Biology Original
Prolonged application of clopidogrel reduces inflammation after percutaneous coronary intervention in the porcine model

https://doi.org/10.1016/j.carrev.2007.03.003Get rights and content

Abstract

Objective

We determined the effect of prolonged treatment with clopidogrel on C-reactive protein (CRP) concentrations and blood thrombogenicity after percutaneous transluminal coronary angioplasty followed by intracoronary brachytherapy in the porcine model.

Animal model

All 48 pigs received antiplatelet therapy, including aspirin (325 mg, daily) and clopidogrel (300 mg, loading dose) 1 day before PCI, followed by a daily dose of clopidogrel (75 mg/day) in addition to aspirin. During PCI, one of two balloon-injured arteries was randomly assigned to receive immediate radiation treatment. Animals were sacrificed after 24 h, 1 month, and 3 months post-PCI. The pigs, which were sacrificed 3 months post-PCI, were divided into two groups. The first group received clopidogrel in addition to aspirin for 3 months, and the second group received clopidogrel in addition to aspirin for only 1 month after PCI and then aspirin alone.

Methods

Blood was taken from all pigs before intervention, immediately after intervention, and before sacrifice. Serum CRP was measured by enzyme-linked immunosorbent assay. To analyze the procoagulant effects of PCI on blood thrombogenicity, a one-stage clotting assay was performed.

Results

Clopidogrel treatment for 3 months reduced CRP levels more than did clopidogrel therapy for 1 month only at 3 months post-PCI (27.9±3.9 vs. 56.6±11.3 μg/ml; P=.019). Baseline CRP levels were found to be 50.4±4.8 μg/ml. Plasma clotting was not affected by prolonged clopidogrel therapy (322.8±59.3 s vs. 295.2±52.5 s; P=ns).

Conclusions

Prolonged treatment with clopidogrel reduced CRP levels post-PCI.

Introduction

Pretreatment with P2Y12 receptor blockers, such as clopidogrel, has been found to reduce death and myocardial infarction after percutaneous coronary intervention (PCI). This benefit may be linked not only to the reduction of platelet reactivity but also to the blunting of procedure-related inflammatory response [1], [2], [3]. By inhibition of an adenosine diphosphate receptor, thienopyridines attenuate platelet degranulation and the expression of multiple platelet surface adhesion molecules involved in platelet interactions with inflammatory cells, such as leukocytes [4], [5]. Clopidogrel provides marked protection from ischemic events and is reported to be most efficacious in patients with high baseline C-reactive protein (CRP) levels [4].

CRP, an acute-phase protein present in circulating plasma, seems to contribute to thrombogenicity in patients with atherosclerotic disease [6]. Increased CRP levels are associated with worse clinical outcome [7]. CRP was suggested to mediate vascular and myocardial damage through enhancement of clotting by induction of the expression of tissue factor (TF), the primary initiator of blood coagulation [8], [9], and the formation of procoagulant microvesicles [10], [11]. Moreover, recent experimental work in animals suggests balloon angioplasty or stenting as being responsible for inflammatory response followed by neointimal growth [12], [13]. A few studies with a limited number of patients found CRP levels after coronary stenting to be also predictive for in-stent restenosis [14], [15].

An increase of CRP in plasma has been documented to occur after thrombogenic procedures such as brachytherapy [16]. Intracoronary brachytherapy (ICBT) using β-emitters is a well-proven therapy for the treatment of coronary in-stent restenosis [17], [18]. Moreover, ionizing radiation is associated with an increased risk of late thrombotic events, which are also a major complication after the implantation of drug-eluting stents (DES) [19], [20]. The duration of treatment with clopidogrel after thrombogenic coronary interventions, such as ICBT or DES implantation, is essential to reduce the occurrence of late thrombotic events and is an issue of controversial discussion at the moment.

The aim of our study was to determine the effect of prolonged treatment with clopidogrel on CRP concentrations and blood thrombogenicity after percutaneous transluminal coronary angioplasty (PTCA) followed by ICBT in the porcine model.

Section snippets

Study design

All studies were carried out in accordance with the Guide for the Care and Use of Laboratory Animals (NIH publication no. 85-23, revised 1996). Forty-eight domestic crossbred pigs (weight, 22–27 kg) received antiplatelet therapy, including aspirin (325 mg, daily) and clopidogrel (300 mg, loading dose; 75 mg, daily dose), starting on the day before intervention. Aspirin was continued until sacrifice in all animals. Animals were sacrificed after 24 h (n=12), 1 month (n=12), and 3 months

Prolonged clopidogrel application was associated with reduced CRP levels

Protein quantification of CRP in citrated plasma by ELISA revealed higher CRP levels immediately postintervention than preintervention (60.4±6.2 vs. 50.4±4.8 μg/ml; P=.006; Table 1). Twenty-four hours postintervention, a more-than-threefold increase in CRP concentration compared to preintervention (169.7±5.3 vs. 50.4±4.8 μg/ml; P<.0001; Table 1) and a more-than-twofold elevation immediately postintervention (169.7±5.3 vs. 60.4±6.2 μg/ml; P<.0001; Table 1) were observed. One month

Discussion

Clopidogrel treatment for 3 months compared to 1 month reduced CRP levels but did not affect plasma clotting times after PCI plus ICBT in a porcine model 3 months postintervention.

In our investigation, we demonstrated PCI plus ICBT to lead to an increase in CRP concentration in the blood immediately postintervention. Maximal CRP levels were found 1 day postintervention and decreased thereafter. Previous studies have shown that increased concentrations of CRP and inflammatory cytokines, both

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    This work was supported by grants from the German Research Foundation [Sonderforschungsbereich Transregio 19 (SFB TR 19) to U.R. and to H.P.S. and Ra 799/3-1 to U.R. and K.P.].

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