Enhanced antiplatelet effect of clopidogrel in patients whose platelets are least inhibited by aspirin: a randomized crossover trial

Eikelboom, John W.; Hankey, Graeme J.; Thom, Jim; Claxton, Anne; Yi, Qilong; Gilmore, Grace; Staton, Janelle; Barden, Anne; Norman, Paul

doi:10.1111/j.1538-7836.2005.01640.x

Cited by 48 publications

(40 citation statements)

References 32 publications

(33 reference statements)

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“…These findings parallel those reported in the literature. 16,17 As expected, neither SCH 602539 nor cangrelor (nor the combination of the 2) had any notable effect on coagulation parameters, a finding that is consistent with the fact that these agents interact with specific platelet receptors and do not interfere with the coagulation cascade. SCH 602539 is structurally related to vorapaxar, a PAR-1 antagonist being evaluated in 2 large ongoing clinical trials (secondary prevention and acute coronary syndromes; clinicaltrials.gov identifiers: NCT00526474 and NCT00527943).…”

Section: Discussionsupporting

confidence: 80%

SCH 602539, a Protease-Activated Receptor-1 Antagonist, Inhibits Thrombosis Alone and in Combination With Cangrelor in a Folts Model of Arterial Thrombosis in Cynomolgus Monkeys

Chintala¹,

Strony²,

Yang³

et al. 2010

ATVB

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Objective-To determine the antithrombotic effects of SCH 602539, an analog of the selective protease-activated receptor (PAR)-1 antagonist vorapaxar (formerly SCH 530348) currently in advanced clinical development, and the P2Y 12 ADP receptor antagonist cangrelor, alone and in combination. Methods and Results-Multiple platelet activation pathways contribute to thrombosis. The effects of SCH 602539 and cangrelor alone and in combination on cyclic flow reductions were evaluated in a Folts model of thrombosis in cynomolgus monkeys. The effects of these treatments on ex vivo platelet aggregation and coagulation parameters were also monitored. Dose-dependent inhibition of cyclic flow reductions was observed after treatment with SCH 602539 alone and cangrelor alone (PϽ0.05 versus vehicle for the 2 highest concentrations of each agent). The combination of SCH 602539 and cangrelor was associated with synergistic antithrombotic effects (PϽ0.05 versus vehicle for all combinations tested). The 2 highest doses of SCH 602539 inhibited platelet aggregation in response to PAR-1-selective high-affinity thrombin receptor agonist peptide by greater than 80% but did not affect platelet aggregation induced by other agonists; also, they did not affect any coagulation parameters. Conclusion-The combined inhibition of the PAR-1 and the P2Y 12 ADP platelet activation pathways had synergistic antithrombotic and antiplatelet effects. The addition of a PAR-1 antagonist to a P2Y 12 ADP receptor antagonist may provide incremental clinical benefits in patients with atherothrombotic disease, both in short-and long-term settings.These hypotheses need to be tested clinically. Key Words: thrombin Ⅲ thrombosis Ⅲ PAR-1 antagonist Ⅲ antiplatelet Ⅲ platelet activation pathways A therothrombotic disease is associated with considerable morbidity and mortality. 1 Although the benefits of dual antiplatelet therapy with aspirin and a P2Y 12 adenosine diphosphate (ADP) receptor antagonist have been demonstrated in a broad range of patients with atherothrombotic disease, many of these patients continue to have recurrent ischemic events. 2,3 This high residual risk can be attributed to the fact that aspirin and P2Y 12 ADP receptor antagonists (eg, clopidogrel and prasugrel) only have a partial inhibitory effect on platelet-mediated thrombosis because they each target only 1 of many platelet activation pathways. 4,5 As a result, thrombosis mediated by other platelet activation pathways, including stimulation of protease-activated receptor (PAR)-1 by thrombin, continues to occur even in the presence of aspirin and a P2Y 12 ADP receptor antagonist, leading to ischemic events.Thrombin is the most potent platelet agonist because it stimulates platelet activation at low subnanomolar concentrations. 6,7 PAR-1 is the principal receptor for thrombin on human platelets, whereas the secondary PAR-4 receptor may contribute to platelet activation at high concentrations of thrombin. 4,8 Because the PAR-1 pathway is a key contributor to platelet-mediated thrombosis, PAR-1...

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Section: Discussionsupporting

confidence: 80%

SCH 602539, a Protease-Activated Receptor-1 Antagonist, Inhibits Thrombosis Alone and in Combination With Cangrelor in a Folts Model of Arterial Thrombosis in Cynomolgus Monkeys

Chintala¹,

Strony²,

Yang³

et al. 2010

ATVB

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“…Alternatively, aspirin resistance has been defined by incomplete suppression of urinary 11-dhTxB 2 excretion for which platelet response to ADP may be important [6, 8, 9]. In our study measurement of urinary 11-dhTxB 2 excretion, a marker for inhibition of thromboxane A 2 production, does not distinguish between those with complete or incomplete inhibition of platelet aggregation [1, 2].…”

Section: Discussionmentioning

confidence: 78%

“…Although using a different marker for platelet inhibition, Grotemeyer et al [3 ]suggested that measured antiplatelet response to aspirin predicts clinical efficacy and others have found this for clopidogrel as well [4]. For those with incomplete inhibition of platelet response to aspirin, a higher dose of aspirin or the addition of clopidogrel may in certain patients achieve complete inhibition of platelet aggregation [1, 2, 5, 6]. In addition to the markers of platelet inhibition used by Helgason et al and Grotemeyer et al, Santos et al [7] described patients taking aspirin at doses associated with suboptimal inhibition of platelet recruitment due to inadequate inhibition of erythrocyte prothrombotic effect.…”

Section: Introductionmentioning

confidence: 99%

Platelet Aggregation and Recruitment with Aspirin-Clopidogrel Therapy

Helgason

Grossi

Pandey³

et al. 2008

Cerebrovasc Dis

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Background: Aspirin-clopidogrel combination therapy inhibits platelet aggregation. The effect on platelet recruitment is unknown. Methods: Thirty chronic ischemic stroke patients taking aspirin alone followed by aspirin-clopidogrel combined therapy had platelet reactivity tests performed over 3 months: ex vivo platelet aggregation, platelet recruitment and urinary 11-dehydro-thromboxane B₂ (11-dhTxB₂)excretion. Statistical analysis of variance compared platelet aggregation and recruitment between aspirin alone and aspirin-clopidogrel, and longitudinal regression analysis estimated platelet recruitment over time. Nonlinear mapping defined variable connections in each patient. Results: Statistically significant differences were found between aspirin alone and aspirin-clopidogrel for (1) adenosine-diphosphate- and collagen-induced platelet aggregation and maximum inhibition of platelet recruitment and (2) increasing inhibition of platelet recruitment over time. Urinary 11-dhTxB₂ excretion did not predict platelet aggregation response. Nonlinear mapping showed patient-unique variable interconnections. Conclusions: Platelet inhibition with aspirin-clopidogrel may increase over time, and future studies should focus on this finding in the context of vascular complications.

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“…Eikelboom et al [89] raised the possibility that the clinical benefits of adding clopidogrel to aspirin may be greatest in patients whose platelets are least inhibited by aspirin. In another study, the addition of clopidogrel to aspirin provided greater inhibition of platelets and could overcome aspirin resistance [90] .…”

Section: Possible Treatment Of Aspirin Resistancementioning

confidence: 99%