Defining platelet response to acetylsalicylic acid: the relation between inhibition of serum thromboxane B2 and agonist-induced platelet aggregation

Journal of Thrombosis and Thrombolysis - Arachidonic acid (AA)-induced platelet aggregation (PA) and serum thromboxane B2 (TxB2) inhibition are widely used to indicate cyclooxygenase-1 activity and...     

Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING Study.

OBJECTIVES: We investigated the relation of high ex vivo platelet reactivity, rapid fibrin generation, and high thrombin-induced clot strength to postdischarge ischemic events in patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: High platelet reactivity and rapid fibrin generation may affect the incidence of ischemic events after PCI. However, limited data is available to link these ex vivo markers to the occurrence of events. METHODS: We measured platelet reactivity to adenosine diphosphate (ADP) by light transmittance aggregometry (LTA) in patients undergoing PCI (n = 192). Clot strength, a measure of thrombin-induced fibrin and platelet interactions, and the time to initial fibrin generation, a marker of thrombin activity, were measured by thrombelastography. The relation of these measurements to ischemic event occurrence was prospectively examined over six months. RESULTS: A total of 100% and 84% of patients were on aspirin and clopidogrel therapy, respectively, at the time of the initial event. Posttreatment ADP-induced aggregation by LTA (63 +/- 12% vs. 56 +/- 15%, p = 0.02) and clot strength (MA) were higher (74 +/- 5 mm vs. 65 +/- 4 mm, p < 0.001) and time to initial fibrin generation was shorter (4.3 +/- 1.3 min vs. 5.9 +/- 1.5 min, p < 0.001) in patients with events (n = 38). The event rates in the highest quartiles of LTA and MA were 32% and 58%, respectively. CONCLUSIONS: High platelet reactivity and clot strength, and rapid fibrin formation are novel risk factors for ischemic events after PCI. Clot strength is more predictive than ADP-induced platelet aggregation and may explain the occurrence of events despite treatment with cyclooxygenase-1 and P2Y12 inhibitors.     

P2Y12 receptor inhibitors for secondary prevention of ischemic stroke

Introduction: Ischemic stroke (IS) is a major cause of death and disability worldwide. The P2Y₁₂ receptor plays a critical role in the formation of a stable thrombus leading to ischemic complications. Therefore, P2Y₁₂ receptor inhibitors constitute a major antiplatelet strategy in the secondary prevention of IS.

Areas covered: We searched articles about P2Y₁₂ receptor inhibitors and stroke in PubMed published until December 2014. This is a comprehensive review of the role of P2Y₁₂ receptor inhibitors alone and in combination with aspirin in the secondary prevention of noncardioembolic stroke.

Expert opinion: The potential benefit of more potent antiplatelet therapy for secondary stroke prevention must be weighed against the risk of bleeding in patients with IS. Short-term (≤ 3 months) dual antiplatelet therapy with clopidogrel and aspirin that is initiated early after IS or transient ischemic attack due to large artery atherosclerosis appears most efficient.     

Pharmacosimulation of delays and interruptions during administration of tirofiban: a systematic comparison between EU and US dosage regimens

Journal of Thrombosis and Thrombolysis - Tirofiban is a glycoproteine (GP) IIb/IIIa receptor antagonist, which inhibits platelet-platelet aggregation and is a potential adjunctive antithrombotic...     

Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes.

OBJECTIVES: In a substudy of DISPERSE (Dose confIrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in non-ST-segment Elevation myocardial infarction)-2, we compared the antiplatelet effects of AZD6140 and clopidogrel and assessed the effects of AZD6140 in clopidogrel-pretreated patients. BACKGROUND: Clopidogrel, in combination with aspirin, reduces cardiovascular events in patients with acute coronary syndromes (ACS). However, patients with poor inhibition of platelet aggregation with clopidogrel may be less well protected. AZD6140 is a reversible oral P2Y(12) receptor antagonist that has been studied in ACS patients in comparison with clopidogrel (DISPERSE-2 study). METHODS: Patients were randomized to receive either AZD6140 90 mg twice a day, AZD6140 180 mg twice a day, or clopidogrel 75 mg once a day for up to 12 weeks in a double-blind, double-dummy design. One-half the patients allocated AZD6140 received a 270-mg loading dose. Patients randomized to receive clopidogrel were given a 300-mg loading dose unless they had already been treated with clopidogrel. Adenosine diphosphate-induced platelet aggregation was assessed by optical aggregometry on day 1 and at 4-week intervals. RESULTS: AZD6140 inhibited platelet aggregation in a dose-dependent fashion and both doses achieved greater levels of inhibition than clopidogrel (e.g., 4 weeks, 4-h postdose [mean (+/-SD)]: clopidogrel 64% [+/-22%], AZD6140 90 mg 79% [+/-22%], AZD6140 180 mg 95% [+/-8%]. AZD6140 also produced further suppression of platelet aggregation in patients previously treated with clopidogrel. CONCLUSIONS: 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.     

Failure of clopidogrel to reduce platelet reactivity and activation following standard dosing in elective stenting: implications for thrombotic events and restenosis

There is no information on long-term platelet reactivity and activation following elective stenting in patients treated with clopidogrel and aspirin. We measured platelet reactivity and activation at baseline and at 2 h, 24 h, 5 days and 30 days following coronary stenting (n = 94). Patients were treated with the standard aspirin (325 mg) and clopidogrel regimen (300 mg load/75 mg qd). Reactivity was measured by aggregation (5 and 20 microM ADP) and activation was determined by the expression of total and active GP IIb/IIIa. Reactivity and activation were defined as heightened when post-stent aggregation and receptor expression exceeded baseline levels, respectively. Prolonged heightened platelet reactivity was detected by both 5 and 20 microM ADP aggregation. Using 20 microM ADP aggregation, heightened reactivity occurred in 55% of patients at 2 h, 26% at 24 h, 21% at 5 days, and 15% at 30 days post-stenting. A high frequency of heightened platelet activation was detected by both total and active GP IIb/IIIa expression. Using expression of the active GP IIb/IIIa receptor as the marker, activation was greater than baseline in 27% of patients at 2 h, 20% at 24 h, 30% at 5 days, and 22% at 30 days post-stenting. This is the first report demonstrating that a significant percentage of patients receiving standard clopidogrel and aspirin therapy for coronary stenting will have post-drug platelet reactivity and activation above baseline that persists for 30 days after the procedure. These finding suggest insufficient platelet inhibition. The clinical importance of these findings should be further investigated to establish the potential link between insufficient platelet inhibition, stent thrombosis, and restenosis.     

The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting

OBJECTIVES: We determined the effect of clopidogrel dosing on the incidence of nonresponsiveness (NR) and high post-treatment platelet aggregation (post-PA). BACKGROUND: We have reported NR after a 300-mg loading dose. Limited information is available on the comparative effect of a 600-mg loading dose on the incidence of NR and high post-PA. METHODS: Clopidogrel responsiveness and post-PA were measured in patients undergoing stenting (n = 190) randomly treated with either a 300-mg or a 600-mg clopidogrel load. Nonresponsiveness was defined as <10% absolute change in platelet aggregation, and high post-PA was defined as >75th percentile aggregation after 300 mg clopidogrel. RESULTS: Nonresponsiveness was lower after 600 mg compared to the 300-mg dose (8% vs. 28% and 8% vs. 32% with 5 and 20 microM ADP, respectively, p < 0.001). Among the patients with high post-PA after 300 mg clopidogrel, 62% to 65% had NR, whereas after the 600-mg dose, all of the patients with high post-PA had NR. CONCLUSIONS: A 600-mg clopidogrel loading dose reduces the incidence of NR and high post-PA as compared to a 300-mg dose. Higher dosing strategies and methods to confirm platelet inhibition should be further investigated in order to optimally use clopidogrel in patients undergoing stenting.