UK), Ernst E. van der Wall (Netherlands), Christiaan J.M. Vrints (Belgium).

No 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.

Background-The antiplatelet effects of the Platelet Inhibition and Patient Outcomes (PLATO) trial dose of ticagrelor in patients nonresponsive to clopidogrel and after they switch agents are unknown. Methods and Results-Patients with stable coronary artery disease on aspirin therapy received a 300-mg clopidogrel load; nonresponders were identified by light transmittance aggregometry. In a 2-way crossover design, nonresponders (nϭ41) and responders (nϭ57) randomly received clopidogrel (600 mg/75 mg once daily) or ticagrelor (180 mg/90 mg twice daily) for 14 days during period 1. In period 2, all nonresponders switched treatment; half of the responders continued the same treatment, whereas the others switched treatment. Inhibition of platelet aggregation was higher in nonresponders treated with ticagrelor compared with clopidogrel (PϽ0.05). Treatment with ticagrelor among nonresponders resulted in a Ͼ10%, Ͼ30%, and Ͼ50% decrease in platelet aggregation from baseline in 100%, 75%, and 13% of patients, respectively. Platelet aggregation fell from 59Ϯ9% to 35Ϯ11% in patients switched from clopidogrel to ticagrelor and increased from 36Ϯ14% to 56Ϯ9% in patients switched from ticagrelor to clopidogrel (PϽ0.0001 for both). Platelet reactivity was below the cut points previously associated with ischemic risk measured by light transmittance aggregometry, VerifyNow P2Y 12 assay, and vasodilator-stimulated phosphoprotein phosphorylation in 98% to 100% of patients after ticagrelor therapy versus 44% to 76% of patients after clopidogrel therapy. Conclusions-Ticagrelor therapy overcomes nonresponsiveness to clopidogrel, and its antiplatelet effect is the same in responders and nonresponders. Nearly all clopidogrel nonresponders and responders treated with ticagrelor will have platelet reactivity below the cut points associated with ischemic risk. Clinical Trial Registration-http://www.clinicaltrials.gov.

Ticagrelor achieves greater antiplatelet effect than clopidogrel in patients with acute coronary syndromes, both in the first hours of treatment and during maintenance therapy.

No abstract

BackgroundElevated lipoprotein-associated phospholipase A 2 activity promotes the development of vulnerable atherosclerotic plaques, and elevated plasma levels of this enzyme are associated with an increased risk of coronary events. Darapladib is a selective oral inhibitor of lipoprotein-associated phospholipase A 2 . MethodsIn a double-blind trial, we randomly assigned 15,828 patients with stable coronary heart disease to receive either once-daily darapladib (at a dose of 160 mg) or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the components of the primary end point as well as major coronary events (death from coronary heart disease, myocardial infarction, or urgent coronary revascularization for myocardial ischemia) and total coronary events (death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization). ResultsDuring a median follow-up period of 3.7 years, the primary end point occurred in 769 of 7924 patients (9.7%) in the darapladib group and 819 of 7904 patients (10.4%) in the placebo group (hazard ratio in the darapladib group, 0.94; 95% confidence interval [CI], 0.85 to 1.03; P = 0.20). There were also no significant between-group differences in the rates of the individual components of the primary end point or in all-cause mortality. Darapladib, as compared with placebo, reduced the rate of major coronary events (9.3% vs. 10.3%; hazard ratio, 0.90; 95% CI, 0.82 to 1.00; P = 0.045) and total coronary events (14.6% vs. 16.1%; hazard ratio, 0.91; 95% CI, 0.84 to 0.98; P = 0.02). ConclusionsIn patients with stable coronary heart disease, darapladib did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction, or stroke. (Funded by GlaxoSmithKline; STABILITY ClinicalTrials.gov number, NCT00799903.)The Darapladib is a potent and reversible oral inhibitor of lipoprotein-associated phospholipase A 2 . 10 In a swine model of atherosclerosis, darapladib reduced levels of lipoprotein-associated phospholipase A 2 in plaque, reduced the necrotic core area, and inhibited the development of lesions in coronary arteries. 11 Darapladib has also been shown to reduce lipoprotein-associated phospholipase A 2 activity in human carotid plaque. 12 In the Integrated Biomarker and Imaging Study 2 (IBIS-2) involving patients with coronary heart disease, darapladib, as compared with placebo, halted the progression in the volume of the necrotic core of coronary-artery plaques (a secondary end point), as determined by intravascular ultrasonographic virtual histologic analysis during a 12-month period. 13 These findings suggest that darapladib could reduce the risk of events associated with coronary heart disease by altering the composition of atherosclerotic plaques to a less vulnerable state. 1 In the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial, we evaluated the clini...

Objective To evaluate efficacy and safety outcomes in patients in the PLATelet inhibition and patient Outcomes (PLATO) trial who at randomisation were planned for a non-invasive treatment strategy.Design Pre-specified analysis of pre-randomisation defined subgroup of prospective randomised clinical trial.Setting 862 centres in 43 countries.Participants 5216 (28%) of 18 624 patients admitted to hospital for acute coronary syndrome who were specified as planned for non-invasive management.Interventions Randomised treatment with ticagrelor (n=2601) versus clopidogrel (2615).Main outcome measurements Primary composite end point of cardiovascular death, myocardial infarction, and stroke; their individual components; and PLATO defined major bleeding during one year.Results 2183 (41.9%) patients had coronary angiography during their initial hospital admission, 1065 (20.4%) had percutaneous coronary intervention, and 208 (4.0%) had coronary artery bypass surgery. Cumulatively, 3143 (60.3%) patients had been managed non-invasively by the end of follow-up. The incidence of the primary end point was lower with ticagrelor than with clopidogrel (12.0% (n=295) v 14.3% (346); hazard ratio 0.85, 95% confidence interval 0.73 to 1.00; P=0.04). Overall mortality was also lower (6.1% (147) v 8.2% (195); 0.75, 0.61 to 0.93; P=0.01). The incidence of total major bleeding (11.9% (272) v 10.3% (238); 1.17, 0.98 to 1.39; P=0.08) and non-coronary artery bypass grafting related major bleeding (4.0% (90) v 3.1% (71); 1.30, 0.95 to 1.77; P=0.10) was numerically higher with ticagrelor than with clopidogrel.Conclusions In patients with acute coronary syndrome initially intended for non-invasive management, the benefits of ticagrelor over clopidogrel were consistent with those from the overall PLATO results, indicating the broad benefits of P2Y12 inhibition with ticagrelor regardless of intended management strategy.Trial registration Clinical trials NCT00391872.