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OUR MISSION: TO REDUCE THE BURDEN OF CARDIOVASCULAR DISEASE
Dr. Davide Capodanno
Dr. Corrado Tamburino,
Inhibition of the adenosine diphosphate (ADP) P2Y12 receptor plays a key role in antithrombotic therapy as shown by many clinical trials demonstrating the clinical benefit associated with adjunctive clopidogrel therapy in high-risk settings. Despite these clinical benefits, clopidogrel has several limitations such as irreversible effect, variability of antiplatelet response and delayed onset of action. This has led clinical investigations to focus on the development of novel ADP P2Y12 receptor antagonists to overcome these drawbacks. This article summarises current knowledge regarding the ADP P2Y12 receptor antagonists prasugrel, ticagrelor, cangrelor and elinogrel.
Antiplatelet therapy with aspirin (acetylsalicylic acid), thienopyridines and glycoprotein (GP) IIb/IIIa inhibitors plays a pivotal role in the treatment and prevention of cardiovascular events in patients with coronary artery disease (CAD) (Figure 1). Thienopyridines were the first family of platelet adenosine diphosphate (ADP)-P2Y12 receptor inhibiting drugs. Among thienopyridines, ticlopidine was the first Food and Drug Administration (FDA)-approved P2Y12 antagonist. The use of ticlopidine is currently discouraged because of the long delay of inhibitory action and most importantly, its risk of life-threatening side effects, including neutropenia, aplastic anemia, thrombotic thrombocytopenic purpura and gastrointestinal effects (1). Clopidogrel, a second-generation thienopyridine, has largely replaced ticlopidine in clinical practice because of a superior tolerability, safety and side-effect profile (1). The clinical benefit of adding clopidogrel to aspirin is well established across the broad spectrum of high-risk manifestations of CAD and current guidelines recommend platelet inhibition with a combination of aspirin and clopidogrel in patients with non-ST segment elevation or ST-elevation acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI) (2-3). On the downside, it has been recognised that up to 40% of patients persist with inadequate platelet inhibition despite aspirin and clopidogrel therapy (4). Among the possible approaches to overcome these limitations, clinical investigations have focused on novel P2Y12 receptor antagonists. These include prasugrel, ticagrelor, cangrelor and elinogrel (5,6).
Prasugrel is a third-generation thienopyridine which, similarly to clopidogrel, needs hepatic conversion to generate an active metabolite which exerts its antiplatelet activity by irreversibly inhibiting the platelet ADP P2Y12 receptor (7). However, this pharmacokinetic process is more efficient with prasugrel than clopidogrel, resulting in a faster onset and more potent mechanism of action as shown in several phase I and II studies (8,9). Clinical evidence supporting the use of prasugrel in clinical practice were provided by the Trial to assess Improvement in Therapeutic Outcomes by optimising platelet inhibition with prasugrel Thrombolisis in Myocardial Infarcgtion-38 (TRITON – TIMI 38) study. This was a phase III trial of 13,608 ACS patients undergoing PCI, which demonstrated the superiority of prasugrel (60 mg loading dose and 10 mg maintenance dose) over clopidogrel (300mg loading dose and 75mg maintenance dose) in reducing the primary efficacy endpoint of death, myocardial infarction or stroke at 15 months (9.9% vs 12.1%, p<0.001) (10). This benefit was primarily driven by a reduction in rates of myocardial infarction and was observed both early (first 3 days) as well as late (up to 15 months). In addition, prasugrel treated patients experienced a 52% relative risk reduction in stent thrombosis rates (1.13 vs 2.35%, p < 0.0001). On the other hand, prasugrel use was associated with higher rates of major (2.4% vs 1.8%, p = 0.03) and life-threatening bleedings (1.4% vs 0.9%, p = 0.01) (Figure 2). Post-hoc assessments in this study showed that patients with prior TIA/stroke, aged =75 years and with a body weight of <60kg showed less clinical efficacy and a greater bleeding risk compared with the overall cohort. In particular, patients with prior TIA/stroke had net harm from prasugrel. The best balance between safety and efficacy was observed among diabetic patients and those presenting with an ST-elevation ACS in whom there was a 25-30% relative risk reduction in the primary end point and no differences in major bleeding compared to clopidogrel (11,12). Prasugrel is currently approved (60 mg loading dose and 10 mg maintenance dose) for clinical use in Europe and the United States for ACS patients undergoing PCI. It is contraindicated in patients with prior TIA/stroke. Reduced dosing can be considered in patients aged =75 years and with a body weight of <60kg. Prasugrel should be discontinued at least 7 days prior to surgery. Several studies on prasugrel are ongoing and will contribute to define its use in other clinical settings. The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) is a phase III trial that will evaluate the efficacy of prasugrel compared to clopidogrel in patients with medically managed ACS in whom revascularisation is not planned. Other ongoing studies are being performed for patients in non ACS settings, such as those undergoing elective PCI.
Ticagrelor forms part of a new chemical class called CPTP(CycloPentylTriazoloPyrimidine) which in contrast to thienopyridines, causes reversible inhibition of the P2Y12 receptor and does not require hepatic metabolism for its activity (13). Compared to clopidogrel, ticagrelor provides earlier onset of action and more consistent platelet inhibition. Conversely, due to its shorter half-life, it requires a twice daily administration. Preclinical, phase I and phase II studies showed higher and less variable levels of platelet inhibition with ticagrelor compared with standard-dose regimens of clopidogrel (14-15). The Phase III Study of Platelet Inhibition and Patients Outcomes (PLATO) trial was conducted in 18,624 patients with ACS (medically managed as well as undergoing percutaneous or surgical revascularisation) showing that ticagrelor (180mg loading dose and a 90mg twice daily maintenance dose) is more effective than clopidogrel (300-600mg loading dose and a 75mg once daily maintenance dose) in terms of the combined endpoint of death from vascular causes, myocardial infarction, or stroke at 12 months (9.8% vs 11.7%, p<0.001) (16). This difference was apparent within the first 30 days of treatment and persisted through the study period. Notably, ticagrelor was associated not only with a significant reduction in myocardial infarction but also mortality. Major bleeding did not differ significantly between ticagrelor and clopidogrel treatments (11.6% vs 11.2%, respectively; p = 0.43) (Figure 3). However, ticagrelor was associated with a higher rate of major bleeding not related to CABG (4.5% vs 3.8%, p=0.03) and fatal intracranial hemorrhages (0.1% vs 0.01%, p=0.02). Dyspnea was more frequent in the ticagrelor than clopidogrel group (13.8% vs 7.8%, p<0.001). Other side effects more commonly observed in patients treated with ticagrelor included increased serum levels of creatinine and uric acid and ventricular pauses =3 seconds during first week. These effects were not life-theatening but led to discontinuation of the study drug in a higher percentage of cases than clopidogrel (7.4% vs 6.0%, p < 0.001). Ticagrelor is still awaiting approval for clinical use in Europe and the United States.
Cangrelor is an adenosine triphosphate (ATP) analogue, which directly determines reversible inhibition of the P2Y12 receptor without needing hepatic biotransformation (17). Unlike the previous ADP-receptor antagonists, cangrelor is administered intravenously, with a very rapid onset of action and time to reach a steady state concentration. Due to its short half-life of 5-6 minutes, cangrelor quickly returns to pre-treatment levels after suspension. Because of this favorable pharmacodynamic profile, cangrelor may be advantageous for patients who need to achieve rapid platelet inhibition for PCI with the ability for a quick reversal in case of need (i.e. patients who require urgent surgery). Two phase III trials investigated the efficacy of cangrelor in reducing cardiovascular events. The Cangrelor vs Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION)-PCI study tried to demonstrate that the efficacy of cangrelor is superior, or at least non-inferior, to that of a 600-mg loading dose of clopidogrel in patients undergoing PCI, as measured by a composite of all-cause mortality, myocardial infarction and ischemia driven revascularization at 48 hours after PCI (18). The second trial, Cangrelor vs Placebo to Achieve Optimal Management of Platelet Inhibition (CHAMPION-PLATFORM), investigated the efficacy of cangrelor combined with clopidogrel over clopidogrel alone in patients undergoing PCI (19). Both trials were discontinued in May 2009 because an interim analysis indicated that CHAMPION trials would not meet the efficacy endpoints. The maintenance of platelet inhiBition with cangRelor after dIscontinuation of thienopyriDines in patients undergoing surGEry (BRIDGE) study is currently investigating whether cangrelor is a safe alternative for “bridging” patients during the pre- and post-surgical period of risk.
Elinogrel (PRT060128) is a direct-acting reversible ADP P2Y12 antagonist. Elinogrel is the only antiplatelet drug in clinical development that can be administered both intravenously and orally. Phase I and IIa trials showed that oral and intravenous administration of elinogrel was well tolerated and presented predictable, dose-dependent platelet inhibition (20,21). The Phase II Safety and Efficacy Study of PRT060128, a Novel Intravenous and Oral P2Y12 inhibitor in Non-Urgent PCI (INNOVATE-PCI) trial assessing the safety and efficacy of elinogrel in patients undergoing elective PCI has recently completed enrollment. Phase III clinical trial design is currently pending.
Figure 1. Platelet targets of the most commonly used antiplatelet drugs and novel P2Y12 receptor antagonists. Figure 2. Primary outcome and primary safety of TRITON-TIMI 38 (adapted from Wiviott et al, N Engl J Med 2007;357:2001-15 with permission). Figure 3. PLATO trial. A: primary outcome. B: primary safety (adapted from Wallentin et al, N Engl J Med 2009;361:1045-57 with permission).
Several novel ADP P2Y12 antagonists (prasugrel, ticagrelor, cangrelor and elinogrel) are currently under advanced clinical testing. These overcome some of the limitations associated with clopidogrel by producing faster, more potent and less variable platelet inhibition, and therefore may have the potential to further reduce recurrent atherothrombotic events in high-risk patients with CAD. Nevertheless, these more potent platelet inhibitory effects come at the expense of a greater potential for bleeding complications. Clinical investigations will further delineate the safety and efficacy profiles of these drugs and allow to identify patients who will best benefit from these novel P2Y12 receptor antagonists.
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Davide Capodanno, MD1,2, Corrado Tamburino, MD, PhD, FESC2, Dominick Angiolillo, MD, PhD, FACC, FESC1
1Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA. 2 Division of Cardiology, Ferrarotto Hospital – University of Catania. Italy CONFLICT OF INTEREST Dominick J Angiolillo: • Honoraria/Lectures: Bristol Myers Squibb; Sanofi-aventis; Eli Lilly and Company; Daiichi Sankyo, Inc. • Honoraria/Advisory board : Bristol Myers Squibb; Sanofi-aventis; Eli Lilly and Company; Daiichi Sankyo, Inc.; Astra Zeneca; The Medicines Company; Portola Pharmaceuticals; Novartis; Arena Pharmaceuticals; Evolva Pharmaceuticals • Research Grants: GlaxoSmithKline; Otsuka; Accumetrics; Eli Lilly and Company; Daiichi Sankyo, Inc.; The Medicines Company; AstraZeneca; Eisai; Portola Pharmaceutical; Schering-Plough; Johnson and Johnson.
Davide Capodanno and Corrado Tamburino: No conflict of interest to report.