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

Cannon, Christopher P.; Husted, Steen; Harrington, Robert A.; Scirica, Benjamin M.; Emanuelsson, Håkan; Peters, Gary; Storey, Robert F.

doi:10.1016/j.jacc.2007.07.053

Cited by 484 publications

(407 citation statements)

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“…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. Collectively, these data indicate that the magnitude of increase in ticagrelor exposure seen with a moderate CYP3A inhibitor is unlikely to result in significant bleeding events.…”

Section: Discussionmentioning

confidence: 85%

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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Section: Discussionmentioning

confidence: 85%

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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“…28 A total of 990 patients were randomized to treatment; after randomization, 984 patients received at least 1 dose of study drug. Baseline characteristics were similar among treatment groups and between the treated patients and all randomized patients ( Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…26 In patients with stable coronary artery disease, clopidogrel compared with placebo had no effect on CRP but significantly decreased the platelet release of sCD40L. 27 Therefore, the objective of this analysis from the Dose Confirmation Study Assessing Anti-Platelet Effects of AZD6140 vs Clopidogrel in NSTEMI 2 (DISPERSE 2) trial 28 was to compare ticagrelor plus acetylsalicylic acid with clopidogrel plus acetylsalicylic acid for effects on the inflammatory biomarkers CRP, sCD40L, MPO, and IL-6 in patients with NSTE-ACS.…”

Section: Introductionmentioning

confidence: 99%

Changes in Inflammatory Biomarkers in Patients Treated With Ticagrelor or Clopidogrel

Husted

Storey

Harrington

et al. 2010

Clinical Cardiology

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Background: Inflammation is a key factor in the development of atherosclerotic disease and acute coronary syndromes (ACS). The P2Y 12 receptor antagonists ticagrelor (AZD6140) and clopidogrel may have antiinflammatory effects. The objective of this analysis from the Dose Confirmation Study Assessing Anti-Platelet Effects of AZD6140 vs Clopidogrel in NSTEMI 2 (DISPERSE 2) trial was to compare ticagrelor and clopidogrel for effects on the inflammatory biomarkers C-reactive protein (CRP), interleukin 6 (IL-6), myeloperoxidase (MPO), and soluble CD40 ligand (sCD40L). Hypothesis: Ticagrelor inhibits the P2Y 12 receptor and inflammation to a greater extent than clopidogrel in nonST-segment elevation ACS (NSTE-ACS) patients. Methods: In a double-blind, double-dummy, multicenter trial, 990 patients who had been hospitalized within the previous 48 hours with NSTE-ACS were randomized to receive ticagrelor 90 mg twice daily, ticagrelor 180 mg twice daily, or clopidogrel 300 mg initially and then 75 mg once daily. Within the ticagrelor groups, patients were also randomized to receive or not receive a loading dose of ticagrelor 270 mg initially. All patients received standard treatment for ACS, which included 325 mg aspirin initially and 75 to 100 mg aspirin each day subsequently. Inflammatory biomarkers were measured at baseline, upon hospital discharge, and after 4 weeks. Results: Inflammatory biomarker measurements were not significantly different among treatment groups at baseline, discharge, and 4 weeks. Conclusions: Ticagrelor and clopidogrel appeared not to differ in this study with respect to the inflammatory biomarkers CRP, IL-6, MPO, and sCD40L in patients with NSTE-ACS.

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“…Based on safety and efficacy profile ticagrelor 90 mg bd was selected for phase III study. 19 OnseteOffset study illustrated that IPA with ticagrelor 180 mg loading dose was greater than clopidogrel 600 mg loading dose at all the time points. Just 30 min post loading, IPA with ticagrelor was 41% versus 8% in clopidogrel group.…”

Section: Ticagrelor: Clinical Developmentmentioning

confidence: 94%

Ticagrelor: molecular discovery to clinical evidence

Sinha

2012

Indian Heart Journal

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1.Acute coronary syndrome e global and Indian perspective Cardiovascular death (CVD) is one of the leading causes in the non-communicable disease (NCD) deaths. According to WHO estimates around 17 million people die of CVD each year, 1 out of which coronary heart disease (CHD) accounts for 7.1 million deaths. Developing countries like India are witnessing economic transition, urbanization and industrialization resulting in major lifestyle changes like increased tobacco use, physical inactivity and unhealthy diet, that has lead to a dramatic increase in CVD and CHD. 2 In Indian context, there are many challenges in managing patients of ACS. ACS patients in India die younger and sicker with average age at 57 years, almost 10e15 years younger than in west. Moreover, they carry high risk factor profile that includes Diabetes, Hypertension, Smoking and Dyslipidemia and close to 20% patients suffer from a 2nd heart attack in India. 3 As per CREATE registry 60% of patients in India were of STEMI whereas as per global registry data 40% patients were of STEMI. This implies that patients admitted to Indian hospitals with acute coronary syndromes are likely to have a worse prognosis than those in developed countries. In spite of being at high risk, in India, <10% ACS patients are managed through PCI with less than 15% receiving DAPT. 3 Experience in the developed world has shown that significant reductions in CAD prevalence and mortality can be

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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

Cited by 484 publications

References 20 publications

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

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

Changes in Inflammatory Biomarkers in Patients Treated With Ticagrelor or Clopidogrel

Ticagrelor: molecular discovery to clinical evidence

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