Regular ArticleIdentification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting
Introduction
In patients undergoing coronary stenting, a rapid efficacy of antithrombotic drugs is needed to overcome the early risk of intraluminal thrombus formation. The combination of aspirin plus clopidogrel represents the therapy of choice to prevent stent thrombosis [1], [2]. According to pharmacodynamic investigations, a loading dose is required in the initial phase of clopidogrel treatment in order to achieve a rapid inhibition of platelet function [3], [4], [5]. In particular, front-loading with 300 mg of clopidogrel is currently recommended since this dose has shown to induce effective clopidogrel plasma levels in the first hours of treatment [3], [4], [5]. However, recent data have demonstrated a broad degree of response to clopidogrel treatment in patients undergoing coronary stenting receiving a standard 300-mg loading dose [6], [7]. Noteworthy, approximately one-third of patients may have a suboptimal antiplatelet response (low responders) early after intervention using this treatment regimen and thus have an increased thrombotic risk [6], [7], [8], [9]. Although recent reports demonstrate that clopidogrel pretreatment reduces the early risk of ischemic events [10], [11], this type of therapeutic approach rarely occurs in real world practice and patients are frequently treated only at the time of intervention.
In the present study, platelet function profiles are assessed in patients undergoing coronary stenting receiving a standard 300-mg clopidogrel loading dose at the time of coronary intervention with the aim to identify patients having a suboptimal response (low responders) to such standard antiplatelet treatment regimen.
Section snippets
Patient population and study protocol
Forty-eight patients undergoing coronary stenting were included. In all patients, a complete analysis of platelet function (platelet aggregation and activation) was performed. Clopidogrel loading (300 mg) was administered at the time of coronary intervention. All patients were on aspirin (250 mg/daily) for at least 7 days before the procedure. Clopidogrel (75 mg/daily) was maintained for 1 month after intervention. During the procedure, unfractioned heparin (100 IU/kg) was administered
Response to dual antiplatelet treatment
Clopidogrel front loading increased the degree of inhibition of platelet aggregation. Four hours after clopidogrel front-loading, there was a 25.9±22.1% inhibition of baseline platelet aggregation. After 24 h, the degree of platelet inhibition further increased to 41.0±26.0% (p=0.002; Fig. 1). A degree of inhibition ≥40% was achieved in 27 patients (56%, normal responders), whereas in 21 patients (44%, low responders) an inhibition <40% was observed.
Baseline demographic, angiographic and
Discussion
In patients undergoing coronary stenting, our study showed that 44% have an inadequate response (low responders) to a standard 300-mg clopidogrel loading dose. Compared to normal responders, low responder patients had a higher activation of the GP IIb/IIIa receptor before intervention which remained increased up to 24 h after clopidogrel front-loading. The increased GPIIb/IIIa receptor activation among low clopidogrel responders are in accordance with the crucial role of the GPIIb/IIIa receptor
Conclusions
A considerable proportion of patients undergoing coronary stenting have an early poor response to a standard 300-mg clopidogrel loading dose. An increased GP IIb/IIIa receptor activation before intervention may help to identify this subgroup of patients with an inadequate response to this standard treatment regimen. Identification of clopidogrel low responders before intervention appears to be an emerging critical direction for tailoring antiplatelet therapy to ensure a more effective
Acknowledgements
This study was supported by a grant from the Spanish Ministry of Health (Fondo de Investigación Sanitaria 00/0026-1). Dominick J Angiolillo was supported by the Marie Curie Individual Fellowship.
References (26)
- et al.
Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting
J. Am. Coll. Cardiol.
(2002) - et al.
Onset and extent of platelet inhibition by clopidogrel loading in patients undergoing elective coronary stenting: the Plavix Reduction Of New Thrombus Occurrence (PRONTO) trial
Am. Heart J.
(2003) - et al.
Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study
Lancet
(2001) - et al.
Effect of 300- and 450-mg clopidogrel loading doses on membrane and soluble P-selectin in patients undergoing coronary stent implantation
Am. Heart J.
(2002) - et al.
Effect of clopidogrel pretreatment on inflammatory marker expression in patients undergoing percutaneous intervention
Am. J. Cardiol.
(2004) - et al.
A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease
J. Am. Coll. Cardiol.
(2003) - et al.
The effectiveness of clopidogrel and aspirin versus ticlopidine and aspirin in preventing stent thrombosis after coronary stent implantation
Circulation
(1999) - et al.
Early potent antithrombotic effect with combined aspirin and loading dose of clopidogrel on experimental arterial thrombogenesis in humans
Circulation
(2000) - et al.
Clopidogrel loading dose regimens: kinetic profile of pharmacodynamic response in healthy subjects
Semin. Thromb. Hemost.
(1999) - et al.
Acute antithrombotic effect of front-loaded regimen of clopidogrel in patients with atherosclerosis on aspirin
Arterioscler. Thromb. Vasc. Biol.
(2000)
Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity
Circulation
Limited early antiplatelet effect of 300 mg clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions
Eur. Heart J.
Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement
Thromb. Haemost.
Cited by (163)
Racial differences in P2Y12 inhibitor responsiveness in patients undergoing neuro-endovascular procedures: A cohort from the Middle East
2024, Clinical Neurology and NeurosurgeryOutcomes and strategy of tailored antiplatelet therapy with ticagrelor in patients undergoing transcarotid artery revascularization
2021, Journal of Vascular SurgeryCoding SNPs in hsa-miR-1343-3p and hsa-miR-6783-3p target sites of CYP2C19 modulates clopidogrel response in individuals with cardiovascular diseases
2020, Life SciencesCitation Excerpt :Resistance to clopidogrel is defined as the failure of the drug to inhibit its target ADP receptor P2Y12. Various studies have reported the prevalence of clopidogrel resistance between 5%–44% which was in concordance with our study (23% were clopidogrel resistant) [21,27,29–33]. Various meta-analysis studies performed on clopidogrel efficacy concerning genetic polymorphisms in coronary artery disease individuals showed inconsistent conclusions [34,35].