Background: A substantial proportion of patients receiving fibrinolytic therapy for myocardial infarction with ST-segment elevation have inadequate reperfusion or reocclusion of the infarct-related artery, leading to an increased risk of complications and death. Methods: We enrolled 3491 patients, 18 to 75 years of age, who presented within 12 hours after the onset of an ST-elevation myocardial infarction and randomly assigned them to receive clopidogrel 8300-mg loading dose, followed by 75 mg once daily) or placebo. Patients received a fibrinolytic agent, aspirin, and when appropriate, heparin (dispensed according to body weight) and were echeduled to undergo angiography 48 to 192 hours after the start of study medication. The primary efficacy end point was a composite of an ocluded infarct-related artery (defined by a Thrombolysus in Myocardial Infarction flow grade of 0 or 1) on angiography or death or recurrent myocardial infarction before angiography. Results: The rates of the primary efficacy end point were 21.7 percent in the placebo group and 15.0 percent in the clopidogrel group, representing an absolute reduction of 6.7 percentage points in the rate and a 36 percent reduction in the odds of the end point with clopidogrel therapy (95 percent confidence interval, 24 to 47 percent; P<0.001). By 30 days, clopidogrel therapy reduced the odds ol the composite end point of death from cardiovascular causes, recurrent myocardial infarction, or recurrent ischemia leading to the need for urgent revascularization by 20 percent (from 14.1 to 11.6 percent, P=0.03). The rates of major bleeding and intracranial hemorrhage were similar in the two groups. Conclusions: In patients 75 years of age or younger who have myocardial infarction with ST-segment elevation and who receive aspirin and a standard fibrinolytic regimen, the addition of clopidogrel improves the patency rate of the infarct-related artery and reduces ischemic complications.

Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation

Consensus and Future Directions on the Definition of High On-Treatment Platelet Reactivity to Adenosine Diphosphate

Background— Ticagrelor is the first reversibly binding oral P2Y 12 receptor antagonist. This is the first study to compare the onset and offset of platelet inhibition (IPA) with ticagrelor using the PLATO (PLATelet inhibition and patient Outcomes) trial loading dose (180 mg) with a high loading dose (600 mg) of clopidogrel. Methods and Results— In a multicenter, randomized, double-blind study, 123 patients with stable coronary artery disease who were taking aspirin therapy (75 to 100 mg/d) received ticagrelor (180-mg load, 90-mg BID maintenance dose [n=57]), clopidogrel (600-mg load, 75-mg/d maintenance dose [n=54]), or placebo (n=12) for 6 weeks. Greater IPA (20 μmol/L ADP, final extent) occurred with ticagrelor than with clopidogrel at 0.5, 1, 2, 4, 8, and 24 hours after loading and at 6 weeks ( P 50% IPA (98% versus 31%, P 70% IPA (90% versus 16%, P P P =NS). IPA for ticagrelor on day 3 after the last dose was comparable to clopidogrel at day 5; IPA on day 5 for ticagrelor was similar to clopidogrel on day 7 and did not differ from placebo ( P =NS). Conclusions— Ticagrelor achieved more rapid and greater platelet inhibition than high-loading-dose clopidogrel; this was sustained during the maintenance phase and was faster in offset after drug discontinuation. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00528411.

Randomized Double-Blind Assessment of the ONSET and OFFSET of the Antiplatelet Effects of Ticagrelor Versus Clopidogrel in Patients With Stable Coronary Artery Disease The ONSET/OFFSET Study

Adjusted Clopidogrel Loading Doses According to Vasodilator-Stimulated Phosphoprotein Phosphorylation Index Decrease Rate of Major Adverse Cardiovascular Events in Patients With Clopidogrel Resistance A Multicenter Randomized Prospective Study

Platelet function monitoring in patients with coronary artery disease

Background— The antiplatelet effect of aspirin is attributed to platelet cyclooxygenase-1 inhibition. Controversy exists on the prevalence of platelet resistance to aspirin in patients with coronary artery disease and effects of aspirin dose on inhibition. Our primary aim was to determine the degree of platelet aspirin responsiveness in patients, as measured by commonly used methods, and to study the relation of aspirin dose to platelet inhibition. Methods and Results— We prospectively studied the effect of aspirin dosing on platelet function in 125 stable outpatients with coronary artery disease randomized in a double-blind, double-crossover investigation (81, 162, and 325 mg/d for 4 weeks each over a 12-week period). At all doses of aspirin, platelet function was low as indicated by arachidonic acid (AA)-induced light transmittance aggregation, thrombelastography, and VerifyNow. At any 1 dose, resistance to aspirin was 0% to 6% in the overall group when AA was used as the agonist, whereas it was 1% to 2...

Evaluation of Dose-Related Effects of Aspirin on Platelet Function Results From the Aspirin-Induced Platelet Effect (ASPECT) Study

Dr Klein appears concerned about the uniform inhibition of arachidonic acid–induced aggregation observed in the Aspirin-Induced Platelet Effect (ASPECT) trial. We would like to reassure Dr Klein that the compliance of the patients in ASPECT was meticulously recorded and, as reported in the manuscript, was overall 98%. Dr Klein should also be aware of the significance of results determined by double crossover studies such as the ASPECT study and the robust statistical analyses performed.1

Why were we not surprised by the results of the ASPECT study? In a previous study of 223 patients undergoing stenting who were treated with long-term aspirin therapy, only 1 compliant patient was …

Response to the Letter Regarding Article, “Evaluation of Dose-Related Effects of Aspirin on Platelet Function: Results From the Aspirin-Induced Platelet Effect (ASPECT) Study”

Assessment of clopidogrel responsiveness: measurements of maximum platelet aggregation, final platelet aggregation and their correlation with vasodilator-stimulated phosphoprotein in resistant patients.

Pharmacological management of thrombotic complications is strongly influenced by antiplatelet treatment strategies. Recent clinical trials have clearly indicated that current antiplatelet strategies may not inhibit recurrent thrombotic events in selected patients and improvement is necessary. Recently, there has been a gradual modification in the guidelines for clopidogrel dosing. In addition, newly developed P2Y12 receptor inhibitors and thrombin inhibitors are undergoing Phase II and III clinical trials. Moreover, research related to novel agents that interfere with other steps in coagulation and platelet adhesion, and platelet thromboxane and thrombin receptor blockers, show promise. An important future step will probably be the development of personalized therapy based on defining the individual patient’s propensity for thrombosis through investigation of platelet–thrombin–fibrin interactions. Such an approach will enhance the targeting of specific therapy based on the pathophysiology of the individua...

Amena Etherington

Papers

Evaluation of Dose-Related Effects of Aspirin on Platelet Function Results From the Aspirin-Induced Platelet Effect (ASPECT) Study

Response to the Letter Regarding Article, “Evaluation of Dose-Related Effects of Aspirin on Platelet Function: Results From the Aspirin-Induced Platelet Effect (ASPECT) Study”

Assessment of clopidogrel responsiveness: measurements of maximum platelet aggregation, final platelet aggregation and their correlation with vasodilator-stimulated phosphoprotein in resistant patients.

Antiplatelet therapy: current strategies and future trends.