Inhibition of Platelet Aggregation by AZD6140, A Reversible Oral P2Y12Receptor Antagonist, Compared With Clopidogrel in Patients With Acute Coronary Syndromes

Storey, Robert F.; Husted, Steen; Harrington, Robert A.; Heptinstall, S; Wilcox, Robert G.; Peters, Gary; Wickens, Mark; Emanuelsson, Håkan; Gurbel, Paul A.; Grande, Peer; Cannon, Christopher P.

doi:10.1016/j.jacc.2007.07.058

Cited by 451 publications

(342 citation statements)

References 14 publications

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“…The differences in baseline characteristics were somewhat unexpected, as the drugs do not greatly differ from each other in terms of platelet inhibition. With the current approved maintenance dosing for both drugs, adequate levels of platelet inhibition 18 are achieved in over 90% of patients 11, 17, 19, 20, 21, 22.…”

Section: Discussionmentioning

confidence: 99%

“Real‐World” Comparison of Prasugrel With Ticagrelor in Patients With Acute Coronary Syndrome Treated With Percutaneous Coronary Intervention in the United States

Larmore

Effron

Molife

et al. 2015

Cathet Cardio Intervent

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ObjectivesThe 30‐day clinical outcomes with prasugrel or ticagrelor were compared using a US payer database in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI).BackgroundPrasugrel and ticagrelor demonstrated superior efficacy with increased non‐coronary artery bypass graft major bleeding compared with clopidogrel in randomized clinical trials. No direct randomized or observational studies have compared clinical outcomes between prasugrel and ticagrelor.MethodsPatients hospitalized for ACS‐PCI between August 1, 2011 and April 30, 2013 and prescribed prasugrel or ticagrelor were selected. Drug treatment cohorts were propensity matched based upon demographic and clinical characteristics. The primary objective compared 30‐day net adverse clinical events (NACE) in prasugrel‐ and ticagrelor‐treated patients using a prespecified 20% noninferiority margin. Secondary objectives included comparisons of major adverse cardiovascular events (MACE) and major bleeding.ResultsData were available for 16,098 patients (prasugrel, n = 13,134; ticagrelor, n = 2,964). In unmatched cohorts, prasugrel‐treated patients were younger with fewer comorbidities than ticagrelor‐treated patients, and 30‐day NACE rates were 5.6 and 9.3%, respectively (P < 0.001). Following propensity matching, NACE was noninferior (P < 0.001) and 22% lower in prasugrel‐treated than in ticagrelor‐treated patients (RR, 0.78; 95% CI, 0.64–0.94). A 30‐day adjusted MACE (RR, 0.80; 95% CI, 0.64–0.98) and major bleeding (RR, 0.65; 95% CI, 0.45–0.95) were also lower in prasugrel‐treated patients compared with ticagrelor‐treated patients.ConclusionsIn this “real‐world,” retrospective, observational study, physicians appear to preferentially use prasugrel in younger patients with lower risk of bleeding or comorbidities compared with ticagrelor. Following adjustment, clinical outcomes associated with prasugrel use appear as good, if not better, than those associated with ticagrelor in ACS‐PCI patients. © 2015 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

“Real‐World” Comparison of Prasugrel With Ticagrelor in Patients With Acute Coronary Syndrome Treated With Percutaneous Coronary Intervention in the United States

Larmore

Effron

Molife

et al. 2015

Cathet Cardio Intervent

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“…17/39 (44%) and 19/37 (51%) of patients in the twice-daily 100 and 200 mg ticagrelor groups, respectively16. In patients with ACS, a similar 277% increase in ticagrelor exposure at week 4 was reported in those receiving 180 mg ticagrelor twice daily compared with 90 mg twice daily (mean AUC ± SD, 90 mg twice daily: 4762 ± 2443 ng·h/mL; 180 mg twice daily: 13,198 ± 4982 ng·h/mL), which was associated with a dose-dependent increase in IPA17. Total bleeding events in these patients with ACS were comparable between the two treatment groups: number of events (Kaplan–Meier event rates) 90 mg twice daily: 32 (9.8) and 180 mg twice daily: 25 (8.0) through week 4; and 90 mg twice daily: 34 (10.9) and 180 mg twice daily: 33 (11.4) through week 1231.…”

Section: Discussionmentioning

confidence: 73%

Effect of the CYP3A inhibitors, diltiazem and ketoconazole, on ticagrelor pharmacokinetics in healthy volunteers

Teng

Butler

2013

Journal of Drug Assessment

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ObjectivesTwo open-label, two-period, crossover studies in healthy volunteers were designed to determine the pharmacokinetic interactions between ticagrelor, a P2Y12 receptor antagonist, and a moderate (diltiazem) and a strong (ketoconazole) cytochrome P450 (CYP) 3A inhibitor.MethodsSeventeen volunteers received diltiazem (240 mg once daily) for 14 days. In the second study, ketoconazole (n = 14) 200 mg twice daily was given for 10 days. A single oral 90-mg ticagrelor dose was administered on day 8 (diltiazem) or day 4 (ketoconazole). In each study, volunteers received a single 90-mg oral dose of ticagrelor before or after washout (≥14 days). Pharmacokinetic parameters for ticagrelor, AR-C124910XX (primary metabolite), diltiazem, and ketoconazole were assessed.ResultsCompared with ticagrelor alone, diltiazem co-administration significantly increased the mean maximum concentration (Cmax) and mean area under the plasma concentration–time curve (AUC) for ticagrelor by 69% and 174%, respectively. Diltiazem co-administration reduced Cmax by 38% but had no significant effect on AUC for AR-C124910XX. Cmax and AUC for ticagrelor were increased by 135% and 632%, respectively, by ketoconazole co-administration, whereas these parameters were reduced by 89% and 56%, respectively, for AR-C124910XX. Diltiazem and ketoconazole pharmacokinetic parameters were not significantly affected by the presence of ticagrelor.ConclusionsThese results suggest that ticagrelor can be co-administered with moderate CYP3A inhibitors. However, co-administration of strong CYP3A inhibitors with ticagrelor is not recommended.

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“…It is an orally active drug that binds reversibly to P2Y 12 , with a stronger and more rapid anti-platelet effect than clopidogrel. 21,22 The PLATO study showed that as compared to clopidogrel, ticagrelor was associated with a 16% relative risk reduction with regard to the primary end point-a composite of death from cardiovascular causes, myocardial infarction and stroke-but no significant increase in the overall risk of major bleeding. 23 The recommended dose is 180-mg loading dose, then 90 mg twice daily.…”

Section: Ticagrelormentioning

confidence: 99%

Platelet adenosine diphosphate receptor antagonists: ticlopidine to ticagrelor—a long continuing journey

Kaul

Mansoor

2012

Indian Heart Journal

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Platelet aggregation plays a central role in the pathogenesis of atherothrombosis. Platelet adenosine diphosphate (ADP) receptor antagonists (ticlopidine, clopidogrel, prasugrel, and ticagrelor) are a major advance in the treatment of atherothrombotic diseases, especially acute coronary syndromes (ACS). Ticlopidine was the first thienopyridine introduced into clinical practice, but its potentially serious haematological side-effects limited its use and it was quickly eclipsed by clopidogrel. Clinical trials established aspirin plus clopidogrel as the standard dual anti-platelet therapy in patients with ACS and patients undergoing percutaneous coronary intervention (PCI) with stenting. Clopidogrel was found to have pharmacokinetic and pharmacodynamic limitations. Prasugrel is the next approved thienopyridine that has shown superior efficacy in ACS patients undergoing PCI in comparison to clopidogrel, although at the cost of a higher bleeding risk. Ticagrelor is the latest non-thienopyridine ADP receptor blocker that is potent, effective, reversible, and relatively safer as compared to clopidogrel.Both prasugrel and ticagrelor are more potent than clopidogrel. The data so far suggests that ticagrelor has a wider applicability in usage in patients with ACS as compared to prasugrel. Prasugrel however seems to be better tolerated. Search is on for newer more potent but safer anti-platelet agents.

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Inhibition of Platelet Aggregation by AZD6140, A Reversible Oral P2Y12Receptor Antagonist, Compared With Clopidogrel in Patients With Acute Coronary Syndromes

Abstract: AZD6140 exhibited greater mean inhibition of platelet aggregation than a standard regimen of clopidogrel in ACS patients. In addition, AZD6140 further suppressed platelet aggregation in clopidogrel pretreated patients.

Cited by 451 publications

References 14 publications

“Real‐World” Comparison of Prasugrel With Ticagrelor in Patients With Acute Coronary Syndrome Treated With Percutaneous Coronary Intervention in the United States

“Real‐World” Comparison of Prasugrel With Ticagrelor in Patients With Acute Coronary Syndrome Treated With Percutaneous Coronary Intervention in the United States

Effect of the CYP3A inhibitors, diltiazem and ketoconazole, on ticagrelor pharmacokinetics in healthy volunteers

Platelet adenosine diphosphate receptor antagonists: ticlopidine to ticagrelor—a long continuing journey

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