirk I, van Giezen JJ. AZD6140 inhibits adenosine uptake into erythrocytes and enhances coronary blood flow after local ischemia or intracoronary adenosine infusion (abstract 245). Circulation2007;116:II_28.
  • 31
    Peters G, Robbie G. Single-dose pharmacokinetics and pharmacodynamics of AZD6140—An oral reversible ADP receptor antagonist (abstract). Haematologica2004;989(suppl 7):14.
  • 32
    Anderson SD, Shah NK, Yim J, Epstein BJ. Efficacy and safety of ticagrelor: A reversible P2Y12 receptor antagonist. Ann Pharmacother2010;44:524537.
  • 33
    Peters G, Buter K, Winter HE, et al. Multiple dose pharmacokinetics and pharmacodynamics of the reversible, orally active ADP receptor antagonist AZD6140 (abstract P4556). Eur Heart J2006;27(suppl 1):758.
  • 34
    Husted S, Emanuelsson H, Heptinstall S, et al. 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 J2006;27:10381047.
  • 35
    Cannon CP, Husted S, Harrington RA, 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 syndrome: Primary results of the DISPERSE-2 trial. J Am Coll Cardiol2007;50:18441851.
  • 36
    Storey RF, Husted S, Harrington RA, et al. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol2007;50:18521856.
  • 37
    Serebruany VL, Stebbing J, Atar D. Dyspnoea after antiplatelet agents: The AZD6140 controversy. Int J Clin Pract2007;61:529533.
  • 38
    Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: The ONSET/OFFSET study. Circulation2009;120:25772585.
  • 39
    Wallentin L, Becker RC, Budaj A, et PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med2009;361:10451057.
  • 40
    Cannon CP, Harrington RA, James S, et PLATO Investigators. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): A randomised double-blind study. Lancet2010;375:283293.
  • 41
    Wang K, Zhou X, Zhou Z, et al. Sustained coronary artery recanalization with adjunctive infusion of a novel P2T-receptor antagonist AR-C69931 in a canine model. J Am Coll Cardiol2000;35(suppl):281A282A.
  • 42
    Akers WS, Oh JJ, Oestreich JH, Ferraris S, et al. Pharmacokinetics and pharmacodynamics of a bolus and infusion of cangrelor: A direct, parenteral P2Y12 receptor antagonist. J Clin Pharmacol2010;50:2735.
  • 43
    Huang J, Driscoll EM, Gonzales ML, et al. Prevention of arterial thrombosis by intravenously administered platelet P2T receptor antagonist AR-C69931MX in a canine model. J Pharmacol Ex Ther2000;295:492499.
  • 44
    Storey RF, Oldroyd KG, Wilcox RG. Open multicentre study of the P2T receptor antagonist AR-C69931MX assessing safety, tolerability and activity in patients with acute coronary syndrome. Thromb Haemost2001;85:401407.
  • 45
    Storey RF, Wilcox RG, Heptinstall S. Comparison of the pharmacodynamic effects of the platelet ADP receptor antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease. Platelets2002;13:407413.
  • 46
    Greenbaum AB, Grines CL, Bittl JA, et al. 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 J2006;151:689.e1–689.e10.
  • 47
    Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med2009;361:23182329.
  • 48
    Bhatt DL, Lincoff AM, Gibson CM, et al. CHAMPION PLATFORM Investigators. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med2009;361:23302341.
  • 49
    Lieu HDCP, Andre P, Leese PT, et al. Initial intravenous experience with PRT060128 (PRT128), an orally-available, direct-acting, and reversible P2y12 inhibitor. J Thromb Haemost2007;5(suppl 1):P-T-292.
  • 50
    Ueno M, Rao SV, Angiolillo DJ. Elinogrel: Pharmacological principles, preclinical and early phase clinical testing. Future Cardiol2010;6:445453.
  • 51
    Gurbel PA, Bliden KP, Antonino MJ, et al. The effect of elinogrel on high platelet reactivity during dual antiplatelet therapy and the relation to CYP2C19*2 genotype: First experience in patients. J Thromb Haemost2010;8:4353.
  • 52
    Berger JS, Roe MT, Gibson CM, et als. Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: The Early Rapid ReversAl of platelet thromboSis with intravenous Elinogrel before PCI to optimize reperfusion in acute Myocardial Infarction (ERASE MI) pilot trial. Am Heart J2009;158:998–1004.e1.