Reversible P2Y12 Inhibitor Research Articles

Rapid P2Y 12 Inhibition

Acute coronary syndrome (ACS) is still a serious condition associated with decreased quality of life, increased healthcare expenditures, and premature death. The prevalence of ACS is expected to increase with aging of the population and with the epidemics of obesity and diabetes. The short- and long-term mortality after an ACS has been dramatically reduced by the development of revascularization techniques and new antithrombotic agents. The past decade has seen many trials evaluating new oral and parenteral antiplatelet agents with greater potency than aspirin and clopidogrel. Several antiplatelet agents have been developed, with the ultimate goal to obtain optimal antiplatelet therapy for both the acute and the chronic phases of disease. Articles see p 336, 347 Ideally, efficiency requires several pharmacodynamic proprieties, such as a fast onset of action (immediate onset for emergency situations), a strong degree of platelet inhibition (at least stronger than the standard of care [aspirin and clopidogrel]), a narrow interindividual variability with no impact of genetic variants and no drug-to-drug interaction, and an easy administration (an oral drug for maintenance therapy and an intravenous formulation for rapid loading). Of course, this drug should also lead to a convincing reduction of recurrent ischemic events in an adequately powered phase 3 trial. With regard to safety, the illusion of having the same dose of a single antiplatelet drug to treat all clinical situations has passed. The degree of platelet activation and aggregation is different across clinical situations (eg, acute ST-segment–elevation myocardial infarction [STEMI] versus secondary prevention) and varies over time in the same patient. Recent large phase 3 trials have confirmed the importance of dosing and the target population treated with the new agents.1–4 From a safety standpoint, an ideal antiplatelet agent would also have an intravenous and oral formulation, with different doses tested in …

Pharmacokinetic and Pharmacodynamic Effects of Elinogrel

Elinogrel is the only selective, competitive and reversible platelet P2Y(12) inhibitor available in both intravenous (IV) and oral formulations. This substudy of the Intravenous and Oral Administration of Elinogrel to Evaluate Tolerability and Efficacy in Nonurgent Percutaneous Coronary Intervention patients (INNOVATE-PCI) trial evaluated the pharmacokinetic and pharmacodynamic effects of two dosing regimens of IV followed by oral elinogrel (120 mg IV plus 100 mg oral twice daily; 120 mg IV plus 150 mg oral twice daily) versus standard clopidogrel therapy (300-600 mg oral loading dose plus 75 mg oral maintenance dose) in 56 patients undergoing nonurgent PCI. At time of randomization, 71.4% (40/56) of patients were using maintenance clopidogrel therapy. In the acute phase, an IV bolus of elinogrel achieved more rapid and potent antiplatelet effects compared with clopidogrel, which were sustained during the transition from the IV to the oral formulation in the first 24 hours of the peri-PCI period. During chronic therapy, elinogrel achieved similar levels of platelet reactivity compared with clopidogrel before the next oral dose and, although platelet reactivity was lower with elinogrel up to 6 hours after daily oral maintenance dosing, these differences were not statistically significant. These pharmacodynamic effects matched the pharmacokinetic profile of elinogrel. There were no differences in pharmacodynamic and pharmacokinetic effects between the two elinogrel dosing regimens. Compared with clopidogrel, the combination of IV and oral elinogrel achieves more rapid and enhanced antiplatelet effects that were sustained through the transition to oral elinogrel in the peri-PCI period, but these were not significant during chronic dosing in this pilot investigation. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00751231.

Why does ticagrelor induce dyspnea?

In studies that compared the reversible P2Y12 inhibitor ticagrelor with the irreversible inhibitor clopidogrel, dyspnea was observed more frequently among ticagrelor-treated patients than among clopidogrel-treated patients. Because dyspnea was not associated with acidosis, pulmonary or cardiac dysfunction, alterations in the mechanisms and pathways of the sensation of dyspnea may be involved in its pathogenesis. It has been hypothesised that the sensation of dyspnea in ticagrelor-treated patients is triggered by adenosine, because ticagrelor inhibits its clearance, thereby increasing its concentration in the circulation. However, dipyridamole, a much stronger inhibitor of adenosine clearance than ticagrelor, usually does not cause dyspnea. We hypothesise that inhibition of P2Y12 on sensory neurons increases the sensation of dyspnea, particularly when reversible inhibitors are used. We base our hypothesis on the following considerations: 1) cangrelor and elinogrel, which, like ticagrelor, are reversible P2Y12 inhibitors, also increase the incidence of dyspnea; 2) it is biologically plausible that inhibition of P2Y12 on sensory neurons increases the sensation of dyspnea; 3) inhibition of P2Y12 on platelets (which do not have a nucleus) by clopidogrel is permanent, despite the once daily administration and the short plasma half-life of the inhibitor; 4) in contrast, inhibition of P2Y12 on neurons by clopidogrel may be temporary and transient, because neurons have a nucleus and can therefore rapidly replace the inhibited receptors with newly synthetised ones; 5) inhibition of P2Y12 on neurons by reversible inhibitors is permanent, because the plasma drug concentration is maintained high by repeated dosing, in order to ensure permanent inhibition of platelet P2Y12.

What is new for emergency physicians in the Heart Foundation's 2011 Addendum to its Guidelines for the management of acute coronary syndromes?

What is new for emergency physicians in the Heart Foundation's 2011 Addendum to its Guidelines for the management of acute coronary syndromes?

Antiplatelet Therapy After Percutaneous Coronary Intervention

Current guidelines recommend dual antiplatelet therapy (DAPT) that includes aspirin and the platelet P2Y12 ADP receptor antagonist clopidogrel after percutaneous coronary intervention (PCI). These recommendations are based on data that DAPT with the P2Y12 inhibitors clopidogrel reduces major adverse cardiac events after PCI in stable angina and acute coronary syndrome (ACS) patients when compared with aspirin, or aspirin in combination with warfarin.1 Despite treatment with DAPT, patients with ACS undergoing PCI are at elevated risk for recurrent ischemic events compared with stable angina patients in part because of increased platelet thrombotic activity in ACS. In addition, there is considerable interindividual variability in the degree of platelet inhibition achieved by clopidogrel, and high residual platelet activity in the setting of clopidogrel therapy (hyporesponsiveness) is associated with adverse cardiovascular (CV) events after PCI. Clopidogrel hyporesponsiveness is related to a variety of clinical and genetic factors that alter pharmacokinetics, and diabetes, congestive heart failure (CHF), and obesity are associated with reduced efficacy. Clopidogrel is a prodrug that requires conversion by the hepatic cytochrome P450 system (CYP) to an active metabolite, and it can take up to 6 hours for clopidogrel to have maximal effect after the loading dose. Genetic polymorphisms that reduce CYP activity result in decreased hepatic metabolism of clopidogrel. Among persons treated with clopidogrel, carriers of specific reduced function CYP2C19 alleles have impaired clopidogrel conversion, significantly lower levels of active metabolite, diminished platelet inhibition, and higher rates of adverse CV events and stent thrombosis after PCI.2 The prevalence of CYP2C19 polymorphisms ranges from 30% to 60% depending on ethnicity.2,3 Medications that inhibit CYP activity also reduce clopidogrel conversion, and some proton pump inhibitors (PPI) that reduce CYP function (eg, omeprazole) diminish clopidogrel metabolite levels and efficacy measured by platelet function testing. The interaction between clopidogrel and …

Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study

Variation in and irreversibility of platelet inhibition with clopidogrel has led to controversy about its optimum dose and timing of administration in patients with acute coronary syndromes. We compared ticagrelor, a more potent reversible P2Y12 inhibitor with clopidogrel in such patients. At randomisation, an invasive strategy was planned for 13 408 (72.0%) of 18 624 patients hospitalised for acute coronary syndromes (with or without ST elevation). In a double-blind, double-dummy study, patients were randomly assigned in a one-to-one ratio to ticagrelor and placebo (180 mg loading dose followed by 90 mg twice a day), or to clopidogrel and placebo (300-600 mg loading dose or continuation with maintenance dose followed by 75 mg per day) for 6-12 months. All patients were given aspirin. The primary composite endpoint was cardiovascular death, myocardial infarction, or stroke. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00391872. 6732 patients were assigned to ticagrelor and 6676 to clopidogrel. The primary composite endpoint occurred in fewer patients in the ticagrelor group than in the clopidogrel group (569 [event rate at 360 days 9.0%] vs 668 [10.7%], hazard ratio 0.84, 95% CI 0.75-0.94; p=0.0025). There was no difference between clopidogrel and ticagrelor groups in the rates of total major bleeding (691 [11.6%] vs 689 [11.5%], 0.99 [0.89-1.10]; p=0.8803) or severe bleeding, as defined according to the Global Use of Strategies To Open occluded coronary arteries, (198 [3.2%] vs 185 [2.9%], 0.91 [0.74-1.12]; p=0.3785). Ticagrelor seems to be a better option than clopidogrel for patients with acute coronary syndromes for whom an early invasive strategy is planned.

Abstract 5603: Oral Dosing of PRT060128, a Novel Direct-acting, Reversible P2Y 12 Antagonist Overcomes High Platelet Reactivity in Patients Non-responsive to Clopidogrel Therapy

Introduction: The ADP receptor P2Y 12 plays a central role in platelet function. Clopidogrel therapy is associated with various limitations including irreversible inhibition, a delayed antiplatelet effect, wide response variability, and non-responsiveness that has been linked to adverse ischemic event occurrence. We report the first pharmacodynamic study of a single oral dose of PRT060128 (PRT128), a novel, direct-acting reversible P2Y 12 inhibitor in patients with high platelet reactivity while on maintenance dose clopidogrel therapy(75mg/d) and aspirin. Methods: Previously stented patients (n=27) on maintenance aspirin and clopidogrel therapy were screened for high platelet reactivity (HPR) defined as upper tertile 5μ M ADP-induced aggregation (>43%) based on prior studies conducted at our Center; 7/27 had HPR and were treated with a single oral dose (60 mg) of PRT128. Platelet function was assessed at baseline, 4 hours, 6 hours, and 24 hours post-dosing by light transmittance aggregometry (LTA) stimulated by 5μ M, 20 μ M ADP, and 4μ g/ml collagen; Thrombelastography PlateletMapping (MA ADP ), Accumetrics P2Y12 assay (PRU), platelet reactivity ratio (%) by vasodilator stimulated phosphoprotein phosphorylation (VASP), and Perfusion Chamber Assay (PCA). Results: Results shown in the Table represent means ± standard deviation for the 7 patients at each time point. Conclusion: Based on results using multiple pharmacodynamic assays, PRT060128 is a potent rapid-acting inhibitor of P2Y 12 that overcomes high platelet reactivity in patients non-responsive to clopidogrel therapy. The pharmacodynamic properties of this novel P2Y 12 antagonist warrant future large scale investigations to determine clinical efficacy.

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.

Addresses at Opening of the Research Institute of the National Dental Association, 8803 Euclid Avenue, Cleveland, Ohio, February 7, 1916

Variation in and irreversibility of platelet inhibition with clopidogrel has led to controversy about its optimum dose and timing of administration in patients with acute coronary syndromes. We compared ticagrelor, a more potent reversible P2Y12 inhibitor with clopidogrel in such patients.At randomisation, an invasive strategy was planned for 13 408 (72·0%) of 18 624 patients hospitalised for acute coronary syndromes (with or without ST elevation). In a double-blind, double-dummy study, patients were randomly assigned in a one-to-one ratio to ticagrelor and placebo (180 mg loading dose followed by 90 mg twice a day), or to clopidogrel and placebo (300–600 mg loading dose or continuation with maintenance dose followed by 75 mg per day) for 6–12 months. All patients were given aspirin. The primary composite endpoint was cardiovascular death, myocardial infarction, or stroke. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00391872.6732 patients were assigned to ticagrelor and 6676 to clopidogrel. The primary composite endpoint occurred in fewer patients in the ticagrelor group than in the clopidogrel group (569 [event rate at 360 days 9·0%] vs 668 [10·7%], hazard ratio 0·84, 95% CI 0·75–0·94; p=0·0025). There was no difference between clopidogrel and ticagrelor groups in the rates of total major bleeding (691 [11·6%] vs 689 [11·5%], 0·99 [0·89–1·10]; p=0·8803) or severe bleeding, as defined according to the Global Use of Strategies To Open occluded coronary arteries, (198 [3·2%] vs 185 [2·9%], 0·91 [0·74–1·12]; p=0·3785).Ticagrelor seems to be a better option than clopidogrel for patients with acute coronary syndromes for whom an early invasive strategy is planned.AstraZeneca.