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

Husted, Steen; Emanuelsson, Håkan; Heptinstall, Stan; Sandset, Per Morten; Wickens, Mark; Peters, Gary

doi:10.1093/eurheartj/ehi754

Cited by 684 publications

(582 citation statements)

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“…Indeed, clopidogrel typically achieves a maximum of only 50% platelet inhibition in combination with aspirin in acute coronary syndromes compared with ≈90% with prasugrel and aspirin26 and ≈94% with ticagrelor and aspirin 27. This remains the case even when the larger 600‐mg clopidogrel loading dose is administered 22, 25.…”

Section: Discussionmentioning

confidence: 99%

Infarct Size Following Treatment With Second‐ Versus Third‐Generation P2Y ₁₂ Antagonists in Patients With Multivessel Coronary Disease at ST‐Segment Elevation Myocardial Infarction in the CvLPRIT Study

Khan

Greenwood

Nazir

et al. 2016

JAHA

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BackgroundThird‐generation P2Y12 antagonists (prasugrel and ticagrelor) are recommended in guidelines on ST‐segment elevation myocardial infarction. Mechanisms translating their more potent antiplatelet activity into improved clinical outcomes versus the second‐generation P2Y12 antagonist clopidogrel are unclear. The aim of this post hoc analysis of the Complete Versus Lesion‐Only PRImary PCI Trial‐CMR (CvLPRIT‐CMR) substudy was to assess whether prasugrel and ticagrelor were associated with reduced infarct size compared with clopidogrel in patients undergoing primary percutaneous coronary intervention.Methods and ResultsCvLPRIT‐CMR was a multicenter, prospective, randomized, open‐label, blinded end point trial in 203 ST‐segment elevation myocardial infarction patients with multivessel disease undergoing primary percutaneous coronary intervention with either infarct‐related artery–only or complete revascularization. P2Y12 inhibitors were administered according to local guidelines. The primary end point of infarct size on cardiovascular magnetic resonance was not significantly different between the randomized groups. P2Y12 antagonist administration was not randomized. Patients receiving clopidogrel (n=70) compared with those treated with either prasugrel or ticagrelor (n=133) were older (67.8±12 versus 61.5±10 years, P<0.001), more frequently had hypertension (49% versus 29%, P=0.007), and tended to have longer symptom‐to‐revascularization time (234 versus 177 minutes, P=0.05). Infarct size (median 16.1% [quartiles 1–3, 10.5–27.7%] versus 12.1% [quartiles 1–3, 4.8–20.7%] of left ventricular mass, P=0.013) and microvascular obstruction incidence (65.7% versus 48.9%, P=0.022) were significantly greater in patients receiving clopidogrel. Infarct size remained significantly different after adjustment for important covariates using both generalized linear models (P=0.048) and propensity score matching (P=0.025).ConclusionsIn this analysis of CvLPRIT‐CMR, third‐generation P2Y12 antagonists were associated with smaller infarct size and lower microvascular obstruction incidence versus the second‐generation P2Y12 antagonist clopidogrel for ST‐segment elevation myocardial infarction.Clinical Trial Registration URL: http://www.isrctn.com/ISRCTN70913605.

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Section: Discussionmentioning

confidence: 99%

Infarct Size Following Treatment With Second‐ Versus Third‐Generation P2Y ₁₂ Antagonists in Patients With Multivessel Coronary Disease at ST‐Segment Elevation Myocardial Infarction in the CvLPRIT Study

Khan

Greenwood

Nazir

et al. 2016

JAHA

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“…17 We aimed to investigate the safety of this novel dual pathway antithrombotic regimen using clinically significant bleeding as a measure of antithrombotic therapy potency. 18,19 …”

Section: Introductionmentioning

confidence: 99%

Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial

et al. 2017

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SummaryBackground Dual antiplatelet therapy (DAPT), aspirin plus a P2Y12 inhibitor, is the standard antithrombotic treatment following acute coronary syndromes. The factor Xa inhibitor rivaroxaban reduced mortality and ischaemic events when added to DAPT, but caused increased bleeding. The safety of a dual pathway antithrombotic therapy approach combining low-dose rivaroxaban (in place of aspirin) with a P2Y12 inhibitor has not been assesssed in acute coronary syndromes. We aimed to assess rivaroxaban 2·5 mg twice daily versus aspirin 100 mg daily, in addition to clopidogrel or ticagrelor (chosen at investigator discretion before randomisation), for patients with acute coronary syndromes started within 10 days after presentation and continued for 6-12 months.

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“…a 283% increase in exposure compared with a dose similar to the recommended dose of ticagrelor16. This almost 3-fold increase in exposure to ticagrelor was only associated with a slight increase in minor bleeding events, i.e.…”

Section: Discussionmentioning

confidence: 89%

“…This almost 3-fold increase in exposure to ticagrelor was only associated with a slight increase in minor bleeding events, i.e. 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.…”

Section: Discussionmentioning

confidence: 90%

“…Ticagrelor is an oral P2Y 12 receptor antagonist that inhibits adenosine diphosphate-induced platelet aggregation1. Results from the PLATelet inhibition and patient Outcomes (PLATO) phase III trial showed that, compared with clopidogrel + aspirin, ticagrelor + aspirin significantly reduced the rate of myocardial infarction/stroke/death from vascular causes in patients with acute coronary syndromes (ACS)2.…”

Section: Introductionmentioning

confidence: 99%

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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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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

Abstract: AZD6140 100 and 200 mg bid were well tolerated and were superior to AZD6140 50 mg bid and clopidogrel 75 mg qd with regard to antiplatelet efficacy.

Cited by 684 publications

References 19 publications

Infarct Size Following Treatment With Second‐ Versus Third‐Generation P2Y ₁₂ Antagonists in Patients With Multivessel Coronary Disease at ST‐Segment Elevation Myocardial Infarction in the CvLPRIT Study

Infarct Size Following Treatment With Second‐ Versus Third‐Generation P2Y ₁₂ Antagonists in Patients With Multivessel Coronary Disease at ST‐Segment Elevation Myocardial Infarction in the CvLPRIT Study

Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial

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

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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

Abstract: AZD6140 100 and 200 mg bid were well tolerated and were superior to AZD6140 50 mg bid and clopidogrel 75 mg qd with regard to antiplatelet efficacy.

Cited by 684 publications

References 19 publications

Infarct Size Following Treatment With Second‐ Versus Third‐Generation P2Y 12 Antagonists in Patients With Multivessel Coronary Disease at ST‐Segment Elevation Myocardial Infarction in the CvLPRIT Study

Infarct Size Following Treatment With Second‐ Versus Third‐Generation P2Y 12 Antagonists in Patients With Multivessel Coronary Disease at ST‐Segment Elevation Myocardial Infarction in the CvLPRIT Study

Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial

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

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Product

Resources

About

Infarct Size Following Treatment With Second‐ Versus Third‐Generation P2Y ₁₂ Antagonists in Patients With Multivessel Coronary Disease at ST‐Segment Elevation Myocardial Infarction in the CvLPRIT Study

Infarct Size Following Treatment With Second‐ Versus Third‐Generation P2Y ₁₂ Antagonists in Patients With Multivessel Coronary Disease at ST‐Segment Elevation Myocardial Infarction in the CvLPRIT Study