Effect of clopidogrel discontinuation at 1 year after drug eluting stent placement on soluble CD40L, P-selectin and C-reactive protein levels: DECADES (Discontinuation Effect of Clopidogrel After Drug Eluting Stent): a multicenter, open-label study
Joanna J Wykrzykowska, Ascan Warnholtz, Peter de Jaeger, Nick Curzen, Keith G Oldroyd, Jean Philippe Collet, Jurrien M Ten Berg, Tessa Rademaker, Dick Goedhart, Jurgen Lissens, Peter-Paul Kint, Patrick W Serruys, Joanna J Wykrzykowska, Ascan Warnholtz, Peter de Jaeger, Nick Curzen, Keith G Oldroyd, Jean Philippe Collet, Jurrien M Ten Berg, Tessa Rademaker, Dick Goedhart, Jurgen Lissens, Peter-Paul Kint, Patrick W Serruys
Abstract
Antiplatelet therapy with clopidogrel has been shown to reduce major adverse cardiac events in acute coronary syndromes and after percutaneous interventions. This effect is not only due to its anti-platelet effect but also possibly due to an anti-inflammatory effect. The effect of clopidogrel cessation after one year of therapy on markers of inflammation has been investigated in diabetics and showed an increase in platelet aggregation as well as hsCRP and surface P-selectin levels. This was an exploratory multicenter prospective open-label single arm study of 98 non-diabetic patients who had received one or more drug eluting stents and were coming to the end of their 12 months course of clopidogrel therapy. The effect of clopidogrel cessation on expression of biomarkers: sCD40L, soluble P-selectin and hsCRP was measured right before clopidogrel cessation (day 0), and subsequently at 1, 2, 3 and 4 weeks after drug withdrawal. A median increase in sCD40L expression from 224 to 324.5 pg/ml was observed between baseline and 4 weeks after clopidogrel cessation, which corresponded to a 39% mean percent change based on an ANCOVA model (P < 0.001). Over the 4 weeks observation period the change in sCD40L expression correlated weakly with soluble P-selectin levels (at 4 weeks Spearman's correlation coefficient = 0.32; P = 0.0024). Increase in P-selectin expression from baseline was statistically significant at week 1 and 2. Conversely, hsCRP level decreased by 21% at 1 week (P = 0.008) and was still reduced by 18% by 4 weeks (P = 0.062). The change in sCD40L expression appeared to vary with the type of drug eluting stent. Patients treated with drug eluting stents at 1 year after implantation display significant increase in sCD40L and decrease in hsCRP after clopidogrel cessation. Further studies should elucidate if this increase in sCD40L levels reflects solely the removal of the inhibitory effects of clopidogrel on platelet activity or rather an increase in pro-inflammatory state. The latter hypothesis may be less likely given decrease in hsCRP levels. Randomized studies are urgently needed to establish potential link of clopidogrel discontinuation and vascular outcomes.
Figures
![Fig. 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2766044/bin/11239_2009_354_Fig1_HTML.jpg)
![Fig. 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2766044/bin/11239_2009_354_Fig2_HTML.jpg)
![Fig. 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2766044/bin/11239_2009_354_Fig3_HTML.jpg)
References
- Steinhubl SR, Berger PB, Mann JT, 3rd, Fry ET, De Lago A, Wilmer C, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288(19):2411–2420. doi: 10.1001/jama.288.19.2411.
- Berger PB, Steinhubl S. Clinical implications of percutaneous coronary intervention-clopidogrel in unstable angina to prevent recurrent events (PCI-CURE) study: a US perspective. Circulation. 2002;106(17):2284–2287. doi: 10.1161/01.CIR.0000035924.70846.20.
- Stettler C, Wandel S, Allemann S, Kastrati A, Morice MC, Schomig A, et al. Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis. Lancet. 2007;370(9591):937–948. doi: 10.1016/S0140-6736(07)61444-5.
- Costa MA, Angiolillo DJ, Tannenbaum M, Driesman M, Chu A, Patterson J, et al. Impact of stent deployment procedural factors on long-term effectiveness and safety of sirolimus-eluting stents (final results of the multicenter prospective STLLR trial) Am J Cardiol. 2008;101(12):1704–1711. doi: 10.1016/j.amjcard.2008.02.053.
- Finn AV, Nakazawa G, Joner M, Kolodgie FD, Mont EK, Gold HK, et al. Vascular responses to drug eluting stents: importance of delayed healing. Arterioscler Thromb Vasc Biol. 2007;27(7):1500–1510. doi: 10.1161/ATVBAHA.107.144220.
- Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005;293(17):2126–2130. doi: 10.1001/jama.293.17.2126.
- Ho PM, Peterson ED, Wang L, Magid DJ, Fihn SD, Larsen GC, et al. Incidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome. JAMA. 2008;299(5):532–539. doi: 10.1001/jama.299.5.532.
- Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Sabate M, Jimenez-Quevedo P, et al. Clopidogrel withdrawal is associated with proinflammatory and prothrombotic effects in patients with diabetes and coronary artery disease. Diabetes. 2006;55(3):780–784. doi: 10.2337/diabetes.55.03.06.db05-1394.
- Saw J, Madsen EH, Chan S, Maurer-Spurej E. The ELAPSE (Evaluation of Long-Term Clopidogrel Antiplatelet and Systemic Anti-Inflammatory Effects) study. J Am Coll Cardiol. 2008;52(23):1826–1833. doi: 10.1016/j.jacc.2008.08.047.
- Angiolillo DJ, Costa MA, Shoemaker SB, Desai B, Bernardo E, Suzuki Y, et al. Functional effects of high clopidogrel maintenance dosing in patients with inadequate platelet inhibition on standard dose treatment. Am J Cardiol. 2008;101(4):440–445. doi: 10.1016/j.amjcard.2007.09.087.
- Biondi-Zoccai GG, Lotrionte M, Agostoni P, Abbate A, Fusaro M, Burzotta F, et al. A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50,279 patients at risk for coronary artery disease. Eur Heart J. 2006;27(22):2667–2674. doi: 10.1093/eurheartj/ehl334.
- Xiao Z, Theroux P. Clopidogrel inhibits platelet-leukocyte interactions and thrombin receptor agonist peptide-induced platelet activation in patients with an acute coronary syndrome. J Am Coll Cardiol. 2004;43(11):1982–1988. doi: 10.1016/j.jacc.2003.10.071.
- Aggarwal A, Blum A, Schneider DJ, Sobel BE, Dauerman HL. Soluble CD40 ligand is an early initiator of inflammation after coronary intervention. Coron Artery Dis. 2004;15(8):471–475. doi: 10.1097/00019501-200412000-00003.
- Vivekananthan DP, Bhatt DL, Chew DP, Zidar FJ, Chan AW, Moliterno DJ, et al. Effect of clopidogrel pretreatment on periprocedural rise in C-reactive protein after percutaneous coronary intervention. Am J Cardiol. 2004;94(3):358–360. doi: 10.1016/j.amjcard.2004.04.035.
- Furman MI, Krueger LA, Linden MD, Fox ML, Ball SP, Barnard MR, et al. GPIIb-IIIa antagonists reduce thromboinflammatory processes in patients with acute coronary syndromes undergoing percutaneous coronary intervention. J Thromb Haemost. 2005;3(2):312–320. doi: 10.1111/j.1538-7836.2005.01124.x.
- Nannizzi-Alaimo L, Alves VL, Phillips DR. Inhibitory effects of glycoprotein IIb/IIIa antagonists and aspirin on the release of soluble CD40 ligand during platelet stimulation. Circulation. 2003;107(8):1123–1128. doi: 10.1161/.
- Heeschen C, Dimmeler S, Hamm CW, van den Brand MJ, Boersma E, Zeiher AM, et al. Soluble CD40 ligand in acute coronary syndromes. N Engl J Med. 2003;348(12):1104–1111. doi: 10.1056/NEJMoa022600.
- Rinder HM, Bonan JL, Rinder CS, Ault KA, Smith BR. Dynamics of leukocyte-platelet adhesion in whole blood. Blood. 1991;78(7):1730–1737.
- Steinhubl SR, Badimon JJ, Bhatt DL, Herbert JM, Luscher TF. Clinical evidence for anti-inflammatory effects of antiplatelet therapy in patients with atherothrombotic disease. Vasc Med. 2007;12(2):113–122. doi: 10.1177/1358863X07077462.
- Bliden KP, DiChiara J, Tantry US, Bassi AK, Chaganti SK, Gurbel PA. Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate? J Am Coll Cardiol. 2007;49(6):657–666. doi: 10.1016/j.jacc.2006.10.050.
- Gurbel PA, Bliden KP, Guyer K, Aggarwal N, Tantry US. Delayed thrombin-induced platelet-fibrin clot generation by clopidogrel: a new dose-related effect demonstrated by thrombelastography in patients undergoing coronary artery stenting. Thromb Res. 2007;119(5):563–570. doi: 10.1016/j.thromres.2006.05.006.
- Gurbel PA, Bliden KP, Guyer K, Cho PW, Zaman KA, Kreutz RP, et al. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING Study. J Am Coll Cardiol. 2005;46(10):1820–1826. doi: 10.1016/j.jacc.2005.07.041.
- Yip HK, Chang LT, Sun CK, Yang CH, Hung WC, Cheng CI, et al. Impact of clopidogrel on suppression of circulating levels of soluble CD40 ligand in patients with unstable angina undergoing coronary stenting. Am J Cardiol. 2006;97(2):192–194. doi: 10.1016/j.amjcard.2005.08.023.
- Gurbel PA, Bliden KP, Tantry US. Effect of clopidogrel with and without eptifibatide on tumor necrosis factor-alpha and C-reactive protein release after elective stenting: results from the CLEAR PLATELETS 1b study. J Am Coll Cardiol. 2006;48(11):2186–2191. doi: 10.1016/j.jacc.2005.12.084.
- Nakazawa G, Finn AV, John MC, Kolodgie FD, Virmani R. The significance of preclinical evaluation of sirolimus-, paclitaxel-, and zotarolimus-eluting stents. Am J Cardiol. 2007;100(8B):36M–44M. doi: 10.1016/j.amjcard.2007.08.020.
- Luscher TF, Steffel J, Eberli FR, Joner M, Nakazawa G, Tanner FC, et al. Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications. Circulation. 2007;115(8):1051–1058. doi: 10.1161/CIRCULATIONAHA.106.675934.
- Azar RR, Kassab R, Zoghbi A, Aboujaoude S, El-Osta H, Ghorra P, et al. Effects of clopidogrel on soluble CD40 ligand and on high-sensitivity C-reactive protein in patients with stable coronary artery disease. Am Heart J. 2006;151(2):521 e1–521 e4. doi: 10.1016/j.ahj.2005.10.021.
- Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Jr, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–2207. doi: 10.1056/NEJMoa0807646.
Source: PubMed